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WO2015018060A1 - Formes cristallines de composés thérapeutiquement actifs et utilisation associée - Google Patents

Formes cristallines de composés thérapeutiquement actifs et utilisation associée Download PDF

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Publication number
WO2015018060A1
WO2015018060A1 PCT/CN2013/081170 CN2013081170W WO2015018060A1 WO 2015018060 A1 WO2015018060 A1 WO 2015018060A1 CN 2013081170 W CN2013081170 W CN 2013081170W WO 2015018060 A1 WO2015018060 A1 WO 2015018060A1
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WO
WIPO (PCT)
Prior art keywords
pyridin
amino
trifluoromethyl
compound
methyl
Prior art date
Application number
PCT/CN2013/081170
Other languages
English (en)
Inventor
Chong-Hui Gu
Hua Yang
Liting GUO
Zhen Tang
Jianming Wang
Yanfeng Zhang
Yan Zhou
Original Assignee
Agios Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Agios Pharmaceuticals, Inc. filed Critical Agios Pharmaceuticals, Inc.
Priority to PCT/CN2013/081170 priority Critical patent/WO2015018060A1/fr
Priority to CN201910707312.9A priority patent/CN110372670B/zh
Priority to SG11201600479WA priority patent/SG11201600479WA/en
Priority to UAA201601999A priority patent/UA121021C2/uk
Priority to PE2016000214A priority patent/PE20160840A1/es
Priority to US14/909,451 priority patent/US9738625B2/en
Priority to TW103126335A priority patent/TWI666208B/zh
Priority to EP14832505.3A priority patent/EP3027193A4/fr
Priority to CA2919382A priority patent/CA2919382A1/fr
Priority to MYPI2016700311A priority patent/MY177994A/en
Priority to EP21178745.2A priority patent/EP3932408A1/fr
Priority to TW108110624A priority patent/TWI701242B/zh
Priority to MX2016001361A priority patent/MX2016001361A/es
Priority to ES19177845T priority patent/ES2886211T3/es
Priority to JP2016531940A priority patent/JP6742905B2/ja
Priority to PCT/US2014/049469 priority patent/WO2015017821A2/fr
Priority to SG10201709187TA priority patent/SG10201709187TA/en
Priority to BR112016002287A priority patent/BR112016002287A2/pt
Priority to CN201480053796.5A priority patent/CN105916507A/zh
Priority to EP19177845.5A priority patent/EP3566706B1/fr
Priority to EA201690322A priority patent/EA030428B1/ru
Priority to CN201910708167.6A priority patent/CN110386922A/zh
Priority to NZ716226A priority patent/NZ716226B2/en
Priority to MX2020011397A priority patent/MX2020011397A/es
Priority to AU2014295938A priority patent/AU2014295938B2/en
Publication of WO2015018060A1 publication Critical patent/WO2015018060A1/fr
Priority to PH12016500164A priority patent/PH12016500164A1/en
Priority to IL243833A priority patent/IL243833A0/en
Priority to SA516370523A priority patent/SA516370523B1/ar
Priority to NI201600022A priority patent/NI201600022A/es
Priority to CL2016000263A priority patent/CL2016000263A1/es
Priority to US15/649,551 priority patent/US10093654B2/en
Priority to CL2017002240A priority patent/CL2017002240A1/es
Priority to US16/121,483 priority patent/US10730854B2/en
Priority to AU2018247242A priority patent/AU2018247242B2/en
Priority to JP2019082794A priority patent/JP2019142930A/ja
Priority to IL270347A priority patent/IL270347B/en
Priority to US16/915,936 priority patent/US20210155603A1/en
Priority to JP2021123814A priority patent/JP2021176893A/ja
Priority to US18/144,695 priority patent/US20240132474A1/en

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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
    • C07D401/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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(+).
  • NAD(+) the electron acceptor
  • NADP(+)-dependent isocitrate dehydrogenases Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer.
  • IDH2 isocitrate dehydrogenase 2 (NADP+), mitochondrial
  • IDH isocitrate dehydrogenase 2 (NADP+), mitochondrial
  • IDP isocitrate dehydrogenase 2
  • IDHM isocitrate dehydrogenase 2
  • IDPM isocitrate dehydrogenase 2
  • ICD-M isocitrate dehydrogenase 2
  • mNADP-IDH mNADP-IDH.
  • 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. The nucleotide and amino acid sequence for human IDH2 are also described in, e.g., Huh et al., Submitted (NOV- 1992) to the
  • Non-mutant e.g., wild type, IDH2 catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate (a-KG) thereby reducing NAD + (NADP + ) to NADH (NADPH), e.g., in the forward reaction:
  • the inhibition of mutant IDH2 and its neoactivity is therefore a potential therapeutic treatment for cancer selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), or lymphoma (e.g., T-cell lymphoma). Accordingly, there is an ongoing need for inhibitors of IDH2 mutants having alpha hydroxyl neoactivity.
  • AML acute myelogenous leukemia
  • MDS myelodysplastic syndrome
  • CMML chronic myelomonocytic leukemia
  • lymphoma e.g., T-cell lymphoma
  • These applications additionally disclose methods for the preparation of inhibitors of mutant IDH2, pharmaceutical compositions containing these compounds, and methods for the therapy of diseases, disorders, or conditions (e.g., cancer) associated with overexpression and/or amplification of mutant IDH2.
  • These applications describe the synthesis of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ - l ,3,5-triazin-2- yl)amino]propan-2-ol, which results in an unpredictable mixture of amorphous and crystalline forms.
  • a primary concern for the manufacture of large-scale pharmaceutical compositions is that the active ingredient should have a stable crystalline morphology to ensure consistent processing parameters and pharmaceutical quality.
  • the active ingredient must possess acceptable properties with respect to hygroscopicity, solubility, and stability, which can be consistently reproduced despite the impact of various environmental conditions such as temperature and humidity. If an unstable crystalline form is used, crystal morphology may change during manufacture and/or storage resulting in quality control problems, and formulation irregularities. Such a change may affect the reproducibility of the manufacturing process and thus lead to pharmaceutical formulations that do not meet the high quality and stringent requirements imposed on
  • polymorphism When a compound crystallizes from a solution or slurry, it may crystallize with different spatial lattice arrangements, a property referred to as "polymorphism.” Each of the crystal forms is a "polymorph.” While polymorphs of a given substance have the same chemical composition, they may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, melting point, crystal shape, compaction behavior, flow properties, and/or solid state stability.
  • polymorphic behavior of pharmaceutically active substances is of great importance in pharmacy and pharmacology.
  • the differences in physical properties exhibited by polymorphs affect practical parameters such as storage stability, compressibility and density (important in pharmaceutical composition manufacturing), and dissolution rates (an important factor in determining bio-availability of an active ingredient).
  • Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when it is one polymorph than when it is another polymorph) or mechanical changes (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity than another polymorph).
  • the physical properties of the crystal may be important in processing: for example, one polymorph might be more likely to form solvates that cause the solid form to aggregate and increase the difficulty of solid handling, or might be difficult to filter and wash free of impurities (i.e., particle shape and size distribution might be different between one polymorph relative to other).
  • COMPOUND 1 and COMPOUND 3 Also disclosed herein is the pharmaceutical use of crystalline forms of COMPOUND 1 and COMPOUND 3 as mutant IDH2 inhibitors.
  • FIGURE 1 is an X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol Form 1.
  • XRPD X-ray powder diffractogram
  • FIGURE 2 is an X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol Form 2.
  • XRPD X-ray powder diffractogram
  • FIGURE 3 is a differential scanning calorimetry (DSC) profile of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol Form 2.
  • DSC differential scanning calorimetry
  • FIGURE 4 is a thermal gravimetric analysis (TGA) profile of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol Form 2.
  • TGA thermal gravimetric analysis
  • FIGURE 5 is an X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate Form 3.
  • XRPD X-ray powder diffractogram
  • FIGURE 6 is a differential scanning calorimetry (DSC) profile of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate Form 3.
  • DSC differential scanning calorimetry
  • FIGURE 7 is a thermal gravimetric analysis (TGA) profile of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate Form 3.
  • TGA thermal gravimetric analysis
  • FIGURE 8 is a dynamic vapor sorption (DVS) profile of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate Form 3.
  • FIGURE 9 is an X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6-
  • FIGURE 10 is a differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) profile of 2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4- yl]amino ⁇ -l ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 4.
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric analysis
  • FIGURE 1 1 is an X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate Form 5.
  • XRPD X-ray powder diffractogram
  • FIGURE 12 is a differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) profile of 2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4- yl]amino ⁇ -l ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 5.
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric analysis
  • FIGURE 13 is an X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate Form 6.
  • XRPD X-ray powder diffractogram
  • FIGURE 14 is a differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) profile of 2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4- yl]amino ⁇ -l ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 6.
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric analysis
  • FIGURE 15 is an X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate Form 7.
  • XRPD X-ray powder diffractogram
  • FIGURE 16 is a differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) profile of 2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4- yl]amino ⁇ -l ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 7.
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric analysis
  • FIGURE 17 is a X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate Form 8.
  • XRPD X-ray powder diffractogram
  • FIGURE 18 is a differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) profile of 2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4- yl]amino ⁇ -l ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 8.
  • FIGURE 19 is an X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6-
  • FIGURE 20 is a differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) profile of 2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4- yl]amino ⁇ -l ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 9.
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric analysis
  • FIGURE 21 is an X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate Form 10.
  • XRPD X-ray powder diffractogram
  • FIGURE 22 is a differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) profile of 2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4- yl]amino ⁇ -l,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 10.
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric analysis
  • FIGURE 23 is an X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate Form 1 1.
  • XRPD X-ray powder diffractogram
  • FIGURE 24 is a differential scanning calorimetry (DSC) profile of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate Form 1 1.
  • DSC differential scanning calorimetry
  • FIGURE 25 is a thermal gravimetric analysis (TGA) profile of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate Form 1 1.
  • TGA thermal gravimetric analysis
  • FIGURE 26 is an X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate Form 12.
  • XRPD X-ray powder diffractogram
  • FIGURE 27 is a differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) profile of 2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4- yl]amino ⁇ -l,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 12.
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric analysis
  • FIGURE 28 is a X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate Form 13.
  • XRPD X-ray powder diffractogram
  • FIGURE 29 is a differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) profile of 2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4- yl]amino ⁇ -l,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 13.
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric analysis
  • FIGURE 30 is an X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate Form 14.
  • XRPD X-ray powder diffractogram
  • FIGURE 31 is a differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) profile of 2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4- yl]amino ⁇ -l,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 14.
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric analysis
  • FIGURE 32 is an X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate Form 15.
  • XRPD X-ray powder diffractogram
  • FIGURE 33 is a differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) profile of 2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4- yl]amino ⁇ -l,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 15.
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric analysis
  • FIGURE 34 is an X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol Form 16.
  • XRPD X-ray powder diffractogram
  • FIGURE 35 is a differential scanning calorimetry (DSC) profile of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol Form 16.
  • DSC differential scanning calorimetry
  • FIGURE 36 is a thermal gravimetric analysis (TGA) profile of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol Form 16.
  • TGA thermal gravimetric analysis
  • FIGURE 37 is an X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol Form 17.
  • XRPD X-ray powder diffractogram
  • FIGURE 38 is an X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol Form 18.
  • FIGURE 39 is an X-ray powder diffractogram (XRPD) of 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-tri
  • Free Base is meant to describe 2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl]amino ⁇ -l ,3,5-triazin-2-yl)amino]propan-2-ol (COMPOUND 3).
  • Mesylate Salt is meant to describe 2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate (COMPOUND 1).
  • Form 1 or "2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl]amino ⁇ -l ,3,5-triazin-2-yl)amino]propan-2-ol Form 1" are used interchangeably, and describe Form 1 COMPOUND 3, as synthesized in Example 3, in the Examples section below, and as described below, and represented by data shown in FIG. 1.
  • Form 2 or "2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl]amino ⁇ -l ,3,5-triazin-2-yl)amino]propan-2-ol Form 2" are used interchangeably, and describe Form 2 of COMPOUND 3, as synthesized in Example 4, in the Examples section below, and as described below, and represented by data shown in FIGS. 2, 3, and 4.
  • Form 3 or "2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl] amino ⁇ - 1 ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 3" are used interchangeably, and describe Form 3 of COMPOUND 1 , as synthesized in Example 6, in the Examples section below, and as described below, and represented by data shown in FIGS. 5, 6, 7, and 8.
  • Form 4" or "2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl] amino ⁇ - 1 ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 4" are used interchangeably, and describe Form 4 of COMPOUND 1 , as synthesized in Example 7, in the Examples section below, and as described below, and represented by data shown in FIGS. 9 and 10.
  • Form 5" or "2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl] amino ⁇ - 1 ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 5" are used interchangeably, and describe Form 5 of COMPOUND 1 , as synthesized in Example 8, in the Examples section below, and as described below, and represented by data shown in FIGS. 1 1 and 12.
  • Form 6 or "2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl] amino ⁇ - 1 ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 6" are used interchangeably, and describe Form 6 of COMPOUND 1 , as synthesized in Example 9, in the Examples section below, and as described below, and represented by data shown in FIGS. 13 and 14.
  • Form 7 or "2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl] amino ⁇ - 1 ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 7" are used interchangeably, and describe Form 7 of COMPOUND 1 , as synthesized in Example 10, in the Examples section below, and as described below, and represented by data shown in FIGS. 15 and 16.
  • Form 8 or "2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl] amino ⁇ - 1 ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 8" are used interchangeably, and describe Form 8 of COMPOUND 1 , as synthesized in Example 11 , in the Examples section below, and as described below, and represented by data shown in FIGS. 17 and 18.
  • Form 9 or "2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl] amino ⁇ - 1 ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 9" are used interchangeably, and describe Form 9 of COMPOUND 1 , as synthesized in Example 12, in the Examples section below, and as described below, and represented by data shown in FIGS. 19 and 20.
  • Form 10 or "2-Methyl-l-[(4-[6-(trifiuoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl] amino ⁇ - 1 ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 10" are used interchangeably, and describe Form 10 of COMPOUND 1 , as synthesized in Example 13, in the Examples section below, and as described below, and represented by data shown in FIGS. 21 and 22.
  • Form 11 or "2-Methyl-l-[(4-[6-(trifiuoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl] amino ⁇ - 1 ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 1 1" are used interchangeably, and describe Form 11 of COMPOUND 1 , as synthesized in Example 14, in the Examples section below, and as described below, and represented by data shown in FIGS. 23, 24, and 25.
  • Form 12 or "2-Methyl-l-[(4-[6-(trifiuoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl] amino ⁇ - 1 ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 12" are used interchangeably, and describe Form 12 of COMPOUND 1 , as synthesized in Example 15, in the Examples section below, and as described below, and represented by data shown in FIGS. 26 and 27.
  • Form 13 or "2-Methyl-l-[(4-[6-(trifiuoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl] amino ⁇ - 1 ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 13" are used interchangeably, and describe Form 13 of COMPOUND 1 , as synthesized in Example 16, in the Examples section below, and as described below, and represented by data shown in FIGS. 28 and 29.
  • Form 14 or "2-Methyl-l-[(4-[6-(trifiuoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl] amino ⁇ - 1 ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 14" are used interchangeably, and describe Form 14 of COMPOUND 1 , as synthesized in Example 17, in the Examples section below, and as described below, and represented by data shown in FIGS. 30 and 31.
  • Form 15 or "2-Methyl-l-[(4-[6-(trifiuoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl] amino ⁇ - 1 ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate Form 15" are used interchangeably, and describe Form 15 of COMPOUND 1 , as synthesized in Example 18, in the Examples section below, and as described below, and represented by data shown in FIGS. 32 and 33.
  • Form 16 or "2-Methyl-l-[(4-[6-(trifiuoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl]amino ⁇ -l ,3,5-triazin-2-yl)amino]propan-2-ol Form 16" are used interchangeably, and describe Form 16 COMPOUND 3, as synthesized in Example 2, in the Examples section below, and as described below, and represented by data shown in FIGS. 34, 35 and 36.
  • Form 17 or "2-Methyl-l-[(4-[6-(trifiuoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl]amino ⁇ -l ,3,5-triazin-2-yl)amino]propan-2-ol Form 16" are used interchangeably, and describe Form 16 COMPOUND 3, as synthesized in Example 20, in the Examples section below, and as described below, and represented by data shown in FIG. 37.
  • Form 18 or "2-Methyl-l-[(4-[6-(trifiuoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl]amino ⁇ -l ,3,5-triazin-2-yl)amino]propan-2-ol Form 16" are used interchangeably, and describe Form 16 COMPOUND 3, as synthesized in Example 21, in the Examples section below, and as described below, and represented by data shown in FIG. 38.
  • Form 19 or "2-Methyl-l-[(4-[6-(trifiuoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl]amino ⁇ -l ,3,5-triazin-2-yl)amino]propan-2-ol Form 16" are used interchangeably, and describe Form 16 COMPOUND 3, as synthesized in Example 22, in the Examples section below, and as described below, and represented by data shown in FIG. 39.
  • crystalline refers to a solid having a highly regular chemical structure.
  • a crystalline Free Base or Mesylate Salt may be produced as one or more single crystalline forms of the Free Base or Mesylate Salt.
  • the terms "crystalline form”, “single crystalline form” and “polymorph” are synonymous; the terms distinguish between crystals that have different properties (e.g., different XRPD patterns and/or different DSC scan results).
  • the term "polymorph” includes pseudopolymorphs, which are typically different solvates of a material, and thus their properties differ from one another. Thus, each distinct polymorph and pseudopolymorph of the Free Base or Mesylate Salt is considered to be a distinct single crystalline form herein.
  • substantially crystalline refers to forms that may be at least a particular weight percent crystalline. Particular weight percentages are 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 10% and 100%.
  • substantially crystalline refers to a Free Base of Mesylate Salt that is at least 70% crystalline.
  • substantially crystalline refers to a Free Base of Mesylate Salt that is at least 90% crystalline.
  • isolated refers to forms that may be at least a particular weight percent of a particular crystalline form of COMPOUND 1 or COMPOUND 3. Particular weight percentages are 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 90% and 100%.
  • solvate or solvated means a physical association of a compound, including a crystalline form thereof, of this invention with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate or solvated” encompasses both solution-phase and isolable solvates. Representative solvates include, for example, a hydrate, ethanolates or a methanolate.
  • hydrate is a solvate wherein the solvent molecule is H 2 0 that is present in a defined stoichiometric amount, and may for example, include hemihydrate, monohydrate, dihydrate, or trihydrate.
  • mixture is used to refer to the combined elements of the mixture regardless of the phase-state of the combination (e.g., liquid or liquid/ crystalline).
  • seeding is used to refer to the addition of a crystalline material to initiate recrystallization or crystallization.
  • antisolvent is used to refer to a solvent in which compounds, including a crystalline forms thereof, are poorly soluble.
  • the term “about” means approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 10%.
  • the term “elevated levels of 2HG” means 10%, 20% 30%, 50%, 75%, 100%, 200%, 500% or more 2HG then is present in a subject that does not carry a mutant IDH2 allele.
  • the term “elevated levels of 2HG” may refer to the amount of 2HG within a cell, within a tumor, within an organ comprising a tumor, or within a bodily fluid.
  • the term "bodily fluid” includes one or more of amniotic fluid surrounding a fetus, aqueous humour, blood (e.g., blood plasma), serum, Cerebrospinal fluid, cerumen, chyme, Cowper's fluid, female ejaculate, interstitial fluid, lymph, breast milk, mucus (e.g., nasal drainage or phlegm), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal secretion, or vomit.
  • blood e.g., blood plasma
  • serum Cerebrospinal fluid
  • cerumen cerumen
  • chyme chyme
  • Cowper's fluid female ejaculate
  • interstitial fluid lymph
  • breast milk mucus (e.g., nasal drainage or phlegm)
  • mucus e.g., nasal drainage or phlegm
  • pleural fluid pus, saliva, sebum, semen, serum
  • inhibitor or “prevent” include both complete and partial inhibition and prevention.
  • An inhibitor may completely or partially inhibit the intended target.
  • treat means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease/disorder (i.e., a cancer selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), or lymphoma (e.g., T-cell lymphoma)), lessen the severity of the disease/disorder (i.e., a cancer selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), or lymphoma (e.g., T-cell lymphoma)) or improve the symptoms associated with the disease/disorder (i.e., a cancer selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), or lymphoma (
  • AML myelogenous leukemia
  • MDS myelodysplastic syndrome
  • CMML chronic myelomonocytic leukemia
  • lymphoma e.g., T-cell lymphoma
  • an amount of a compound, including a crystalline form thereof, effective to treat a disorder refers to an amount of the compound, including a crystalline form thereof, which is effective, upon single or multiple dose
  • the term "subject" is intended to mean human.
  • exemplary human subjects include a human patient (referred to as a patient) having a disorder, e.g., a disorder described herein or a normal subject.
  • COMPOUND 1 is a single crystalline form, or any one of the single crystalline forms described herein.
  • pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier or diluent; and COMPOUND 1 , wherein COMPOUND 1 is a single crystalline form, or any one of the crystalline forms being described herein.
  • uses of COMPOUND 1 wherein COMPOUND 1 is a single crystalline form, or any one of the single crystalline forms described herein, to prepare a pharmaceutical composition.
  • COMPOUND 3 is a single crystalline form, or any one of the single crystalline forms described herein.
  • pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier or diluent; and COMPOUND 3, wherein COMPOUND 3 is a single crystalline form, or any one of the crystalline forms being described herein.
  • Also provided are methods of treating a cancer selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), or lymphoma (e.g., T-cell lymphoma) characterized by the presence of a mutant allele of IDH2 comprising the step of administering to subject in need thereof (a) a single crystalline form of COMPOUND 1 or COMPOUND 3, or (b) a pharmaceutical composition comprising (a) and a pharmaceutically acceptable carrier.
  • the single crystalline form in (a) is any percentage between 90% and 100% pure.
  • Crystalline forms of COMPOUND 1 have physical properties that are suitable for large scale pharmaceutical formulation manufacture. Many of the crystalline forms of COMPOUND 1 described herein exhibit high crystallinity, high melting point, and limited occluded or solvated solvent. Crystalline forms of COMPOUND 1 have improved bioavailability as compared to amporphous forms of COMPOUND 1. In particular, Form 3 is non-hygroscopic, and exhibits stability advantages (e.g., thermodynamic, chemical, or physical stability) at a relative humidity of up to 40%.
  • At least a particular percentage by weight of COMPOUND 3 is crystalline. Particular weight percentages may be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 10% and 100%.
  • a particular percentage by weight of COMPOUND 3 is crystalline
  • the remainder of COMPOUND 3 is the amorphous form of COMPOUND 3.
  • Non-limiting examples of crystalline COMPOUND 3 include a single crystalline form of COMPOUND 3 or a mixture of different single crystalline forms.
  • COMPOUND 3 is at least 90% by weight crystalline. In some other
  • COMPOUND 3 is at least 95% by weight crystalline.
  • COMPOUND 3 is a specific single crystalline form or a combination of single crystalline forms. Particular weight percentages may be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 10% and 100%.
  • COMPOUND 3 is at least 90% by weight of a single crystalline form.
  • COMPOUND 3 is at least 95% by weight of a single crystalline form.
  • At least a particular percentage by weight of COMPOUND 1 is crystalline. Particular weight percentages may be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 10% and 100%.
  • a particular percentage by weight of COMPOUND 1 is crystalline
  • the remainder of COMPOUND 1 is the amorphous form of COMPOUND 1.
  • Non-limiting examples of crystalline COMPOUND 1 include a single crystalline form of COMPOUND 1 or a mixture of different single crystalline forms.
  • COMPOUND 1 is at least 90% by weight crystalline. In some other
  • COMPOUND 1 is at least 95% by weight crystalline.
  • COMPOUND 1 is a specific single crystalline form or a combination of single crystalline forms. Particular weight percentages may be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 10% and 100%.
  • COMPOUND 1 is at least 90% by weight of a single crystalline form.
  • COMPOUND 1 is at least 95% by weight of a single crystalline form.
  • COMPOUND 3 embodiments of the invention may be described with reference to a particular crystalline form of COMPOUND 3, as characterized by one or more properties as discussed herein.
  • the descriptions characterizing the crystalline forms may also be used to describe the mixture of different crystalline forms that may be present in a crystalline COMPOUND 3.
  • the particular crystalline forms of COMPOUND 3 may also be characterized by one or more of the characteristics of the crystalline form as described herein, with or without regard to referencing a particular crystalline form.
  • COMPOUND 1 embodiments of the invention may be described with reference to a particular crystalline form of COMPOUND 1 , as characterized by one or more properties as discussed herein.
  • the descriptions characterizing the crystalline forms may also be used to describe the mixture of different crystalline forms that may be present in a crystalline COMPOUND 1.
  • the particular crystalline forms of COMPOUND 1 may also be characterized by one or more of the characteristics of the crystalline form as described herein, with or without regard to referencing a particular crystalline form.
  • the crystalline forms are further illustrated by the detailed descriptions and illustrative examples given below.
  • the XRPD peaks described in Tables 1 to 19 may vary by ⁇ 0.2 depending upon the instrument used to obtain the data.
  • a single crystalline form, Form 1, of the COMPOUND 3 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 1 , and data shown in Table 1 , obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 1 , as shown in Table 1.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 1.
  • Form 1 can be characterized by the peaks identified at 20angles of 8.9, 13.0, 18.9, 23.8, and 28.1°. In another embodiment, Form 1 can be characterized by the peaks identified at 20angles of 8.9, 18.9, and 24.8°.
  • a single crystalline form, Form 2, of the COMPOUND 3 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 2, and data shown in Table 2, obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG.2, as shown in Table 2.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 2.
  • Form 2 can be characterized by the peaks identified at 20angles of 12.7, 17.1, 19.2, 23.0, and 24.2°. In another embodiment, Form 2 can be characterized by the peaks identified at 20angles of 12.7, 19.2, and 24.2°.
  • Form 2 can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 3.
  • DSC differential scanning calorimetry profile
  • the DSC graph plots the heat flow as a function of temperature from a sample, the temperature rate change being about 10 °C /min.
  • the profile is characterized by a strong endothermic transition with an onset temperature of about 88.2 °C with a melt at about 91.0 °C.
  • Form 2 can be characterized by thermal gravimetric analysis (TGA) shown in FIG. 4.
  • TGA thermal gravimetric analysis
  • the TGA profile graphs the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C /min.
  • the weight loss represents a loss of about 9.9 % of the weight of the sample as the temperature is changed from about 26.6°C to 150.0 °C.
  • a single crystalline form, Form 3, of the COMPOUND 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 5, and data shown in Table 3, obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 5, as shown in Table 3.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine or ten of the peaks shown in Table 3.
  • Form 3 can be characterized by the peaks identified at 20angles of 7.5, 9.3, 14.5, 18.8, 21.3, and 24.8°. In a further embodiment, Form 3 can be characterized by the peaks are identified at 20angles of 7.5, 14.5, 18.8, and 24.8°. In another, embodiment, Form 3 can be characterized by the peaks identified at 20angles of 7.5, 14.5, and 24.8°.
  • Form 3 can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 6.
  • DSC differential scanning calorimetry profile
  • the DSC graph plots the heat flow as a function of temperature from a sample, the temperature rate change being about 10 °C /min.
  • the profile is characterized by a strong endothermic transition with an onset temperature of about 210.7 °C with a melt at about 213.4 °C.
  • Form 3 can be characterized by thermal gravimetric analysis (TGA) shown in FIG. 7.
  • TGA thermal gravimetric analysis
  • the TGA profile graphs the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C /min.
  • the weight loss represents a loss of about 0.03% of the weight of the sample as the temperature is changed from about 21°C to 196 °C and about 7.5% of the weight of the sample as the temperature is changed from about 196°C to 241°C.
  • Form 3 is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 5.
  • Form 3 is characterized by a differential scanning calorimetry (DSC) profile substantially similar to FIG. 6.
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric analysis
  • a single crystalline form of Form 3 is characterized by one or more of the features listed in this paragraph.
  • Form 3 is characterized by a DVS profile substantially similar to FIG. 8.
  • a single crystalline form, Form 4, of the COMPOUND 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 9, and data shown in Table 4, obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 9, as shown in Table 4.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 4.
  • Form 4 can be characterized by the peaks identified at 20angles of 6.5, 19.0, 19.4, 19.9, and 24.7°. In a further embodiment, Form 4 can be characterized by the peaks are identified at 20angles of 6.5, 19.4, and 19.9°.
  • Form 4 can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 10.
  • the DSC graph plots the heat flow as a function of temperature from a sample, the temperature rate change being about 10 °C /min.
  • the profile is characterized by a weak endothermic transition with an onset temperature of about 59.2 °C with a melt at about 85.5 °C and a strong endothermic transition with an onset temperature of about 205.2 °C with a melt at about 209.1 °C.
  • Form 4 can be characterized by thermal gravimetric analysis (TGA) shown in FIG. 10.
  • TGA thermal gravimetric analysis
  • the TGA profile graphs the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C /min.
  • the weight loss represents a loss of about 1.8 % of the weight of the sample as the temperature is changed from about 44.8 °C to 140.0 °C.
  • a single crystalline form, Form 5, of the COMPOUND 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 11 , and data shown in Table 5, obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 1 1, as shown in Table 5.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 5.
  • Form 5 can be characterized by the peaks identified at 20angles of 7.1, 14.5, 17.1, and 21.8°. In a further embodiment, Form 5 can be characterized by the peaks are identified at 20angles of 7.1 and 21.8°.
  • Form 5 can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 12.
  • DSC differential scanning calorimetry profile
  • the DSC graph plots the heat flow as a function of temperature from a sample, the temperature rate change being about 10 °C /min.
  • the profile is characterized by a weak endothermic transition with an onset temperature of about 50.1 °C with a melt at about 77.5 °C and a strong endothermic transition with an onset temperature of about 203.1 °C with a melt at about 208.2 °C.
  • Form 5 can be characterized by thermal gravimetric analysis (TGA) shown in FIG. 12.
  • TGA thermal gravimetric analysis
  • the TGA profile graphs the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C /min.
  • the weight loss represents a loss of about 0.3 % of the weight of the sample as the temperature is changed from about 36.0 °C to 120.0 °C.
  • a single crystalline form, Form 6, of the COMPOUND 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 13, and data shown in Table 6, obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 13, as shown in Table 6.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 6.
  • Form 6 can be characterized by the peaks identified at 20angles of 6.3, 7.2, 8.1, 12.7, and 14.9°. In a further embodiment, Form 6 can be characterized by the peaks are identified at 20angles of 6.3, 7.2, and 8.1°.
  • Form 6 can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 14.
  • the DSC graph plots the heat flow as a function of temperature from a sample, the temperature rate change being about 10 °C /min.
  • the profile is characterized by three weak endothermic transitions: with an onset temperature of about 61.7 °C with a melt at about 86.75 °C, an onset temperature of about 140.0 °C with a melt at about 149.0 °C, and an onset temperature of about 175.3 °C with a melt at about 192.1 °C.
  • Form 6 can be characterized by thermal gravimetric analysis (TGA) shown in FIG. 14.
  • TGA thermal gravimetric analysis
  • the TGA profile graphs the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C /min.
  • the weight loss represents a loss of about 5.4 % of the weight of the sample as the temperature is changed from about 31.8 °C to 150.0 °C.
  • a single crystalline form, Form 7, of the COMPOUND 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 15, and data shown in Table 7, obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 15, as shown in Table 7.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 7.
  • Form 7 can be characterized by the peaks identified at 20angles of 14.1, 19.1, 21.8, 23.5, and 25.7°. In a further embodiment, Form 7 can be characterized by the peaks are identified at 20angles of 19.1 , 21.8, and 23.5°.
  • Form 7 can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 16.
  • DSC differential scanning calorimetry profile
  • the DSC graph plots the heat flow as a function of temperature from a sample, the temperature rate change being about 10 °C /min.
  • the profile is characterized by a strong endothermic transition with an onset temperature of about 213.6 °C with a melt at about 214.7 °C.
  • Form 7 can be characterized by thermal gravimetric analysis (TGA) shown in FIG. 16.
  • TGA thermal gravimetric analysis
  • the TGA profile graphs the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C /min.
  • the weight loss represents a loss of about 0.01 % of the weight of the sample as the temperature is changed from about 32.2 °C to 150.0 °C.
  • a single crystalline form, Form 8, of the COMPOUND 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 17, and data shown in Table 8, obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 17, as shown in Table 8.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 8.
  • Form 8 can be characterized by the peaks identified at 20angles of 9.0, 9.2, 21.9, 22.1, 24.2, and 24.6°. In a further embodiment, Form 8 can be characterized by the peaks are identified at 20angles of 21.9, 22.1, 24.2, and 24.6°.
  • Form 8 can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 18.
  • the DSC graph plots the heat flow as a function of temperature from a sample, the temperature rate change being about 10 °C /min.
  • the profile is characterized by a strong endothermic transition with an onset temperature of about 211.5 °C with a melt at about 212.8 °C.
  • Form 8 can be characterized by thermal gravimetric analysis (TGA) shown in FIG. 18.
  • TGA thermal gravimetric analysis
  • the TGA profile graphs the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C /min.
  • the weight loss represents a loss of about 0.2 % of the weight of the sample as the temperature is changed from about 31.2 °C to 150.0 °C.
  • a single crystalline form, Form 9, of the COMPOUND 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 19, and data shown in Table 9, obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 19, as shown in Table 9.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 9.
  • Form 9 can be characterized by the peaks identified at 20angles of 6.5, 19.6, 20.1, and 21.6°. In a further embodiment, Form 9 can be characterized by the peaks are identified at 20angles of 19.6 and 20.1°. In another embodiment, Form 9 can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 20.
  • the DSC graph plots the heat flow as a function of temperature from a sample, the temperature rate change being about 10 °C /min. The profile is characterized by a strong endothermic transition with an onset temperature of about 172.3°C with a melt at about 175.95 °C and an endothermic transition with an onset temperature of about 192.3 °C with a melt at about 202.1 °C.
  • Form 9 can be characterized by thermal gravimetric analysis (TGA) shown in FIG. 20.
  • TGA thermal gravimetric analysis
  • the TGA profile graphs the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C /min.
  • the weight loss represents a loss of about 0.7 % of the weight of the sample as the temperature is changed from about 24.7 °C to 150.0 °C.
  • a single crystalline form, Form 10, of the COMPOUND 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 21, and data shown in Table 10, obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 21 , as shown in Table 10.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 10.
  • Form 10 can be characterized by the peaks identified at 20angles of 6.7, 9.1, 10.8, 19.9, and 21.9°. In a further embodiment, Form 10 can be characterized by the peaks are identified at 20angles of 9.1, 10.8, and 19.9°.
  • Form 10 can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 22.
  • DSC differential scanning calorimetry profile
  • the DSC graph plots the heat flow as a function of temperature from a sample, the temperature rate change being about 10 °C /min.
  • the profile is characterized by an endothermic transition with an onset temperature of about 139.9 °C with a melt at about 150.9 °C and an endothermic transition with an onset temperature of about 197.3 °C with a melt at about 201.3 °C.
  • Form 10 can be characterized by thermal gravimetric analysis (TGA) shown in FIG. 22.
  • TGA thermal gravimetric analysis
  • the TGA profile graphs the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C /min.
  • the weight loss represents a loss of about 0.5 % of the weight of the sample as the temperature is changed from about 31.0 °C to 120.0 °C.
  • a single crystalline form, Form 1 1, of the COMPOUND 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 23, and data shown in Table 1 1 , obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 23, as shown in Table 11.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine or ten or eleven of the peaks shown in Table 1 1.
  • Form 1 1 can be characterized by the peaks identified at 20angles of 6.3, 20.0, 20.2, 20.5, 21.2, and 26.5°.
  • Form 11 can be characterized by the peaks are identified at 20angles of 20.0, 20.2, 20.5, and 21.2°.
  • Form 1 1 can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 24.
  • the DSC graph plots the heat flow as a function of temperature from a sample, the temperature rate change being about 10 °C /min.
  • the profile is characterized by an endothermic transition with an onset temperature of about 144.3 °C with a melt at about 154.5 °C and an endothermic transition with an onset temperature of about 193.4 °C with a melt at about 201.6 °C.
  • Form 1 1 can be characterized by thermal gravimetric analysis (TGA) shown in FIG. 25.
  • TGA thermal gravimetric analysis
  • the TGA profile graphs the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C /min.
  • the weight loss represents a loss of about 3.0 % of the weight of the sample as the temperature is changed from about 25.7 °C to 98.4 °C.
  • a single crystalline form, Form 12, of the COMPOUND 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 26, and data shown in Table 12, obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 26, as shown in Table 12.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 12.
  • Form 12 can be characterized by the peaks identified at 20angles of 7.2, 7.4, 8.0, 8.2, 16.5, and 18.6°. In a further embodiment, Form 12 can be characterized by the peaks are identified at 20angles of 7.2, 7.4, 8.0, and 8.2°.
  • Form 12 can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 27.
  • the DSC graph plots the heat flow as a function of temperature from a sample, the temperature rate change being about 10 °C /min.
  • the profile is characterized by an endothermic transition with an onset temperature of about 80.9 °C with a melt at about 106.3 °C, an endothermic transition with an onset temperature of about 136.32 °C with a melt at about 150.3 °C, and a strong endothermic transition with an onset temperature of about 199.0 °C with a melt at about 203.1 °C.
  • Form 12 can be characterized by thermal gravimetric analysis (TGA) shown in FIG. 27.
  • TGA thermal gravimetric analysis
  • the TGA profile graphs the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C /min.
  • the weight loss represents a loss of about 6.4 % of the weight of the sample as the temperature is changed from about 25.9 °C to 80.0 °C, and a loss of about 7.2 % of the weight of the sample as the temperature is changed from about 25.9 °C to 150.0 °C.
  • a single crystalline form, Form 13, of the COMPOUND 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 28, and data shown in Table 13, obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 28, as shown in Table 13.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 13.
  • Form 13 can be characterized by the peaks identified at 20angles of 6.3, 12.7, 20.3, 20.8, and 26.5°. In a further embodiment, Form 13 can be characterized by the peaks are identified at 20angles of 6.3, 12.7, and 20.3°.
  • Form 13 can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 29.
  • DSC differential scanning calorimetry profile
  • the DSC graph plots the heat flow as a function of temperature from a sample, the temperature rate change being about 10 °C /min.
  • the profile is characterized by a weak endothermic transition with an onset temperature of about 144.1 °C with a melt at about 152.4 °C, and a strong endothermic transition with an onset temperature of about 198.1 °C with a melt at about 204.8 °C.
  • Form 13 can be characterized by thermal gravimetric analysis (TGA) shown in FIG. 29.
  • TGA thermal gravimetric analysis
  • the TGA profile graphs the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C /min.
  • the weight loss represents a loss of about 4.1 % of the weight of the sample as the temperature is changed from about 24.9 °C to 150.0 °C.
  • a single crystalline form, Form 14, of the COMPOUND 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 30, and data shown in Table 14, obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 30, as shown in Table 14.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 14.
  • Form 14 can be characterized by the peaks identified at 20angles of 6.6, 17.5, 20.8 and 23.3°. In a further embodiment, Form 14 can be characterized by the peaks are identified at 20angles of 6.6 and 20.8°.
  • Form 14 can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 31.
  • the DSC graph plots the heat flow as a function of temperature from a sample, the temperature rate change being about 10 °C /min.
  • the profile is characterized by a weak endo thermic transition with an onset temperature of about 122.3 °C with a melt at about 134.5 °C, and a strong endothermic transition with an onset temperature of about 207.6 °C with a melt at about 211.8 °C.
  • Form 14 can be characterized by thermal gravimetric analysis (TGA) shown in FIG. 31.
  • TGA thermal gravimetric analysis
  • the TGA profile graphs the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C /min.
  • the weight loss represents a loss of about 5.71 % of the weight of the sample as the temperature is changed from about 28.1 °C to 150.0 °C.
  • Form 15 in one embodiment, a single crystalline form, Form 15, of the COMPOUND 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 32, and data shown in Table 15, obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 32, as shown in Table 15.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 15.
  • Form 15 can be characterized by the peaks identified at 20angles of 6.4, 12.9, 20.2, and 26.1°. In a further embodiment, Form 15 can be characterized by the peaks are identified at 20angles of 6.4, 12.9, and 26.1°.
  • Form 15 can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 33.
  • the DSC graph plots the heat flow as a function of temperature from a sample, the temperature rate change being about 10 °C /min.
  • the profile is characterized by a weak endo thermic transition with an onset temperature of about 136.5 °C with a melt at about 140.1 °C, and a strong endo thermic transition with an onset temperature of about 213.1 °C with a melt at about 215.2 °C.
  • Form 15 can be characterized by thermal gravimetric analysis (TGA) shown in FIG. 33.
  • TGA thermal gravimetric analysis
  • the TGA profile graphs the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C /min.
  • the weight loss represents a loss of about 7.6 % of the weight of the sample as the temperature is changed from about 28.7 °C to 150.0 °C.
  • a single crystalline form, Form 16, of the COMPOUND 3 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 34, and data shown in Table 16, obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 34, as shown in Table 16.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 16.
  • Form 16 can be characterized by the peaks identified at 20angles of 6.8, 10.6, 13.6, 14.2, and 19.2°. In another embodiment, Form 16 can be characterized by the peaks identified at 20angles of 10.6, 14.2, and 19.2°.
  • Form 16 can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 35.
  • DSC differential scanning calorimetry profile
  • the DSC graph plots the heat flow as a function of temperature from a sample, the temperature rate change being about 10 °C /min.
  • the profile is characterized by a strong endothermic transition with an onset temperature of about 169.7 °C with a melt at about 172.1 °C.
  • Form 16 can be characterized by thermal gravimetric analysis (TGA) shown in FIG. 36.
  • TGA thermal gravimetric analysis
  • the TGA profile graphs the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C /min.
  • the weight loss represents a loss of about 0.1 % of the weight of the sample as the temperature is changed from about 23.9 °C to 150.0 °C.
  • a single crystalline form, Form 17, of the COMPOUND 3 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 37, and data shown in Table 16, obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 37, as shown in Table 17.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 17.
  • Form 17 can be characterized by the peaks identified at 20angles of 7.2, 13.6, 18.5, 19.3, 21.9, and 23.5°. In another embodiment, Form 16 can be characterized by the peaks identified at 20angles of 13.6, 18.5, and 23.5°.
  • a single crystalline form, Form 18, of the COMPOUND 3 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 38, and data shown in Table 18, obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 38, as shown in Table 18.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 18.
  • Form 18 can be characterized by the peaks identified at 20angles of 6.4, 8.4, 9.8, 17.8, and 19.7°. In another embodiment, Form 18 can be characterized by the peaks identified at 20angles of 8.4 and 9.8°.
  • a single crystalline form, Form 19, of the COMPOUND 3 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 39, and data shown in Table 19, obtained using CuKa radiation.
  • the polymorph can be characterized by one or more of the peaks taken from FIG. 39, as shown in Table 19.
  • the polymorph can be characterized by one or two or three or four or five or six or seven or eight of the peaks shown in Table 19.
  • Form 19 can be characterized by the peaks identified at 20angles of 8.1, 14.1 , 16.4, 17.3, 20.5, and 24.1°. In another embodiment, Form 19 can be characterized by the peaks identified at 20angles of 8.1 , 16.4, 17.3, and 24.1°.
  • COMPOUND 1 or COMPOUND 3 characterized by a combination of the aforementioned characteristics of any of the single crystalline forms discussed herein.
  • the characterization may be by any combination of one or more of the XRPD, TGA, DSC, and DVS described for a particular polymorph.
  • the single crystalline form of COMPOUND 1 or COMPOUND 3 may be characterized by any combination of the XRPD results regarding the position of the major peaks in a XRPD scan; and/or any combination of one or more of parameters derived from data obtained from a XRPD scan.
  • the single crystalline form of COMPOUND 1 or COMPOUND 3 may also be characterized by TGA determinations of the weight loss associated with a sample over a designated temperature range; and/or the temperature at which a particular weight loss transition begins. DSC determinations of the temperature associated with the maximum heat flow during a heat flow transition and/ or the temperature at which a sample begins to undergo a heat flow transition may also characterize the crystalline form. Weight change in a sample and/or change in sorption desorption of water per molecule of COMPOUND 1 or COMPOUND 3 as determined by water sorption/desorption measurements over a range of relative humidity (e.g., 0% to 90%) may also characterize a single crystalline form of COMPOUND 1 or COMPOUND 3. The combinations of characterizations that are discussed above may be used to describe any of the polymorphs of COMPOUND 1 or COMPOUND 3 discussed herein, or any combination of these polymorphs.
  • compositions and routes of administration are provided.
  • COMPOUND 1 and COMPOUND 3 utilized in the methods described herein may be formulated together with a pharmaceutically acceptable carrier or adjuvant into pharmaceutically acceptable compositions prior to being administered to a subject.
  • pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a subject, together with a compound, including a crystalline form thereof, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound, including a crystalline form thereof.
  • pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions 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, polyethylene
  • Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl- -cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds, including crystalline forms thereof, of the formulae described herein.
  • the pharmaceutical compositions 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 of one aspect of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound, including a crystalline form thereof, or its delivery form.
  • parenteral as used herein 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.
  • 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.
  • the pharmaceutical compositions may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • 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.
  • the pharmaceutical compositions may also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing crystalline forms of COMPOUND 1 or COMPOUND 3 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.
  • topical administration of the pharmaceutical compositions is useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • COMPOUND 3 include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound, including a crystalline form thereof, suspended or dissolved in a carrier with suitable emulsifying agents.
  • 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. Topically-transdermal patches are also included in one aspect of this invention.
  • the pharmaceutical 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 compounds, including crystalline forms thereof, described 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 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug.
  • the methods herein contemplate administration of an effective amount of compound, including a crystalline form thereof, or compound composition 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. Such administration can be used as a chronic or acute therapy.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host 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.
  • a subject may be administered a dose of COMPOUND 1 or COMPOUND 3 as described in Example 25. Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular subject will depend upon a variety of factors, including the activity of the specific compound, including a crystalline form thereof, employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the subject's disposition to the disease, condition or symptoms, and the judgment of the treating physician.
  • a maintenance dose of a compound, including a crystalline form thereof,, composition or combination of one aspect of this invention may be administered, if necessary. Subsequently, 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. Subjects may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • Some embodiments of the invention are directed toward a tablet comprising at least one pharmaceutically acceptable carrier or diluent; and a crystalline form of COMPOUND 1 or COMPOUND 3.
  • the crystalline form of COMPOUND 1 or COMPOUND 3 is at least 90% by weight a of a particular crystalline form; the particular crystalline form being a form described herein.
  • the crystalline form of COMPOUND 1 or COMPOUND 3 is at least 95% by weight a of a particular crystalline form; the particular crystalline form being a form described herein.
  • IDH2R140Q and IDH2R172K The inhibitory activities of crystalline forms of COMPOUND 1 or COMPOUND 3 provided herein against IDH2 mutants (e.g., IDH2R140Q and IDH2R172K) can be tested by methods described in Example 12 of PCT Publication No. WO 2013/102431 and US Publication No. US 2013/0190287 hereby incorporated by reference in their entirety, or analogous methods.
  • a method for treating a cancer selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), or lymphoma (e.g., T-cell lymphoma) comprising contacting a subject in need thereof with a crystalline form of COMPOUND 1 or COMPOUND 3.
  • AML acute myelogenous leukemia
  • MDS myelodysplastic syndrome
  • CMML chronic myelomonocytic leukemia
  • lymphoma e.g., T-cell lymphoma
  • the acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), or lymphoma (e.g., T-cell lymphoma) to be treated is characterized by a mutant allele of IDH2 wherein the IDH2 mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of a-ketoglutarate to ii(-)-2-hydroxyglutarate in a patient.
  • the mutant IDH2 has an R140X mutation.
  • the R140X mutation is a R140Q mutation.
  • the R140X mutation is a R140W mutation. In another aspect of this embodiment, the R140X mutation is a R140L mutation. In another aspect of this embodiment, the mutant IDH2 has an R172X mutation. In another aspect of this embodiment, the R172X mutation is a R172K mutation. In another aspect of this embodiment, the R172X mutation is a R172G mutation.
  • a cancer selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), or lymphoma can be analyzed by sequencing cell samples to determine the presence and specific nature of (e.g., the changed amino acid present at) a mutation at amino acid 140 and/or 172 of IDH2.
  • Also provided are methods of treating a cancer selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), or lymphoma (e.g., T-cell lymphoma) characterized by the presence of a mutant allele of IDH2 comprising the step of administering to subject in need thereof (a) a crystalline form of COMPOUND 1 or COMPOUND 3, or (b) a pharmaceutical composition comprising (a) and a pharmaceutically acceptable carrier.
  • AML acute myelogenous leukemia
  • MDS myelodysplastic syndrome
  • CMML chronic myelomonocytic leukemia
  • lymphoma e.g., T-cell lymphoma
  • a pharmaceutical composition comprising (a) and a pharmaceutically acceptable carrier.
  • mutant alleles of IDH2 wherein the IDH2 mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of a-ketoglutarate to ii(-)-2-hydroxyglutarate, and in particular R140Q and/or R172K mutations of IDH2, characterize a subset of all types of cancers described herein, without regard to their cellular nature or location in the body.
  • the compounds, including crystalline forms thereof, and methods of one aspect of this invention are useful to treat cancer selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), or lymphoma (e.g., T-cell lymphoma) 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.
  • AML acute myelogenous leukemia
  • MDS myelodysplastic syndrome
  • CMML chronic myelomonocytic leukemia
  • lymphoma e.g., T-cell lymphoma
  • the efficacy of treatment is monitored by measuring the levels of 2HG in the subject.
  • levels of 2HG are measured prior to treatment, wherein an elevated level is indicated for the use of a crystalline form of COMPOUND 1 or COMPOUND 3 to treat the cancer selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), or lymphoma (e.g., T-cell lymphoma).
  • AML acute myelogenous leukemia
  • MDS myelodysplastic syndrome
  • CMML chronic myelomonocytic leukemia
  • lymphoma e.g., T-cell lymphoma
  • a reduction of 2HG levels during the course of treatment and following treatment is indicative of efficacy.
  • a determination that 2HG levels are not elevated during the course of or following treatment is also indicative of efficacy.
  • the these 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 subject, and alterations in other biomarkers that are associated with cancer treatment efficacy.
  • 2HG can be detected in a sample by the methods of PCT Publication No. WO
  • 2HG is directly evaluated.
  • a derivative of 2HG formed in 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.
  • a metabolic derivative of 2HG is evaluated.
  • 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:
  • the cancer selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), or lymphoma 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.
  • the pharmacological properties of crystalline forms of COMPOUND 1 or COMPOUND 3 are such that they are suitable for use in the treatment of a cancer selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), or lymphoma (e.g., T-cell lymphoma) in a patient by administering to the patient a crystalline form of COMPOUND 1 or COMPOUND 3 in an amount effective to treat the cancer.
  • the cancer to be treated is AML.
  • the AML is relapsed and/or primary refractory.
  • the AML is untreated.
  • the cancer to be treated is MDS with refractory anemia with excess blasts (subtype RAEB-1 or RAEB-2). In other embodiments, the MDS is untreated. In another embodiment, the cancer to be treated is relapsed and/or primary refractory CMML.
  • Treatment methods described herein can additionally comprise various evaluation steps prior to and/or following treatment with a crystalline form of COMPOUND 1 or COMPOUND 3.
  • the method further comprises the step of evaluating the growth, size, weight, invasiveness, stage and/or other phenotype of the cancer selected from acute myelogenous leukemia (AML), myelodysplasia syndrome (MDS), chronic myelogenous leukemia (AML), myelodysplasia syndrome (MDS), chronic myelogenous leukemia (AML), myelodysplasia syndrome (MDS), chronic myelogenous leukemia (AML), myelodysplasia syndrome (MDS), chronic myelogenous leukemia (AML), myelodysplasia syndrome (MDS), chronic myelogenous leukemia (AML), myelodysplasia syndrome (MDS), chronic myelogenous leukemia (AML), myelodysplasia syndrome (MDS), chronic myelogenous leukemia (AML), myelodysplasia syndrome (MDS), chronic myelogenous leukemia (AML
  • CMML myelomonocytic leukemia
  • lymphoma e.g., T-cell lymphoma
  • the method further comprises the step of evaluating the IDH2 genotype of the cancer selected from acute myelogenous leukemia (AML),
  • MDS myelodysplasia syndrome
  • CMML chronic myelomonocytic leukemia
  • lymphoma e.g., T-cell lymphoma
  • the method further comprises the step of determining the 2HG level in the subject.
  • 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 blood, plasma, urine, or spinal cord fluid analysis, or by analysis of surgical material, e.g., by mass-spectroscopy (e.g. LC-MS, GC-MS).
  • spectroscopic analysis e.g., magnetic resonance-based analysis, e.g., MRI and/or MRS measurement
  • sample analysis of bodily fluid such as blood, plasma, urine, or spinal cord fluid analysis
  • surgical material e.g., by mass-spectroscopy (e.g. LC-MS, GC-MS).
  • reagents were purchased from commercial sources (including Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company), and used without further purification.
  • Nuclear magnetic resonance (NMR) spectra were obtained on a Brucker AMX-400 NMR (Brucker, Switzerland). Chemical shifts were reported in parts per million (ppm, ⁇ ) downfield from tetramethylsilane.
  • Mass spectra were run with electrospray ionization (ESI) from a Waters LCT TOF Mass Spectrometer (Waters, USA).
  • a stereoisomer e.g., an (R) or (S) stereoisomer
  • a preparation of that compound such that the compound is enriched at the specified stereocenter by at least about 90%, 95%, 96%, 97%, 98%, or 99%.
  • the chemical name of each of the exemplary compound described below is generated by ChemDraw software.
  • XRPD X-Ray Powder Diffraction
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric Analysis
  • TGA analysis was performed using a TA Q500/Q5000 TGA from TA Instruments. The temperature was ramped from room temperature to the desired temperature at a heating rate of 10 °C/min or 20 °C/min using N 2 as the purge gas.
  • Dynamic Vapor Sorption (DVS) parameters DVS was measured via a SMS (Surface Measurement Systems) DVS Intrinsic. The relative humidity at 25°C were calibrated against deliquescence point of LiCl, Mg(N0 3 ) 2 and KC1. The DVS Parameters used are listed in Table 22.
  • RH range 60%RH-95%RH-0%RH-95%RH
  • Example 1 Synthesis of 2-Methyl-l-r(4-r6-(trifluoromethyl)pyridin-2-yll-6- ⁇ r2- (trifluoromethyl)pyridin-4-yllamino
  • Example 1 preparation of4-chloro-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoro- methyl)- pyridin-4-yl)-l,3,5-triazin-2-amine
  • Example 1 preparation of2-methyl-l-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-(2- (trifluoromethyl)- pyridin-4-ylamino)-l,3,5-triazin-2-ylamino)propan-2-ol (COMPOUND 3)
  • reaction mixture is poured over crushed dry ice under N 2 , then brought to a temperature of 0 to 5 °C while stirring (approx. 1.0 to 1.5 h) followed by the addition of water (1.8 L).
  • the reaction mixture is stirred for 5-10 mins and allowed to warm to 5-10 °C.
  • 6N HC1 (900 mL) is added dropwise until the mixture reached pH 1.0 to 2.0, then the mixture is stirred for 10-20 min. at 5-10 °C.
  • the reaction mixture is diluted with ethyl acetate at 25-35 °C, then washed with brine solution.
  • the reaction is concentrated and rinsed with n-heptane and then dried to yield 6-trifluoromethyl-pyridine-2-carboxylic acid.
  • the mixture is concentrated at temp 35-45 U C under vacuum and cooled to 25-35 °C, then rinsed with n-heptane and concentrated at temp 35-45 °C under vacuum, then degassed to obtain brown solid, which is rinsed with n- heptane and stirred for 10-15 minute at 25-35 °C.
  • the suspension is cooled to -40 to -30 °C while stirring, and filtered and dried to provide 6-trifiuoromethyl-pyridine-2-carboxylic acid methyl ester.
  • the off white to light brown solid of 6-(6-Trifiuoromethyl-pyridin-2-yl)-lH-l ,3,5-triazine-2,4-dione is dried under vacuum for 8 to 10 hrs at 50 °C to 60 °C under 600mm/Hg pressure to provide 6-(6- Trifiuoromethyl-pyridin-2-yl)- 1 H- 1 ,3 ,5 -triazine-2 ,4-dione .
  • the reaction mixture is cooled to 50-55 °C, and concentrated at below 55 °C then cooled to 20-30 °C.
  • the reaction mixture is rinsed with ethyl acetate and the ethyl acetate layer is slowly added to cold water (temperature ⁇ 5 °C) while stirring and maintaining the temperature below 10 °C.
  • the mixture is stirred 3-5 minutes at a temperature of between 10 to 20 °C and the ethyl acetate layer is collected.
  • the reaction mixture is rinsed with sodium bicarbonate solution and dried over anhydrous sodium sulphate. The material is dried 2-3 h under vacuum at below 45 °C to provide 2, 4-Dichloro-6-(6-trifiuoromethyl-pyridin-2-yl)-l , 3, 5-triazine.
  • the reaction mixture is cooled to 20-35 °C and rinsed with ethyl acetate and water, and the ethyl acetate layer collected and rinsed with 0.5 N HC1 and brine solution.
  • the organic layer is concentrated under vacuum at below 45 °C then rinsed with dichloromethane and hexanes, filtered and washed with hexanes and dried for 5-6h at 45-50 °C under vacuum to provide 4-chloro-6-(6-(trifiuoromethyl)pyridin- 2-yl)-N-(2-(trifiuoro-methyl)- pyridin-4-yl)- 1 ,3,5-triazin-2-amine.
  • reaction is cooled to 30-40 °C and THF evaporated at below 45 °C under reduced pressure.
  • the reaction mixture is cooled to 20-35 °C and rinsed with ethyl acetate and water, and the ethyl acetate layer collected.
  • the organic layer is concentrated under vacuum at below 45 °C then rinsed with
  • Method A Slurry conversion is conducted by suspending ca 10 mg of Form 3 in 0.5-1.0 mL of water. After the suspension is stirred at 50°C for 48 h, the remaining solids are centrifuged to provide Form 1.
  • Form 3 9.61 mg of Form 3 is dissolved in 0.2 mL of ethanol. The solution is placed at ambient condition and ethanol is evaporated to get Form 1.
  • Form 3 is dissolved in 0.2 mL of isopropyl acetate. The solution is placed at ambient temprerature and isopropyl acetate is evaporated to get Form 1.
  • Slurry conversion is conducted by suspending ca 10 mg of Form 3 in 0.5-1.0 mL of water. After the suspension is stirred at RT for 48 h, the remaining solids are centrifuged to provide Form 2.
  • Form 3 6.07 mg of Form 3 is suspended in 1.0 mL of water. The suspension is stirred at room temperature for about 24 hours. The solid is isolated to obtain Form 2.
  • Reactive crystallization is conducted by mixing 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol (0.1 mol/L) and methanesulfonic acid (0.1 mol/L) in MeCN to provide Form 4.
  • Example 8 Synthesis of 2-Methyl-l-r(4-r6-(trifluoromethyl)pyridin-2-yll-6-ir2- (trifluoromethyl)pyridin-4-yllainino
  • Reactive crystallization is conducted by mixing 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(triflu ⁇
  • Slow evaporation is performed by dissolving ca 10 mg of Form 3 in 0.4-3.0 mL of solvent in a 3-mL glass vial.
  • the vials are covered with foil with about 6 to 8 holes and the visually clear solutions are subjected to slow evaporation at RT to induce precipitation. Then the solids are isolated.
  • Reactive crystallization is conducted by quickly adding methanesulfonic acid (0.1 mol/L) to 2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ - l ,3,5-triazin-2-yl)amino]propan-2-ol (0.1 mol/L) in acetone or MeCN to provide Form 7.
  • Methanesulfonic acid (0.1 mol/L) is quickly added to 2 -Methyl- 1-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(tri)
  • Form 12 is heated to 155°C in TGA and cooled to RT to provide Form 8.
  • Example 12 Synthesis of 2-Methyl-l-r(4-r6-(trifluoromethyl)pyridin-2-yll-6-ir2- (trifluoromethyl)pyridin-4-yllamino
  • Form 10 is produced by either heating Form 12 to 80°C at 10°C/min or keeping Form 12 under N 2 sweeping condition for 1 h in TGA.
  • Form 1 1 is obtained by heating Form 6 to 80 °C or heating Form 13 to 100°C in the
  • Solution vapor diffusion is conducted in solvents at RT by dissolving ca 10 mg of Form 3 in MeOH to obtain a clear solution in a 3-mL vial.
  • the vial is sealed into a 20-mL vial filled with ca 3 mL water, and kept at RT for 5 to 7 days, allowing sufficient time to precipitate.
  • the solids are separated to provide Form 12.
  • Form 13 is obtained by heating Form 6 to 80 °C and cooling to RT.
  • Slurry conversion is conducted starting from mixtures of Form 6 and Form 12 at water activity of 0.31 at RT.
  • Example 17 Synthesis of 2-Methyl-l-r(4-r6-(trifluoromethyl)pyridin-2-yll-6-ir2- (trifluoromethyl)pyridin-4-yllamino
  • Solution vapor diffusion is conducted in solvents at RT by dissolving ca 10 mg of Form 3 in MeOH to obtain a clear solution in a 3-mL vial.
  • the vial is sealed into a 20-mL vial filled with ca 3 mL heptane, and kept at RT for 5 to 7 days, allowing sufficient time to precipitate.
  • the solids are separated to provide Form 14.
  • Solution vapor diffusion is conducted in solvents at RT by dissolving ca 10 mg of Form 3 in EtOH to obtain a clear solution in a 3-mL vial.
  • the vial is sealed into a 20-mL vial filled with ca 3 mL IP Ac or MTBE, and kept at RT for 5 to 7 days, allowing sufficient time to precipitate.
  • the solids are separated to provide Form 15.
  • Form 16 10.26 mg of Form 16 is suspended in 0.4 mL heptane. The suspension is stirred at RT for about 24 hours. The solid is isolated to obtain Form 17.
  • Form 16 10.10 mg of Form 16 is suspended in 0.2 mL methyl tert-butyl ether. The suspension is stirred at RT for about 24 hours. The solid is isolated to obtain Form 17.
  • Form 16 8.17 mg of Form 16 is dissolved in 0.2 mL MeOH. The solution is kept at ambient RT and MeOH is evaporated to provide Form 18.
  • Form 16 905.61 mg is suspended in 5.0 mL of water. The suspension is stirred at RT for about 4 hours, and the solid is isolated to provide Form 19.
  • COMPOUND 1 may be amorphous, or a mixture of crystalline forms, or a single crystalline form.
  • l,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate reduces intracellular and extracellular levels of2-HG in a dose -dependent manner
  • TF-1/IDH2 (R140Q) mutant cells are treated in vitro for 7 days with vehicle
  • the intracellular levels of 2-HG are reduced in the mutant cell line (from 15.5 mM with DMSO to 0.08 mM with 5 ⁇ 2-Methyl- 1 - [(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l ,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate) and the reduction is concentration-dependent.
  • the intracellular IC 50 for 2-HG inhibition is calculated as 16 nM and the inhibitory concentration, 90% (IC 90 ) is 160 nM.
  • histone hypermethylation induced by IDH2 (R140Q) in TF-1 cells is reversed based on Western blot analysis. A concentration-dependent reduction in histone methylation is observed at all 4 histone marks (H3K4me3, H3K9me3, H3K27me3, and H3K36me3).
  • l,3,5-triazin-2-yl)aminolpropan-2-ol methanesulfonate reverses the differentiation block induced by the IDH2 (R140Q) mutation in TF-1 erythroleukemia cell lines
  • methanesulfonate leads to an increase in cellular differentiation
  • IDH2 (R140Q) mutant patient samples are treated in an ex vivo assay with 2-Methyl- 1 - [(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l ,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate.
  • Living cells are sorted and cultured in the presence or absence of 2-Methyl- l -[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4- yl]amino ⁇ -l ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate (500, 1000, and 5000 nM). Cells are counted at Days 3, 6, 9, and 13 and normalized to DMSO control. Upon compound treatment, a proliferative burst is seen starting at Day 6 consistent with the onset of cellular differentiation.
  • the bone marrow blasts are analyzed for morphology and differentiation status in the presence or absence of 2-Methyl-l -[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ - l ,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate; the cytologic analysis is blinded with regard to treatment.
  • Cytology reveals that the percentage of blast cells decreases from 90% to 55% by Day 6 and is further reduced to 40% by Day 9 of treatment with 2-Methyl-l -[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ - l ,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate. Furthermore, there is a clear increase in the population of more differentiated cells as noted by an increase in metamyelocytes.
  • PK/PD Pharmacokinetic/pharmacodynamic studies are conducted in female nude mice inoculated subcutaneously with U87MG IDH2 (R140Q) tumor. Animals receive vehicle or single or multiple oral doses of 2-Methyl-l-[(4-[6-(trifiuoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl]amino ⁇ -l ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate at doses ranging from 10 to 150 mg/kg.
  • Tumor 2-HG concentration decreases rapidly following a single oral dose of 2-Methyl- 1 - [(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l ,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate.
  • Tumor 2-HG concentration increases when the plasma concentration of 2-Methyl- l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl] amino ⁇ - 1 ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate decreases below 1000 ng/mL.
  • tumor 2-HG levels decrease to baseline, as found in wild-type tissue, following 3 consecutive 2-Methyl-l-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6- ⁇ [2- (trifiuoromethyl)pyridin-4-yl] amino ⁇ - 1 ,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate doses of 25 mg/kg or above (twice daily, 12 hour dosing interval).
  • mice 40 NOD/SCID mice are engrafted on Day 1 with 2* 10 6 /mouse of AMM7577-P2 (HuKemia® model, Crown BioScience Inc.) frozen cells that may be thawed out from liquid N 2 .
  • Peripheral blood samples are collected weekly for FACS analysis of human leukemia cells starting at Week 3 post-cell inoculation. Plasma and urine samples are collected weekly starting at Week 3 until the termination point.
  • the engrafted mice may be randomly allocated into 5 groups using the treatment schedule denoted in Table 23.
  • the clinical study is a Phase 1, multicenter, open-label, dose-escalation, safety, PK/PD, and clinical activity evaluation of orally administered 2-Methyl-l-[(4-[6- (trifluoromethyl)pyridin-2-yl]-6- ⁇ [2-(trifluoromethyl)pyridin-4-yl]amino ⁇ -l,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate (COMPOUND 1) in subjects with advanced
  • Primary study objectives include 1) assessment of the safety and tolerability of treatment with COMPOUND 1 administered continuously as a single agent dosed orally twice daily (approximately every 12 hours) on Days 1 to 28 of a 28-day cycle in subjects with advanced hematologic malignancies, and 2) determination of the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose of COMPOUND 1 in subjects with advanced hematologic malignancies.
  • MTD maximum tolerated dose
  • Secondary study objectives include 1) description of the dose-limiting toxicities (DLTs) of COMPOUND 1 in subjects with advanced hematologic malignancies, 2) characterization of the pharmacokinetics (PK) of COMPOUND 1 and its metabolite 6-(6-(trifiuoromethyl)pyridin-2-yl)-N2-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine (COMPOUND 2) in subjects with advanced hematologic malignancies, 3) characterization of the PK/pharmacodynamic (PD) relationship of COMPOUND 1 and 2-hydroxygluturate (2-HG), and 4) characterization of the clinical activity associated with COMPOUND 1 in subjects with advanced hematologic malignancies.
  • DLTs dose-limiting toxicities
  • PK pharmacokinetics
  • Exploratory study objectives include 1) characterization of the PD effects of
  • COMPOUND 1 in subjects with advanced hematologic malignancies by the assessment of changes in the patterns of cellular differentiation of isocitrate dehydrogenase-2 (IDH2)-mutated tumor cells and changes in histone and deoxyribonucleic acid (DNA) methylation in IDH2- mutated tumor cells, and 2) evaluation of gene mutation status, global gene expression profiles, and other potential prognostic markers (cytogenetics) in IDH2-mutated tumor cells, as well as subclonal populations of non-IDH2 mutated tumor cells, to explore predictors of anti-tumor activity and/or resistance, and 3) evaluation of changes in the metabolic profiles in IDH2- mutated tumor cells.
  • IDH2 isocitrate dehydrogenase-2
  • DNA histone and deoxyribonucleic acid
  • the study includes a dose escalation phase to determine MTD followed by expansion cohorts to further evaluate the safety and tolerability of the MTD.
  • the dose escalation phase will utilize a standard "3 + 3" design.
  • consented eligible subjects will be enrolled into sequential cohorts of increasing doses of COMPOUND 1.
  • Each dose cohort will enroll a minimum of 3 subjects.
  • Non-hematologic includes all clinically significant non-hematologic toxicities CTCAE >Grade 3. (For example, alopecia is not considered a clinically significant event). Hematologic includes prolonged myelosuppression, defined as persistence of >3 Grade neutropenia or thrombocytopenia (by NCI CTCAE, version 4.03, leukemia-specific criteria, i.e., marrow cellularity ⁇ 5% on Day 28 or later from the start of study drug without evidence of leukemia) at least 42 days after the initiation of Cycle 1 therapy.
  • NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events
  • dose escalation may continue for 2 dose levels above the projected maximum biologically effective dose, as determined by an ongoing assessment of PK/PD and any observed clinical activity, to determine the recommended Phase 2 dose.
  • 3 expansion cohorts (in specific hematologic malignancy indications) of approximately 12 subjects each will be treated at that dose.
  • the purpose of the expansion cohorts is to evaluate and confirm the safety and tolerability of the recommended Phase 2 dose in specific disease indications. Subjects enrolled in these cohorts will undergo the same procedures as subjects in the dose escalation cohorts with the exception that they will not be required to undergo the Day -3 through Day 1 PK/PD assessments.
  • Screening procedures include medical, surgical, and medication history, confirmation of IDH2 mutation in leukemic blasts (if not documented previously), physical examination, vital signs, Eastern Cooperative Oncology Group (ECOG) performance status (PS), 12-lead electrocardiogram (ECG), evaluation of left ventricular ejection fraction (LVEF), clinical laboratory assessments (hematology, chemistry, coagulation, urinalysis, and serum pregnancy test), bone marrow biopsy and aspirate, and blood and urine samples for 2- HG measurement.
  • ECOG Eastern Cooperative Oncology Group
  • PS 12-lead electrocardiogram
  • LVEF left ventricular ejection fraction
  • clinical laboratory assessments hematology, chemistry, coagulation, urinalysis, and serum pregnancy test
  • bone marrow biopsy and aspirate for 2- HG measurement.
  • Twice daily treatment with COMPOUND 1 will begin on C1D1; for subjects who did not undergo the Day -3 PK/PD assessments, clinical observation and serial 12-lead ECGs and vital signs assessments will be conducted over 8 hours following their first dose of COMPOUND 1 on C1D1.
  • Safety assessments conducted during the treatment period include physical examination, vital signs, ECOG PS, 12-lead ECGs, evaluation of LVEF, and clinical laboratory assessments (hematology, chemistry, coagulation, and urinalysis).
  • Subjects will have the extent of their disease assessed, including bone marrow aspirates and biopsies and peripheral blood, at screening, on Day 15, Day 29 and Day 57, and every 56 days thereafter while on study drug treatment, independent of dose delays and/or dose interruptions, and/or at any time when progression of disease is suspected. Response to treatment will be determined by the Investigators based on modified International Working Group (IWG) response criteria for acute myelogenous leukemia (AML).
  • IWG International Working Group
  • Subjects may continue treatment with COMPOUND 1 until disease progression, occurrence of a DLT, or development of other unacceptable toxicity. All subjects are to undergo an end of treatment assessment (within approximately 5 days of the last dose of study drug); in addition, a follow-up assessment is to be scheduled 28 days after the last dose.
  • a patient must meet all of the following inclusion criteria to be enrolled in the clinical study. 1) Subject must be >18 years of age; 2) Subjects must have advanced hematologic malignancy including: a) Relapsed and/or primary refractory AML as defined by World Health Organization (WHO) criteria, b) untreated AML, >60 years of age and are not candidates for standard therapy due to age, performance status, and/or adverse risk factors, according to the treating physician and with approval of the Medical Monitor, c) Myelodysplastic syndrome with refractory anemia with excess blasts (subtype RAEB-1 or RAEB-2), or considered high-risk by the Revised International Prognostic Scoring System (IPSS-R) (Greenberg et al. Blood.
  • WHO World Health Organization
  • Subjects must be amenable to serial bone marrow biopsies, peripheral blood sampling, and urine sampling during the study; 5) Subjects or their legal representatives must be able to understand and sign an informed consent; 6) Subjects must have ECOG PS of 0 to 2; 7) Platelet count >20,000/ ⁇ (Transfusions to achieve this level are allowed.) Subjects with a baseline platelet count of ⁇ 20,000/ ⁇ due to underlying malignancy are eligible with Medical Monitor approval; 8) Subjects must have adequate hepatic function as evidenced by: a) Serum total bilirubin ⁇ 1.5 x upper limit of normal (ULN), unless considered due to Gilbert's disease or leukemic organ involvement, and b) Aspartate aminotransferase, ALT, and alkaline phosphatase (ALP) ⁇ 3.0 x ULN, unless considered due to leukemic organ involvement;
  • UPN Serum total bilirubin ⁇ 1.5 x upper limit of normal
  • ALP Aspartate amino
  • Subjects must have adequate renal function as evidenced by a serum creatinine ⁇ 2.0 x ULN;
  • Subjects must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer. (Subjects with residual Grade 1 toxicity, for example Grade 1 peripheral neuropathy or residual alopecia, are allowed with approval of the Medical Monitor.); and 11) Female subjects with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of therapy. Subjects with reproductive potential are defined as one who is biologically capable of becoming pregnant. Women of childbearing potential as well as fertile men and their partners must agree to abstain from sexual intercourse or to use an effective form of contraception during the study and for 90 days (females and males) following the last dose of COMPOUND 1.
  • COMPOUND 1 will be provided as 5, 10, 50, and 200 mg free-base equivalent strength tablets to be administered orally.
  • the first 3 subjects in each cohort in the dose escalation portion of the study will receive a single dose of study drug on Day -3; their next dose of study drug will be administered on C1D1 at which time subjects will start dosing twice daily (approximately every 12 hours) on Days 1 to 28 in 28-day cycles. Starting with C1D1, dosing is continuous; there are no inter-cycle rest periods. Subjects who are not required to undergo the Day -3 PK/PD assessments will initiate twice daily dosing (approximately every 12 hours) with COMPOUND 1 on C1D1. Subjects are required to fast (water is allowed) for 2 hours prior to study drug administration and for 1 hour following study drug administration.
  • the dose of COMPOUND 1 administered to a subject will be dependent upon which dose cohort is open for enrollment when the subject qualifies for the study.
  • the starting dose of COMPOUND 1 to be administered to the first cohort of subjects is 30 mg (free-base equivalent strength) administered orally twice a day.
  • Subjects may continue treatment with COMPOUND 1 until disease progression, occurrence of a DLT, or development of other unacceptable toxicity.
  • AEs including determination of DLTs, serious adverse events (SAEs), and AEs leading to discontinuation; safety laboratory parameters; physical examination findings; vital signs;
  • Serial blood samples will be evaluated for determination of concentration-time profiles of COMPOUND 1 and its metabolite COMPOUND 2.
  • Urine samples will be evaluated for determination of urinary excretion of COMPOUND 1 and its metabolite COMPOUND 2.
  • Blood, bone marrow, and urine samples will be evaluated for determination of 2-HG levels.
  • Serial blood samples will be drawn before and after dosing with COMPOUND 1 in order to determine circulating plasma concentrations of COMPOUND 1 (and, if technically feasible, the metabolite COMPOUND 2).
  • the blood samples will also be used for the determination of 2- HG concentrations.
  • a single dose of COMPOUND 1 will be administered on Day -3 (i.e., 3 days prior to their scheduled C1D1 dose). Blood samples will be drawn prior to the single-dose administration of COMPOUND 1 and at the following time points after administration: 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours. After 72 hours of blood sample collection, subjects will begin oral twice daily dosing of COMPOUND 1 (i.e., C1D1).
  • the PK/PD profile from Day -3 through Day 1 is optional for additional subjects enrolled in the dose escalation phase (i.e., for any subjects beyond the 3 initial subjects enrolled in a cohort) and is not required for subjects enrolled in the expansion cohorts.
  • the timing of blood samples drawn for COMPOUND 1 concentration determination may be changed if the emerging data indicates that an alteration in the sampling scheme is needed to better characterize COMPOUND 1 's PK profile.
  • Urine sampling from Day -3 through Day 1 is optional for additional subjects enrolled in the dose escalation phase (i.e., for any subjects beyond the 3 initial subjects enrolled in a cohort) and is not required for subjects enrolled in the expansion cohorts.
  • Serial blood samples will be drawn before and after dosing with COMPOUND 1 in order to determine circulating concentrations of 2-HG.
  • Samples collected for PK assessments also will be used to assess 2-HG levels.
  • subjects will have blood drawn for determination of 2-HG levels at the screening assessment.
  • the timing of blood samples drawn for 2-HG concentration determination may be changed if the emerging data indicate that an alteration in the sampling scheme is needed to better characterize the 2-HG response to COMPOUND 1 treatment.
  • Bone marrow also will be assessed for 2-HG levels.
  • the volume of each collection will be measured and recorded and sent to a central laboratory for determination of urinary 2-HG concentration. An aliquot from each collection will be analyzed for urinary creatinine concentration.
  • Serial blood and bone marrow sampling will be evaluated during the clinical study to determine response to treatment based on modified IWG response criteria in AML.
  • the clinical activity of COMPOUND 1 will be evaluated by assessing response to treatment according to the 2006 modified IWG criteria for MDS, MDS/myeloproliferative neoplasms (MPN) or AML (Cheson BD, et al. J Clin Oncol. 2003;21(24):4642-9, Cheson BD, et al. Blood.
  • Disease response to treatment will be assessed through the evaluation of bone marrow aspirates and biopsies, along with complete blood counts and examination of peripheral blood films. Subjects will have the extent of their disease assessed and recorded at screening, on Days 15, 29, and 57, every 56 days thereafter while on study drug treatment, independent of dose- delays and/or dose interruptions, and/or at any time when progression of disease is suspected. An assessment also will be conducted at the End of Treatment visit for subjects who discontinue the study due to reasons other than disease progression.
  • Bone marrow aspirates and biopsies are to be obtained at screening, Day 15, Day 29, Day 57, every 56 days thereafter independent of dose delays and/or interruptions, at any time when progression of disease is suspected, and at the End of Treatment visit. Bone marrow aspirates and core sampling should be performed according to standard of care and analyzed at the local site's laboratory in accordance with the International Council for Standardization in Hematology (ICSH) Guidelines (Lee SH, et al. Int J Lab Hematol. 2008;30(5):349-64). Bone marrow core biopsies and aspirate are to be evaluated for morphology, flow cytometry, and for karyotype to assess potential clinical activity.
  • ICSH International Council for Standardization in Hematology
  • Aliquots of the bone marrow and/or peripheral blood blast cells also will be evaluated at central laboratories for 2-HG levels, gene expression profiles, histone and DNA methylation patterns, and metabolomic profiling.
  • Peripheral blood for the evaluation of leukemic blast cells is to be obtained at screening, Dayl5, Day 29, Day 57, every 56 days thereafter independent of dose delays and/or interruptions, at any time when progression of disease is suspected, and at the End of Treatment visit. Cell counts and flow cytometry will be used to assess the state of differentiation of blast cells collected from bone marrow and peripheral blood. Side scatter also will be analyzed to determine the complexity of the blast cells in response to COMPOUND 1.
  • Adverse events will be summarized by Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. Separate tabulations will be produced for all treatment- emergent AEs (TEAEs), treatment-related AEs (those considered by the Investigator as at least possibly drug related), SAEs, discontinuations due to AEs, and AEs of at least Grade 3 severity. By-subject listings will be provided for deaths, SAEs, DLTs, and AEs leading to discontinuation of treatment.
  • TEAEs treatment- emergent AEs
  • SAEs discontinuations due to AEs
  • AEs of at least Grade 3 severity.
  • Descriptive statistics will be provided for clinical laboratory, ECG interval, LVEF, and vital signs data, presented as both actual values and changes from baseline relative to each on- study evaluation and to the last evaluation on study. Shift analyses will be conducted for laboratory parameters and ECOG PS.
  • Descriptive statistics will be used to summarize PK parameters for each dose group and, where appropriate, for the entire population.
  • the potential relationship between plasma levels of COMPOUND 1 and blood, plasma or urine 2-HG levels will be explored with descriptive and graphical methods.

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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des formes cristallines de 2-méthyl-1-[(4-[6-(trifluorométhyl)pyridin-2-yl]-6-{[2-(trifluorométhyle)pyridin-4-yl] amino}-1, 3, 5-triazin-2-yl)amino]propan-2-ol (COMPOSÉ 3), de 2-méthyl-1-[(4-[6-(trifluorométhyl)pyridin-2-yl]-6-{[2-(trifluorométhyle)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol méthanesulfonate (COMPOSÉ 1) et leur utilisation.
PCT/CN2013/081170 2013-08-02 2013-08-09 Formes cristallines de composés thérapeutiquement actifs et utilisation associée WO2015018060A1 (fr)

Priority Applications (39)

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PCT/CN2013/081170 WO2015018060A1 (fr) 2013-08-09 2013-08-09 Formes cristallines de composés thérapeutiquement actifs et utilisation associée
EA201690322A EA030428B1 (ru) 2013-08-02 2014-08-01 Терапевтически активные соединения и способы их применения
EP19177845.5A EP3566706B1 (fr) 2013-08-02 2014-08-01 Composés thérapeutiquement actifs et leurs méthodes d'utilisation
UAA201601999A UA121021C2 (uk) 2013-08-02 2014-08-01 Терапевтично активні сполуки і способи їх застосування
PE2016000214A PE20160840A1 (es) 2013-08-02 2014-08-01 Formas cristalinas de compuestos inhibidores de isocitrato deshidrogenasa 2 (idh2)
US14/909,451 US9738625B2 (en) 2013-08-02 2014-08-01 Therapeutically active compounds and their methods of use
TW103126335A TWI666208B (zh) 2013-08-02 2014-08-01 治療活性化合物及其使用方法（三）
EP14832505.3A EP3027193A4 (fr) 2013-08-02 2014-08-01 Composés thérapeutiquement actifs et leurs méthodes d'utilisation
CA2919382A CA2919382A1 (fr) 2013-08-02 2014-08-01 Composes therapeutiquement actifs et leurs methodes d'utilisation
MYPI2016700311A MY177994A (en) 2013-08-02 2014-08-01 Therapeutically active compounds and their methods of use
EP21178745.2A EP3932408A1 (fr) 2013-08-02 2014-08-01 Composés thérapeutiquement actifs et leurs méthodes d'utilisation
TW108110624A TWI701242B (zh) 2013-08-02 2014-08-01 治療活性化合物及其使用方法(三)
MX2016001361A MX2016001361A (es) 2013-08-02 2014-08-01 Compuestos terapeuticamente activos y sus metodos de uso.
ES19177845T ES2886211T3 (es) 2013-08-02 2014-08-01 Compuestos terapéuticamente activos y sus métodos de uso
CN201910708167.6A CN110386922A (zh) 2013-08-02 2014-08-01 治疗活性化合物及其使用方法
PCT/US2014/049469 WO2015017821A2 (fr) 2013-08-02 2014-08-01 Composés thérapeutiquement actifs et leurs méthodes d'utilisation
SG11201600479WA SG11201600479WA (en) 2013-08-02 2014-08-01 Therapeutically active compounds and their methods of use
BR112016002287A BR112016002287A2 (pt) 2013-08-02 2014-08-01 compostos terapeuticamente ativos e seus métodos de uso
CN201480053796.5A CN105916507A (zh) 2013-08-02 2014-08-01 治疗活性化合物及其使用方法
CN201910707312.9A CN110372670B (zh) 2013-08-02 2014-08-01 治疗活性化合物及其使用方法
SG10201709187TA SG10201709187TA (en) 2013-08-02 2014-08-01 Therapeutically active compounds and their methods of use
JP2016531940A JP6742905B2 (ja) 2013-08-02 2014-08-01 治療活性のある化合物及びその使用方法
NZ716226A NZ716226B2 (en) 2013-08-02 2014-08-01 Therapeutically active compounds and their methods of use
MX2020011397A MX2020011397A (es) 2013-08-02 2014-08-01 Compuestos inhibidores de isocitrato deshidrogenasa 2 (idh2) y el uso de los mismos.
AU2014295938A AU2014295938B2 (en) 2013-08-02 2014-08-01 Therapeutically active compounds and their methods of use
PH12016500164A PH12016500164A1 (en) 2013-08-02 2016-01-22 Therapeutically active compounds and their methods of use
IL243833A IL243833A0 (en) 2013-08-02 2016-01-28 Therapeutically active compounds and methods of use
SA516370523A SA516370523B1 (ar) 2013-08-02 2016-02-01 مركبات نشطة علاجيًا وطرق استخدامها
NI201600022A NI201600022A (es) 2013-08-02 2016-02-01 Compuestos terapéuticamente activos y sus métodos de uso
CL2016000263A CL2016000263A1 (es) 2013-08-02 2016-02-02 Compuestos terapéuticamente activos y sus métodos de uso.
US15/649,551 US10093654B2 (en) 2013-08-02 2017-07-13 Therapeutically active compounds and their methods of use
CL2017002240A CL2017002240A1 (es) 2013-08-02 2017-09-04 Formas cristalinas del compuesto 2-metil-1-[(4-[6-(trifluorometil)piridin-2-il]-6-{[2-(trifluorometil)piridin-4-il]amino}-1,3,5-triazin-2-il)amino]propan-2-ol metanosulfonato; composición farmacéutica; usos en el tratamiento de neoplasias hematológicas avanzadas (divisional solicitud 263-2016).
US16/121,483 US10730854B2 (en) 2013-08-02 2018-09-04 Therapeutically active compounds and their methods of use
AU2018247242A AU2018247242B2 (en) 2013-08-02 2018-10-10 Therapeutically active compounds and their methods of use
JP2019082794A JP2019142930A (ja) 2013-08-02 2019-04-24 治療活性のある化合物及びその使用方法
IL270347A IL270347B (en) 2013-08-02 2019-10-31 Therapeutically active compounds and methods of use
US16/915,936 US20210155603A1 (en) 2013-08-02 2020-06-29 Therapeutically active compounds and their methods of use
JP2021123814A JP2021176893A (ja) 2013-08-02 2021-07-29 治療活性のある化合物及びその使用方法
US18/144,695 US20240132474A1 (en) 2013-08-02 2023-05-08 Therapeutically active compounds and their methods of use

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US10434105B2 (en) 2015-02-04 2019-10-08 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
KR20170113628A (ko) * 2015-02-04 2017-10-12 아지오스 파마슈티컬스 아이엔씨. 치료적 활성 화합물 및 이들의 사용 방법
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WO2016126798A1 (fr) * 2015-02-04 2016-08-11 Agios Pharmaceuticals, Inc. Composés thérapeutiquement actifs et leurs méthodes d'utilisation
US10905692B2 (en) 2015-10-15 2021-02-02 Agios Pharmaceuticals, Inc. Combination therapy for treating malignancies
US10695352B2 (en) 2015-10-15 2020-06-30 Celgene Corporation Combination therapy for treating malignancies
EP3365336A4 (fr) * 2015-10-21 2018-11-21 Neuform Pharmaceuticals, Inc. Composés deutérés pour le traitement d'hémopathies malignes, compositions et procédés associés
WO2018048847A1 (fr) 2016-09-07 2018-03-15 Celgene Corporation Compositions de comprimés
US11389454B2 (en) 2016-09-07 2022-07-19 Celgene Corporation Tablet compositions
US20180064715A1 (en) * 2016-09-07 2018-03-08 Celgene Corporation Tablet compositions
US11229653B2 (en) 2017-05-05 2022-01-25 Celgene Corporation Methods of treatment of myeloproliferative neoplasm
US11833154B2 (en) 2017-05-05 2023-12-05 Memorial Sloan Kettering Cancer Center Methods of treatment of myeloproliferative neoplasm
WO2020239759A1 (fr) 2019-05-27 2020-12-03 Sandoz Ag Énasidénib amorphe sous une forme stabilisée
CN112437765A (zh) * 2019-06-21 2021-03-02 艾斯柏伦治疗公司 贝派地酸的盐形式及其使用方法

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