Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
  • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
  • C07C57/13—Dicarboxylic acids
  • C07C57/145—Maleic acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/235—Saturated compounds containing more than one carboxyl group
  • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
  • C07C59/265—Citric acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., a-ketoglutarate). These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other
• NADP(+)-dependent isocitrate dehydrogenases one of which is mitochondrial and the other predominantly cytosolic.
• Each NADP(+)-dependent isozyme is a homodimer.
• IDH1 isocitrate dehydrogenase 1 (NADP+), cytosolic
• IDP isocitrate dehydrogenase 1
• IDCD isocitrate dehydrogenase 1
• PICD PICD
• the protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS- 1 peroxisomal targeting signal sequence.
• cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production.
• the human IDH1 gene encodes a protein of 414 amino acids.
• the nucleotide and amino acid sequences for human IDH1 can be found as GenBank entries
• NM_005896.2 and NP_005887.2 respectively.
• IDH1 sequences for IDH1 are also described in, e.g., Nekrutenko et al., Mol. Biol. Evol.
• Non-mutant e.g., wild type
• IDH1 catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate.
• mutations of IDH1 present in certain cancer cells result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of a- ketoglutarate to R(-)-2-hydroxyglutarate (2HG).
• the production of 2HG is believed to contribute to the formation and progression of cancer (Dang, L et al., Nature 2009, 462:739-44).
• IDH2 isocitrate dehydrogenase 2 (NADP+), mitochondrial
• IDH isocitrate dehydrogenase 2 (NADP+), mitochondrial
• IDH isocitrate dehydrogenase 2
• IDHM isocitrate dehydrogenase 2
• ICD-M ICD-M
• mNADP-IDH The protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the mitochondria. It plays a role in intermediary metabolism and energy production. This protein may tightly associate or interact with the pyruvate dehydrogenase complex.
• Human IDH2 gene encodes a protein of 452 amino acids. The nucleotide and amino acid sequences for IDH2 can be found as GenBank entries NM_002168.2 and NP_002159.2 respectively.
• nucleotide and amino acid sequence for human IDH2 are also described in, e.g., Huh et al., Submitted (NOV-1992) to the EMBL/GenBank/DDBJ databases; and The MGC Project Team, Genome Res. 14:2121 -2127(2004).
• Non-mutant e.g., wild type, IDH2 catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate (a-KG).
• U.S. Publication No. 2015/0018328 A1 discloses a compound described by 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 has been shown to act as an inhibitor of mutant IDH1 and IDH2 proteins in biochemical and cellular assays.
• the present disclosure relates to solid forms (e.g., cocrystals and other crystalline forms) of a compound of formula (I)
• the disclosure relates to a cocrystal comprising the compound of formula (I) and citric acid.
• the disclosure relates to a cocrystal comprising the compound of formula (I) and maleic acid.
• the disclosure relates to crystalline forms of the free compound of formula (I).
• the disclosure relates to a drug substance comprising a solid form of the compound of formula (I).
• the disclosure relates to methods of preparing solid forms of the compound of formula (I).
• the present application relates to a pharmaceutical composition
• a pharmaceutical composition comprising a solid form of the compound of formula (I) and one or more pharmaceutical excipients.
• the present 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 a therapeutically effective amount of a solid form of the compound of formula (I), or a pharmaceutical composition thereof, to the patient.
• Figure 1 depicts one-dimensional 1 H NMR spectra of Compound 1 in CD3OD, taken over a range of temperatures from 25 °C to 85 °C.
• Figure 2 depicts portions of one-dimensional 1 H NMR spectra of Compound 1 in CD3OD, taken over a range of temperatures from 25 °C to 85 °C.
• Figure 3 depicts a one-dimensional 1 H NMR spectrum of Compound 1 in DMSO-d6.
• Figure 4 depicts a one-dimensional 13 C NMR spectrum of Compound 1 in DMSO-d6.
• Figure 5 depicts a one-dimensional NOE enhanced 15 N NMR spectrum of Compound 1 in DMSO-d6.
• Figure 6 depicts an X-Ray Powder Diffraction (XRPD) pattern of the Citric Acid Cocrystal Type A of the compound of formula (I), prepared as described in
• Figure 7 depicts a 1 H Nuclear Magnetic Resonance (NMR) spectrum of the Citric Acid Cocrystal Type A of the compound of formula (I), prepared as described in Example 1 1 .
• FIG. 8 depicts Differential Scanning Calorimetry (DSC)
• Figure 9 depicts a Dynamic Vapor Sorption (DVS) isotherm plot of the Citric Acid Cocrystal Type A of the compound of formula (I), prepared as described in
• Figure 10 depicts an Oak Ridge Thermal Ellipsoid Plot (ORTEP) of a single crystal of the Citric Acid Cocrystal Type A of the compound of formula (I), prepared as described in Example 12.
• ORTEP Oak Ridge Thermal Ellipsoid Plot
• Figure 1 1 depicts a unit cell diagram of a single crystal of the Citric Acid Cocrystal Type A of the compound of formula (I), prepared as described in Example 12.
• Figure 12 depicts an X-Ray Powder Diffraction (XRPD) pattern of the Maleic Acid Cocrystal Type A of the compound of formula (I), prepared as described in
• Figure 13 depicts a 1 H Nuclear Magnetic Resonance (NMR) spectrum of the Maleic Acid Cocrystal Type A of the compound of formula (I), prepared as described in Example 13.
• Figure 14 depicts Differential Scanning Calorimetry (DSC) and
• Figure 15 depicts a Dynamic Vapor Sorption (DVS) isotherm plot of the Maleic Acid Cocrystal Type A of the compound of formula (I), prepared as described in Example 13.
• Figure 16 depicts a 1 H NMR spectrum of the Citric Acid Cocrystal Type A of the compound of formula (I), prepared as described in Example 14.
• Figure 17 depicts a 13 C NMR spectrum of the Citric Acid Cocrystal Type A of the compound of formula (I), prepared as described in Example 14.
• Figure 18 depicts a Fourier Transform Infrared (FTIR) spectrum of the Citric
• FIG. 19 depicts an Ultra-Violet (UV)/visible spectrum of the Citric Acid
• Figure 20 depicts an XRPD pattern of the Citric Acid Cocrystal Type A of the compound of formula (I), prepared as described in Example 14.
• Figure 21 depicts a DSC thermogram of the Citric Acid Cocrystal Type A of the compound of formula (I), prepared as described in Example 14.
• Figure 22 depicts a TGA thermogram of the Citric Acid Cocrystal Type A of the compound of formula (I), prepared as described in Example 14.
• Figure 23 depicts an XRPD pattern of the Free Form Type A of the compound of formula (I), prepared as described in Example 17.
• Figure 24 depicts a DSC thermogram of the Free Form Type A of the compound of formula (I), prepared as described in Example 17.
• Figure 25 depicts a TGA thermogram of the Free Form Type A of the compound of formula (I), prepared as described in Example 17.
• Figure 26 depicts an Oak Ridge Thermal Ellipsoid Plot (ORTEP) of a single crystal of the Free Form Type A of the compound of formula (I), prepared as described in Example 18.
• Figure 27 depicts a unit cell diagram of a single crystal of the Free Form Type A of the compound of formula (I), prepared as described in Example 18.
• Figure 28 depicts an XRPD pattern of the Free Form Type B of the compound of formula (I), prepared as described in Example 19.
• Figure 29 depicts DSC and TGA thermograms of the Free Form Type B of the compound of formula (I), prepared as described in Example 19.
• Figure 30 depicts an Oak Ridge Thermal Ellipsoid Plot (ORTEP) of a single crystal of the Free Form Type B of the compound of formula (I), prepared as described in Example 20.
• ORTEP Oak Ridge Thermal Ellipsoid Plot
• Figure 31 depicts a unit cell diagram of a single crystal of the Free Form Type B of the compound of formula (I), prepared as described in Example 20.
• Figure 32 depicts an XRPD pattern of the Free Form Type C of the compound of formula (I), prepared as described in Example 21 .
• Figure 33 depicts DSC and TGA thermograms of the Free Form Type C of the compound of formula (I), prepared as described in Example 21.
• Figure 34 depicts an 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.
• ORTEP Oak Ridge Thermal Ellipsoid Plot
• Figure 35 depicts a unit cell diagram of a single crystal of the Free Form Type C of the compound of formula (I), prepared as described in Example 22.
• Figure 36 depicts an XRPD pattern of the Free Form Type D of the compound of formula (I), prepared as described in Example 23.
• Figure 37 depicts DSC and TGA thermograms of the Free Form Type D of the compound of formula (I), prepared as described in Example 23.
• Figure 38 depicts a 1 H NMR spectrum of the Free Form Type D of the compound of formula (I), prepared as described in Example 23.
• Figure 39 depicts mean plasma-concentration time profiles of Compound 1 measured in the pharmacokinetic study described in Example 25. DETAILED DESCRIPTION
• the present disclosure relates to solid forms of a 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.
• the compound of formula (I) includes the compound having the identified chemical structure, as well as any tautomer or rotamer thereof.
• each atom of the compound of formula (I) is meant to represent any stable isotope of the specified element.
• 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, the isotopes for which no decay mode is identified in V.S. Shirley & CM. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).
• the compound of formula (I) includes each constituent atom at approximately the natural abundance isotopic composition of the specified element.
• the disclosure relates to a cocrystal comprising a compound of formula (I)
• citric acid cocrystal citric acid
• cocrystal refers to a crystalline solid made up of two or more neutral chemical species in a defined stoichiometric ratio that possesses distinct crystallographic and spectroscopic properties when compared to the species individually.
• a "cocrystal” is distinct from a "salt,” which is made up of charged-balanced charged species.
• the species making up a cocrystal typically are linked by hydrogen bonding and other non-covalent and non-ionic interactions.
• a pharmaceutical cocrystal of a drug typically comprises the drug and one or more coformers.
• the combinations of drug and coformer(s) that will form cocyrstals generally cannot be predicted ab initio, and cocrystal formation typically affects the physicochemical properties of a drug in unpredictable ways.
• crystalline refers to a solid material whose constituent particles (e.g., molecules) are arranged spatially in a regular and repeating lattice.
• the citric acid cocrystal is citric acid cocrystal type A.
• citric acid cocrystal type A is characterized by an X- ray powder diffraction pattern, acquired in reflection mode (sometimes referred to as reflectance mode), comprising one or more peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), selected from the peak positions set forth in Tables 7 and 1 1 below.
• the X-ray powder diffraction pattern comprises at least one peak position, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), selected from the group consisting of 5.7, 8.4, 1 1 .4, 15.8, 18.1 , 19.2, 21 .1 , 22.5, and 23.0.
• 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 5.7, 8.4, 1 1 .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, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), selected from the group consisting of 5.7, 8.4, 1 1.4, 15.8, 18.1 , 19.2, 21 .1 , 22.5, and 23.0.
• 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, 1 1 .4, 15.8, 18.1 , 19.2, 21 .1 , 22.5, and 23.0.
• degrees 2-theta ⁇ 0.2 degrees 2-theta
• the X-ray powder diffraction pattern comprises peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), of 5.7 and 8.4, and at least three peak positions select from the group consisting of 1 1 .4, 15.8, 18.1 , 19.2, 21 .1 , 22.5, and 23.0.
• the X-ray powder diffraction pattern comprises peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), of 5.7, 8.4, 1 1 .4, 15.8, 18.1 , 19.2, 21 .1 , 22.5, and 23.0.
• the X-ray powder diffraction pattern comprises the peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), set forth in Table 7.
• the X-ray powder diffraction pattern comprises the peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), set forth in Table 1 1.
• the X-ray powder diffraction pattern is similar to the X-ray powder diffraction pattern shown in Figure 6.
• the X-ray powder diffraction pattern is similar to the X-ray powder diffraction pattern shown in Figure 20.
• citric acid cocrystal type A is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak having an onset temperature of 170.6 °C ( ⁇ 5.0 °C). In other embodiments, citric acid cocrystal type A is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak having an onset temperature of 170.6 °C ( ⁇ 2.0 °C).
• citric acid cocrystal type A further comprises water.
• citric acid cocrystal type A comprises the compound of formula (I), citric acid, and water in a molar ratio of 2: 1 : 1 .
• the measured molar ratio of the compound of formula (I), citric acid, and water in a given sample of the cocrystal may differ slightly from 2: 1 : 1 due to the experimental error associated with available analytical methods, the presence of impurities (e.g., water or citric acid that is not incorporated in the crystal lattice), etc. It will be understood that cocrystals having a molar ratio of 2: 1 : 1 fall within this
• citric acid cocrystal type A comprises four molecules of the compound of formula (I), two citric acid molecules, and two water molecules per unit cell.
• unit cell refers to the smallest group of particles (e.g., molecules) in a crystalline solid that makes up the repeating pattern of the crystalline solid.
• unit cell refers to the smallest group of the two or more neutral chemical species that makes up the repeating pattern of the cocrystal.
• citric acid cocrystal 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.
• the disclosure relates to a cocrystal comprising a
• maleic acid cocrystal a compound of formula (I) and maleic acid (hereinafter “maleic acid cocrystal”).
• the maleic acid cocrystal is maleic acid cocrystal type A.
• the maleic acid cocrystal type A is characterized by an X-ray powder diffraction pattern, acquired in reflection mode (sometimes referred to as reflectance mode), comprising one or more peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), selected from the peak positions set forth in Table 9 below.
• the X-ray powder diffraction pattern comprises at least one peak position, 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.
• 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 5.9, 8.1 , 15.0, 15.2, 16.9, 17.8, 18.5, 21 .1 , 23.4, 26.9, and 28.2.
• 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.
• 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 5.9, 8.1 , 15.0, 15.2, 16.9, 17.8, 18.5, 21.1 ,
• the X-ray powder diffraction pattern comprises peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), of 8.1 , 17.8, and
• the X-ray powder diffraction pattern comprises peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), of 5.9, 8.1 , 15.0, 15.2, 16.9, 17.8, 18.5, 21.1 , 23.4, 26.9, and 28.2.
• the X-ray powder diffraction pattern comprises peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), of 5.9, 8.1 , 15.0, 15.2, 16.9, 17.8, 18.5, 21.1 , 23.4, 26.9, and 28.2.
• the X-ray powder diffraction pattern comprises the 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 Figure 12.
• maleic acid cocrystal type A is characterized by a differential scanning calorimetry thermogram comprising endothermic peaks having onset temperatures of 91 .2 °C and 128.4 °C ( ⁇ 5.0 °C). In other embodiments, maleic acid cocrystal type A is characterized by a differential scanning calorimetry thermogram comprising endothermic peaks having onset temperatures of 91 .2 °C and 128.4 °C ( ⁇ 2.0 °C).
• maleic acid cocrystal type A comprises the compound of formula (I) and maleic acid in a molar ratio of 1 : 1 .
• the measured molar ratio of the compound of formula (I) and maleic acid in a given sample of the cocrystal may differ slightly from 1 : 1 due to the experimental error associated with available analytical methods, the presence of impurities (e.g., maleic acid that is not incorporated in the crystal lattice), etc.
• cocrystals having a molar ratio of 1 :1 fall within this embodiment, even if the measured ratio of the compound of formula (l):maleic acid differs slightly from 1 : 1 .
• the disclosure relates to a crystalline form of a compound of formula (I)
• the Free Form Type A wherein the crystalline form is characterized by an X-ray powder diffraction pattern, acquired in reflection mode (sometimes referred to as reflectance mode), comprising one or more peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), selected from the peak positions set forth in Table 15 below.
• the X-ray powder diffraction pattern comprises at least one peak position, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), selected from the group consisting of 1 1.7, 12.8, 14.2, 17.8, 19.8, 20.7, 21 .8, 22.2, and 25.0.
• 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 1 1 .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 two peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), selected from the group consisting of 1 1 .7, 12.8, 14.2, 17.8, 19.8, 20.7, 21 .8, 22.2, and 25.0.
• 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 1 1.7, 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, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), selected from the group consisting of 1 1.7, 12.8, 14.2, 17.8, 19.8, 20.7, 21 .8, 22.2, and 25.0.
• the X-ray powder diffraction pattern comprises peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), of 1 1 .7, 17.8, and 21.8, and at least three peak positions select from the group consisting of 12.8, 14.2, 19.8, 20.7, 22.2, and 25.0.
• the X-ray powder diffraction pattern comprises peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), of 1 1 .7, 12.8, 14.2, 17.8, 19.8, 20.7, 21.8, 22.2, and 25.0.
• the X-ray powder diffraction pattern comprises the peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), set forth in Table 15.
• the X-ray powder diffraction pattern is similar to the X-ray powder diffraction pattern shown in Figure 23.
• the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak having an onset temperature of 221 .9 °C ( ⁇ 5.0 °C). In other embodiments, the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an onset temperature of 221.9 °C ( ⁇ 2.0 °C).
• the disclosure relates to a crystalline form of a compound of formula (I) sometimes referred to as the Free Form Type B, wherein the crystalline form is characterized by an X-ray powder diffraction pattern, acquired in reflection mode
• the X-ray powder diffraction pattern comprises at least one peak position, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), selected from the group consisting of 1 1.9, 13.2, 15.5, 17.8, 18.6, 20.8, 23.2, 23.9, and 26.5.
• 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 1 1 .9, 13.2, 15.5, 17.8, 18.6, 20.8, 23.2, 23.9, and 26.5.
• 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 1 1 .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, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), selected from the group consisting of 1 1 .9, 13.2, 15.5, 17.8, 18.6,
• the X-ray powder diffraction pattern comprises peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), of 1 1.9, 17.8, and
• the X-ray powder diffraction pattern comprises peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), of 1 1.9, 13.2, 15.5, 17.8, 18.6, 20.8, 23.2, 23.9, and 26.5.
• the X-ray powder diffraction pattern comprises the peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2- theta), set forth in Table 19.
• the X-ray powder diffraction pattern is similar to the X-ray powder diffraction pattern shown in Figure 28.
• the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak having an onset temperature of 221 .5 °C ( ⁇ 5.0 °C). In other embodiments, the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an onset temperature of 221.5 °C ( ⁇ 2.0 °C).
• the crystalline form is anhydrous.
• the disclosure relates to a crystalline form of a compound of formula (I)
• Free Form Type C wherein the crystalline form is characterized by an X-ray powder diffraction pattern, acquired in reflection mode
• the X-ray powder diffraction pattern comprises at least one peak position, 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. 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, 10.5, 18.2, 20.2, 21 .1 , and 25.9.
• 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, 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, 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. In other embodiments, 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.
• the X-ray powder diffraction pattern comprises peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), of 8.6 and 21 .1 , and at least three peak positions select from the group consisting of 8.6, 10.5, 18.2, 20.2, 21 .1 , and 25.9.
• the X-ray powder diffraction pattern comprises peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), of 8.6, 10.5, 18.2, 20.2, 21 .1 , and 25.9.
• the X-ray powder diffraction pattern comprises the peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), set forth in Table 21 .
• the X-ray powder diffraction pattern is similar to the X-ray powder diffraction pattern shown in Figure 32.
• the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak having an onset temperature of 221 .3 °C ( ⁇ 5.0 °C). In other embodiments, the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an onset temperature of 221.3 °C ( ⁇ 2.0 °C).
• the crystalline form is a trihydrate.
• the disclosure relates to a crystalline form of a compound of formula (I)
• the Free Form Type D wherein the crystalline form is characterized by an X-ray powder diffraction pattern, acquired in reflection mode (sometimes referred to as reflectance mode), comprising one or more peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), selected from the peak positions set forth in Table 23 below.
• the X-ray powder diffraction pattern comprises at least one peak position, 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.
• 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.
• 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.
• 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.
• the X-ray powder diffraction pattern comprises peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), of 15.9, 16.7, and 21.2, and at least three peak positions select from the group consisting of 8.6, 9.7, 10.5, 15.6, 17.9, 20.3, 24.9, 26.6, and 27.0.
• the X-ray powder diffraction pattern comprises peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), 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.
• the X-ray powder diffraction pattern comprises the 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.
• the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak having an onset temperature of 221 .3 °C ( ⁇ 5.0 °C). In other embodiments, the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an onset temperature of 221.3 °C ( ⁇ 2.0 °C).
• the crystalline form is a dioxane solvate.
• the disclosure relates to an amorphous solid dispersion comprising a compound of formula (I)
• 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).
• the dispersed phases can be solids, liquids, or gases.
• the dispersed and continuous phases are both solids.
• amorphous solid dispersion generally refers to a solid dispersion of two or more components, usually a therapeutically active compound and a polymer (or plurality of polymers), but possibly containing other components such as surfactants or other pharmaceutical excipients, where the therapeutically active compound is in the amorphous phase.
• an amorphous solid dispersion includes the polymer(s) (and optionally a surfactant) constituting the dispersed phase, and the therapeutically active compound constitutes the continuous phase.
• an amorphous solid dispersion includes the polymer(s) (and optionally a surfactant) constituting the continuous phase, and the therapeutically active compound constitutes the dispersed phase.
• the polymer is selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP),
• HPMCAS hydroxypropyl cellulose
• ethylcellulose ethylcellulose
• cellulose acetate phthalate cellulose acetate phthalate
• PVP polyvinylpyrrolidone
• the polymer is HPMCAS.
• the polymer is present in the amorphous solid dispersion in an amount of between about 10% w/w and 90% w/w (e.g., between about 20% w/w and about 80% w/w; between about 30% w/w and about 70% w/w; between about 40% w/w and about 60% w/w; or between about 15% w/w and about 35% w/w).
• the polymer is (or the one or more polymers are) present in the amorphous solid dispersion in an amount of from about 10% w/w to about 80% w/w, for example 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, for example, about 46% w/w, about 47% w/w, about 48% w/w, about 49% w/w, about 50% w/w, about 51 % w/w, about 52% w/w, about 53% w/w, or about 54% w/w.
• the polymer is (or the one or more polymers are) present in the amorphous solid dispersion in an amount of about 48% w/w, about 48.5% w/w, about 49% w/w, about 49.5% w/w, about 50% w/w, about 50.5% w/w, about 51 % w/w, about 51 .5% w/w, about 52% w/w, or about 52.5% w/w.
• the compound of formula (I) is present in the amorphous solid dispersion in an amount of from about 10% w/w and 90% w/w (e.g., between about 20% w/w and about 80% w/w; between about 30% w/w and about 70% w/w; between about 40% w/w and about 60% w/w; or between about 15% w/w and about 35% w/w).
• 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, for example 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, for example, about 46% w/w, about 47% w/w, about 48% w/w, about 49% w/w, about 50% w/w, about 51 % w/w, about 52% w/w, about 53% w/w, or about 54% w/w.
• the compound of formula (I) is present in the amorphous solid dispersion in an amount of about 48% w/w, about 48.5% w/w, about 49% w/w, about 49.5% w/w, about 50% w/w, about 50.5% w/w, about 51 % w/w, about 51 .5% w/w, about 52% w/w, or about 52.5% w/w.
• the amorphous solid dispersion further comprises a surfactant.
• 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.
• the surfactant is SLS.
• the surfactant is present in the amorphous solid dispersion in an amount of from about 0.1 % w/w to about 10% w/w, for example from about 0.5% w/w to about 2% w/w, or from about 1 % w/w to about 3% w/w, from about 1 % w/w to about 4% w/w, or from about 1 % w/w to about 5% w/w.
• the surfactant is present in the amorphous solid dispersion in an amount of from about 0.1 % w/w to about 10% w/w, for example from about 0.5% w/w to about 2% w/w, or from about 1 % w/w to about 3% w/w, from about 1 % w/w to about 4% w/w, or from about 1 % w/w to about 5% w/w.
• 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.
• 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.
• the amorphous solid dispersion comprises the compound of formula (I) and HPMCAS. In some embodiments, the amorphous solid dispersion consists essentially of the compound of formula (I) and HPMCAS. In some embodiments, the amorphous solid dispersion consists of the compound of formula (I) and HPMCAS. In some embodiments, the compound of formula (I) and HPMCAS are present in a weight ratio of between about 3: 1 and about 1 :3, or between about 2:1 and about 1 :2, or between about 1 .5: 1 and about 1 : 1.5. In some embodiments, the compound of formula (I) and HPMCAS are present in a weight ratio of about 1 : 1 .
• the amorphous solid dispersion has a glass transition temperature (T g ) of at least about 80 °C. In other embodiments, the amorphous solid dispersion has a T g of between about 80 °C and about 130 °C, between about 80 °C and about 120 °C, between about 80 °C and about 100 °C, or between about 80 °C and about 90 °C.
• Drug Substances [00101] The disclosure also relates to drug substances comprising the solid forms of the compound of formula (I) described herein.
• drug substance refers to an active pharmaceutical ingredient.
• the term includes, but is not limited to, an active pharmaceutical ingredient that is incorporated in a pharmaceutical composition with one or more pharmaceutical excipients.
• the disclosure relates to drug substances having no more than specified concentrations of certain impurities, namely (R)-4-chloro-6-(6- chloropyridin-2-yl)-/V-(1 , 1 , 1 -trifluoropropan-2-yl)-1 ,3,5-triazin-2-amine (Compound 2), (R)-6-(6-chloropyridin-2-yl)-/V 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)-/V 2 -is
• 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) 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 measured by HPLC Method 2, as described in Examples 14 and 16.
• the disclosure relates to a drug substance comprising a citric acid cocrystal of the compound of formula (I), as described in any of the embodiments described herein.
• the drug substance contains no more than 1 .0% (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-/V 2 -(1 , 1 , 1 -trifluoropropan-2-yl)- 1 ,3,5-triazine-2,4-diamine.
• the drug substance contains no more than 1 .0% (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-/V 2 -ethyl-/V 4 -(1 , 1 , 1 - trifluoropropan-2-yl)-1 ,3,5-triazine-2,4-diamine.
• the drug substance contains no more than 1.0% (area % by HPLC) of (R)-6-(6-chloropyridin-2- yl)-/V 2 -isopropyl-/V 4 -(1 , 1 , 1 -trifluoropropan-2-yl)-1 ,3,5-triazine-2,4-diamine. In some embodiments, the drug substance contains no more than 1 .0% (area % by HPLC) of 6- (6-chloropyridin-2-yl)-/V 2 ,/V 4 -bis((S)-1 , 1 , 1 -trifluoropropan-2-yl)-1 ,3,5-triazine-2,4-diamine.
• the drug substance contains no more than 1 .0% (area % by HPLC) of 6-(6-chloropyridin-2-yl)-/V 2 -((R)-1 , 1 ,1 -trifluoropropan-2-yl)-/V4-((S)-1 , 1 ,1 - trifluoropropan-2-yl)-1 ,3,5-triazine-2,4-diamine.
• the drug substance contains no more than 1.0% (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 no more than 1 .0% (area % by HPLC) of (R)-4-chloro-6-(6- chloropyridin-2-yl)-/V-(1 , 1 , 1 -trifluoropropan-2-yl)-1 ,3,5-triazin-2-amine.
• the drug substance contains no more than 1 .0% (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.
• the disclosure relates to a drug substance comprising a Free Form Type A of the compound of formula (I), as described in any of the
• the drug substance contains no more than 1 .0% (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-/V 2 -(1 , 1 , 1 - trifluoropropan-2-yl)-1 ,3,5-triazine-2,4-diamine.
• the drug substance contains no more than 1.0% (area % by HPLC) of (R)-6-(6-chloropyridin-2- yl)-/V 2 -ethyl-/V 4 -(1 , 1 , 1 -trifluoropropan-2-yl)-1 ,3,5-triazine-2,4-diamine.
• the drug substance contains no more than 1 .0% (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-/V 2 -isopropyl-/V 4 -(1 , 1 , 1 -trifluoropropan-2-yl)-1 ,3,5-triazine- 2,4-diamine.
• the drug substance contains no more than 1 .0% (area % by HPLC) of 6-(6-chloropyridin-2-yl)-/V 2 ,/V 4 -bis((S)-1 , 1 , 1 -trifluoropropan-2-yl)- 1 ,3,5-triazine-2,4-diamine.
• the drug substance contains no more than 1 .0% (area % by HPLC) of 6-(6-chloropyridin-2-yl)-/V 2 -((R)-1 , 1 , 1 - trifluoropropan-2-yl)-/V4-((S)-1 , 1 , 1 -trifluoropropan-2-yl)-1 ,3,5-triazine-2,4-diamine.
• the drug substance contains no more than 1.0% (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 no more than 1.0% (area % by HPLC) of (R)-4-chloro-6-(6-chloropyridin-2-yl)-/V-(1 ,1 , 1 -trifluoropropan-2-yl)-1 ,3,5-triazin-2- amine.
• the drug substance contains no more than 1 .0% (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.
• the 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 (e.g., cocrystals, drug substances, crystalline forms, and amorphous solid dispersions) described herein.
• Such compounds are useful as standards for determining the purity of the solid forms (e.g., cocrystals, drug substances, crystalline forms, and amorphous solid dispersions) described herein.
• the disclosure relates to a compound selected from the group consisting of:
• compound is (R)-6-(6-chloropyridin-2-yl)-/V 2 -(1 , 1 ,1 - trifluoropropan-2-yl)-1 ,3,5-triazine-2,4-diamine.
• compound is (R)-6-(6-chloropyridin-2-yl)-/V 2 -ethyl-/V 4 - (1,1,1 -thfluoropropan-2-yl)-1 ,3,5-thazine-2,4-diamine.
• compound is (R)-6-(6-chloropyridin-2-yl)-/V 2 -isopropyl-/V 4 - (1,1,1 -trifluoropropan-2-yl)-1 ,3,5-triazine-2,4-diamine.
• compound is (R)-4-(6-chloropyridin-2-yl)-6-((1 ,1,1- trifluoropropan-2-yl)amino)-1,3,5-triazin-2-ol.
• compound is (R)-4-chloro-6-(6-chloropyridin-2-yl)-/V- (1,1,1 -trifluoropropan-2-yl)-1 ,3,5-triazin-2-amine.
• compound is 6-(4,6-bis(((R)-1 ,1,1 -trifluoropropan-2- yl)amino)-1 ,3,5-triazin-2-yl)pyridin-2-ol.
• the disclosure also relates to tautomers of the chemical structure identified as the compound of formula (I).
• tautomers include:
• the tautomers include the specified compounds, as well as any double bond isomers thereof.
• the disclosure relates to a compound that is:
• the disclosure relates to a compound that is:
• the disclosure relates to a compound that is:
• the disclosure relates to a compound that is:
• the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• a "pharmaceutically acceptable salt” of a compound includes any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, the compound.
• Pharmaceutically acceptable salts are described in detail in S. M. Berge, et a/., J. Pharmaceutical Sciences, 1977, 66, 1 -19, incorporated herein by reference.
• the disclosure also relates to methods of preparing solid forms of the compound of formula (I).
• the disclosure relates to a method of preparing a citric acid cocrystal, comprising
• the cocrystal precipitated in the method is citric acid cocrystal type A (as described in any of the embodiments herein ).
• the disclosure relates to a cocrystal prepared by any of the methods of preparing a citric acid cocrystal disclosed herein.
• the citric acid employed in the method may be crystalline or amorphous and may be in any state of hydration or solvation.
• the citric acid is anhydrous citric acid or citric acid monohydrate.
• the citric acid is anhydrous citric acid.
• the citric acid is citric acid monohydrate.
• the solvent employed in the method may be any liquid or mixture of liquids suitable to dissolve the compound of formula (I) and citric acid.
• 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/heptanes (1/3 v/v)).
• the solvent comprises acetonitrile or acetone.
• the compound of formula (I) and citric acid may be dissolved in the solvent in any molar ratio and in any concentration that allows for subsequent precipitation of the cocrystal from the solution.
• the compound of formula (I) and citric acid are contacted with the solvent in a molar ratio of between about 1 :2 and 4: 1 , or a molar ratio between about 1 : 1 and 3: 1 , or a molar ratio between about 1 .5: 1 and 2.5: 1 , or a molar ratio of about 2: 1 .
• the amount of the solvent in a molar ratio of between about 1 :2 and 4: 1 , or a molar ratio between about 1 : 1 and 3: 1 , or a molar ratio between about 1 .5: 1 and 2.5: 1 , or a molar ratio of about 2: 1 .
• the amount of the amount of the solvent in a molar ratio of between about 1 :2 and 4: 1 , or a molar
• compound of formula (I) contacted with the solvent is sufficient to form about a 0.01 M to 3 M solution, or about a 1 M to 2 M solution, or about a 1 .5 M solution, based on the amount of the compound of formula (I).
• the actual molar ratio of citric acid and the compound of formula (I) in solution, and the actual concentration of the compound of formula (I) the solution may differ from that which would be calculated from the amounts of the compound of formula (I) and citric acid contacted with the solvent.
• the disclosure relates to a method of preparing a maleic acid cocrystal, comprising
• the cocrystal precipitated in the method is maleic acid cocrystal type A (as described in any of the embodiments herein).
• the disclosure relates to a cocrystal prepared by any of the methods of preparing a maleic acid cocrystal disclosed herein.
• the solvent employed in the method may be any liquid or mixture of liquids suitable to dissolve the compound of formula (I) and maleic acid. In some embodiments,
• the solvent comprises acetonitrile or acetone.
• the disclosure relates to a method of preparing a crystalline form of the compound of formula (I), comprising
• the crystalline form precipitated in the method is the Free Form Type A (as described in any of the embodiments herein).
• the disclosure relates to a crystalline form prepared by any of the methods of preparing a crystalline form of the compound of formula (I) disclosed herein.
• precipitating the crystalline form comprises adding heptane to the solution.
• the disclosure relates to a method of preparing a crystalline form of the compound of formula (I), comprising
• the crystalline form precipitated in the method is the Free Form Type B (as described in any of the embodiments herein).
• the disclosure relates to a crystalline form prepared by any of the methods of preparing a crystalline form of the compound of formula (I) disclosed herein.
• precipitating the crystalline form comprises adding heptane to the solution.
• the disclosure relates to a method of preparing a crystalline form of the compound of formula (I), comprising
• the crystalline form precipitated in the method is the Free Form Type C (as described in any of the embodiments herein).
• the disclosure relates to a crystalline form prepared by any of the methods of preparing a crystalline form of the compound of formula (I) disclosed herein.
• precipitating the crystalline form comprises adding water to the solution.
• the disclosure relates to a method of preparing an amorphous solid dispersion of the compound of formula (I).
• the method comprises spray-drying a mixture comprising the compound of formula (I), a polymer, and an appropriate solvent or solvent mixture.
• the solvent is a volatile solvent (e.g., methylene chloride, acetone, methanol, ethanol, chloroform, tetrahydrofuran (THF), or a mixture thereof).
• the solvent is acetone.
• the compound of formula (I) used in the spray-drying procedure is in the form of a cocrystal or crystalline form in accordance with any of the embodiments described herein.
• Spray drying involves atomization of a liquid mixture containing, e.g., a solid and a solvent or solvent mixture, and removal of the solvent or solvent mixture.
• Atomization may be done, for example, through a two-fluid or pressure or electrosonic nozzle or on a rotating disk. Removal of the solvent or solvent mixture may require a subsequent drying step, such as tray drying, fluid bed drying (e.g., from about room temperature to about 100 °C), vacuum drying, microwave drying, rotary drum drying or biconical vacuum drying (e.g., from about room temperature to about 200 °C).
• a subsequent drying step such as tray drying, fluid bed drying (e.g., from about room temperature to about 100 °C), vacuum drying, microwave drying, rotary drum drying or biconical vacuum drying (e.g., from about room temperature to about 200 °C).
• dissolving when referring to dissolving one or more substances in a solvent to afford a solution, means contacting the substance(s) with an amount of solvent sufficient to dissolve at least some of each of the
• the mixture comprising the substance(s) and solvent may be stirred and/or warmed to facilitate the dissolution of the substance(s) in the solvent.
• some undissolved material may be stirred and/or warmed to facilitate the dissolution of the substance(s) in the solvent.
• suspended in the solution may be separated from the solution (e.g., by filtration or decantation) prior to precipitation of a solid form.
• water is added to the solution prior to precipitation of a solid form.
• concentration means that the molar ratio or concentration has the specified value ⁇ 10%.
• concentration e.g., molarity
• concentration means that the molar ratio or concentration has the specified value ⁇ 10%.
• a molar ratio of “about 2: 1 " would include molar ratios between 1 .8:1 and 2.2: 1 .
• a concentration of "about 1 .5 M” would include concentrations between 1 .35 M and 1 .65 M.
• precipitating when referring to precipitating a solid form from a solution, means causing the solid form to precipitate from the solution.
• precipitation may 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).
• cooling comprises cooling the solution.
• cooling the solution may cause precipitation of the solid form by decreasing the solubility of the solid form in the solution, such that the solid form reaches its saturation concentration.
• "precipitating” comprises evaporating a portion of the solvent from the solution.
• evaporating solvent from the solution may cause precipitation of the solid form by increasing the concentration of the solid form in the solution to its saturation concentration.
• "precipitating” comprises adding an antisolvent to the solution.
• the term "antisolvent” refers to a liquid in which the solid form is less soluble than the solvent used to form the solution. Without intending to be bound by any theory, the addition of an antisolvent to the solution may cause precipitation of the solid form by decreasing the solubility of the solid form in the solution, such that the solid form reaches its saturation concentration.
• the antisolvent comprises a non-polar organic solvent.
• the antisolvent comprises toluene.
• the antisolvent comprises methyl tert-butyl ether.
• the antisolvent comprises a C5-C12 alkane or cycloalkane.
• "precipitating” comprises seeding the solution with crystals of the solid form to be precipitated from solution.
• seeding refers to the addition of a particular crystalline material to a solution to initiate recrystallization or crystallization of that particular crystalline material.
• C5-C12 alkane or cycloalkane means a saturated straight-chain, branched, or cyclic hydrocarbon having five to twelve carbon atoms. Examples include pentane, hexane, heptane, octane, cyclohexane, and the like.
• the method further comprises isolating the solid form.
• isolated means separating the precipitated solid form from the solution. Such separation may be accomplished by any means known in the art, including without limitation filtration of the precipitated solid form and decantation of the solution from the precipitated solid form.
• the disclosure relates to a pharmaceutical composition
• a pharmaceutical composition comprising a solid form, drug substance, or compound or pharmaceutically acceptable salt, as described in any of the embodiments herein, and one or more pharmaceutical excipients.
• the disclosure relates to a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of a solid form, drug substance, or compound or pharmaceutically acceptable salt, as described in any of the embodiments herein, and one or more pharmaceutical excipients.
• the term "therapeutically effective amount,” when referring to an amount of the solid form, drug substance, or compound or pharmaceutically acceptable salt described herein, refers to an amount that will elicit a biological or medical response in a patient, such as reducing or inhibiting an enzyme or a protein activity, alleviating or ameliorating certain symptoms, curing a disease, lessening the severity of a disease, slowing or delaying the progression of a disease, or preventing a disease.
• the term “therapeutically effective amount” refers to the amount of 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.
• the term “therapeutically effective amount” refers to the amount of the solid form, drug substance, or compound or pharmaceutically acceptable salt that, when administered to a patient, is effective to treat a cancer in the patient.
• the term "pharmaceutical excipient” refers to a carrier, adjuvant, or vehicle that may be administered to a patient together with the solid form, drug substance, or compound or pharmaceutically acceptable salt, that does not destroy the pharmacological activity of the compound of formula (I), and that is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound of formula (I).
• compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, 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, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes,
• SEDDS self-emulsifying drug delivery systems
• polyethylene-polyoxypropylene-block polymers polyethylene glycol and wool fat.
• Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-p-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of the compound of formula (I).
• the pH of the pharmaceutical composition may be adjusted with pharmaceutically acceptable acids, bases or buffers.
• compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
• the pharmaceutical compositions may contain any conventional non-toxic pharmaceutically acceptable excipients.
• parenteral administration includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
• the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
• This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
• suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• 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 versions.
• These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or
• carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
• Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
• 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.
• excipients which are commonly used include lactose, corn starch, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, colloidal silicon dioxide, and sodium lauryl sulfate.
• Lubricating agents such as magnesium stearate, are also typically added.
• useful diluents include lactose and dried corn starch.
• the active ingredient When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
• compositions may also be administered in the form of suppositories for rectal administration.
• These compositions can be prepared by mixing the solid form, drug substance, or compound or pharmaceutically acceptable salt with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
• suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
• the pharmaceutical compositions may be administered topically to the skin.
• the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a pharmaceutically acceptable excipient suitable for topical administration, including without limitation mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
• a pharmaceutically acceptable excipient suitable for topical administration including without limitation mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
• composition can be formulated with a suitable lotion or cream
• 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 compositions of one aspect of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Transdermal patches are also included in one aspect of this invention.
• compositions may be administered by nasal aerosol or inhalation.
• Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
• the amount of active ingredient that may be combined with one or more pharmaceutical excipients to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration.
• a typical preparation will contain from about 5% to about 95% active compound (w/w).
• such preparations contain from about 20% to about 80% active compound.
• 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), apart from the weight of any coformer, salt former, water of hydration, solvent of solvation, and the like).
• the pharmaceutical composition comprises 20-30% w/w of the compound of formula (I) (based on the weight of the free compound of formula (I), apart from the weight of any coformer, salt former, water of hydration, solvent of solvation, and the like). 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
• 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), apart from the weight of any coformer, salt former, water of hydration, solvent of solvation, and the like).
• compositions may further comprise a therapeutically effective amount of an additional therapeutic agent, including without limitation any one of the additional therapeutic agents identified below as being useful in combination therapy.
• the term "therapeutically effective amount,” when referring to an amount of an additional therapeutic agent, refers to an amount of the agent that will elicit a biological or medical response in a patient, such as reducing or inhibiting an enzyme or a protein activity, alleviating or ameliorating certain symptoms, curing a disease, lessening the severity of a disease, slowing or delaying the progression of a disease, or preventing a disease.
• the invention in another aspect, relates to a pharmaceutical composition prepared by a process comprising mixing a therapeutically effective amount of a solid form, drug substance, or compound or pharmaceutically acceptable salt, as described in any of the embodiments herein, with one or more pharmaceutical excipients to afford the pharmaceutical composition.
• mixing means includes any process in which the solid form, drug substance, or compound or pharmaceutically acceptable salt is contacted with one or more pharmaceutical excipients to afford a pharmaceutical composition, regardless of whether the pharmaceutical composition so obtained contains the solid form, drug substance, or compound or pharmaceutically acceptable salt.
• mixing includes processes in which the solid form, drug
• 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 a therapeutically effective amount of a solid form, drug substance, or compound or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, as described in any of the embodiments herein, to the patient.
• the invention relates to the use of a solid form, drug substance, or compound or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, as described in any of the embodiments herein, for the
• the invention relates to a solid form, drug substance, or compound or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, as described in any of the embodiments herein, for use in treating a cancer characterized by the presence of an IDH1 or IDH2 mutation in a patient in need thereof.
• the terms "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 symptoms associated with the disease.
• the term "patient” refers to a mammal, including mice, rats, dogs and humans, which is afflicted with a cancer characterized by the presence of an IDH1 or IDH2 mutation.
• the patient is a human.
• the patient is a human adult (i.e., a human at least 18 years of age).
• the patient is a human child (i.e., a human under 18 years of age).
• the cancer is characterized by the presence of an IDH1 mutation.
• the IDH1 mutation is an R132X mutation.
• the IDH1 mutation is an R132H or R132C mutation.
• the IDH1 mutation is an R132H, R132C, R132L, R132V, R132S, or R132G mutation.
• the IDH1 mutation is an R132H mutation.
• the IDH1 mutation is an R132C mutation.
• the IDH1 mutation results in accumulation of R(-)-2-hydroxyglutarate in the patient.
• the IDH1 mutation results in a new ability of IDH1 to catalyze the NADPH-dependent reduction of a-ketoglutarate to R(-)-2-hydroxyglutarate.
• treating a cancer characterized by an IDH1 mutation comprises inhibiting mutant IDH1 activity.
• the cancer is a tumor wherein at least 30, 40, 50, 60, 70, 80 or 90% of the tumor cells carry an IDH1 mutation, and in particular an IDH1 R132H or R132C mutation, at the time of diagnosis or treatment.
• NADPH-dependent reduction of a-ketoglutarate to R(-)-2-hydroxyglutarate, and in particular R132H and R132C mutations of IDH1 characterize a subset of all types of cancers, without regard to their cellular nature or location in the body.
• the compounds and methods of this invention are useful to treat any type of cancer that is characterized by the presence of a mutant allele of IDH1 imparting such activity, and in particular IDH1 R132H and R132C mutations.
• IDH1 R132X mutations are known to occur in a variety of cancers.
• ALL leukemia
• the cancer is a cancer selected from the cancer types listed in Table 1
• the IDH1 mutation is one or more of the IDH1 R132X mutations listed in Table 1 for that particular cancer type.
• IDH1 R132H mutations have been identified in glioma, acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer, cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer, and angio-immunoblastic non-Hodgkin's lymphoma (NHL).
• the cancer is selected from glioma, acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer, or angio-immunoblastic non- Hodgkin's lymphoma (NHL).
• the cancer is glioma, and the glioma is a low grade glioma or a secondary high grade glioma.
• the cancer is glioma, and the glioma is a low grade glioma (grade II), anaplastic (grade III) or glioblastoma (GBM, grade IV).
• the cancer is characterized by the presence of an IDH2 mutation.
• the IDH2 mutation is an R140X mutation.
• the IDH2 mutation is an R140Q, R140W, or R140L mutation.
• the IDH2 mutation is an R172X mutation.
• the IDH2 mutation is an R172K or R172G mutation.
• the IDH2 mutation is an R140X mutation.
• the IDH2 mutation is an R140Q mutation.
• the IDH2 mutation is an R140W mutation.
• the IDH2 mutation is an R140L mutation.
• the IDH2 mutation is an R172X mutation.
• 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 accumulation of R(-)-2- hydroxyglutarate in the patient. In other embodiments, the IDH2 mutation results in a new ability of IDH2 to catalyze the NADPH-dependent reduction of a-ketoglutarate to R(-)-2-hydroxyglutarate. Thus, in some embodiments, treating a cancer characterized by an IDH2 mutation comprises inhibiting mutant IDH2 activity.
• mutant alleles of IDH2 wherein the IDH2 mutation results in a new ability of the enzyme to catalyze the NADPH-dependent reduction of a-ketoglutarate to R(-)-2-hydroxyglutarate, and in particular R140Q and/or R172K mutations of IDH2, characterize a subset of all types of cancers, without regard to their cellular nature or location in the body.
• the compounds and methods of one aspect of this invention are useful to treat any type of cancer that is characterized by the presence of a mutant allele of IDH2 imparting such activity and in particular an IDH2 R140Q and/or R172K mutation.
• the cancer is a tumor wherein at least 30, 40, 50, 60, 70, 80 or 90% of the tumor cells carry an IDH2 mutation, and in particular an IDH2 R140Q, R140W, or R140L and/or R172K or R172G mutation, at the time of diagnosis or treatment.
• a cancer can be analyzed by sequencing cell samples to determine the presence and specific nature of any mutation(s) characterizing the cancer.
• the cancer is glioma, acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinomas (e.g., intrahepatic choiangiocarcinoma (IHCC)), chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), prostate cancer, chronic myelomonocytic leukemia (CMML), B-acute lymphoblastic leukemias (B-ALL), B-acute lymphoblastic leukemias (B-ALL), myeloid sarcoma, multiple myeloma, lymphoma colon cancer, or angio-immunoblastic non-Hodgkin's lymphoma (NHL).
• NSCLC non-small cell lung cancer
• cholangiocarcinomas e.g., intrahepatic choiangiocarcinoma (
• 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, the glioma is a low grade glioma (grade II), anaplastic (grade III) or glioblastoma (GBM, grade IV).
• the cancer is lymphoma (e.g., Non-Hodgkin
• B-cell lymphoma such B-cell lymphoma (e.g., Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, or mantle cell lymphoma) or T-cell lymphoma (e.g., mycosis fungoides, anaplastic large cell lymphoma, or precursor T-lymphoblastic lymphoma)).
• B-cell lymphoma e.g., Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, or mantle cell lympho
• the cancer is glioma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myelogenous leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma,
• MDS myelodysplastic syndrome
• MPN myeloproliferative neoplasm
• AML acute myelogenous leukemia
• sarcoma melanoma
• non-small cell lung cancer chondrosarcoma
• the cancer is glioma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm
• MPN acute myelogenous leukemia
• AML acute myelogenous leukemia
• melanoma chondrosarcoma
• 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).
• the cancer is refractory or relapsed. In other embodiments the cancer is newly diagnosed or previously untreated.
• the efficacy of cancer treatment is monitored by measuring the levels of 2HG as described herein.
• the efficacy of cancer treatment is monitored by measuring the levels of 2HG in the patient.
• levels of 2HG are measured prior to treatment, wherein an elevated level is indicated for the use of the compound of formula (I), including in the form of the solid form, drug substance, or compound or pharmaceutically acceptable salt or pharmaceutical composition thereof, as described in any of the embodiments herein, to treat the cancer.
• the level of 2HG is determined during the course of and/or following termination of treatment to establish efficacy.
• the level of 2HG is only determined during the course of and/or following termination of treatment. A reduction of 2HG levels during the course of treatment and following treatment is indicative of efficacy.
• 2HG measurements will be utilized together with other well-known determinations of efficacy of cancer treatment, such as reduction in number and size of tumors and/or other cancer-associated lesions, improvement in the general health of the patient, and alterations in other biomarkers that are associated with cancer treatment efficacy.
• 2HG can be detected in a sample by LC/MS.
• the sample is mixed 80:20 with methanol, and centrifuged at 3,000 rpm for 20 minutes at 4 degrees Celsius.
• the resulting supernatant can be collected and stored at -80 degrees Celsius prior to LC- MS/MS to assess 2-hydroxyglutarate levels.
• LC separation methods can be used. Each method can be coupled by negative electrospray ionization (ESI, -3.0 kV) to triple-quadrupole mass
• Metabolites can be separated by reversed phase chromatography using 10 mM tributyl-amine as an ion pairing agent in the aqueous mobile phase, according to a variant of a previously reported method (Luo et al. J Chromatogr A 1 147, 153-64, 2007).
• Another method is specific for 2-hydroxyglutarate, running a fast linear gradient from 50% -95% B (buffers as defined above) over 5 minutes.
• a Synergi Hydro-RP, 100mm ⁇ 2 mm, 2.1 pm 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 concentration. Metabolite flux studies from 13 C-glutamine can be performed as described, e.g., in Munger et al. Nat Biotechnol 26, 1 179-86, 2008.
• 2HG is directly evaluated.
• a derivative of 2HG formed in the process of performing the analytic method is evaluated.
• a derivative can be a derivative formed in MS analysis.
• Derivatives can include a salt adduct, e.g., a Na adduct, a hydration variant, or a hydration variant which is also a salt adduct, e.g. , a Na adduct, e.g. , as formed in MS analysis.
• Examples include species that build up or are elevated, or reduced, as a result of the presence of 2HG, such as glutarate or glutamate that will be correlated to 2HG, e.g., R- 2HG.
• Exemplary 2HG derivatives include dehydrated derivatives such as the compounds provided below or a salt adduct thereof:
• various evaluation steps are performed prior to and/or following treatment of a cancer with the solid form, drug substance, or compound or pharmaceutically acceptable salt or pharmaceutical composition thereof.
• the method described herein further comprises an evaluation step prior to and/or after treatment with the solid form, drug substance, or compound or pharmaceutically acceptable salt or pharmaceutical composition thereof.
• the evaluation steps comprise evaluating the growth, size, weight, invasiveness, stage and/or other phenotype of the cancer.
• the method described herein further comprises the step of evaluating the growth, size, weight, invasiveness, stage and/or other phenotype of the cancer prior to and/or after treatment with the solid form, drug substance, or compound or
• the method prior to and/or after treatment with the solid form, drug substance, or compound or pharmaceutically acceptable salt or pharmaceutical composition thereof, the method further comprises the step of evaluating the IDH1 genotype of the cancer. This may be achieved by ordinary methods in the art, such as DNA sequencing, immuno analysis, and/or evaluation of the presence, distribution or level of 2HG.
• the method prior to and/or after treatment with the solid form, drug substance, or compound or pharmaceutically acceptable salt or pharmaceutical composition thereof, the method further comprises the step of determining the 2HG level in the patient.
• This may be achieved by spectroscopic analysis, e.g., magnetic resonance-based analysis, e.g., MRI and/or MRS measurement, sample analysis of bodily fluid, such as serum or spinal cord fluid analysis, or by analysis of surgical material, e.g., by mass-spectroscopy.
• transaminases which allow utilization of glutamate nitrogen for amino and nucleic acid biosynthesis
• aKG-dependent prolyl hydroxylases such as those which regulate HIF1 -alpha levels.
• one aspect of the invention provides a method of treating 2-hydroxyglutaric aciduria, particularly D-2-hydroxyglutaric aciduria, in a patient by administering to the patient a therapeutically effective amount of the solid form, drug substance, or compound or pharmaceutically acceptable salt, or a
• Also provided are methods of treating a disease selected from Maffucci syndrome and Oilier disease, characterized by the presence of a mutant allele of IDH1 comprising the step of administering to patient in need thereof a therapeutically effective amount of the solid form, drug substance, or compound or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, as described in any one of the
• Treatment methods described herein can additionally comprise various evaluation steps prior to and/or following treatment with the solid form, drug substance, or compound or pharmaceutically acceptable salt or pharmaceutical composition thereof.
• the method prior to and/or after treatment with the solid form, drug substance, or compound or pharmaceutically acceptable salt or pharmaceutical composition thereof, the method further comprises the step of evaluating the growth, size, weight, invasiveness, stage and/or other phenotype of the cancer.
• the method prior to and/or after treatment with the solid form, drug substance, or compound or pharmaceutically acceptable salt or pharmaceutical composition thereof, the method further comprises the step of evaluating the IDH2 genotype of the cancer. This may be achieved by ordinary methods in the art, such as DNA sequencing, immuno analysis, and/or evaluation of the presence, distribution or level of 2HG.
• the solid form, drug substance, or compound or pharmaceutically acceptable salt, and pharmaceutical compositions thereof, as described in any of the embodiments herein, can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight, alternatively dosages between about 1 mg and about 1000 mg/dose, every 4 to 120 hours, based on the amount of the compound of formula (I).
• the solid form, drug substance, or compound or pharmaceutically acceptable salt or pharmaceutical composition thereof is administered once, twice, or three times a day. In other embodiments, the solid form, drug substance, or compound or pharmaceutically acceptable salt or pharmaceutical composition thereof is administered once a day. In other embodiments, the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof is administered twice a day. In other embodiments, the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof is administered three times a day.
• the methods herein contemplate administration of a therapeutically effective amount of the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof so as to achieve the desired or stated effect.
• the pharmaceutical compositions of one aspect of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion.
• the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof is administered once a day.
• the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof is administered twice a day. Such administration can be used as a chronic or acute therapy.
• the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof, as described in any of the embodiments herein, is administered in a dosage, based on the amount of the compound of formula (I), of: (1 ) from 1 to 100 mg/day, 2 to 50 mg/day, 3 to 30 mg/day, 4 to 20 mg/day, 5 to 15 mg/day, 8 to 12 mg/day, or about 10 mg/day; (2) from 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) from 1 to 500 mg/day, 10 to 250 mg/day, 20 to 100 mg/day, 30 to 80 mg/day, 40 to 60 mg/day, 45 to 55 mg/day, or about 50 mg/day; (4) from 1 to 500 mg/day, 20 to 400 mg/day, 40 to 200 mg/day, 50 to 150 mg/day;
• the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof, as described in any of the embodiments herein, is administered in a dosage, based on the amount of the compound of formula (I), of from 0.01 to 10 mg/kg of body weight per day, 0.2 to 8.0 mg/kg of body weight per day, 0.4 to 6.0 mg/kg of body weight per day, 0.6 to 4.0 mg/kg of body weight per day, 0.8 to 2.0 mg/kg of body weight per day, 0.1 to 1 mg/kg of body weight per day, 0.2 to 1 .0 mg/kg of body weight per day, 0.15 to 1 .5 mg/kg of body weight per day, or 0.1 to 0.5 mg/kg of body weight per day.
• a dosage based on the amount of the compound of formula (I), of from 0.01 to 10 mg/kg of body weight per day, 0.2 to 8.0 mg/kg of body weight per day, 0.4 to 6.0 mg/kg of body weight per day, 0.6 to 4.0 mg/kg of body weight per
• the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof, as described in any of the embodiments herein is administered once per day or more than once per day (e.g., twice per day, three times per day, four times per day, etc.) to achieve administration of the daily dosages described herein.
• composition thereof as described in any of the embodiments herein, is administered once per day to achieve administration of the daily dosages described herein.
• solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof, as described in any of the embodiments herein is administered twice per day to achieve
• composition thereof is administered once per day in a dosage, based on the amount of the compound of formula (I), 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 per administration.
• the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof, as described in any of the embodiments herein is administered twice per day in a dosage, based on the amount of the compound of formula (I), of: (1 ) 30-70 mg, 35-65 mg, 40-60 mg, 45-55 mg, or about 50 mg per administration; or (2) 5-35 mg, 5-20 mg, 5-15 mg, or about 10 mg per administration.
• the amounts of the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof, set forth herein are based on the amount of the compound of formula (I). Specific dosage and treatment regimens for any particular subject will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug
• the term "about,” when referring to a dosage, means that the dosage has the specified value ⁇ 10%.
• a dosage of "about 100 mg/kg” would include dosages between 90 mg/kg and 1 10 mg/kg.
• a maintenance dose of the compound of formula (I), administered as the solid form, drug substance, or compound or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, as described in any of the embodiments herein, or combination of one aspect of this invention may be administered, if necessary.
• the dosage or frequency of administration, or both may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level.
• Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
• the patient in need of treatment for a cancer characterized by the presence of an IDH1 or IDH2 mutation was previously
• cancer therapy refers to a cancer therapeutic agent or a cancer treatment.
• cancer therapeutic agent refers to a therapeutic agent (other than the compound of formula (I), the solid form, drug substance, or compound or pharmaceutically acceptable salt, or the pharmaceutical composition thereof) that is indicated for treating a cancer.
• Cancer therapeutic agents include, for example, chemotherapy, targeted therapy agents, antibody therapies, immunotherapy agents, hormonal therapy agents, and check point inhibitors. Examples of each of these classes of cancer therapeutic agents are provided below.
• cancer treatment refers to a treatment that is indicated for treating a cancer. Cancer treatments include, for example, surgery and radiation therapy.
• the cancer therapeutic agent is a chemotherapy agent.
• chemotherapy 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, spindle poison, cytotoxic agents, topoisomerase inhibitors and others), and hypomethylating agents ⁇ e.g., decitabine (5-aza-deoxycytidine), zebularine,
• isothiocyanates azacitidine (5-azacytidine), 5-flouro-2'-deoxycytidine, 5,6-dihydro-5- azacytidine and others.
• exemplary agents include Aclarubicin, Actinomycin,
• Carboplatin Carboquone, Carmofur, Carmustine, Celecoxib, Chlorambucil,
• Liposomal doxorubicin Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone, Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate, Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin, Mitoxantrone,
• Testolactone Tetranitrate, Thiotepa, Tiazofurine, Tioguanine, Tipifarnib, Topotecan, Trabectedin, Triaziquone, Triethylenemelamine, Triplatin, Tretinoin, Treosulfan,
• Trofosfamide Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vorinostat, Zorubicin, and other cytostatic or cytotoxic agents described herein.
• the cancer therapeutic agent is a differentiation agent.
• Differentiation agents include retinoids (such as all-trans-retinoic acid (ATRA), 9-cis retinoic acid, 13-c/s-retinoic acid (13-cRA) and 4-hydroxy-phenretinamide (4-HPR)); arsenic trioxide; histone deacetylase inhibitors HDACs (such as azacytidine (Vidaza) and butyrates (e.g., sodium phenylbutyrate)); hybrid polar compounds (such as hexamethylene bisacetamide ((HMBA)); vitamin D; and cytokines (such as colony- stimulating factors including G-CSF and GM-CSF, and interferons).
• retinoids such as all-trans-retinoic acid (ATRA), 9-cis retinoic acid, 13-c/s-retinoic acid (13-cRA) and 4-hydroxy-phenretinamide (4-HPR)
• the cancer therapeutic agent is a targeted therapy agent.
• Targeted therapy constitutes the use of agents specific for the deregulated proteins of cancer cells.
• Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell.
• Prominent examples are the tyrosine kinase inhibitors such as Axitinib, Bosutinib, Cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Vandetanib, and also cyclin-dependent kinase inhibitors such as Alvocidib and Seliciclib.
• tyrosine kinase inhibitors such as Axitinib, Bosutinib, Cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Vandetanib
• Targeted therapy agents include biguanides such as metformin or phenformin.
• Targeted therapy can also involve small peptides as "homing devices” which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to these peptides ⁇ e.g., RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell.
• RGDs Radionuclides which are attached to these peptides ⁇ e.g., RGDs
• An example of such therapy includes BEXXAR®.
• the cancer therapeutic agent is an antibody.
• Monoclonal antibody therapy is a strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells.
• the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells.
• examples include the anti-HER2/neu antibody trastuzumab (HERCEPTIN®) typically used in breast cancer, and the anti-CD20 antibody rituximab and Tositumomab typically used in a variety of B-cell malignancies.
• Other exemplary antibodies include Cetuximab, Panitumumab, Trastuzumab, Alemtuzumab, Bevacizumab, Edrecolomab, and
• Exemplary fusion proteins include Aflibercept and Denileukin diftitox.
• the cancer therapeutic agent is an immunotherapy agent.
• Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumors include intravesicular BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients.
• Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a graft-versus-tumor effect.
• the cancer therapeutic agent is a hormonal therapy agent.
• the growth of some cancers can be inhibited by providing or blocking certain hormones.
• hormone-sensitive tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment.
• administration of hormone agonists, such as progestogens may be therapeutically beneficial.
• the cancer therapeutic agent is a check point inhibitor.
• Check point inhibitor therapy is a form of cancer treatment in which manipulation of immune system checkpoints is used restore immune system function against cancer cells. Examples of check point inhibitors include ipilimumab, nivolumab,
• pembrolizumab pembrolizumab, atezolizumab, avelumab, durvalumab, and the like.
• cancer therapeutic agents include imatinib, gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins, radiolabeled drugs and antibodies, Chimeric antigen receptors or CAR-Ts (e.g., Kymriah® (tisagenlecleucel), Yescarta® (axicabtagene ciloleucel)), Gliadel® (carmustine implant), and Avastin® (bevacizumab).
• CAR-Ts e.g., Kymriah® (tisagenlecleucel), Yescarta® (axicabtagene ciloleucel)
• Gliadel® carmustine implant
• Avastin® bevacizumab
• the cancer treatment is radiation therapy.
• Radiation therapy involves the use of high-energy radiation (e.g., x-rays, gamma rays, or charged particles) to damage and/or kill cancer cells and to shrink tumors.
• high-energy radiation e.g., x-rays, gamma rays, or charged particles
• radiation may be delivered to the brain tumor (e.g., glioma) by a machine positioned outside the body (external-beam radiation therapy), by radioactive material placed in the body near the brain tumor (internal radiation therapy, also called
• radioactive substances administered systemically e.g., radioactive iodine
• these delivery methods can be used in combination.
• the 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, and the like), where the radiation is delivered to the brain tumor (e.g., glioma) by an instrument outside the body. External radiation therapy may be given as a course of several treatments over days or weeks. In one aspect of these embodiments, the radiation is administered in the form of x-rays.
• the radiation therapy comprises internal radiation therapy, where the radiation comes from an implant or a material (liquid, solid, semisolid or other substance) placed inside the body.
• the internal radiation therapy is brachytherapy, where a solid radioactive source is placed inside the body near the brain tumor.
• the internal radiation therapy comprises the systemic administration of a radiation source, typically a radionuclide (radioisotope or unsealed source).
• the radiation source may be orally administered or may be injected into a vein.
• the methods described herein comprise the additional step of co-administering to a patient in need thereof an additional therapy.
• the medicament 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 co-administration of an additional therapy.
• 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 co-administration of an additional therapy.
• 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) administered to treat symptoms and/or secondary effects of the cancer.
• additional therapy includes additional therapeutic agents (i.e., cancer therapeutic agents and non-cancer therapeutic agents) and additional treatments (i.e., cancer treatments and non-cancer treatments).
• the additional therapy is a cancer therapy (i.e., a cancer therapeutic agent or cancer treatment), as described above.
• the additional therapy is a non-cancer therapy (i.e., a non-cancer therapeutic agent or non-cancer treatment).
• the additional therapy comprises one or more of a DNA-reactive agent, a PARP inhibitor, an anti-emesis agent, an anti-convulsant or anti-epileptic agent, a checkpoint inhibitor, PVC chemotherapy, bevacizumab, and gemcitabine.
• the additional therapy comprises a DNA-reactive agent.
• DNA-reactive agents are those agents, such as alkylating agents, cross-linking agents, and DNA intercalating agents, which interact covalently or non-covalently with cellular DNA.
• 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, diethylnitrosoamine, benzo(a)pyrene, doxorubicin, mitomycin-C, and the like. Many of these DNA- reactive agents are useful in cancer therapy as DNA-reactive chemotherapeutic agents.
• the additional therapy comprises a PARP inhibitor.
• PARP inhibitor refers to an inhibitor of the enzyme poly ADP ribose polymerase (PARP).
• PARP poly ADP ribose polymerase
• PARP inhibitors include pamiparib, olaparib, rucaparib, velaparib, iniparib, talazoparib, niraparib, and the like.
• the additional therapy is a checkpoint inhibitor.
• checkpoint inhibitor refers to a therapeutic agent that inhibits an immune checkpoint (e.g., CTLA-4, PD-1/PD-L1 , and the like) that otherwise would prevent immune system attacks on cancer cells, thereby allowing the immune system to attack the cancer cells.
• immune checkpoint e.g., CTLA-4, PD-1/PD-L1 , and the like
• check point inhibitors include ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, BGB- A317, spartalizumab, and the like.
• the additional therapy is PVC chemotherapy.
• PVC chemotherapy refers to a chemotherapy regimen comprising the combined administration of procarbazine, lomustine (which is sold under the trade name CCNU®), and vincristine (which is sold under the trade name Onocovin®).
• the vincristine is administered intravenously, while the procarbazine, and lomustine are administered orally.
• PCV chemotherapy often is administered in cycles, wherein each cycle comprises a single administration of vincristine and lomustine and a 10-day course of treatment with procarbazine.
• the additional therapy is bevacizumab.
• Bevacizumab which is sold under the trade name Avastin®, is a recombinant humanized monoclonal antibody.
• the additional therapy is gemcitabine.
• Gemcitabine which is sold under the trade name Gemzar®, is a pyrimidine nucleoside analog.
• the additional therapy is a non-cancer therapeutic agent.
• non-cancer therapeutic agent refers to a therapeutic agent that is used to treat symptoms suffered by patients afflicted with a cancer, and/or undergoing treatment for a cancer, but that is not indicated for treating the cancer itself.
• non-cancer therapeutic agents include anti-seizure and anti-epileptic agents, anti-emesis agents, anti-diarrheal agents, and the like.
• the additional therapy is an anti-seizure or anti- epileptic agent.
• anti-seizure or anti-epileptic agent refers to a drug that is effective for treating or preventing seizures, including epileptic seizures.
• anti-seizure and anti-epileptic agents examples 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, nimetazepam, nitrazepam, oxcarbazepine, paraldehyde, paramethadoine, perampanel, piracetam, phenacemide, pheneturide, phenobarbital, phensuximide, phenyto
• the additional therapy is an anti-emesis agent.
• anti-emesis agent refers to a drug that is effective to reduce vomiting and nausea symptoms.
• anti-emesis agents include 5- ⁇ 3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron, tropisetron, palonosetron, mirtazapine, and the like), dopamine agonists (e.g., domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, prochlorperazine, alizapride,
• prochlorperazine, metoclopramide, and the like NK1 receptor antagonists (e.g., aprepitant, casopitant, rolapitant, and the like), antihistamines (e.g., cinnarizine, cyclizine, diphenhydramine, dimenhydrinate, doxylamine, meclizine, promethazine, hydroxyzine, and the like), cannabinoids (e.g, cannabis, dronabinol, synthetic cannabinoids, and the like), benzodiazepines (e.g., midazolam, lorazepam, and the like), anticholinergics (e.g., scopolamine and the like), steroids (e.g,,,,,
• glucose/fructose/phosphoric acid which is sold under the trade name Emetrol®
• peppermint peppermint
• muscimol ajwain
• bismuth-subsalicylate and the like.
• the additional therapy is an anti-diarrheal agent.
• anti-diarrheal 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.
• the additional therapy is a non-cancer treatment.
• non-cancer treatment refers to a treatment that is used to treat symptoms suffered by patients afflicted with a cancer, and/or undergoing treatment for a cancer, but that is not indicated for treating the cancer itself.
• non-cancer treatments include acupuncture, biofeedback, distraction, emotional support and counseling, hypnosis, imagery, relaxation, skin stimulation, and the like.
• co-administering means that the additional therapy is administered prior to, concurrently with, consecutively with, or following the
• 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 this invention comprising a cocrystal, drug substance, crystalline form, or amorphous solid dispersion and the therapeutic agent) or as separate, multiple dosage forms.
• the therapeutic agent may be administered prior to, consecutively with, or following the administration of the solid form, drug substance, or compound or pharmaceutically acceptable salt.
• 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 of a composition of one aspect of this invention, comprising both a solid form, drug substance, or compound or pharmaceutically acceptable salt and an additional therapeutic agent, to a patient does not preclude the separate administration of that same therapeutic agent, any other additional therapeutic agent or the solid form, drug substance, or compound or pharmaceutically acceptable salt to said patient at another time during a course of treatment.
• the additional therapy is an additional treatment
• the additional treatment may be administered prior to, consecutively with, concurrently with or following the administration of the solid form, drug substance, or compound or pharmaceutically acceptable salt or pharmaceutical composition thereof.
• both the solid form, drug substance, or compound or pharmaceutically acceptable salt and the cancer therapy are administered at dosage levels of between about 1 to 100%, or between about 5 to 95%, of the dosage normally administered in a monotherapy regimen.
• the disclosure relates to:
• a cocrystal comprising a com ound of formula (I)
• cocrystal of embodiment 1 wherein the cocrystal is characterized by an X- ray powder diffraction pattern, acquired in reflection mode, comprising at least one peak position, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), selected from the group consisting of 5.7, 8.4, 1 1 .4, 15.8, 18.1 , 19.2, 21.1 , 22.5, and 23.0.
• a drug substance comprising the cocrystal of any one of embodiments 1 -10. 12. The drug substance of embodiment 11 , wherein the drug substance contains no more than 1.0% (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-/V 2 -(1 , ,1- trifluoropropan-2-yl)-1 ,3,5-triazine-2,4-diamine.
• a pharmaceutical composition comprising a therapeutically effective amount of the cocrystal of any one of embodiments 1 -10 or the drug substance of any one of embodiments 1 1 -19 and one or more pharmaceutical excipients.
• 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).
• a pharmaceutical composition prepared by a process comprising:
• citric acid comprising:
• a cocrystal comprising a com ound of formula (I)
• the cocrystal of embodiment 37 wherein the cocrystal is characterized by an X- ray powder diffraction pattern, acquired in reflection mode, comprising at least one peak position, 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. 39.
• the cocrystal of embodiment 37 or 38, wherein 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 5.9, 8.1 , 15.0, 15.2, 16.9, 17.8, 18.5, 21.1 ,
• the cocrystal of any one of embodiments 37-41 wherein the X-ray powder diffraction pattern comprises peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), of 8.1 , 17.8, and 18.5, and at least three peak positions select from the group consisting of 5.9, 15.0, 15.2, 16.9, 21 .1 , 23.4, 26.9, and 28.2.
• 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).
• composition of embodiment 49 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).
• composition of embodiment 50 wherein the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of formula (I).
• 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 having an onset temperature of 221 .9 °C ( ⁇ 2.0 °C).
• a drug substance comprising the crystalline form of any one of embodiments 57- 62.
• a pharmaceutical composition comprising 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 and one or more pharmaceutical excipients.
• 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).
• composition 75 The pharmaceutical composition of embodiment 74, wherein the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of formula (I).
• composition of embodiment 72 wherein the pharmaceutical composition comprises 20-30% w/w of the compound of formula (I).
• pharmaceutical composition 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).
• the crystalline form is characterized by an X-ray powder diffraction pattern, acquired in reflection mode, comprising at least one peak position, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), selected from the group consisting of 1 1 .9, 13.2, 15.5, 17.8, 18.6, 20.8, 23.2, 23.9, and 26.5.
• 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 1 1 .9, 13.2, 15.5, 17.8, 18.6, 20.8, 23.2, 23.9, and 26.5. 88.
• a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of any one of embodiments 84-90 and one or more pharmaceutical excipients.
• 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).
• composition of 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).
• precipitating the crystalline form comprises adding heptane to the solution.
• said precipitating comprises seeding the solution with crystals of the crystalline form.
• the crystalline form is characterized by an X-ray powder diffraction pattern, acquired in reflection mode, comprising at least one peak position, 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.
• 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.
• crystalline form of any one of embodiments 103-106 wherein the X-ray powder diffraction pattern comprises peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), of 8.6 and 21 .1 , and at least three peak positions select from the group consisting of 8.6, 10.5, 18.2, 20.2, 21 .1 , and 25.9.
• a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of any one of embodiments 103-109 and one or more
• composition comprises 1 -10% w/w of the compound of formula (I).
• composition of embodiment 1 10 or 1 1 1 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). 1 13. The pharmaceutical composition of embodiment 1 12, wherein the
• composition comprises about 10 mg or about 50 mg of the compound of formula (I).
• composition comprises 20-30% w/w of the compound of formula (I).
• 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).
• composition comprises about 10 mg or about 50 mg of the compound of formula (I).
• a pharmaceutical composition prepared by a process comprising:
• the crystalline form is characterized by an X-ray powder diffraction pattern, acquired in reflection mode, comprising at least one peak position, 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.
• crystalline form of any one of embodiments 122-125 wherein the X-ray powder diffraction pattern comprises peak positions, in degrees 2-theta ( ⁇ 0.2 degrees 2-theta), of 15.9, 16.7, and 21 .2, and at least three peak positions select from the group consisting of 8.6, 9.7, 10.5, 15.6, 17.9, 20.3, 24.9, 26.6, and 27.0.
• a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of any one of embodiments 122-128 and one or more
• composition comprises 1 -10% w/w of the compound of formula (I).
• composition 131 The pharmaceutical composition of 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).
• composition comprises about 10 mg or about 50 mg the compound of formula (I).
• composition of embodiment 29, wherein the pharmaceutical composition comprises 20-30% w/w of the compound of formula (I).
• 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).
• composition comprises about 10 mg or about 50 mg of the compound of formula (I).
• a pharmaceutical composition comprising a therapeutically effective amount of the amorphous solid dispersion of any one of embodiments 137-139 and one or more pharmaceutical excipients.
• composition comprises 1 -10% w/w of the compound of formula (I).
• composition comprises about 10 mg or about 50 mg of the compound of formula (I).
• composition comprises 20-30% w/w of the compound of formula (I).
• 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.
• composition comprises about 10 mg or about 50 mg of the compound of formula (I).
• a pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of embodiments 1 14-1 17, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical excipients.
• a method of treating a cancer characterized by the presence of an IDH1 or IDH2 mutation in a patient in need thereof comprising administering a therapeutically effective amount of the cocrystal of any one of embodiments 1 -10 and 37-44, the crystalline form of any one of embodiments 57-62, 84-90, 103-109, and 122-128, the amorphous solid dispersion of any one of embodiments 137-139, the drug substance of any one of embodiments 1 1 -19 and 63-71 , the compound or pharmaceutically acceptable salt of any one of embodiments 155-158, or the pharmaceutical composition of any one of embodiments 20-27, 45-52, 72-79, 91 -98, 1 10-1 17, 129-136, 147-154, and 159, to the patient.
• a method of treating a cancer characterized by the presence of an IDH1 mutation and an IDH2 mutation in a patient in need thereof comprising administering a therapeutically effective amount of the cocrystal of any one of embodiments 1 -10 and 37-44, the crystalline form of any one of embodiments 57-62, 84-90, 103-109, and 122- 128, the amorphous solid dispersion of any one of embodiments 137-139, the drug substance of any one of embodiments 1 1 -19 and 63-71 , the compound or
• compositions of any one of embodiments 20-27, 45-52, 72-79, 91 -98, 1 10-1 17, 129-136, 147-154, and 159, to the patient.
• any one of embodiments 160-171 wherein the cancer is selected from glioma, acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer, and angio-immunoblastic non-Hodgkin's lymphoma (NHL).
• NSCLC non-small cell lung cancer
• MDS myelodysplastic syndromes
• MN myeloproliferative neoplasm
• NDL angio-immunoblastic non-Hodgkin's lymphoma
• glioma is a low grade glioma or a secondary high grade glioma.
• 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).
• 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).
• 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, twice per day, based on the amount of the compound of formula (I).
• 183. The method of any one of embodiments 160-179, wherein the cocrystal, 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, twice per day, based on the amount of the compound of formula (I).
• reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company), and used without further purification.
• X-Ray Powder Diffraction (XRPD) Analysis was conducted on either a PANalytical Empyrean X-ray powder diffractometer with a 12-auto sample stage or a Bruker D8 Advance X-ray powder diffractometer. [00263] The parameters used for XRPD analysis on the PANalytical Empyrean diffractometer are provided in Table 2.
• DVS Dynamic Vapor Sorption Analysis.
• DVS was measured via a SMS (Surface Measurement Systems) DVS Intrinsic. The relative humidity at 25 °C were calibrated against deliquescence point of LiCI, Mg(N03)2 and KCI. The parameters used for DVS analysis are listed in Table 4.
• HPLC High Performance Liquid Chromatography
• HPLC High Performance Liquid Chromatography
• Compound 1 exists at least in part in one or more tautomeric forms, including without limitation one or more of the following:
• Compound 1 shall be understood to refer 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 geometries of the foregoing tautomers were not determined, and therefore the chemical structures representing the foregoing tautomers are not intended to imply a particular double bond geometry.
• the one-dimensional NOE enhanced 15 N NMR spectrum of Compound 1 in DMSO-d6 ( Figure 5) also includes multiple resonances that would have been expected to appear as single resonances in the absence of tautomerism.
• the spectrum includes three resonances corresponding to -NH groups (-285.0, -284.9, and -284.4 ppm).
• DIPEA /V,/V-diisopropylethylamine
• Step 1 Preparation of 6-(6-chloropyridin-2-yl)-1 ,3,5-triazine-2, 4(1 H,3H)-dione (Compound A).
• Step 2 Preparation of 2,4-dichloro-6-(6-chloropyridin-2-yl)-1 ,3,5-triazine (Compound B).
• benzyltriethylammonium chloride (19.0 kg, 79.4 mol), and POC (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 x 53.0 kg) was added, and the resulting solution was concentrated under reduced pressure to 18-36 L.
• Additional ethyl acetate (1 12.0 kg) was added, and the resulting mixture was cooled to 10-20°C.
• a 1000 L reactor was charged with Na 2 HP0 4 (6.6 kg), NaH 2 P0 4 2H 2 0 (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 over to the 1000 L reactor.
• the resulting solution was stirred at 15-25°C for 2-4 hours and was then allowed to stand for 30-60 min.
• 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.
• Step 3 Preparation of 6-(6-chloropyridin-2-yl)-N 2 , N 4 -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), ( )-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 about 1 hour.
• the mixture was stirred for about 10 minutes at 10-20°C, for about 1 -2 hours at 45-55°C, and for about 20 hours at 95- 105°C, and was then cooled to 45-55°C.
• Process water (4 kg) was added dropwise over about 1 hour, and the resulting solution was transferred to a 500 L reactor, washing with N-methyl-2-pyrrolidone (2 kg). Additional process water (34.0 kg) was added dropwise over about 3 hours at 45-55°C, and the resulting mixture was stirred for about 3.5 hours at 20-30°C. Additional process water (7.4 kg) was added, and the resulting mixture was centrifuged, washing with process water (9 kg). The wet cake was slurried with process water (89 kg), and the resulting slurry was centrifuged, washing with process water (21 kg). The wet cake was transferred back to the 500 L reactor, and acetonitrile (2 x 133 kg) was added. The resulting solution was
• 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 hr, during which time a precipitate was formed. The precipitate was collected by filtration through a buchner funnel, and the solids were dried at room temperature for 15.5 hr to afford citric acid cocrystal Type A of Compound 1 . The cocrystal was analyzed by XRPD, 1 H NMR, DSC, TGA, and DVS analysis.
• the DSC and TGA thermograms of the cocrystal are shown in Figure 8.
• DSC analysis was performed with a TA instruments Q2000 DSC in crimped Aluminum pan. The temperature and heat flow were calibrated against indium melting. DSC analysis was performed over a temperature range from room temperature to the desired temperature at a ramp rate of 10 °C per minute, with N2 as the purge gas.
• TGA was conducted at 10°C/min ramping from RT to desired temperature in open Aluminum pan using a TA Instruments Q5000 TGA, with N2 as the purge gas.
• the DSC thermogram comprises an endothermic peak having an onset temperature of 171 .5 °C.
• the TGA thermogram indicates a 3.5% weight loss up to 120 °C.
• Crystal data and structure refinement are listed in Table 8.
• An ORTEP drawing of the crystal structure is shown in Figure 10, and the unit cell is shown in Figure 1 1 .
• the molar ratio of Compound 1 : citric acid : H2O is 2: 1 : 1 .
• the DSC and TGA thermograms of the cocrystal are shown in Figure 14.
• DSC analysis was performed with a TA instruments Q2000 DSC in crimped Aluminum pan. The temperature and heat flow were calibrated against indium melting. DSC analysis was performed over a temperature range from room temperature to the desired temperature and a ramp rate of 10 °C per minute, with N2 as the purge gas.
• TGA was conducted at 10°C/min ramping from RT to desired temperature in open Aluminum pan using a TA Instruments Q5000 TGA, with N2 as the purge gas.
• the DSC thermogram comprises two endothermic peaks having onset temperatures of 91 .2 °C and 128.4 °C. The TGA thermogram indicates a 2.5% weight loss up to 1 15 °C.
• the hygroscopicity of the cocrystal was determined by DVS analysis at 25 °C, over a range of 0-95% relative humidity.
• the DVS isotherm plot is shown in Figure 15 and indicates a 2.0% water uptake at 80% relative humidity, revealing that the maleic acid cocyrstal is slightly hygroscopic.
• XRPD analysis of the material remaining after DVS analysis confirmed that no form change had occurred.
• 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 agitated at 20-30 °C until the citric acid dissolved completely ( ⁇ 30-90 min), 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 agitated at 20- 30 °C until Compound 1 had dissolved completely ( ⁇ 1 h).
• the resulting mixture was stirred for an additional 2-3 hours at 20-30 °C, 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 volumes/25 volumes) and then dried for 10-20 hours at ⁇ 30 °C to afford 7.15 kg of the citric acid cocrystal Type A.
• the isolated cocrystal was characterized by elemental analysis, 1 H NMR analysis, 13 C NMR analysis, FTIR analysis, UV/visible spectroscopy, XRPD analysis, DSC analysis, TGA analysis, and HPLC analysis.
• the DSC thermogram of the cocrystal is shown in Figure 21.
• DSC analysis was performed on a TA Q20 DSC instrument, with a ramp rate of 10.0 °C/minute and using N2 as the purge gas.
• the thermogram comprises an endothermic peak having an onset temperature of 170.6 °C and a peak temperature of 173.0 °C.
• TGA The TGA curve of the cocrystal is shown in Figure 22.
• TGA was performed on a TA Q5000 IR TGA system at a ramp rate of 10 °C/minute and using N2 as the purge gas.
• the cocrystal exhibited a 1 .692% weight loss up to 136.06 °C. Rapid weight loss was observed above approximately 165 °C, which is believed to result from decomposition.
• 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.
• the concentrations (w/w %) were determined by HPLC peak area, based on the assumption that Compounds 1 -7 have a relative response factor of 1.
• the concentration (w/w %) of each compound reported in Table 12 reflects the HPLC peak area attributed to the compound, as a percentage of the total peak area attributable to Compounds 1 and any organic impurities.
• the concentration (w/w %) of total impurities reported in Table 12 reflects the total HPLC peak area attributed to organic impurities (Compounds 2-7), as a percentage of the total peak area attributable to Compound 1 and any organic impurities.
• the stereoisomers of Compound 1 (Compounds 8 and 9) co-elute with Compound 1 under the conditions of HPLC Method 1 and therefore are not included in the concentration of total impurities.
• the stereochemical purity of the cocrystal was determined by HPLC analysis (Method 2).
• the concentrations (w/w %) of Compounds 8 and 9 are reported in Table 13.
• the concentrations (w/w %) were determined by HPLC peak area, based on the assumption that Compounds 1 , 8, and 9 have a relative response factor of 1.
• the concentrations (w/w %) of Compounds 8 and 9 reported in Table 13 reflect the HPLC peak area attributed to the compound, as a percentage of the total peak area attributable to Compounds 1 , 8, and 9.
• Table 13 Batch Analysis of Citric Acid Cocrystal by HPLC Method 2
• 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 for 0.5 hours at 25-28 °C.
• 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 for 0.5 hours at 25-28 °C.
• Half of the contents of Reactor 2 were transferred to Reactor 1 at 37-43 °C, and then seed crystals of citric acid cocrystal Type A (6 g) were added to Reactor 1.
• Reactor 1 The resulting mixture in Reactor 1 was stirred for 1 .5 hours at 37-43 °C.
• the remaining contents of Reactor 2 were transferred to Reactor 1 over a period of 0.5-1.5 hours at 37-43 °C, and then n-heptane (6690 g) were added to Reactor 1 over a period of 2.5 hours at 37-43 °C.
• Reactor 1 was cooled to 8-12 °C over a period of 2.5 hours, and stirring was continued for 1 -3 hours at 8-12 °C.
• thermogram comprises an endothermic peak having an onset temperature of 221 .9 °C and a peak temperature of 223.1 °C.
• TGA curve of the free form type A is shown in Figure 25.
• TGA was performed on a TA Q5000 IR TGA system at a ramp rate of 10 °C/minute and using N2 as the purge gas.
• the curve reflects a 0.01 1 % loss of weight.
• the purity profile of the 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.
• the concentrations (w/w %) were determined by HPLC peak area, based on the assumption that Compounds 1 -7 have a relative response factor of 1 .
• the concentration (w/w %) of each compound reported in Table 16 reflects the HPLC peak area attributed to the compound, as a percentage of the total peak area attributable to Compound 1 and any organic impurities.
• the concentration (w/w %) of total impurities reported in Table 16 reflects the total HPLC peak area attributed to organic impurities (Compounds 2-7), as a percentage of the total peak area attributable to Compound 1 and any organic impurities.
• the stereoisomers of Compound 1 (Compounds 8 and 9) co-elute with Compound 1 under the conditions of HPLC Method 1 and therefore are not included in the concentration of total impurities.
• the stereochemical purity of the 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.
• the concentrations (w/w %) were determined by HPLC peak area, based on the assumption that Compounds 1 , 8, and 9 have a relative response factor of 1.
• the concentrations of Compounds 8 and 9 reported in Table 17 reflect the HPLC peak area attributed to the compound, as a percentage of the total peak area attributable to Compounds 1 , 8, and 9.
• Flack parameter was refined to 0.025(5), confirming the absolute stereochemistry. Determination of absolute structure using Bayesian statistics on Bijvoet differences using the program within PLATON (A.L. Spek, Single-crystal structure validation with the program PLATON, J. Appl. Cryst., (2003), 36, 7-13) also report that we have the correct enantiomer based on this comparison.
• the DSC and TGA thermograms of Free Form Type B are shown in Figure 29.
• DSC analysis was performed with a TA instruments Q2000 DSC in crimped Aluminum pan.
• DSC analysis was performed over a temperature range from room temperature to 300 °C at a ramp rate of 10 °C per minute, with N2 as the purge gas.
• TGA was conducted at 10°C/min ramping from RT to 350 °C in open Platinum pan using a TA Instruments Q5000 TGA, with N2 as the purge gas.
• the DSC thermogram comprises an endothermic peak having an onset temperature of 221 .5 °C.
• the TGA thermogram indicates a 2.3% weight loss up to 150 °C.
• THF/heptane (1/3, v/v) co-solvents The solution was filtered with a nylon filter (0.45 pm) and collected into three 4-mL vials. Seeds of Free form Type B were added into the vials. The vials were placed into a 20-mL vial (with 4 ml_ heptane as anti-solvent), and the 20-mL vial was capped. The vials were kept at room temperature, and the heptane was allowed to diffuse into the THF/heptane solution. After three days, plate-like crystals of Free Form Type B were obtained.
• An XRPD pattern of an authentic sample of Free Form Type B was collected with an XPERT-3 Empyrean system at RT.
• Free Form Type B was confirmed to be an anhydrate and to have eight molecules of Compound 1 per unit cell. The details of crystal data and structure refinement are listed in Table 20.
• An ORTEP drawing of the crystal structure is shown in Figure 30, and the unit cell is shown in Figure 31 .
• a simulated XRPD pattern based on the single crystal data and an experimental XRPD pattern obtained from an authentic sample of Free Form Type B were in good agreement.
• 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 afford Free Form Type C of Compound 1 .
• Free Form Type C was analyzed by XRPD, DSC, and TGA analysis.
• the DSC and TGA thermograms of Free Form Type C are shown in Figure 33.
• DSC analysis was performed with a TA instruments Q2000 DSC in crimped Aluminum pan.
• DSC analysis was performed over a temperature range from room temperature to 300 °C at a ramp rate of 10 °C per minute, with N2 as the purge gas.
• TGA was conducted at 10°C/min ramping from RT to 350 °C in open Platinum pan using a TA Instruments Q5000 TGA, with N2 as the purge gas.
• the DSC thermogram comprises endothermic peaks at 81 .9 °C (peak temperature) and 221 .3 °C (onset temperature).
• the TGA thermogram indicates a 14.1 % weight loss up to 150 °C.
• An XRPD pattern of an authentic sample of Free Form Type C was collected with an XPERT-3 Empyrean system at RT.
• Free Form Type C was confirmed to be a trihydrate having two molecules of Compound 1 and six molecules of water per unit cell. The details of crystal data and structure refinement are listed in Table 22.
• An ORTEP drawing of the crystal structure is shown in Figure 34, and the unit cell is shown in Figure 35.
• a simulated XRPD pattern based on the single crystal data and an experimental XRPD pattern obtained from an authentic sample of Free Form Type C were in good agreement.
• 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 separated and air dried to afford Free Form Type D of Compound 1 .
• Free Form Type D was analyzed by XRPD, 1 H NMR, DSC, and TGA analysis.
• a 50:50 spray-dried dispersion of Compound 1 and HPMCAS hydroxypropyl methylcellulose acetate succinate
• HPMCAS hydroxypropyl methylcellulose acetate succinate
• 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.
• Example 24 Pharmacokinetics of Compound 1 Solid Forms in Plasma Following Single PO Administration in Male Sprague Dawley Rats
• Blood Collection Blood was serially collected from each animal 0.083 hr, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 8 hr, 24 hr, 48 hr, and 72 hrs post-dose. For each collection, the animal was restrained manually, and approximately 150 ⁇ of blood sample was collected via the tail vein into K2EDTA tubes. The blood samples were put on ice and centrifuged at 2000 g for 5 min to obtain plasma. Plasma samples were stored at approximately -70 °C until analysis.
• Compound 1 was 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 intravenous (IV) bolus dose to a separate group of male Sprague-Dawley rats, and blood samples were collected at similar time points to those shown above. Further, plasma samples were obtained from the collected blood samples and stored at approximately -70 °C until analysis.
• NMP N-Methyl-2-pyrrolidone
• IV intravenous
• the amorphous solid dispersion of Compound 1 was suspended in an aqueous vehicle containing 0.5% methyl cellulose (MC) and 0.2% Tween80 at 0.2 mg/mL concentration and dosed at 1 mg/kg as a single oral dose to a separate group of male Sprague-Dawley rats after an overnight fasting. Blood samples were collected at similar time points to those shown above. Further, plasma was harvested and stored at approximately -70 °C until analysis.
• MC methyl cellulose
• a 20 ⁇ _ aliquot of each sample was diluted with 200 ⁇ _ of acetonitrile containing dexamethasone as an internal standard (40ng/ml_). The resulting mixture was vortexed for 2 min and centrifuged at 5800 rpm for 10min. A 2 ⁇ _ sample was injected into LC-MS/MS.
• LC-MS/MS analysis was conducted on a UPLC/MS-MS-018 (API-5500) system under the conditions set forth in Table 25.

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