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WO2025064745A1 - Inhibiteur de parg - Google Patents

Inhibiteur de parg Download PDF

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Publication number
WO2025064745A1
WO2025064745A1 PCT/US2024/047591 US2024047591W WO2025064745A1 WO 2025064745 A1 WO2025064745 A1 WO 2025064745A1 US 2024047591 W US2024047591 W US 2024047591W WO 2025064745 A1 WO2025064745 A1 WO 2025064745A1
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Prior art keywords
xrpd
salt form
pattern
peaks
ray powder
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Inventor
Xin Linghu
Ian Scott Young
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Ideaya Biosciences Inc
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Ideaya Biosciences Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • Cancer is caused by uncontrolled and unregulated cellular proliferation.
  • the consequence of this often-rapid proliferation is a high level of oxidative stress within the tumor which damages DNA and leads to a much-increased mutation rate.
  • Tumor cells therefore engage and rely heavily upon DNA damage repair mechanisms.
  • Single-strand breaks are the most common type of lesion arising in cells and PARG (Poly ADP-ribose glycohydrolase) together with PARP (poly ADP-ribose polymerase) is involved along with a number of other proteins in single strand break repair (SSBR) and another repair mechanism called base excision repair (BER).
  • PARG Poly ADP-ribose glycohydrolase
  • PARP poly ADP-ribose polymerase
  • PARG is derived from a single gene with isoforms that reside in the nucleus, mitochondria and cytosol.
  • Another known protein with glycohydrolase activity is ARH3 which is localized to the mitochondria (Mashimo, Kato et al. 2014).
  • PARG impacts PAR signaling in splicing, transcriptional and epigenetic pathways (Ji and Tulin 2009) (Le May, litis et al. 2012) (Dahl, Maturi et al. 2014) (Guastafierro, Catizone et al. 2013) (Caiafa, Guastafierro et al. 2009).
  • Cancer cells may become reliant upon a specific DNA repair pathway when other mechanisms of DNA repair are non-functional.
  • Tumors carrying mutations in proteins involved in double strand break repair are often more sensitive to PARP inhibitors of SSBR.
  • PARP inhibitors of SSBR There is already some evidence that PARG depletion inhibits SSBR and reduces survival of BRCA2-deficient cells (Fathers, Drayton et al. 2012).
  • BRCA-ness double strand DNA repair mechanisms
  • PARG depletion sensitizes lung, cervical and pancreatic cancer cells to y- irradiation or experimental DNA damaging agents (e.g. hydrogen peroxide, Methylmethanesulfonate) (Ame, Fouquerel et al. 2009) (Nakadate, Kodera et al. 2013) (Shirai, Poetsch et al. 2013).
  • DNA damaging agents e.g. hydrogen peroxide, Methylmethanesulfonate
  • PARP inhibitors are currently undergoing multiple clinical trials where the concept of synthetic lethality or chemo-sensitization is being explored. Clinical resistance to PARP inhibitors has already been described (Drost and Jonkers 2014) (Barber, Sandhu et al. 2013) and therefore there is a requirement that alternative inhibitors targeting the DNA damage repair machinery are found. [0012] Although current models show that PARG depletion leads to PARP-dependent effects on DNA repair, recent research has shown a mechanistic differentiation from PARP inhibition. Following a genotoxic stimulus depletion of PARG, in contrast to PARP depletion, leads to a drop in NAD levels. This leads to lung cancer cell death as a result of energy failure (Erdelyi, Bai et al. 2009).
  • the present disclosure provides salt and free base crystalline forms of l-(5- (difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide (Compound 1), represented by the formula: (Compound 1).
  • an HC1 salt of Compound 1 is provided herein.
  • a crystalline form of Compound 1 which is HC1 salt Form I.
  • the crystalline form is a single crystalline form substantially free of other crystalline or amorphous forms.
  • provided herein is a free base of Compound 1.
  • a crystalline form of Compound 1 which is free base Form I In some embodiments, provided herein is a crystalline form of Compound 1 which is free base Form II. In some embodiments, the crystalline form is a single crystalline form substantially free of other crystalline or amorphous forms.
  • provided herein is a tosylate salt of Compound 1.
  • a crystalline form of Compound 1 which is tosylate salt Form I In some embodiments, provided herein is a crystalline form of Compound 1 which is tosylate salt Form II. In some embodiments, provided herein is a crystalline form of Compound 1 which is tosylate salt Form III. In some embodiments, the crystalline form is a single crystalline form substantially free of other crystalline or amorphous forms.
  • a besylate salt of Compound 1 is a crystalline form of Compound 1 which is besylate salt Form I. In some embodiments, provided herein is a crystalline form of Compound 1 which is besylate salt Form II. In some embodiments, the crystalline form is a single crystalline form substantially free of other crystalline or amorphous forms.
  • provided herein is a mesylate salt of Compound 1.
  • a crystalline form of Compound 1 which is mesylate salt Form I In some embodiments, provided herein is a crystalline form of Compound 1 which is mesylate salt Form II. In some embodiments, provided herein is a crystalline form of Compound 1 which is mesylate salt Form III. In some embodiments, the crystalline form is a single crystalline form substantially free of other crystalline or amorphous forms.
  • provided herein is a maleate salt of Compound 1.
  • a crystalline form of Compound 1 which is maleate salt Form I In some embodiments, provided herein is a crystalline form of Compound 1 which is maleate salt Form II. In some embodiments, the crystalline form is a single crystalline form substantially free of other crystalline or amorphous forms.
  • a citrate salt of Compound 1 In some embodiments, provided herein is a crystalline form of Compound 1 which is citrate salt Form I. In some embodiments, the crystalline form is a single crystalline form substantially free of other crystalline or amorphous forms. [0023] In some aspects, provided herein is a fumarate salt of Compound 1. In some embodiments, provided herein is a crystalline form of Compound 1 which is fumarate salt Form I. In some embodiments, provided herein is a crystalline form of Compound 1 which is fumarate salt Form II. In some embodiments, provided herein is a crystalline form of Compound 1 which is fumarate salt Form III. In some embodiments, the crystalline form is a single crystalline form substantially free of other crystalline or amorphous forms.
  • provided herein is a malate salt of Compound 1.
  • a crystalline form of Compound 1 which is malate salt Form I In some embodiments, provided herein is a crystalline form of Compound 1 which is malate salt Form II. In some embodiments, the crystalline form is a single crystalline form substantially free of other crystalline or amorphous forms.
  • a succinate salt of Compound 1 is provided herein.
  • a crystalline form of Compound 1 which is succinate salt Form I.
  • the crystalline form is a single crystalline form substantially free of other crystalline or amorphous forms.
  • compositions comprising at least 50 percent by weight (wt%), 60 wt%, 70 wt%, 80 wt%, 90 wt%, 95 wt%, or 99 wt% of a particular crystalline form as described herein.
  • compositions of the crystalline forms of Compound 1 described herein are provided herein.
  • compositions comprising a crystalline form of Compound 1 described herein or pharmaceutical compositions prepared using a crystalline form of Compound 1 described herein.
  • pharmaceutical compositions comprising a solid state form as described herein, or a pharmaceutical compositions prepared using a solid state form described herein.
  • Pharmaceutical compositions will include one or more pharmaceutically acceptable excipients.
  • provided herein are methods of inhibiting PARG in vivo in a patient, comprising administering to the patient an effective amount of a crystalline form of Compound 1 described herein.
  • methods of inhibiting PARG in vivo in a patient comprising administering to the patient an effective amount of a solid state form of Compound 1 described herein.
  • kits for inhibiting PARG in vivo in a patient comprising administering to the patient an effective amount of a pharmaceutical composition described herein, wherein the pharmaceutical composition i) comprises a crystalline form of Compound 1 described herein, ii) is prepared using a crystalline form of Compound 1 described herein, iii) comprises a solid state form as described herein, or iv) is prepared using a solid state form described herein.
  • provided herein are methods of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a crystalline form of Compound 1 described herein.
  • methods of inhibiting cell proliferation, in vitro or in vivo the method comprising contacting a cell with an effective amount of a solid state form of Compound 1 described herein.
  • kits for inhibiting cell proliferation comprising contacting a cell with an effective amount of a pharmaceutical composition described herein, wherein the pharmaceutical composition i) comprises a crystalline form of Compound 1 described herein, ii) is prepared using a crystalline form of Compound 1 described herein, iii) comprises a solid state form as described herein, or iv) is prepared using a solid state form described herein.
  • provided herein are methods of treating a cancer resistant to one or more platins or one or more PARP inhibitors in a patient in need thereof, comprising administering to the patient an effective amount of a crystalline form of Compound 1 described herein.
  • methods of treating a cancer resistant to one or more platins or one or more PARP inhibitors in a patient in need thereof comprising administering to the patient an effective amount of a solid state form of Compound 1 described herein.
  • kits for treating a cancer resistant to one or more platins or one or more PARP inhibitors in a patient in need thereof comprising administering to the patient an effective amount of a pharmaceutical composition described herein, wherein the pharmaceutical composition i) comprises a crystalline form of Compound 1 described herein, ii) is prepared using a crystalline form of Compound 1 described herein, iii) comprises a solid state form as described herein, or iv) is prepared using a solid state form described herein.
  • provided herein are methods of treating and/or preventing a homologous recombinant deficient (HRD) cancer in a patient, comprising administering to the patient an effective amount of a crystalline form of Compound 1 described herein.
  • methods of treating and/or preventing a homologous recombinant deficient (HRD) cancer in a patient comprising administering to the patient an effective amount of a solid state form of Compound 1 described herein.
  • a homologous recombinant deficient (HRD) cancer comprising administering to the patient an effective amount of a pharmaceutical composition described herein, wherein the pharmaceutical composition i) comprises a crystalline form of Compound 1 described herein, ii) is prepared using a crystalline form of Compound 1 described herein, iii) comprises a solid state form as described herein, or iv) is prepared using a solid state form described herein.
  • HRD homologous recombinant deficient
  • kits for treating and/or preventing a cancer in a patient comprising administering to the patient an effective amount of a crystalline form of Compound 1 described herein.
  • kits for treating and/or preventing a cancer in a patient comprising administering to the patient an effective amount of a solid state form of Compound 1 described herein.
  • a cancer in a patient where the cancer is characterized by a reduction or absence of BRCA1 and/or BRCA2 gene expression, the absence or mutation of BRCA1 and/or BRCA2 genes, or reduced function of BRCA1 and/or BRCA2 proteins, comprising administering to the patient an effective amount of a pharmaceutical composition described herein, wherein the pharmaceutical composition i) comprises a crystalline form of Compound 1 described herein, ii) is prepared using a crystalline form of Compound 1 described herein, iii) comprises a solid state form as described herein, or iv) is prepared using a solid state form described herein.
  • the crystalline forms provided herein and pharmaceutical compositions thereof are useful in the treatment of cancer.
  • FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of free base Form I of Compound 1.
  • FIG. 2 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of free base Form I of Compound 1.
  • FIG. 3 shows a representative polarized light microscopy (PLM) image of free base Form I of Compound 1.
  • FIG. 4 shows the X-ray powder diffraction (XRPD) pattern of free base Form II of Compound 1.
  • FIG. 5 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of free base Form II of Compound 1.
  • FIG. 6 shows a representative polarized light microscopy (PLM) image of free base Form II of Compound 1.
  • FIG. 7 shows the X-ray powder diffraction (XRPD) pattern of HC1 salt Form I of Compound 1.
  • FIG. 8 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of HC1 salt Form I of Compound 1.
  • FIG. 9 shows dynamic vapor sorption (DVS) plot of HC1 salt Form I of Compound 1.
  • FIG. 10 shows a representative polarized light microscopy (PLM) image of HC1 salt Form I of Compound 1.
  • FIG. 11 shows the X-ray powder diffraction (XRPD) pattern of sulfate salt Form I of Compound 1.
  • FIG. 12 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of sulfate salt Form I of Compound 1.
  • FIG. 13 shows a representative polarized light microscopy (PLM) image of sulfate salt Form I of Compound 1.
  • FIG. 14 shows the X-ray powder diffraction (XRPD) pattern of tosylate salt Form I of Compound 1.
  • FIG. 15 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of tosylate salt Form I of Compound 1.
  • FIG. 16 shows a representative polarized light microscopy (PLM) image of tosylate salt Form I of Compound 1.
  • FIG. 17 shows the X-ray powder diffraction (XRPD) pattern of tosylate salt Form II of Compound 1.
  • FIG. 18 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of tosylate salt Form II of Compound 1.
  • FIG. 19 shows a representative polarized light microscopy (PLM) image of tosylate salt Form II of Compound 1.
  • FIG. 20 shows the X-ray powder diffraction (XRPD) pattern of tosylate salt Form III of Compound 1.
  • FIG. 21 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of tosylate salt Form III of Compound 1.
  • FIG. 22 shows dynamic vapor sorption (DVS) plot of tosylate salt Form III of Compound 1.
  • FIG. 23 shows a representative polarized light microscopy (PLM) image of tosylate salt Form III of Compound 1.
  • FIG. 24 shows the X-ray powder diffraction (XRPD) pattern of besylate salt Form I of Compound 1.
  • FIG. 25 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of besylate salt Form I of Compound 1.
  • FIG. 26 shows a representative polarized light microscopy (PLM) image of besylate salt Form I of Compound 1.
  • FIG. 27 shows the X-ray powder diffraction (XRPD) pattern of besylate salt Form II of Compound 1.
  • FIG. 28 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of besylate salt Form II of Compound 1.
  • FIG. 29 shows a representative polarized light microscopy (PLM) image of besylate salt Form II of Compound 1.
  • FIG. 30 shows the X-ray powder diffraction (XRPD) pattern of mesylate salt Form
  • FIG. 31 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of mesylate salt Form I of Compound 1.
  • FIG. 32 shows dynamic vapor sorption (DVS) plot of mesylate salt Form I of Compound 1.
  • FIG. 33 shows a representative polarized light microscopy (PLM) image of mesylate salt Form I of Compound 1.
  • FIG. 34 shows the X-ray powder diffraction (XRPD) pattern of mesylate salt Form
  • FIG. 35 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of mesylate salt Form II of Compound 1.
  • FIG. 36 shows a representative polarized light microscopy (PLM) image of mesylate salt Form II of Compound 1.
  • FIG. 37 shows the X-ray powder diffraction (XRPD) pattern of mesylate salt Form
  • FIG. 38 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of mesylate salt Form III of Compound 1.
  • FIG. 41 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of maleate salt Form I of Compound 1.
  • FIG. 42 shows a representative polarized light microscopy (PLM) image of maleate salt Form I of Compound 1.
  • FIG. 44 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of maleate salt Form II of Compound 1.
  • FIG. 46 shows the X-ray powder diffraction (XRPD) pattern of citrate salt Form I of Compound 1.
  • FIG. 57 shows a representative polarized light microscopy (PLM) image of fumarate salt Form III of Compound 1.
  • FIG. 58 shows the X-ray powder diffraction (XRPD) pattern of malate salt Form I of Compound 1.
  • FIG. 59 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of malate salt Form I of Compound 1.
  • FIG. 60 shows a representative polarized light microscopy (PLM) image of malate salt Form I of Compound 1.
  • FIG. 61 shows the X-ray powder diffraction (XRPD) pattern of malate salt Form II of Compound 1.
  • FIG. 62 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of malate salt Form II of Compound 1.
  • FIG. 64 shows a representative polarized light microscopy (PLM) image of malate salt Form II of Compound 1.
  • FIG. 65 shows the X-ray powder diffraction (XRPD) pattern of succinate salt Form I of Compound 1.
  • FIG. 66 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of succinate salt Form I of Compound 1.
  • FIG. 67 shows a representative polarized light microscopy (PLM) image of succinate salt Form I of Compound 1.
  • the present disclosure provides crystalline forms of Compound 1 . These forms are characterized by an X-ray powder diffraction (XRPD) pattern. Selected crystalline forms are further characterized by a differential scanning calorimetry (DSC), a thermal gravimetric analysis (TGA), a dynamic vapor sorption analysis (DVS), and/or a polarized light microscope (PLM) profile.
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric analysis
  • DVD dynamic vapor sorption analysis
  • PLM polarized light microscope
  • the present disclosure further provides pharmaceutical compositions of the crystalline forms of Compound 1 described herein.
  • the present disclosure provides a pharmaceutical composition described herein, wherein the pharmaceutical composition i) comprises a crystalline form of Compound 1 described herein, ii) is prepared using a crystalline form of Compound 1 described herein, iii) comprises a solid state form as described herein, or iv) is prepared using a solid state form described herein.
  • the present disclosure further provides methods of inhibiting PARG in vivo in a patient, the method comprising administering to the patient a therapeutically effective amount of a crystalline form of Compound 1 described herein.
  • the present disclosure further provides methods of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a crystalline form of Compound 1 described herein.
  • the present disclosure further provides methods of treating a cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a crystalline form of Compound 1 described herein.
  • the present disclosure further provides methods of treating a cancer resistant to one or more platins or one or more PARP inhibitors in a patient in need thereof, the method comprising administering to the patient an effective amount of a crystalline form of Compound 1 described herein.
  • the present disclosure further provides methods of treating and/or preventing a homologous recombinant deficient (HRD) cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a crystalline form of Compound 1 described herein.
  • HRD homologous recombinant deficient
  • the present disclosure further provides methods of treating and/or preventing a cancer in a patient, where the cancer is characterized by a reduction or absence of BRCA1 and/or BRCA2 gene expression, the absence or mutation of BRCA1 and/or BRCA2 genes, or reduced function of BRCA1 and/or BRCA2 proteins, the method comprising administering to the individual a therapeutically effective amount of a crystalline form of Compound 1 described herein.
  • the present disclosure further provides methods of inhibiting PARG in vivo in a patient, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.
  • the present disclosure further provides methods of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a pharmaceutical composition described herein.
  • the present disclosure further provides methods of treating a cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.
  • the present disclosure further provides methods of treating a cancer resistant to one or more platins or one or more PARP inhibitors in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.
  • the present disclosure further provides methods of treating and/or preventing a homologous recombinant deficient (HRD) cancer in a patient, the method comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition described herein.
  • HRD homologous recombinant deficient
  • the present disclosure further provides methods of treating and/or preventing a cancer in a patient, where the cancer is characterized by a reduction or absence of BRCA1 and/or BRCA2 gene expression, the absence or mutation of BRCA1 and/or BRCA2 genes, or reduced function of BRCA1 and/or BRCA2 proteins, the method comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition described herein.
  • substantially free refers to that an amount of 10% or less of another form is present in a particular desired form, preferably 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.5%, or less of another form.
  • “Crude” refers to a mixture including a desired compound (e.g., the compound of Formula (I)) and at least one other species (e.g., a solvent, a reagent such as an acid or base, a starting material, or a byproduct of a reaction giving rise to the desired compound).
  • a desired compound e.g., the compound of Formula (I)
  • at least one other species e.g., a solvent, a reagent such as an acid or base, a starting material, or a byproduct of a reaction giving rise to the desired compound.
  • “Solvate” refers to a compound provided herein or a salt thereof that binds to a stoichiometric or non-stoichiometric amount of solvent by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
  • “Hydrate” refers to a compound that is complexed to a stoichiometric or non- stoichiometric amount of water.
  • the compounds of the present invention can be complexed with from 'Z> or 1 to 10 water molecules.
  • the compounds of the present invention can be complexed with '/i water molecule, the compounds of the present invention can be complexed with 1 water molecule, or the compounds of the present invention can be complexed with 2 water molecules.
  • Crystal form refers to a solid form of a compound wherein the constituent molecules are packed in a regularly ordered, repeating pattern.
  • a crystalline form can include triclinic, monoclinic, orthorhombic, tetragonal, trigonal, hexagonal, and cubic crystal geometries.
  • a crystalline form can include one or more regions, i.e., grains, with distinct crystal boundaries.
  • a crystalline solid can include two or more crystal geometries.
  • Amorphous form refers to a solid form of a compound having no definite crystal structure, i.e., lacking a regularly ordered, repeating pattern of constituent molecules.
  • FeSSIF stands for Fed State Simulated Intestinal Fluid.
  • FaSSIF stands for Fasted State Simulated Intestinal Fluid.
  • SGF stands for Simulated Gastric Fluid.
  • “About” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In some embodiments, the term “about” means within a standard deviation using measurements generally acceptable in the art. In some embodiments, “about” means a range extending to +/- 10% of the specified value.
  • “Pharmaceutically acceptable salts” as used herein is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally- occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N’- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogen carbonic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, sulfuric, monohydrogen sulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S.M., et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • Compound 1 is a chemical compound having an IUPAC name of l-(5- (difluoromethyl)- 1 ,3 ,4-thiadiazol-2-yl)-4-((3 S,5S)-3 ,5 -dimethylpiperazin- 1 -yl)-N-( 1 - methylcyclopropyl)- lH-indazole-6-sulfonamide, and the structure shown below: (Compound 1).
  • “Free base of Compound 1” or “Compound 1 in free base” refers to Compound 1 represented by the formula: (Compound 1).
  • treating encompasses both disease-modifying treatment and symptomatic treatment, either of which may be prophylactic (i.e., before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms) or therapeutic (i.e., after the onset of symptoms, in order to reduce the severity and/or duration of symptoms).
  • free base Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 15% as listed in Table 1. In some embodiments, free base Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 15% as listed in Table 1. In some embodiments, free base Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 15% as listed in Table 1.
  • XRPD X-ray powder diffraction
  • free base Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 15% as listed in Table 1. In some embodiments, free base Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 15% as listed in Table 1. In some embodiments, free base Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 15% as listed in Table 1.
  • tosylate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG. 15.
  • tosylate salt Form I is characterized by 1.2% weight loss upon heating from 110 °C to 230 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, tosylate salt Form I is characterized by about 1.2% weight loss upon heating from about 110 °C to about 230 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, tosylate salt Form I is characterized by a weight loss of no greater than about 10%, 5%, 4%, 3%, or 2% by weight upon heating from about 110 °C to about 230 °C, as measured by a thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • tosylate salt Form I is characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 16.
  • PLM polarized light microscope
  • tosylate salt Form I is substantially free of other crystalline or amorphous forms.
  • the crystalline form is a tosylate salt of Compound 1.
  • the crystalline form is tosylate salt Form II.
  • tosylate salt Form II is anhydrate.
  • tosylate salt Form II of Compound 1.
  • tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.7, 14.3, 15.4, 17.3, and 19.1degrees 29 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • tosylate salt Form II is characterized by an XRPD pattern further comprising one or more peaks selected from 9.1, 10.2, 13.0, 17.0, and 18.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • tosylate salt Form II is characterized by an XRPD pattern further comprising one or more peaks selected from 20.1, 20.5, 23.8, 24.2, and 26.2 degrees 20 ( ⁇ 0.2 degrees 20).
  • tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.7, 15.4, 17.3, 20.1, and 24.2 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, the XRPD pattern further comprises peaks at 14.3, 17.0, 19.1, 20.5, and 26.2 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.7, 14.3, 15.4, 17.0, 17.3, 19.1, 20.1, 20.5, 24.2, and 26.2 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 15% as listed in Table 6. In some embodiments, tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 15% as listed in Table 6. In some embodiments, tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 15% as listed in Table 6.
  • XRPD X-ray powder diffraction
  • tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 15% as listed in Table 6. In some embodiments, tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 15% as listed in Table 6. In some embodiments, tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 15% as listed in Table 6.
  • tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 15% as listed in Table 6. In some embodiments, tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 15% as listed in Table 6. In some embodiments, tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 15% as listed in Table 6.
  • tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 20% as listed in Table 6. In some embodiments, tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 20% as listed in Table 6. In some embodiments, tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 20% as listed in Table 6.
  • XRPD X-ray powder diffraction
  • tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 20% as listed in Table 6. In some embodiments, tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 20% as listed in Table 6. In some embodiments, tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 20% as listed in Table 6.
  • tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 20% as listed in Table 6. In some embodiments, tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 20% as listed in Table 6. In some embodiments, tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 20% as listed in Table 6.
  • tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 30% as listed in Table 6. In some embodiments, tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 30% as listed in Table 6. In some embodiments, tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 30% as listed in Table 6.
  • XRPD X-ray powder diffraction
  • tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 30% as listed in Table 6. In some embodiments, tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 30% as listed in Table 6. In some embodiments, tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 30% as listed in Table 6.
  • tosylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 17.
  • XRPD X-ray powder diffraction
  • tosylate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 229 °C.
  • tosylate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram including an onset temperature of about 223 °C and an endothermic peak at about 229 °C.
  • tosylate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG. 18.
  • tosylate salt Form II is characterized by 1.4% weight loss upon heating from 90 °C to 230 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, tosylate salt Form II is characterized by about 1.4% weight loss upon heating from about 90 °C to about 230 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, tosylate salt Form II is characterized by a weight loss of no greater than about 10%, 5%, 4%, 3%, or 2% by weight upon heating from about 90 °C to about 230 °C, as measured by a thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • tosylate salt Form II is characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 18.
  • tosylate salt Form II is characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 19.
  • PLM polarized light microscope
  • tosylate salt Form II is substantially free of other crystalline or amorphous forms.
  • the crystalline form is a tosylate salt of Compound 1.
  • the crystalline form is tosylate salt Form III.
  • tosylate salt Form III is an anhydrate.
  • tosylate salt Form III of Compound 1.
  • tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.9, 14.5, 15.5, 18.2, and 19.5 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • tosylate salt Form III is characterized by an XRPD pattern further comprising one or more peaks selected from 9.7, 14.1, 14.9, 16.0, and 16.9 degrees 20 ( ⁇ 0.2 degrees 20).
  • tosylate salt Form III is characterized by an XRPD pattern further comprising one or more peaks selected from 21.2,
  • tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 18.2, 19.5, 21.2, 22.0, and 24.0 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • the XRPD pattern further comprises peaks at 6.9,
  • tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.9, 14.5, 15.5, 18.2, 19.5, 21.2, 21.4, 22.0, 24.0, and 24.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising three, four, five, or seven, ten, or more peaks listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising three peaks listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising five peaks listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising seven peaks listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising ten peaks listed in Table 7.
  • XRPD X-ray powder diffraction
  • tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 15% as listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 15% as listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 15% as listed in Table 7.
  • XRPD X-ray powder diffraction
  • tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 15% as listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 15% as listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 15% as listed in Table 7.
  • tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 15% as listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 15% as listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 15% as listed in Table 7.
  • tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 20% as listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 20% as listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 20% as listed in Table 7.
  • XRPD X-ray powder diffraction
  • tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 20% as listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 20% as listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 20% as listed in Table 7.
  • tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 20% as listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 20% as listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 20% as listed in Table 7.
  • XRPD X-ray powder diffraction
  • tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 30% as listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 30% as listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 30% as listed in Table 7.
  • XRPD X-ray powder diffraction
  • tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 30% as listed in able 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 30% as listed in Table 7. In some embodiments, tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 30% as listed in Table 7.
  • tosylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 20.
  • tosylate salt Form III is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 222 °C. In some embodiments, tosylate salt Form III is characterized by a differential scanning calorimetry (DSC) thermogram including an onset temperature of about 206 °C and an endothermic peak at about 222 °C.
  • DSC differential scanning calorimetry
  • tosylate salt Form III is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG. 21.
  • tosylate salt Form III is characterized by 2.6% weight loss upon heating from about 110 °C to about 222 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, tosylate salt Form III is characterized by about 2.6% weight loss upon heating from about 110 °C to about 222 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, tosylate salt Form III is characterized by a weight loss loss of no greater than about 10%, 5%, 4%, or 3% by weight upon heating from about 110 °C to about 222 °C, as measured by a thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • tosylate salt Form III is characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 21.
  • tosylate salt Form III is characterized by a weight gain of about 3.2% after undergoing a dynamic vapor sorption profile cycle from about 0% relative humidity (RH) to about 90% RH at 25 °C.
  • tosylate salt Form III is characterized by a dynamic vapor sorption (DVS) profile substantially as shown in FIG. 22.
  • tosylate salt Form III is characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 23.
  • tosylate salt Form III is substantially free of other crystalline or amorphous forms.
  • the crystalline form is a besylate salt of Compound 1.
  • the crystalline form is besylate salt Form I.
  • besylate salt Form I is anhydrate.
  • besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.8, 14.5, 15.4, 17.3, and 19.1 degrees 20 ( ⁇ 0.2 degrees 20).
  • besylate salt Form I is characterized by an XRPD pattern further comprising one or more peaks selected from 15.0, 15.9, 17.7, 18.3, and 19.6 degrees 20 ( ⁇ 0.2 degrees 20).
  • besylate salt Form I is characterized by an XRPD pattern further comprising one or more peaks selected from 20.3,
  • besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.8, 17.3, 19.1, 24.0, and 25.2 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, the XRPD pattern further comprises peaks at 14.5, 15.4, 17.7, 20.3, and 26.0 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at
  • besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising three, four, five, or seven, ten, or more peaks listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising three peaks listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising five peaks listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising seven peaks listed in Table 8.
  • XRPD X-ray powder diffraction
  • besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising ten peaks listed in Table 8. [0248] In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 15% as listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 15% as listed in Table 8.
  • besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 15% as listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 15% as listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 15% as listed in Table 8.
  • besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 15% as listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 15% as listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 15% as listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 15% as listed in Table 8.
  • XRPD X-ray powder diffraction
  • besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 20% as listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 20% as listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 20% as listed in Table 8.
  • XRPD X-ray powder diffraction
  • besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 20% as listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 20% as listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 20% as listed in Table 8.
  • besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 20% as listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 20% as listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 20% as listed in Table 8.
  • besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 30% as listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 30% as listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 30% as listed in Table 8.
  • XRPD X-ray powder diffraction
  • besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 30% as listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 30% as listed in Table 8. In some embodiments, besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 30% as listed in Table 8.
  • besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 24. [0252] In some embodiments, besylate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 202 °C. In some embodiments, besylate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram including an onset temperature of about 190 °C and an endothermic peak at about 202 °C.
  • DSC differential scanning calorimetry
  • besylate salt Form I is characterized by 0.6% weight loss upon heating from 100 °C to 210 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, besylate salt Form I is characterized by about 0.6% weight loss upon heating from about 100 °C to about 210 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, besylate salt Form I is characterized by a weight loss of no greater than about 10%, 5%, 4%, 3%, 2%, or 1% by weight upon heating from about 100 °C to about 210 °C, as measured by a thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • besylate salt Form I is characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 25.
  • besylate salt Form I is characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 26.
  • PLM polarized light microscope
  • besylate salt Form I is substantially free of other crystalline or amorphous forms.
  • the crystalline form is a besylate salt of Compound 1.
  • the crystalline form is besylate salt Form II.
  • besylate salt Form II is an anhydrate.
  • besylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.6, 15.2, 15.7, 19.2, and 19.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • besylate salt Form II is characterized by an XRPD pattern further comprising one or more peaks selected from 9.0, 10.0, 12.4, 14.7, and 18.1degrees 20 ( ⁇ 0.2 degrees 20).
  • besylate salt Form II is characterized by an XRPD pattern further comprising one or more peaks selected from 10.4,
  • besylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.6, 15.2, 19.2, 22.9, and 26.5 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, the XRPD pattern further comprises peaks at 15.7,
  • besylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.6, 15.2, 15.7, 18.1, 19.2, 19.7, 20.1, 22.9, 25.0, and 26.5 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • besylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising three, four, five, or seven, ten, or more peaks listed in Table 9. In some embodiments, besylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising three peaks listed in Table 9. In some embodiments, besylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising five peaks listed in Table 9. In some embodiments, besylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising seven peaks listed in Table 9. In some embodiments, besylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising ten peaks listed in Table 9.
  • XRPD X-ray powder diffraction
  • besylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 27.
  • besylate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 165 °C. In some embodiments, besylate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram including an onset temperature of about 154°C and an endothermic peak at about 165 °C.
  • DSC differential scanning calorimetry
  • besylate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG. 28
  • besylate salt Form II is characterized by 0.5% weight loss upon heating from 64 °C to 185 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, besylate salt Form II is characterized by about 0.5% weight loss upon heating from about 64 °C to about 185 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, besylate salt Form II is characterized by a weight loss of no greater than about 10%, 5%, 4%, 3%, 2%, or 1% by weight upon heating from about 64 °C to about 185 °C, as measured by a thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • besylate salt Form II is characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 28.
  • besylate salt Form II is characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 29.
  • PLM polarized light microscope
  • besylate salt Form II is substantially free of other crystalline or amorphous forms.
  • viii. Mesylate salt of Compound 1 (Form I)
  • the crystalline form is a mesylate salt of Compound 1.
  • the crystalline form is mesylate salt Form I.
  • mesylate salt Form I is an anhydrate.
  • mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 14.2, 17.0, 18.0, 18.6, and 19.3 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • mesylate salt Form I is characterized by an XRPD pattern further comprising one or more peaks selected from 11.0, 11.9, 12.7,
  • mesylate salt Form I is characterized by an XRPD pattern further comprising one or more peaks selected from 20.7,
  • mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 14.2, 17.0, 18.6, 22.1, and 24.1 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, the XRPD pattern further comprises peaks at 18.0,
  • mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 14.2, 17.0, 18.0, 18.6, 19.3, 21.2, 21.5, 22.1, 24.1, and 24.9 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising three, four, five, or seven, ten, or more peaks listed in Table 10. In some embodiments, mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising three peaks listed in Table 10. In some embodiments, mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising five peaks listed in Table 10. In some embodiments, mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising seven peaks listed in Table 10. In some embodiments, mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising ten peaks listed in Table 10.
  • XRPD X-ray powder diffraction
  • mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 15% as listed in Table 10. In some embodiments, mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 15% as listed in Table 10. In some embodiments, mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 15% as listed in Table 10.
  • XRPD X-ray powder diffraction
  • mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 15% as listed in Table 10. In some embodiments, mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 15% as listed in Table 10. In some embodiments, mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 15% as listed in Table 10.
  • mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 15% as listed in Table 10. In some embodiments, mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 15% as listed in Table 10. In some embodiments, mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 15% as listed in Table 10.
  • mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 20% as listed in Table 10. In some embodiments, mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 20% as listed in Table 10. In some embodiments, mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 20% as listed in Table 10. In some embodiments, mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 20% as listed in Table 10.
  • XRPD X-ray powder diffraction
  • mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 30% as listed in Table 10. In some embodiments, mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 30% as listed in Table 10. In some embodiments, mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 30% as listed in Table 10.
  • XRPD X-ray powder diffraction
  • mesylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 30.
  • mesylate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 222 °C. In some embodiments, mesylate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram including an onset temperature of about 218°C and an endothermic peak at about 222°C.
  • DSC differential scanning calorimetry
  • mesylate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG. 31.
  • mesylate salt Form I is characterized by 0.5% weight loss upon heating from 125 °C to 225 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, mesylate salt Form I is characterized by about 0.5% weight loss upon heating from about 125 °C to about 225 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, mesylate salt Form I is characterized by a weight loss of no greater than about 10%, 5%, 4%, 3%, 2%, or 1% by weight upon heating from about 125 °C to about 225 °C, as measured by a thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • mesylate salt Form I is characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 31.
  • mesylate salt Form I is characterized by a weight gain of about 19% after undergoing a dynamic vapor sorption profile cycle from about 0% relative humidity (RH) to about 90% RH at 25 °C.
  • mesylate salt Form I is characterized by a dynamic vapor sorption (DVS) profile substantially as shown in FIG. 32.
  • mesylate salt Form I is characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 33.
  • PLM polarized light microscope
  • mesylate salt Form I is substantially free of other crystalline or amorphous forms.
  • the crystalline form is a mesylate salt of Compound 1.
  • the crystalline form is mesylate salt Form II.
  • mesylate salt Form II is an anhydrate.
  • mesylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.7, 15.4, 17.2, 17.6, and 19.1 degrees 20 ( ⁇ 0.2 degrees 20).
  • mesylate salt Form II is characterized by an XRPD pattern further comprising one or more peaks selected from 10.0, 10.3, 11.4, 15.0, and 16.5degrees 20 ( ⁇ 0.2 degrees 20).
  • mesylate salt Form II is characterized by an XRPD pattern further comprising one or more peaks selected from 12.1,
  • mesylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.7, 15.4, 17.5, 19.1, and 23.2 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, the XRPD pattern further comprises peaks at 9.9,
  • mesylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.7, 9.9, 10.3, 15.0, 15.4, 17.2, 17.5, 19.1, 20.2, and 23.2 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • mesylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising three, four, five, or seven, ten, or more peaks listed in Table 11. In some embodiments, mesylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising three peaks listed in Table 11. In some embodiments, mesylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising five peaks listed in Table 11. In some embodiments, mesylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising seven peaks listed in Table 11. In some embodiments, mesylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising ten peaks listed in Table 11.
  • XRPD X-ray powder diffraction
  • mesylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 15% as listed in Table 11. In some embodiments, mesylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 15% as listed in Table 11. In some embodiments, mesylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 20% as listed in Table 11.
  • XRPD X-ray powder diffraction
  • mesylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 34.
  • mesylate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 190 °C. In some embodiments, mesylate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram including an onset temperature of about 176 °C and an endothermic peak at about 190 °C.
  • DSC differential scanning calorimetry
  • mesylate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG. 35.
  • mesylate salt Form II is characterized by 0.2% weight loss upon heating from 140 °C to 205 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, mesylate salt Form II is characterized by about 0.2% weight loss upon heating from about 140 °C to about 205 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, mesylate salt Form II is characterized by a weight loss of no greater than about 10%, 5%, 4%, 3%, 2%, or 1% by weight upon heating from about 140 °C to about 205 °C, as measured by a thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • mesylate salt Form II is characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 35.
  • mesylate salt Form II is characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 36. [0296] In some embodiments, mesylate salt Form II is substantially free of other crystalline or amorphous forms. x. Mesylate salt of Compound 1 (Form III)
  • the crystalline form is a mesylate salt of Compound 1.
  • the crystalline form is mesylate salt Form III.
  • mesylate salt Form III is a solvate or anhydrate.
  • mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.5, 8.9, 17.5, 18.5, and 19.6 degrees 20 ( ⁇ 0.2 degrees 20).
  • mesylate salt Form III is characterized by an XRPD pattern further comprising one or more peaks selected from 6.1, 13.1, 13.8, 14.4, and 19.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • mesylate salt Form III is characterized by an XRPD pattern further comprising one or more peaks selected from 13.3, 18.0, 21.4, 23.6, and 26.0 degrees 20 ( ⁇ 0.2 degrees 20).
  • mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.5, 8.9, 18.5, 19.6, and 21.4 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, the XRPD pattern further comprises peaks at 6.1, 13.8, 17.5, 19.4, and 23.6 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.1, 6.5, 8.9, 13.8, 17.5, 18.5, 19.4, 19.6, 21.4, and 23.6 degrees 20 ( ⁇ 0.2 degrees 20).
  • mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising three, four, five, or seven, ten, or more peaks listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising three peaks listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising five peaks listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising seven peaks listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising ten peaks listed in Table 12.
  • XRPD X-ray powder diffraction
  • mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 15% as listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 15% as listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 15% as listed in Table 12.
  • XRPD X-ray powder diffraction
  • mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 15% as listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 15% as listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 15% as listed in Table 12.
  • mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 15% as listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 15% as listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 15% as listed in Table 12.
  • mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 20% as listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 20% as listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 20% as listed in Table 12.
  • XRPD X-ray powder diffraction
  • mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 20% as listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 20% as listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 20% as listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 20% as listed in Table 12.
  • XRPD X-ray powder diffraction
  • mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 30% as listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 30% as listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 30% as listed in Table 12.
  • XRPD X-ray powder diffraction
  • mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 30% as listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 30% as listed in Table 12. In some embodiments, mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 30% as listed in Table 12.
  • mesylate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FTG. 37.
  • mesylate salt Form III is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 173 °C. In some embodiments, mesylate salt Form III is characterized by a differential scanning calorimetry (DSC) thermogram including an onset temperature of about 138 °C and an endothermic peak at about 173 °C.
  • DSC differential scanning calorimetry
  • mesylate salt Form III is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG. 38.
  • mesylate salt Form III is characterized by 1.5% weight loss upon heating from 80 °C to 180 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, mesylate salt Form III is characterized by about 1.5% weight loss upon heating from about 80 °C to about 180 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, mesylate salt Form III is characterized by a weight loss of no greater than about 10%, 5%, 4%, 3%, or 2% by weight upon heating from about 80 °C to about 180 °C, as measured by a thermal gravimetric analysis (TGA). [0308] In some embodiments, mesylate salt Form III is characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 38.
  • TGA thermal gravimetric analysis
  • mesylate salt Form III is characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 39.
  • PLM polarized light microscope
  • mesylate salt Form III is substantially free of other crystalline or amorphous forms.
  • the crystalline form is a maleate salt of Compound 1. In some embodiments, the crystalline form is maleate salt Form I. In some embodiments, maleate salt Form I is an anhydrate.
  • maleate salt Form I of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.7, 14.8, 15.5, 18.7, and 20.0 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • maleate salt Form I is characterized by an XRPD pattern further comprising one or more peaks selected from 7.9, 8.3, 9.9, 12.7, and 18.1degrees 20 ( ⁇ 0.2 degrees 20).
  • maleate salt Form I is characterized by an XRPD pattern further comprising one or more peaks selected from 16.7, 21.2, 22.5,
  • maleate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 14.8, 15.5, 18.7, 22.5, and 23.3 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, the XRPD pattern further comprises peaks at 7.9,
  • maleate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.9, 8.3, 8.7, 9.9, 14.8, 15.5, 18.7, 20.0, 22.5, and 23.3 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • maleate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising three, four, five, or seven, ten, or more peaks listed in Table 13. In some embodiments, maleate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising three peaks listed in Table 13. In some embodiments, maleate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising five peaks listed in Table 13. In some embodiments, maleate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising seven peaks listed in Table 13. In some embodiments, maleate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising ten peaks listed in Table 13.
  • XRPD X-ray powder diffraction
  • maleate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 40.
  • maleate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 195°C. In some embodiments, maleate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram including an onset temperature of about 191 °C and an endothermic peak at about 195°C.
  • DSC differential scanning calorimetry
  • maleate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG. 41.
  • maleate salt Form I is characterized by no weight loss prior to decomposition, as measured by a thermal gravimetric analysis (TGA). In some embodiments, maleate salt Form I is characterized by no substantial weight loss prior to decomposition, as measured by a thermal gravimetric analysis (TGA). In some embodiments, maleate salt Form I is characterized by a weight loss of no greater than 5%, 4%, 3%, 2%, 1%, or 0.5% by weight upon heating prior to decomposition, as measured by a thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • maleate salt Form I is characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 41.
  • maleate salt Form I is characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 42.
  • PLM polarized light microscope
  • maleate salt Form I is substantially free of other crystalline or amorphous forms.
  • the crystalline form is a maleate salt of Compound 1.
  • the crystalline form is maleate salt Form II.
  • maleate salt Form II is an acetone solvate.
  • the present disclosure provides maleate salt Form II of Compound 1.
  • maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 14.3, 15.3, 17.5, 18.3, and 18.8 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • maleate salt Form II is characterized by an XRPD pattern further comprising one or more peaks selected from 9.6, 11.9, 13.3,
  • maleate salt Form II is characterized by an XRPD pattern further comprising one or more peaks selected from 17.9, 21.4, 24.0, 24.3, and 24.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 14.3, 15.3, 17.5, 18.3, and 24.0 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, the XRPD pattern further comprises peaks at 11.9,
  • maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.9, 13.3, 14.2, 14.3, 15.3, 17.5, 18.3, 18.8, 21.4, and 24.0 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising three, four, five, or seven, ten, or more peaks listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising three peaks listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising five peaks listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising seven peaks listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising ten peaks listed in Table 14.
  • XRPD X-ray powder diffraction
  • maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 15% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 15% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 15% as listed in Table 14.
  • XRPD X-ray powder diffraction
  • maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 15% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 15% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 15% as listed in Table 14.
  • maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 15% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 15% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 15% as listed in Table 14.
  • XRPD X-ray powder diffraction
  • maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 20% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 20% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 20% as listed in Table 14.
  • XRPD X-ray powder diffraction
  • maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 20% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 20% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 20% as listed in Table 14.
  • XRPD X-ray powder diffraction
  • maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 20% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 20% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 20% as listed in Table 14.
  • XRPD X-ray powder diffraction
  • maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 30% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 30% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 30% as listed in Table 14.
  • XRPD X-ray powder diffraction
  • maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 30% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 30% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 30% as listed in Table 14.
  • XRPD X-ray powder diffraction
  • maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 30% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 30% as listed in Table 14. In some embodiments, maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 30% as listed in Table 14.
  • XRPD X-ray powder diffraction
  • maleate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 43.
  • XRPD X-ray powder diffraction
  • maleate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram including a first endothermic peak at about 142 °C and/or a second endothermic peak at about 162 °C.
  • maleate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram including a first endothermic onset and peak temperature of about 135 °C and 142 °C, respectively, and/or a second endothermic onset and endothermic peak at about 155 °C and 162 °C, respectively.
  • maleate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram including a first endothermic onset and peak temperature of about 135 °C and about 142 °C, respectively, and/or a second endothermic onset and endothermic peak at about 155 °C and about 162 °C, respectively.
  • DSC differential scanning calorimetry
  • maleate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG. 44.
  • the crystalline form is a citrate salt of Compound 1.
  • the crystalline form is citrate salt Form I.
  • citrate salt Form I is an acetone solvate or anhydrate.
  • citrate salt Form I of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.4, 15.8, 17.9, 19.2, and 19.5 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, citrate salt Form I is characterized by an XRPD pattern further comprising one or more peaks selected from 10.6, 13.1, 15.1, 17.0, and 18.9 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, citrate salt Form I is characterized by an XRPD pattern further comprising one or more peaks selected from 20.3, 22.6, 23.1, 24.5, and 27.1 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • citrate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.4, 15.8, 19.2, 20.3, and 27.1 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, the XRPD pattern further comprises peaks at 17.9, 19.5, 22.6, 23.1, and 24.5 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, citrate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.4, 15.8, 17.9, 19.2, 19.5, 20.3, 22.6, 23.1, 24.5, and 27.1 degrees 20 ( ⁇ 0.2 degrees 20).
  • citrate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising three, four, five, or seven, ten, or more peaks listed in Table 15. In some embodiments, citrate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising three peaks listed in Table 15. In some embodiments, citrate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising five peaks listed in Table 15. In some embodiments, citrate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising seven peaks listed in Table 15. In some embodiments, citrate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising ten peaks listed in Table 15.
  • XRPD X-ray powder diffraction
  • citrate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 15% as listed in Table 15. In some embodiments, citrate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 20% as listed in Table 15.
  • XRPD X-ray powder diffraction
  • citrate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 46.
  • citrate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 167 °C. In some embodiments, citrate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram including an onset temperature of about 159 °C and an endothermic peak at about 167 °C.
  • DSC differential scanning calorimetry
  • citrate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG. 47.
  • citrate salt Form I is characterized by 22% weight loss upon heating from 95 °C to 225 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, citrate salt Form I is characterized by about 22% weight loss upon heating from about 95 °C to about 225 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, citrate salt Form I is characterized by a weight loss of no greater than about 30%, 25%, or 22% by weight upon heating from about 95 °C to about 225 °C, as measured by a thermal gravimetric analysis (TGA).
  • citrate salt Form I is characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 47.
  • citrate salt Form I is characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 48.
  • PLM polarized light microscope
  • citrate salt Form I is substantially free of other crystalline or amorphous forms.
  • the crystalline form is a fumarate salt of Compound 1. In some embodiments, the crystalline form is fumarate salt Form I. In some embodiments, fumarate salt Form I is a THF solvate.
  • fumarate salt Form I of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.2, 8.5, 10.6, 18.8, and 19.8 degrees 20 ( ⁇ 0.2 degrees 20).
  • fumarate salt Form I is characterized by an XRPD pattern further comprising one or more peaks selected from 12.7, 13.0, 15.9, 17.0, and 19.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • fumarate salt Form I is characterized by an XRPD pattern further comprising one or more peaks selected from 21.1, 21.4, 23.4, 25.7, and 27.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.2, 10.6, 19.8, 21.4, and 23.4 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, the XRPD pattern further comprises peaks at 8.5, 17.0, 18.8, 19.4, and 25.7 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.2, 8.5, 10.6, 17.0, 18.8, 19.4, 19.8, 21.4, 23.4, and 25.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising three, four, five, or seven, ten, or more peaks listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising three peaks listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising five peaks listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising seven peaks listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising ten peaks listed in Table 16.
  • XRPD X-ray powder diffraction
  • fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 15% as listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 15% as listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 15% as listed in Table 16.
  • XRPD X-ray powder diffraction
  • fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 15% as listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 15% as listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 15% as listed in Table 16.
  • fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 15% as listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 15% as listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 15% as listed in Table 16.
  • fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 20% as listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 20% as listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 20% as listed in Table 16.
  • XRPD X-ray powder diffraction
  • fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 20% as listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 20% as listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 20% as listed in Table 16.
  • XRPD X-ray powder diffraction
  • fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 20% as listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 20% as listed in Table 16.
  • XRPD X-ray powder diffraction
  • fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 30% as listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 30% as listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 30% as listed in Table 16. In some embodiments, fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 30% as listed in Table 16.
  • XRPD X-ray powder diffraction
  • fumarate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 49.
  • XRPD X-ray powder diffraction
  • fumarate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 198°C. In some embodiments, fumarate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram including an onset temperature of about 194°C and an endothermic peak at about 198 °C.
  • DSC differential scanning calorimetry
  • fumarate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG. 50.
  • fumarate salt Form I is characterized by 9.7% weight loss upon heating from 100 °C to 210 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, fumarate salt Form I is characterized by about 9.7% weight loss upon heating from about 100 °C to about 210 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, fumarate salt Form I is characterized by a weight loss of no greater than about 20%, 15%, or 10% by weight upon heating from about 100 °C to about 210 °C, as measured by a thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • fumarate salt Form I is characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 50.
  • fumarate salt Form I is characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 51.
  • PLM polarized light microscope
  • fumarate salt Form I is substantially free of other crystalline or amorphous forms.
  • the crystalline form is a fumarate salt of Compound 1.
  • the crystalline form is fumarate salt Form II.
  • fumarate salt Form II is an acetone solvate.
  • the present disclosure provides fumarate salt Form II of Compound 1.
  • fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.2, 8.5, 10.5, 12.9, and 18.9 degrees 29 ( ⁇ 0.2 degrees 20).
  • fumarate salt Form II is characterized by an XRPD pattern further comprising one or more peaks selected from 15.1, 16.0, 18.6, 19.6, and 20.0 degrees 20 ( ⁇ 0.2 degrees 20).
  • fumarate salt Form II is characterized by an XRPD pattern further comprising one or more peaks selected from 21.7, 23.3, 23.6, 26.1, and 27.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.2, 8.5, 12.9, 21.7, and 23.6 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments the XRPD pattern further comprises peaks at 10.5, 16.0, 18.9, 20.0, and 26.1 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.2, 8.5, 10.5, 12.9, 16.0, 18.9, 20.0, 21.7, 23.6, and 26.1 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 15% as listed in Table 17. In some embodiments, fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 15% as listed in Table 17. In some embodiments, fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 15% as listed in Table 17.
  • XRPD X-ray powder diffraction
  • fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 15% as listed in Table 17. In some embodiments, fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 15% as listed in Table 17. In some embodiments, fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 15% as listed in Table 17.
  • XRPD X-ray powder diffraction
  • fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 20% as listed in Table 17. In some embodiments, fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 20% as listed in Table 17. In some embodiments, fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 20% as listed in Table 17.
  • XRPD X-ray powder diffraction
  • fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 20% as listed in Table 17. In some embodiments, fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 20% as listed in Table 17. In some embodiments, fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 20% as listed in Table 17.
  • XRPD X-ray powder diffraction
  • fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 20% as listed in Table 17. In some embodiments, fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 20% as listed in Table 17. In some embodiments, fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 20% as listed in Table 17.
  • XRPD X-ray powder diffraction
  • fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 30% as listed in Table 17. In some embodiments, fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 30% as listed in Table 17. In some embodiments, fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 30% as listed in Table 17.
  • XRPD X-ray powder diffraction
  • fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 30% as listed in Table 17. In some embodiments, fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 30% as listed in Table 17. In some embodiments, fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 30% as listed in Table 17. [0369] In some embodiments, fumarate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 52.
  • XRPD X-ray powder diffraction
  • fumarate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram including a first endothermic peak at about 144 °C and/or a second endothermic peak at about 200 °C. In some embodiments, fumarate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram including a first endothermic onset and peak at about 144 °C, and/or a second endothermic onset and peak at about 197 °C and 200 °C, respectively.
  • DSC differential scanning calorimetry
  • fumarate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG. 53.
  • fumarate salt Form II is characterized by 2.1% weight loss upon heating from 90 °C to 175 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, fumarate salt Form II is characterized by about 2.1% weight loss upon heating from about 90 °C to about 175 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, fumarate salt Form II is characterized by a weight loss of no greater than about 10%, 5%, 4%, or 3% by weight upon heating from about 90 °C to about 175 °C, as measured by a thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • fumarate salt Form II is characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 53.
  • fumarate salt Form II is characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 54.
  • PLM polarized light microscope
  • fumarate salt Form II is substantially free of other crystalline or amorphous forms.
  • the crystalline form is a fumarate salt of Compound 1.
  • the crystalline form is fumarate salt Form III.
  • fumarate salt Form III is an ethyl acetate solvate.
  • fumarate salt Form III of Compound 1.
  • fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.7, 7.9, 8.9, 10.6, and 17.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • fumarate salt Form III is characterized by an XRPD pattern further comprising one or more peaks selected from 10.3, 11.5, 16.1, 17.9, and 18.5 degrees 20 ( ⁇ 0.2 degrees 20).
  • fumarate salt Form III is characterized by an XRPD pattern further comprising one or more peaks selected from 2.1,
  • fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.7, 7.9, 8.9, 10.6, and 17.4 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, the XRPD pattern further comprises peaks at 11.5, 16.1,
  • fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.7, 7.9, 8.9, 10.6, 11.5, 16.1, 17.4, 17.9, 18.5, and 25.1 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising three, four, five, or seven, ten, or more peaks listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising three peaks listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising five peaks listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising seven peaks listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising ten peaks listed in Table 18.
  • XRPD X-ray powder diffraction
  • fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 15% as listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 15% as listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 15% as listed in Table 18.
  • XRPD X-ray powder diffraction
  • fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 15% as listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 15% as listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 15% as listed in Table 18.
  • fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 15% as listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 15% as listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 15% as listed in Table 18.
  • XRPD X-ray powder diffraction
  • fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 20% as listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 20% as listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 20% as listed in Table 18.
  • XRPD X-ray powder diffraction
  • fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 20% as listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 20% as listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 20% as listed in Table 18.
  • XRPD X-ray powder diffraction
  • fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 20% as listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 20% as listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 20% as listed in Table 18.
  • XRPD X-ray powder diffraction
  • fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 30% as listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 30% as listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 30% as listed in Table 18.
  • XRPD X-ray powder diffraction
  • fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 30% as listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 30% as listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 30% as listed in Table 18.
  • XRPD X-ray powder diffraction
  • fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 30% as listed in Table 18. In some embodiments, fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 30% as listed in Table 18.
  • XRPD X-ray powder diffraction
  • fumarate salt Form III is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 55.
  • XRPD X-ray powder diffraction
  • fumarate salt Form III is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG. 56.
  • fumarate salt Form III is characterized by 3.1% weight loss upon heating from 85 °C to 135 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, fumarate salt Form III is characterized by about 3.1% weight loss upon heating from about 85 °C to about 135 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, fumarate salt Form III is characterized by a weight loss of no greater than about 10%, 5%, or 4% by weight upon heating from about 85 °C to about 135 °C, as measured by a thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • fumarate salt Form III is characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 56.
  • fumarate salt Form III is characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 57.
  • PLM polarized light microscope
  • fumarate salt Form III is substantially free of other crystalline or amorphous forms.
  • the crystalline form is a malate salt of Compound 1.
  • the crystalline form is malate salt Form I.
  • malate salt Form I is acetone solvate.
  • malate salt Form I of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.9, 12.4, 13.9, 18.7, and 19.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • malate salt Form I is characterized by an XRPD pattern further comprising one or more peaks selected from 4.1, 8.3, 10.5, 16.0, and 16.3 degrees 20 ( ⁇ 0.2 degrees 20).
  • malate salt Form I is characterized by an XRPD pattern further comprising one or more peaks selected from 20.0, 20.5, 21.1, 22.9, and 24.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • malate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.9, 12.4, 19.4, 20.0, and 20.5 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, the XRPD pattern further comprises peaks at 10.5,
  • malate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at
  • malate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising three, four, five, or seven, ten, or more peaks listed in Table 19. In some embodiments, malate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising three peaks listed in Table 19. In some embodiments, malate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising five peaks listed in Table 19. In some embodiments, malate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising seven peaks listed in Table 19. In some embodiments, malate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising ten peaks listed in Table 19.
  • XRPD X-ray powder diffraction
  • malate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 15% as listed in Table 19. In some embodiments, malate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 15% as listed in Table 19. In some embodiments, malate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 15% as listed in Table 19. In some embodiments, malate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 15% as listed in Table 19.
  • XRPD X-ray powder diffraction
  • malate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 20% as listed in Table 19. In some embodiments, malate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 20% as listed in Table 19. In some embodiments, malate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 20% as listed in Table 19.
  • XRPD X-ray powder diffraction
  • malate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 30% as listed in Table 19.
  • XRPD X-ray powder diffraction
  • malate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 58.
  • malate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram including a first endothermic peak at about 157 °C, and/or a second endothermic peak at about 206 °C. In some embodiments, malate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram including a first endothermic onset and peak at about 147 °C and 157 °C, respectively, and/or a second endothermic onset and peak at about 181 °C and 206 °C, respectively.
  • DSC differential scanning calorimetry
  • malate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram including a first endothermic onset and peak at about 147 °C and about 157 °C, respectively, and/or a second endothermic onset and peak at about 181 °C and about 206 °C, respectively.
  • DSC differential scanning calorimetry
  • malate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG. 59.
  • malate salt Form I is characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 59.
  • malate salt Form I is characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 60.
  • PLM polarized light microscope
  • malate salt Form I is substantially free of other crystalline or amorphous forms.
  • xviii Malate salt of Compound 1 (Form II)
  • the crystalline form is a malate salt of Compound 1.
  • the crystalline form is malate salt Form II.
  • malate salt Form II is an anhydrate.
  • malate salt Form II of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.2, 12.4, 14.7, 15.8, and 18.3 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • malate salt Form II is characterized by an XRPD pattern further comprising one or more peaks selected from 4.0, 15.6, 16.4, 17.0, and 19.1 degrees 20 ( ⁇ 0.2 degrees 20).
  • malate salt Form II is characterized by an XRPD pattern further comprising one or more peaks selected from 21.5, 22.2, 22.9, 24.4, and 26.2 degrees 20 ( ⁇ 0.2 degrees 20).
  • malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.2, 14.7, 15.8, 18.3, and 24.4 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, the XRPD pattern further comprises peaks at 12.4, 19.1, 21.5, 22.9, and 26.2 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.2, 12.4, 14.7, 15.8, 18.3, 19.1, 21.5, 22.9, 24.4, and 26.2 degrees 20 ( ⁇ 0.2 degrees 20).
  • malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising three, four, five, or seven, ten, or more peaks listed in able 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising three peaks listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising five peaks listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising seven peaks listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising ten peaks listed in Table 20.
  • XRPD X-ray powder diffraction
  • malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 15% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 15% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 15% as listed in Table 20.
  • XRPD X-ray powder diffraction
  • malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 15% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 15% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 15% as listed in Table 20.
  • XRPD X-ray powder diffraction
  • malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 15% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 15% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 15% as listed in Table 20.
  • XRPD X-ray powder diffraction
  • malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 20% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 20% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 20% as listed in Table 20.
  • XRPD X-ray powder diffraction
  • malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 20% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 20% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 20% as listed in Table 20.
  • XRPD X-ray powder diffraction
  • malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 20% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 20% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 20% as listed in Table 20.
  • XRPD X-ray powder diffraction
  • malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 30% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 30% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 30% as listed in Table 20.
  • XRPD X-ray powder diffraction
  • malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 30% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 30% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 30% as listed in Table 20.
  • XRPD X-ray powder diffraction
  • malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 30% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 30% as listed in Table 20. In some embodiments, malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 30% as listed in Table 20.
  • XRPD X-ray powder diffraction
  • malate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 61.
  • malate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 183 °C. In some embodiments, malate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram including an onset temperature of about 180 °C and an endothermic peak at about 183 °C.
  • DSC differential scanning calorimetry
  • malate salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG. 62.
  • malate salt Form II is characterized by 0.5% weight loss upon heating from about 95 °C to about 170 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, malate salt Form II is characterized by about 0.5% weight loss upon heating from about 95 °C to about 170 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, malate salt Form II is characterized by a weight loss of no greater than about 10%, 5%, 4%, 3%, 2%, or 1% by weight upon heating from about 95 °C to about 170 °C, as measured by a thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • malate salt Form II is characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 62.
  • malate salt Form II is characterized by a weight gain of about 1.8% after undergoing a dynamic vapor sorption profile cycle from about 0% relative humidity (RH) to about 90% RH at 25 °C.
  • malate salt Form II is characterized by a dynamic vapor sorption (DVS) profile substantially as shown in FIG. 63.
  • malate salt Form II is substantially free of other crystalline or amorphous forms.
  • xix Succinate salt of Compound 1 (Form I)
  • the crystalline form is a succinate salt of Compound 1.
  • the crystalline form is succinate salt Form I.
  • succinate salt Form I is an acetone solvate.
  • succinate salt Form I of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.5, 12.8, 15.0, 18.8, and 19.9 degrees 20 ( ⁇ 0.2 degrees 20).
  • succinate salt Form I is characterized by an XRPD pattern further comprising one or more peaks selected from 8.5, 10.7, 12.1, 15.9, and 18.5 degrees 20 ( ⁇ 0.2 degrees 20).
  • succinate salt Form I is characterized by an XRPD pattern further comprising one or more peaks selected from 21.4,
  • succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.8, 15.0, 18.8, 21.4, and 24.8 degrees 20 ( ⁇ 0.2 degrees 20). In some embodiments, the XRPD pattern further comprises peaks at 10.5,
  • succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.5, 12.8, 15.0, 18.8, 19.9, 21.4, 22.8, 23.3, 24.5, and 24.8 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising three, four, five, or seven, ten, or more peaks listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising three peaks listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising five peaks listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising seven peaks listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising ten peaks listed in Table 21.
  • XRPD X-ray powder diffraction
  • succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 15% as listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 15% as listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 15% as listed in Table 21.
  • XRPD X-ray powder diffraction
  • succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 15% as listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 15% as listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 15% as listed in Table 21.
  • XRPD X-ray powder diffraction
  • succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 15% as listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 15% as listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 15% as listed in Table 21.
  • XRPD X-ray powder diffraction
  • succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 20% as listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 20% as listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 20% as listed in Table 21.
  • XRPD X-ray powder diffraction
  • succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 20% as listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 20% as listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks having a relative intensity of at least 20% as listed in Table 21.
  • XRPD X-ray powder diffraction
  • succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks having a relative intensity of at least 20% as listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine peaks having a relative intensity of at least 20% as listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least ten peaks having a relative intensity of at least 20% as listed in Table 21.
  • XRPD X-ray powder diffraction
  • succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks having a relative intensity of at least 30% as listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks having a relative intensity of at least 30% as listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks having a relative intensity of at least 30% as listed in Table 21.
  • XRPD X-ray powder diffraction
  • succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 30% as listed in Table 21. In some embodiments, succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six peaks having a relative intensity of at least 30% as listed in Table 21.
  • XRPD X-ray powder diffraction
  • succinate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 65.
  • succinate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 136 °C. In some embodiments, succinate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram including an onset temperature of about 128 °C and an endothermic peak at about 136 °C. [0429] In some embodiments, succinate salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG. 66.
  • succinate salt Form I is characterized by 2.8% weight loss upon heating from 85 °C to 145 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, succinate salt Form I is characterized by about 2.8% weight loss upon heating from about 85 °C to about 145 °C, as measured by a thermal gravimetric analysis (TGA). In some embodiments, succinate salt Form I is characterized by a weight loss of no greater than about 10%, 5%, 4%, or 3% by weight upon heating from about 85 °C to about 145 °C, as measured by a thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • succinate salt Form I is characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 66.
  • succinate salt Form I is characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 67.
  • succinate salt Form I is substantially free of other crystalline or amorphous forms.
  • solid state forms of Compound 1, comprising at least 50 wt% of a particular crystalline form as described herein.
  • the solid state form comprises at least 60 wt% of a particular crystalline form as described herein.
  • the solid state form comprises at least 70 wt% of a particular crystalline form as described herein.
  • the solid state form comprises at least 80 wt% of a particular crystalline form as described herein.
  • the solid state form comprises at least 90 wt% of a particular crystalline form as described herein.
  • the solid state form comprises at least 95 wt% of a particular crystalline form as described herein.
  • the solid state form comprises at least 99 wt% of a particular crystalline form as described herein.
  • the particular crystalline form is HC1 salt Form I.
  • the particular crystalline form is free base Form I.
  • the particular crystalline form is free base Form II.
  • compositions comprising a crystalline form of Compound 1 described herein or pharmaceutical compositions prepared using a crystalline form of Compound 1 described herein. Also provided are pharmaceutical compositions comprising a solid state form as described herein, or a pharmaceutical compositions prepared using a solid state form described herein. Pharmaceutical compositions will include one or more pharmaceutically acceptable excipients. In some embodiments, provided herein are pharmaceutical compositions comprising a crystalline form of Compound 1 described herein and one or more pharmaceutically acceptable excipients. In some embodiments, provided herein are pharmaceutical compositions prepared using a crystalline form of Compound 1 described herein and one or more pharmaceutically acceptable excipients.
  • compositions comprising a solid state form described herein and one or more pharmaceutically acceptable excipients.
  • pharmaceutical compositions prepared using a solid state form described herein and one or more pharmaceutically acceptable excipients are provided herein.
  • compositions provided herein may be used in the methods disclosed herein; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic methods and uses described herein.
  • compositions may be in the form suitable for administration to a patient.
  • the pharmaceutical compositions can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein.
  • the pharmaceutical compositions may be used in combination with other therapeutically active agents or compounds as described herein in order to treat the diseases, disorders and conditions contemplated by the present disclosure.
  • compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elix
  • compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • Tablets, capsules and the like contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets, capsules, and the like.
  • excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents for example, com starch, or alginic acid
  • binding agents for example starch, gelatin or acacia
  • lubricating agents for example magnesium stearate, stearic acid or talc.
  • the tablets, capsules and the like suitable for oral administration may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action.
  • a time-delay material such as glyceryl monostearate or glyceryl di-stearate may be employed.
  • the tablets may also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release.
  • Additional agents include biodegradable or biocompatible particles or a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide and glycolide copolymers, polylactide and glycolide copolymers, or ethylene vinyl acetate copolymers in order to control delivery of an administered composition.
  • a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide and glycolide copolymers, polylactide and glycolide copolymers, or ethylene vinyl acetate copolymers in order to control delivery of an administered composition.
  • the oral agent can be entrapped in microcapsules prepared by coacervation techniques or by interfacial polymerization, by the use of hydroxymethyl cellulose or gelatin-microcapsules or poly (methyl methacrylate) microcapsules, respectively, or in a colloid drug delivery system.
  • Colloidal dispersion systems include macromolecule complexes, nanocapsules, microspheres, microbeads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for the preparation of the above-mentioned formulations are known in the art.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture thereof.
  • excipients can be suspending agents, for example sodium carboxymethylcellulose, methylcellulose, (hydroxypropyl)methyl cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, for example a naturally-occurring phosphatide (e.g., lecithin), or condensation products of an alkylene oxide with fatty acids (e.g., poly-oxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., for heptdecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate).
  • the aqueous suspensions may
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • the pharmaceutical compositions may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or mixtures of these.
  • Suitable emulsifying agents may be naturally occurring gums, for example, gum acacia or gum tragacanth; naturally occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • Liquid compositions for parenteral administration for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing) are also contemplated.
  • Suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p- hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents, and/or adjuvants.
  • a suitable vehicle may be physiological saline solution or citrate buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration.
  • Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.
  • buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein.
  • Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof.
  • the buffer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof.
  • Acceptable buffering agents include, for example, a Tris buffer, N-(2-Hydroxyethyl)piperazine-N'-(2- ethanesulfonic acid) (HEPES), 2-(N-Morpholino)ethanesulfonic acid (MES), 2-(N- Morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-Morpholino)propanesulfonic acid (MOPS), and N-tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).
  • HEPES N-(2-Hydroxyethyl)piperazine-N'-(2- ethanesulfonic acid)
  • MES 2-(N-Morpholino)ethanesulfonic acid
  • MES 2-(N- Morpholino)ethanesulfonic acid sodium salt
  • MOPS 3-(N-Morpholino)propanes
  • a pharmaceutical composition After a pharmaceutical composition has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored either in a ready-to-use form, a lyophilized form requiring reconstitution prior to use, a liquid form requiring dilution prior to use, or other acceptable form.
  • the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampoule, syringe, or autoinjector (similar to, e.g., an EpiPen®)), whereas a multi-use container (e.g., a multi-use vial) is provided in other embodiments.
  • a single-use container e.g., a single-use vial, ampoule, syringe, or autoinjector (similar to, e.g., an EpiPen®)
  • a multi-use container e.g., a multi-use vial
  • Formulations can also include carriers to protect the composition against rapid degradation or elimination from the body, such as a controlled release formulation, including liposomes, hydrogels, prodrugs and microencapsulated delivery systems.
  • a controlled release formulation including liposomes, hydrogels, prodrugs and microencapsulated delivery systems.
  • a time delay material such as glyceryl monostearate or glyceryl stearate alone, or in combination with a wax, may be employed.
  • Any drug delivery apparatus may be used to deliver a composition described herein, including implants (e.g., implantable pumps) and catheter systems, slow injection pumps and devices, all of which are well known to the skilled artisan.
  • An effective amount of a crystalline form of Compound 1 described herein for use in therapy is an amount of Compound 1 sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • An effective amount of a pharmaceutical composition described herein i.e., a pharmaceutical composition comprising a crystalline form of Compound 1 described herein, a pharmaceutical composition prepared using a crystalline form of Compound 1 described herein, a pharmaceutical composition comprising a solid state form as described herein, or a pharmaceutical composition prepared using a solid state form described herein
  • an amount of Compound 1 sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • the size of the dose for therapeutic or prophylactic purposes of a crystalline form of Compound 1 described herein will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
  • the size of the dose for therapeutic or prophylactic purposes of a pharmaceutical composition described herein will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
  • Compound 1 described herein for therapeutic or prophylactic purposes it will generally be administered so that a total daily dose of Compound 1 in the range, for example, 0.01 mg/kg to 100 mg/kg body weight is received.
  • a pharmaceutical composition described herein for therapeutic or prophylactic purposes it will generally be administered so that a total daily dose of Compound 1 in the range, for example, 0.01 mg/kg to 100 mg/kg body weight is received.
  • Oral administration may also be suitable, particularly in tablet form.
  • the present invention therefore provides a method of inhibiting PARG enzyme activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a crystalline form of Compound 1 described herein, or a pharmaceutical composition thereof as defined and described herein.
  • the present invention also provides a method of treating a disease or disorder in which PARG activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, or a pharmaceutical composition thereof as defined and described herein.
  • the disease or disorder is an advanced or metastatic solid tumor.
  • the disease or disorder is cancer.
  • the cancer is ovarian, gastric, or breast cancer.
  • the cancer is lung, cervical, or pancreatic cancer.
  • the cancer is non-small cell lung cancer (NSCLC).
  • the cancer is prostate cancer.
  • the cancer is triple negative breast cancer (TNBC).
  • the cancer is a homologous recombinant deficient (HRD) cancer.
  • a method of inhibiting cell proliferation, in vitro or in vivo comprising contacting a cell with an effective amount of a crystalline form of Compound 1 described herein, or a pharmaceutical composition thereof as defined and described herein.
  • the proliferative disorder is a solid tumor.
  • the proliferative disorder is a metastatic solid tumor.
  • the proliferative disorder is cancer.
  • the cancer is ovarian, gastric, or breast cancer.
  • the cancer is lung, cervical or pancreatic cancer.
  • the cancer is prostate cancer.
  • the cancer is prostate cancer, colorectal cancer, or endometrial cancer.
  • the cancer is colorectal cancer. In an embodiment, the cancer is prostate cancer. In an embodiment, the cancer is endometrial cancer. In an embodiment, the cancer is ovarian cancer, gastric cancer, breast cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, or endometrial cancer. In an embodiment, the cancer is a homologous recombinant deficient (HRD) cancer.
  • HRD homologous recombinant deficient
  • Provided herein is a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, or a pharmaceutical composition thereof as defined and described herein.
  • the cancer is ovarian, gastric, or breast cancer.
  • the cancer is lung, cervical or pancreatic cancer.
  • the cancer is a homologous recombinant deficient (HRD) cancer.
  • a method of treating and/or preventing a homologous recombinant deficient (HRD) cancer in a patient comprising administering to the patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, or a pharmaceutical composition thereof as defined and described herein.
  • the patient is in recognized need of such treatment.
  • the homologous recombinant deficient (HRD) cancer is breast cancer, ovarian cancer, gastric cancer, prostate cancer, lung cancer, cervical cancer, or pancreatic cancer.
  • the homologous recombinant deficient (HRD) cancer is breast cancer, ovarian cancer, gastric cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, or endometrial cancer.
  • kits for treating and/or preventing a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 described herein, or a pharmaceutical composition thereof as defined and described herein, thereby treating the cancer in the subject, wherein the cancer is a homologous recombinant deficient (HRD) cancer, and the cancer is Estrogen Receptor (ER) positive.
  • the cancer is breast cancer or ovarian cancer.
  • the cancer is an HRD cancer
  • the cancer is ER positive
  • PR Progesterone Receptor
  • the cancer is breast cancer or ovarian cancer.
  • the cancer is an HRD cancer
  • the cancer is ER positive
  • the cancer is optionally human epidermal growth factor receptor 2 (HER2) negative.
  • HER2 human epidermal growth factor receptor 2
  • the cancer is breast or ovarian cancer.
  • the cancer is breast or ovarian cancer.
  • a method of treating and/or preventing a cancer in a patient where the cancer is characterized by a reduction or absence of BRCA1 and/or BRCA2 gene expression, an absence or mutation of BRCA1 and/or BRCA2 genes, or a reduced function of BRCA1 and/or BRCA2 proteins, comprising administering to the patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, or a pharmaceutical composition thereof as defined and described herein.
  • the cancer is ovarian, gastric, or breast cancer.
  • the cancer is lung, cervical or pancreatic cancer.
  • the cancer is prostate cancer.
  • the cancer is PARP inhibitor-resistant.
  • the PARP inhibitor-resistant cancer is resistant to any one or more of niraparib, olaparib, rucaparib, talazoparib, veliparib, AZD5305, and AZD9574.
  • the PARP inhibitor-resistant cancer is resistant to niraparib.
  • the PARP inhibitor-resistant cancer is resistant to olaparib.
  • the PARP inhibitorresistant cancer is ovarian cancer, breast cancer, or pancreatic cancer.
  • the cancer is platin-resistant.
  • the platin- resistant cancer is resistant to any one or more of cisplatin, carboplatin, satraplatin, heptaplatin, picoplatin, nedaplatin, triplatin, lipoplatin, and oxaliplatin.
  • the platin-resistant cancer is resistant to cisplatin.
  • the platin-resistant cancer is resistant to carboplatin.
  • kits for treating cancer in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, or a pharmaceutical composition thereof as defined and described herein, wherein the patient has been determined to be resistant to one or more PARP inhibitors.
  • said methods comprise administering to said patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, or a pharmaceutical composition thereof as defined and described herein, wherein said patient has been diagnosed as resistant to one or more PARP inhibitors.
  • kits for treating cancer in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, or a pharmaceutical composition thereof as defined and described herein, wherein the patient has been determined to be resistant to platinum based chemotherapeutics.
  • said methods comprise administering to said patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, or a pharmaceutical composition thereof as defined and described herein, wherein said patient has been diagnosed as resistant to one or more platinum based chemotherapeutics.
  • a crystalline form of Compound 1 described herein, or a pharmaceutical composition thereof as defined and described herein for use in therapy is provided herein.
  • the cancer is human cancer.
  • the cancer is ovarian, gastric, or breast cancer.
  • the cancer is lung, cervical or pancreatic cancer.
  • the cancer is prostate cancer.
  • the cancer is a homologous recombinant deficient (HRD) cancer.
  • the medicament is for use in the treatment of human cancers.
  • the cancer is ovarian, gastric, or breast cancer.
  • the cancer is lung, cervical or pancreatic cancer.
  • the cancer is prostate cancer.
  • the cancer is a homologous recombinant deficient (HRD) cancer.
  • a crystalline form of Compound 1 described herein, or a pharmaceutical composition thereof as defined and described herein in the manufacture of a medicament for the inhibition of PARG enzyme activity is provided herein.
  • a use of a crystalline form of Compound 1 described herein, or a pharmaceutical composition thereof as defined and described herein in the manufacture of a medicament for the treatment of a disease or disorder in which PARG activity is implicated is provided herein.
  • the present disclosure also contemplates the use of a crystalline form of Compound 1 described herein, or a pharmaceutical composition thereof as defined and described herein in combination with other therapeutically active agents or compounds as described herein in order to treat the diseases, disorders and conditions contemplated by the present disclosure.
  • the additional therapeutic agent is a chemotherapeutic agent.
  • the additional therapeutic agent is a MAT2A inhibitor.
  • the additional therapeutic agent is a PRMT5 inhibitor.
  • the PRMT5 inhibitor is a MTA-cooperative PRMT5 inhibitor.
  • the additional therapeutic agent is a cell cycle checkpoint inhibitor.
  • the additional therapeutic agent is immunecheckpoint inhibitor.
  • proliferative disorder and “proliferative condition” are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo.
  • proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumors, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, gastric, liver, pancreas, brain, and skin.
  • Proliferative disorders also include, for example, advanced or metastatic solid tumors.
  • the anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumor from its origin), the inhibition of invasion (the spread of tumor cells into neighboring normal structures), or the promotion of apoptosis (programmed cell death).
  • the proliferative condition to be treated is cancer.
  • Compound 1 can be prepared, for example, as described in Example 1.
  • the present disclosure provides a method for preparing a crystalline form of Compound 1. In one aspect, the present disclosure provides a method for preparing a crystalline salt form of Compound 1. In some embodiments, the method includes:
  • the method for preparing a crystalline form of Compound 1 includes:
  • the present disclosure provides a method for preparing a crystalline free base form of Compound 1.
  • the method includes:
  • the method for preparing a crystalline free base form of Compound 1 includes:
  • all steps as described above are performed at room temperature. In some embodiments, all steps as described above are conducted at 10 °C to 40 °C.
  • the first mixture is formed at room temperature. In some embodiments, the first mixture is heated to a temperature of between about 40 °C and about 70 °C. In some embodiments, the first mixture is heated to a temperature of about 50 °C. In some embodiments, the first mixture is heated to a temperature of about 60 °C.
  • the first solvent is selected from the group consisting of acetone, acetonitrile, ethyl acetate, methanol, ethanol, isopropanol, and tetrahydrofuran. In some embodiments, the first solvent is selected from the group consisting of acetone, acetonitrile, ethyl acetate, methanol, ethanol, isopropanol, NMP (N-methyl pyrrolidone), DMSO (dimethylsulfoxide), and tetrahydrofuran.
  • the acid is selected from the group consisting of HC1, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, maleic acid, citric acid, fumaric acid, L-malic acid, and succinic acid.
  • the second solvent is selected from the group consisting of heptane, methyl tert-butyl ether (MTBE), and water. In some embodiments, the second solvent is selected from the group consisting of hexane, heptane, methyl tert-butyl ether (MTBE), and water.
  • a method of preparing HC1 salt Form I of Compound 1 includes 1) forming a first mixture comprising Compound 1 and methanol, and heating the first mixture to a temperature of about 50 °C, 2) adding HC1 to form a second mixture, 3) adding MTBE to the second mixture, 4) stirring the second mixture at room temperature, 5) isolating the solids, and 6) drying the solids.
  • the method includes 1) forming a first mixture comprising Compound 1 and methanol, and heating the first mixture to a temperature of about 50 °C, 2) adding HC1 to form a second mixture, 3) adding MTBE to the second mixture to form a third mixture, 4) stirring the third mixture at room temperature, 5) isolating the solids, and 6) drying the solids.
  • the solids are dried under vacuum.
  • the solids are dried at elevated temperature.
  • the solids are dried under vacuum at a temperature of about at 50 °C.
  • the method includes 1) forming a first mixture comprising Compound 1 and an alcohol solvent, 3) stirring the first mixture, 4) isolating the precipitate, and 5) drying the precipitate.
  • the alcohol solvent is methanol or ethanol.
  • the method includes slurrying Compound 1 in methanol or ethanol at elevated temperature.
  • the method includes slurrying Compound 1 in methanol or ethanol at about 50 °C.
  • the method includes slurrying Compound 1 in ethanol at about 50 °C.
  • the method includes isolating the solids, e.g. by filtration.
  • the solids are dried under vacuum.
  • the solids are dried at elevated temperature.
  • the solids are dried under vacuum at a temperature of about at 50 °C.
  • the method includes 1) forming a first mixture comprising Compound 1 and DMSO, 2) adding water to the first mixture, 3) stirring the first mixture, 4) isolating the precipitate, and 5) drying the precipitate.
  • the method includes 1) forming a first mixture comprising Compound 1 and DMSO, 2) adding water to the first mixture to form a second mixture, 3) stirring the second mixture, 4) isolating the precipitate, and 5) drying the precipitate.
  • the method includes isolating the solids, e.g. by filtration.
  • the solids are dried under vacuum.
  • the solids are dried at elevated temperature.
  • the solids are dried under vacuum at a temperature of about at 50 °C.
  • Embodiment 1 A crystalline form of Compound 1 (Compound 1), or a salt thereof.
  • Embodiment 2 The crystalline form of embodiment 1, wherein the crystalline form is a single crystalline form substantially free of other crystalline or amorphous forms.
  • Embodiment s The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is HC1 salt Form I.
  • Embodiment 4 The HC1 salt Form I, according to embodiment 3, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 13.2 and 17.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 5 The HC1 salt Form I, according to embodiment 3, characterized by an X-ray powder diffraction (XRPD) pattern comprising three peaks selected from 11.7, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4, and 19.9.
  • Embodiment 6. The HC1 salt Form I, according to embodiment 3, characterized by an X-ray powder diffraction (XRPD) pattern comprising four peaks selected from 11.7,
  • Embodiment 7 The HC1 salt Form I, according to embodiment 3, characterized by an X-ray powder diffraction (XRPD) pattern comprising five peaks selected from 11.7,
  • Embodiment 8 The HC1 salt Form I, according to embodiment 3, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 13.2, 13.7, and 17.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 9 The HC1 salt Form I, according to embodiment 3, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.7, 13.2, 13.7, and 17.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 12 The HC1 salt Form I, according to embodiment 3, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.7, 13.2, 13.7, 17.7, and 18.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 11 The HC1 salt Form I, according to embodiment 3, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.7, 13.2, 13.7, 17.2, 17.7, and 18.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 12 The HC1 salt Form I, according to embodiment 3, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.7, 13.2, 13.7, 17.2, 17.7, 18.4, and 20.0 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 13 The HC1 salt Form I, according to embodiment 3, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.7, 13.2, 13.7, 15.3,
  • Embodiment 14 The HC1 salt Form I, according to embodiment 3, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.0, 11.7, 13.2, 13.7,
  • Embodiment 15 The HC1 salt Form I, according to embodiment 3, characterized by an XRPD pattern comprising peaks at 7.0, 11.7, 12.2, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4, and 20.0 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 16 The HC1 salt Form I, according to any one of embodiments 8 to 15, characterized by an XRPD pattern further comprising one or more peaks selected from 20.9, 24.3, 25.3, 26.1, and 28.9 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 17 The HC1 salt Form I, according to any one of embodiments 8 to 15, characterized by an XRPD pattern further comprising one or more peaks selected from 20.6, 20.9, 21.2, 21.7, 22.3, 24.3, 25.0, 25.3, 25.6, 26.1, 28.9 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 18 The HC1 salt Form I, according to any one of embodiments 8 to 15, characterized by an XRPD pattern further comprising a peak at 28.9 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 19 The HC1 salt Form I, according to any one of embodiments 8 to 15, characterized by an XRPD pattern further comprising peaks at 26.1 and 28.9 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 20 The HC1 salt Form I, according to any one of embodiments 8 to 15, characterized by an XRPD pattern further comprising peaks at 24.3, 26.1, and 28.9 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 21 The HC1 salt Form I, according to any one of embodiments 8 to 15, characterized by an XRPD pattern further comprising peaks at 20.9, 24.3, 26.1, and 28.9 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 22 The HC1 salt Form I, according to any one of embodiments 8 to 15, characterized by an XRPD pattern further comprising peaks at 20.9, 24.3, 25.3, 26.1, and 28.9 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 23 The HC1 salt Form I, according to embodiment 3, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 15% as listed in Table 3.
  • XRPD X-ray powder diffraction
  • Embodiment 24 The HC1 salt Form I, according to embodiment 3, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 20% as listed in Table 3.
  • XRPD X-ray powder diffraction
  • Embodiment 25 The HC1 salt Form I, according to embodiment 3, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks having a relative intensity of at least 30% as listed in Table 3.
  • Embodiment 26 The HC1 salt Form I, according to embodiment 3, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 7.
  • Embodiment 27 The HC1 salt Form I, according to any one of embodiments 3 to 26, characterized by a differential scanning calorimetry thermogram (DSC) comprising no endotherm prior to decomposition.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 28 The HC1 salt Form I, according to any one of embodiments 3 to 26, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 8.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 29 The HC1 salt Form I, according to any one of embodiments 3 to 28, characterized by no weight loss upon heating prior to decomposition, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 30 The HC1 salt Form I, according to any one of embodiments 3 to 28, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 8.
  • TGA thermal gravimetric analysis
  • Embodiment 31 The HC1 salt Form I, according to any one of embodiments 3 to
  • Embodiment 32 The HC1 salt Form I, according to any one of embodiments 3 to
  • Embodiment 33 The HC1 salt Form I, according to any one of embodiments 3 to
  • PLM polarized light microscope
  • Embodiment 34 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is free base Form I.
  • Embodiment 35 The free base Form I of embodiment 34, characterized by an X- ray powder diffraction (XRPD) pattern comprising peaks at 9.0 and 18.3 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X- ray powder diffraction
  • Embodiment 36 The free base Form I of embodiment 34, characterized by an X- ray powder diffraction (XRPD) pattern comprising three peaks selected from 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4, and 19.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 37 The free base Form I of embodiment 34, characterized by an X- ray powder diffraction (XRPD) pattern comprising four peaks selected from 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4, and 19.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 38 The free base Form I of embodiment 34, characterized by an X- ray powder diffraction (XRPD) pattern comprising five peaks selected from 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4, and 19.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X- ray powder diffraction
  • Embodiment 39 The free base Form I of embodiment 34, characterized by an X- ray powder diffraction (XRPD) pattern comprising peaks at 9.0, 16.4, and 18.3 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X- ray powder diffraction
  • Embodiment 40 The free base Form I of embodiment 34, characterized by an X- ray powder diffraction (XRPD) pattern comprising peaks at 9.0, 16.4, 18.0, and 18.3 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X- ray powder diffraction
  • Embodiment 41 The free base Form I of embodiment 34, characterized by an X- ray powder diffraction (XRPD) pattern comprising peaks at 9.0, 16.4, 18.0, 18.3, and 19.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X- ray powder diffraction
  • Embodiment 42 The free base Form I of embodiment 34, characterized by an X- ray powder diffraction (XRPD) pattern comprising peaks at 9.0, 12.7, 16.4, 18.0, 18.3, and 19.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X- ray powder diffraction
  • Embodiment 43 The free base Form I of embodiment 34, characterized by an X- ray powder diffraction (XRPD) pattern comprising peaks at 9.0, 12.7, 16.4, 18.0, 18.3, 18.9, and 19.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X- ray powder diffraction
  • Embodiment 44 The free base Form I of embodiment 34, characterized by an X- ray powder diffraction (XRPD) pattern comprising peaks at 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, and 19.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X- ray powder diffraction
  • Embodiment 45 The free base Form I of embodiment 34, characterized by an X- ray powder diffraction (XRPD) pattern comprising peaks at 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4, and 19.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X- ray powder diffraction
  • Embodiment 46 The free base Form I of embodiment 34, characterized by an X- ray powder diffraction (XRPD) pattern comprising peaks at 9.0, 11.5, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4, and 19.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 47 The free base Form I of any one of embodiments 39 to 46, characterized by an XRPD pattern further comprising one or more peaks selected from 22.5, 23.2, 23.5, 24.6, and 27.8 degrees 26 ( ⁇ 0.2 degrees 26).
  • Embodiment 48 The free base Form I of any one of embodiments 39 to 46, characterized by an XRPD pattern further comprising one or more peaks selected from 23.2, 23.5, and 24.6 degrees 26 ( ⁇ 0.2 degrees 20).
  • Embodiment 49 The free base Form I of embodiment 34, characterized by an X- ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 1.
  • XRPD X- ray powder diffraction
  • Embodiment 50 The free base Form I, according to any one of embodiments 34 to 49, characterized by a differential scanning calorimetry thermogram (DSC) comprising a melting point peak at about 200 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 51 The free base Form I, according to any one of embodiments 34 to 49, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 2.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 52 The free base Form I, according to any one of embodiments 34 to 51, characterized by no weight loss upon heating prior to decomposition, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 53 The free base Form I, according to any one of embodiments 34 to 51, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 2.
  • TGA thermal gravimetric analysis
  • Embodiment 54 The free base Form I, according to any one of embodiments 34 to 53, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 3.
  • PLM polarized light microscope
  • Embodiment 55 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is free base Form II.
  • Embodiment 56 The free base Form II of embodiment 55, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.3 and 18.7 degrees 26 ( ⁇ 0.2 degrees 26).
  • Embodiment 57 The free base Form II of embodiment 55, characterized by an X-ray powder diffraction (XRPD) pattern comprising three peaks selected from 12.3, 15.6,
  • Embodiment 58 The free base Form II of embodiment 55, characterized by an X-ray powder diffraction (XRPD) pattern comprising four peaks selected from 12.3, 15.6, 17.1, 18.7, 19.5, and 19.7 degrees 26 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 59 The free base Form II of embodiment 55, characterized by an X-ray powder diffraction (XRPD) pattern comprising five peaks selected from 12.3, 15.6,
  • Embodiment 60 The free base Form II of embodiment 55, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.3, 15.6, and 18.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 61 The free base Form II of embodiment 55, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks atl2.3, 15.6, 17.1, and 18.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 62 The free base Form II of embodiment 55, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.3, 15.6, 17.1, 18.7, and 19.5 degrees 26 ( ⁇ 0.2 degrees 26).
  • XRPD X-ray powder diffraction
  • Embodiment 63 The free base Form II of embodiment 55, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.3, 15.6, 17.1, 18.7, 19.5, and 19.7 degrees 20 ( ⁇ 0.2 degrees 26).
  • XRPD X-ray powder diffraction
  • Embodiment 64 The free base Form II of embodiment 55, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.3, 15.6, 16.4, 17.1, 18.7,
  • XRPD X-ray powder diffraction
  • Embodiment 65 The free base Form II of embodiment 55, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.3, 13.4, 15.6, 16.4, 17.1, 18.7, 19.5, and 19.7 degrees 26 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 66 The free base Form II of embodiment 55, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.3, 13.4, 15.6, 16.1, 16.4, 17.1, 18.7, 19.5, and 19.7 degrees 26 ( ⁇ 0.2 degrees 20).
  • Embodiment 67 The free base Form II of embodiment 55, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.3, 13.4, 14.1, 15.6, 16.1, 16.4, 17.1, 18.7, 19.5, and 19.7 degrees 26 ( ⁇ 0.2 degrees 20).
  • Embodiment 68 The free base Form II of any one of embodiments 60 to 67, characterized by an XRPD pattern further comprising one or more peaks selected from 20.2, 20.7, 23.0, 25.0, 25.7, 26.5, and 31.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 69 The free base Form II of any one of embodiments 60 to 67, characterized by an XRPD pattern further comprising one or more peaks selected from 20.2, 20.7, 23.0, 25.7, and 26.5 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 70 The free base Form I of embodiment 55, characterized by an X- ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 4.
  • XRPD X- ray powder diffraction
  • Embodiment 71 The free base Form II, according to any one of embodiments 55 to 70, characterized by a differential scanning calorimetry thermogram (DSC) comprising a first endotherm peak at about 148 °C and/or a second endotherm peak at about 198 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 72 The free base Form II, according to any one of embodiments 55 to 70, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 5.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 73 The free base Form II, according to any one of embodiments 55 to 72, characterized by a 15.1% weight loss upon heating to about 158 °C, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 74 The free base Form II, according to any one of embodiments 55 to 72, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 5.
  • TGA thermal gravimetric analysis
  • Embodiment 75 The free base Form II, according to any one of embodiments 55 to 74, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 6.
  • PLM polarized light microscope
  • Embodiment 76 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is sulfate salt Form I.
  • Embodiment 77 The sulfate salt Form I of embodiment 76, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.0, 8.5, 13.2, 15.6, and 16.1 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 78 The sulfate salt Form I of embodiment 77, characterized by an XRPD pattern further comprising one or more peaks selected from 8.8, 12.9, 15.0, 17.2, and 19.0 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 79 The sulfate salt Form I of embodiment 77 or 78, characterized by an XRPD pattern further comprising one or more peaks selected from 20.2, 22.1, 24.3, 25.1, and 26.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 80 The sulfate salt Form I of embodiment 76, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 11.
  • XRPD X-ray powder diffraction
  • Embodiment 81 The sulfate salt Form I, according to any one of embodiments 76 to 80, characterized by a differential scanning calorimetry thermogram (DSC) comprising a first endotherm peak at about 118 °C, a second endotherm peak at about 220 °C, an exotherm peak at about 231 °C, and/or a third endotherm peak at about 279 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 82 The sulfate salt Form I, according to any one of embodiments 76 to 80, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 12.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 83 The sulfate salt Form I, according to any one of embodiments 76 to 82, characterized by about 2.8% weight loss upon heating to around 130 °C, as measured by thermal gravimetric analysis (TGA).
  • Embodiment 84 The sulfate salt Form I, according to any one of embodiments 76 to 82, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 12.
  • TGA thermal gravimetric analysis
  • Embodiment 85 The sulfate salt Form I, according to any one of embodiments 76 to 84, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 13.
  • PLM polarized light microscope
  • Embodiment 86 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is tosylate salt Form I.
  • Embodiment 87 The tosylate salt Form I of embodiment 86, characterized by an
  • XRPD X-ray powder diffraction
  • Embodiment 88 The tosylate salt Form I of embodiment 87, characterized by an XRPD pattern further comprising one or more peaks selected from 4.7, 11.7, 13.7, 15.5, and 15.9 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 89 The tosylate salt Form I of embodiment 87 or 88, characterized by an XRPD pattern further comprising one or more peaks selected from 21.4, 22.8, 24.0, 24.3, and 29.3 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 90 The tosylate salt Form I of embodiment 86, characterized by an
  • X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 14.
  • Embodiment 91 The tosylate salt Form I, according to any one of embodiments 86 to 90, characterized by a differential scanning calorimetry thermogram (DSC) comprising a melthing point peak at about 231 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 92 The tosylate salt Form I, according to any one of embodiments 86 to 90, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 15.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 93 The tosylate salt Form I, according to any one of embodiments 86 to 92, characterized by about 1.2% weight loss upon heating from about 110 °C to about 230 °C, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 94 The tosylate salt Form I, according to any one of embodiments 86 to 92, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 15.
  • TGA thermal gravimetric analysis
  • Embodiment 95 The tosylate salt Form I, according to any one of embodiments 86 to 94, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 16.
  • PLM polarized light microscope
  • Embodiment 96 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is tosylate salt Form II.
  • Embodiment 97 The tosylate salt Form II of embodiment 96, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.7, 14.3, 15.4, 17.3, and 19.1 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 98 The tosylate salt Form II of embodiment 97, characterized by an XRPD pattern further comprising one or more peaks selected from 9.1, 10.2, 13.0, 17.0, and 18.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 99 The tosylate salt Form II of embodiment 97 or 98, characterized by an XRPD pattern further comprising one or more peaks selected from 20.1, 20.5, 23.8, 24.2, and 26.2 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 100 The tosylate salt Form II of embodiment 96, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 17.
  • XRPD X-ray powder diffraction
  • Embodiment 101 The tosylate salt Form II, according to any one of embodiments 96 to 100, characterized by a differential scanning calorimetry thermogram (DSC) comprising a melting point peak at about 229 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 102 The tosylate salt Form II, according to any one of embodiments 96 to 100, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 18.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 103 The tosylate salt Form II, according to any one of embodiments 96 to 102, characterized by about 1.4% weight loss upon heating from about 90 °C to about 230 °C, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 104 The tosylate salt Form II, according to any one of embodiments 96 to 102, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 18.
  • TGA thermal gravimetric analysis
  • Embodiment 105 The tosylate salt Form II, according to any one of embodiments 96 to 104, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 19.
  • PLM polarized light microscope
  • Embodiment 106 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is tosylate salt Form III.
  • Embodiment 107 The tosylate salt Form III of embodiment 106, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.9, 14.5, 15.5, 18.2, and 19.5 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 108 The tosylate salt Form III of embodiment 107, characterized by an XRPD pattern further comprising one or more peaks selected from 9.7, 14.1, 14.9, 16.0, and 16.9 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 109 The tosylate salt Form III of embodiment 107 or 108, characterized by an XRPD pattern further comprising one or more peaks selected from 21.2, 21.4, 22.0, 24.0, and 24.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 110 The tosylate salt Form III of embodiment 106, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 20.
  • XRPD X-ray powder diffraction
  • Embodiment 111 The tosylate salt Form III, according to any one of embodiments 106 to 110, characterized by a differential scanning calorimetry thermogram (DSC) comprising a melting point peak at 222 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 112. The tosylate salt Form III, according to any one of embodiments 106 to 110, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 21.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 113 The tosylate salt Form III, according to any one of embodiments 106 to 112, characterized by about 2.6% weight loss upon heating from about 110 °C to about 222 °C, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 114 The tosylate salt Form III, according to any one of embodiments 106 to 112, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 21.
  • TGA thermal gravimetric analysis
  • Embodiment 115 The tosylate salt Form III, according to any one of embodiments 106 to 114, characterized by a weight gain of about 3.2% after undergoing a dynamic vapor sorption cycle from about 0 % relative humidity (RH) to about 90 % RH at 25 °C.
  • Embodiment 116 The tosylate salt Form III, according to any one of embodiments 106 to 114, characterized by a dynamic vapor sorption profile substantially as shown in FIG. 22.
  • Embodiment 117 The tosylate salt Form III, according to any one of embodiments 106 to 116, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 23.
  • PLM polarized light microscope
  • Embodiment 118 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is besylate salt Form I.
  • Embodiment 119 The besylate salt Form I of embodiment 118, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.8, 14.5, 15.4, 17.3, and 19.1 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 120 The besylate salt Form I of embodiment 119, characterized by an XRPD pattern further comprising one or more peaks selected from 15.0, 15.9, 17.7, 18.3, and 19.6 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 121 The besylate salt Form I of embodiment 119 or 120, characterized by an XRPD pattern further comprising one or more peaks selected from 20.3, 20.8, 24.0, 25.2, and 26.0 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 122 The besylate salt Form I of embodiment 118, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 24.
  • XRPD X-ray powder diffraction
  • Embodiment 123 The besylate salt Form I, according to any one of embodiments 119 to 122, characterized by a differential scanning calorimetry thermogram (DSC) comprising an endothermic peak at about 202 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 124 The besylate salt Form I, according to any one of embodiments 118 to 122, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 25.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 125 The besylate salt Form I, according to any one of embodiments 118 to 124, characterized by about 0.6% weight loss upon heating from about 100 °C to about 210 °C, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 126 The besylate salt Form I, according to any one of embodiments 118 to 124, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 25.
  • Embodiment 127 The besylate salt Form I, according to any one of embodiments 118 to 126, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 26.
  • PLM polarized light microscope
  • Embodiment 128 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is besylate salt Form II.
  • Embodiment 129 The besylate salt Form II of embodiment 128, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.6, 15.2, 15.7, 19.2, and 19.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 130 The besylate salt Form II of embodiment 129, characterized by an XRPD pattern further comprising one or more peaks selected from 9.0, 10.0, 12.4, 14.7, and 18.1 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 131 The besylate salt Form II of embodiment 129 or 130, characterized by an XRPD pattern further comprising one or more peaks selected from 10.4, 20.1, 22.9, 25.0, and 26.5 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 132 The besylate salt Form II of embodiment 128, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 27.
  • XRPD X-ray powder diffraction
  • Embodiment 133 The besylate salt Form II, according to any one of embodiments 128 to 132, characterized by a differential scanning calorimetry thermogram (DSC) comprising an endotherm peak at about 165 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 134 The besylate salt Form II, according to any one of embodiments 128 to 132, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 28.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 135. The besylate salt Form II, according to any one of embodiments 128 to 134, characterized by about 0.5% weight loss upon heating from about 64 °C to about 185 °C, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 136 The besylate salt Form II, according to any one of embodiments 128 to 134, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 28.
  • Embodiment 137 The besylate salt Form II, according to any one of embodiments 128 to 136, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 29.
  • PLM polarized light microscope
  • Embodiment 138 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is mesylate salt Form I.
  • Embodiment 139 The mesylate salt Form I of embodiment 138, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 14.2, 17.0, 18.0, 18.6, and 19.3 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 140 The mesylate salt Form I of embodiment 139, characterized by an XRPD pattern further comprising one or more peaks selected from 11.0, 11.9, 12.7, 15.1, and 17.5 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 141 The mesylate salt Form I of embodiment 139 or 140, characterized by an XRPD pattern further comprising one or more peaks selected from 20.7, 21.2, 22.1, 24.1, and 25.0 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 142 The mesylate salt Form I of embodiment 139, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 30.
  • XRPD X-ray powder diffraction
  • Embodiment 143 The mesylate salt Form I, according to any one of embodiments 138 to 142, characterized by a differential scanning calorimetry thermogram (DSC) comprising an endotherm peak at about 222 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 144 The mesylate salt Form I, according to any one of embodiments 138 to 142, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 31.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 145 The mesylate salt Form I, according to any one of embodiments 138 to 144, characterized by about 0.5% weight loss upon heating from about 125 °C to about 225 °C, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 146 The mesylate salt Form I, according to any one of embodiments 138 to 144, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 31.
  • Embodiment 147 The mesylate salt Form I, according to any one of embodiments 138 to 146, characterized by a weight gain of about 19 % after undergoing a dynamic vapor sorption cycle from about 0 % relative humidity (RH) to about 90 % RH at 25 °C.
  • RH relative humidity
  • Embodiment 148 The mesylate salt Form I, according to any one of embodiments 138 to 146, characterized by a dynamic vapor sorption profile substantially as shown in FIG.
  • Embodiment 149 The mesylate salt Form I, according to any one of embodiments 138 to 148, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 33.
  • PLM polarized light microscope
  • Embodiment 150 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is mesylate salt Form II.
  • Embodiment 151 The mesylate salt Form II of embodiment 150, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.7, 15.4, 17.2, 17.6, and 19.1 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 152 The mesylate salt Form II of embodiment 151, characterized by an XRPD pattern further comprising one or more peaks selected from 10.0, 10.3, 11.4, 15.0, and 16.5 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 153 The mesylate salt Form II of embodiment 151 or 153, characterized by an XRPD pattern further comprising one or more peaks selected from 12.1, 20.2, 22.7, 23.2, and 24.1 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 154 The mesylate salt Form II of embodiment 150, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 34.
  • XRPD X-ray powder diffraction
  • Embodiment 155 The mesylate salt Form II, according to any one of embodiments 150 to 154, characterized by a differential scanning calorimetry thermogram (DSC) comprising an endotherm peak at about 190 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 156 The mesylate salt Form II, according to any one of embodiments 150 to 154, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 35.
  • Embodiment 157 The mesylate salt Form II, according to any one of embodiments 150 to 156, characterized by about 0.2% weight loss upon heating from about 140 °C to about 205 °C, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 158 The mesylate salt Form II, according to any one of embodiments 150 to 156, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 35.
  • TGA thermal gravimetric analysis
  • Embodiment 159 The mesylate salt Form II, according to any one of embodiments 150 to 158, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 36.
  • PLM polarized light microscope
  • Embodiment 160 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is mesylate salt Form III.
  • Embodiment 161 The mesylate salt Form III of embodiment 160, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.5, 8.9, 17.5, 18.5, and 19.6 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 162 The mesylate salt Form III of embodiment 161, characterized by an XRPD pattern further comprising one or more peaks selected from 6.1, 13.1, 13.8, 14.4, and 19.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 163 The mesylate salt Form III embodiment 161 or 162, characterized by an XRPD pattern further comprising one or more peaks selected from 13.3, 18.0, 21.4, 23.6, and 26.0 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 164 The mesylate salt Form III of embodiment 160, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 37.
  • XRPD X-ray powder diffraction
  • Embodiment 165 The mesylate salt Form III, according to any one of embodiments 160 to 164, characterized by a differential scanning calorimetry thermogram (DSC) comprising a melting peak at about 173 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 166 The mesylate salt Form III, according to any one of embodiments 160 to 164, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 38.
  • Embodiment 167 The mesylate salt Form III, according to any one of embodiments 160 to 166, characterized by 1.5% weight loss upon heating from about 80 °C to about 180 °C as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 168 The mesylate salt Form III, according to any one of embodiments 160 to 166, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 38.
  • TGA thermal gravimetric analysis
  • Embodiment 169 The mesylate salt Form III, according to any one of embodiments 160 to 168, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 39.
  • PLM polarized light microscope
  • Embodiment 170 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is maleate salt Form I.
  • Embodiment 171 The maleate salt Form I of embodiment 170, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.7, 14.8, 15.5, 18.7, and 20.0 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 172 The maleate salt Form I of embodiment 171, characterized by an XRPD pattern further comprising one or more peaks selected from 7.9, 8.3, 9.9, 12.7, and 18.1 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 173 The maleate salt Form I of embodiment 171 or 172, characterized by an XRPD pattern further comprising one or more peaks selected from 16.7, 21.2, 22.5, 23.3, and 24.0 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 174 The maleate salt Form I of embodiment 170, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 40.
  • XRPD X-ray powder diffraction
  • Embodiment 175. The maleate salt Form I, according to any one of embodiments 170 to 174, characterized by a differential scanning calorimetry thermogram (DSC) comprising an endotherm peak at about 195 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 176 The maleate salt Form I, according to any one of embodiments 170 to 174, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 41.
  • Embodiment 177 The maleate salt Form I, according to any one of embodiments 170 to 176, characterized by no weight loss prior to decomposition, as measured by thermal gravimetric analysis (TGA).
  • Embodiment 178 The maleate salt Form I, according to any one of embodiments 170 to 176, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 41.
  • TGA thermal gravimetric analysis
  • Embodiment 179 The maleate salt Form I, according to any one of embodiments 170 to 178, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 42.
  • PLM polarized light microscope
  • Embodiment 180 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is maleate salt Form II.
  • Embodiment 181 The maleate salt Form II of embodiment 180, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 14.3, 15.3, 17.5, 18.3, and 18.8 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 182 The maleate salt Form II of embodiment 181, characterized by an XRPD pattern further comprising one or more peaks selected from 9.6, 11.9, 13.3, 14.2, and 19.3 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 183 The maleate salt Form II of embodiment 181 or 182, characterized by an XRPD pattern further comprising one or more peaks selected from 17.9, 21.4, 24.0, 24.3, and 24.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 185 The maleate salt Form II, according to any one of embodiments 180 to 184, characterized by a differential scanning calorimetry thermogram (DSC) comprising a first endotherm peak at about 142 °C, and/or a second endotherm peak at about 162 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 186 The maleate salt Form II, according to any one of embodiments 180 to 184, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 44.
  • Embodiment 187 The maleate salt Form II, according to any one of embodiments 180 to 186, characterized by about 1.6% weight loss upon heating from about 80 °C to about 144 °C, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 188 The maleate salt Form II, according to any one of embodiments 180 to 186, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 44.
  • TGA thermal gravimetric analysis
  • Embodiment 189 The maleate salt Form II, according to any one of embodiments 180 to 188, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 45.
  • PLM polarized light microscope
  • Embodiment 190 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is citrate salt Form I.
  • Embodiment 191 The citrate salt Form I of embodiment 190, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.4, 15.8, 17.9, 19.2, and 19.5 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 192 The citrate salt Form I of embodiment 191, characterized by an XRPD pattern further comprising one or more peaks selected from 10.6, 13.1, 15.1, 17.0, and 18.9 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 193 The citrate salt Form I of embodiment 191 or 192, characterized by an XRPD pattern further comprising one or more peaks selected from 20.3, 22.6, 23.1, 24.5, and 27.1 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 194 The citrate salt Form I of embodiment 190, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 46.
  • XRPD X-ray powder diffraction
  • Embodiment 195 The citrate salt Form I, according to any one of embodiments 190 to 194, characterized by a differential scanning calorimetry thermogram (DSC) comprising an endothermic peak at about 167 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 196 The citrate salt Form I, according to any one of embodiments 190 to 194, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 47.
  • Embodiment 197 The citrate salt Form I, according to any one of embodiments 190 to 196, characterized by about 22% weight loss upon heating from about 95 °C to about 225 °C, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 198 The citrate salt Form I, according to any one of embodiments 190 to 196, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 47.
  • TGA thermal gravimetric analysis
  • Embodiment 199 The citrate salt Form I, according to any one of embodiments 190 to 198, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 48.
  • PLM polarized light microscope
  • Embodiment 200 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is fumarate salt Form I.
  • Embodiment 201 The fumarate salt Form I of embodiment 200, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.2, 8.5, 10.6, 18.8, and 19.8 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 202 The fumarate salt Form I of embodiment 201, characterized by an XRPD pattern further comprising one or more peaks selected from 12.7, 13.0, 15.9, 17.0, and 19.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 203 The fumarate salt Form I of embodiment 201 or 202, characterized by an XRPD pattern further comprising one or more peaks selected from 21.1, 21.4, 23.4, 25.7, and 27.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 204 The fumarate salt Form I of embodiment 200, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 49.
  • XRPD X-ray powder diffraction
  • Embodiment 205 The fumarate salt Form I, according to any one of embodiments 200 to 205, characterized by a differential scanning calorimetry thermogram (DSC) comprising a melting peak at about 198 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 206 The fumarate salt Form I, according to any one of embodiments 200 to 205, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 50.
  • Embodiment 207 The fumarate salt Form I, according to any one of embodiments 200 to 206, characterized by about 9.7% weight loss upon heating from about 100 °C to about 210 °C, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 208 The fumarate salt Form I, according to any one of embodiments 200 to 206, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 50.
  • TGA thermal gravimetric analysis
  • Embodiment 209 The fumarate salt Form I, according to any one of embodiments 200 to 208, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 51.
  • PLM polarized light microscope
  • Embodiment 210 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is fumarate salt Form II.
  • Embodiment 211 The fumarate salt Form II of embodiment 210, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.2, 8.5, 10.5, 12.9, and 18.9 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 212 The fumarate salt Form II of embodiment 211, characterized by an XRPD pattern further comprising one or more peaks selected from 15.1, 16.0, 18.6, 19.6, and 20.0 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 21 The fumarate salt Form II of any one of embodiments 211 or 212, characterized by an XRPD pattern further comprising one or more peaks selected from 21.7, 23.3, 23.6, 26.1, and 27.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 214 The fumarate salt Form II of embodiment 210, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 52.
  • XRPD X-ray powder diffraction
  • Embodiment 215. The fumarate salt Form II, according to any one of embodiments 210 to 214, characterized by a differential scanning calorimetry thermogram (DSC) comprising a first endotherm peak at about 144 °C, and/or a second endotherm peak at about 200 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 216 The fumarate salt Form II, according to any one of embodiments 210 to 214, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 53.
  • Embodiment 217 The fumarate salt Form II, according to any one of embodiments 210 to 216, characterized by about 2.1% weight loss upon heating from about 90 °C to about 175 °C, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 218 The fumarate salt Form II, according to any one of embodiments 210 to 216, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 53.
  • TGA thermal gravimetric analysis
  • Embodiment 219. The fumarate salt Form II, according to any one of embodiments 210 to 218, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 54.
  • PLM polarized light microscope
  • Embodiment 220 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is fumarate salt Form III.
  • Embodiment 22 The fumarate salt Form III of embodiment 220, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.7, 7.9, 8.9, 10.6, and 17.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 222 The fumarate salt Form III of embodiment 221, characterized by XRPD pattern further comprising one or more peaks selected from 10.3, 11.5, 16.1, 17.9, and 18.5 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 223. The fumarate salt Form III of embodiment 221 or 222, characterized by an XRPD pattern further comprising one or more peaks selected from 2.1, 21.9, 24.0, 25.1, and 26.9 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 224 The fumarate salt Form III of embodiment 221, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 55.
  • XRPD X-ray powder diffraction
  • Embodiment 225 The fumarate salt Form III, according to any one of embodiments 220 to 224, characterized by a differential scanning calorimetry thermogram (DSC) comprising a first endotherm peak at about 113 °C, and/or a second endotherm peak at about 164 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 226 The fumarate salt Form III, according to any one of embodiments 220 to 224, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 56.
  • Embodiment 227 The fumarate salt Form III, according to any one of embodiments 220 to 226, characterized by about 3.1% weight loss upon heating from about 85 °C to about 135 °C, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 228 The fumarate salt Form III, according to any one of embodiments 220 to 226, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 56.
  • TGA thermal gravimetric analysis
  • Embodiment 229. The fumarate salt Form in, according to any one of embodiments 220 to 228, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 57.
  • PLM polarized light microscope
  • Embodiment 230 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is malate salt Form I.
  • Embodiment 23 The malate salt Form I of embodiment 230, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.9, 12.4, 13.9, 18.7, and 19.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 232 The malate salt Form I of embodiment 231 , characterized by an XRPD pattern further comprising one or more peaks selected from 4.1, 8.3, 10.5, 16.0, and 16.3 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 233 The malate salt Form I of embodiment 231 or 232, characterized by an XRPD pattern further comprising one or more peaks selected from 20.0, 20.5, 21.1, 22.9, and 24.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 234 The malate salt Form I of embodiment 230, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 58.
  • XRPD X-ray powder diffraction
  • Embodiment 235 The malate salt Form I, according to any one of embodiments 230 to 234, characterized by a differential scanning calorimetry thermogram (DSC) comprising a first endothermic peak at about 157 °C and/or a second endothermic peak at about 206 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 236 The malate salt Form I, according to any one of embodiments 230 to 234, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 59.
  • Embodiment 237 The malate salt Form I, according to any one of embodiments 230 to 236, characterized by about 1.9% weight loss upon heating from about 75 °C to about 157 °C, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 238 The malate salt Form I, according to any one of embodiments 230 to 236, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 59.
  • TGA thermal gravimetric analysis
  • Embodiment 239. The malate salt Form I, according to any one of embodiments 230 to 238, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 60.
  • PLM polarized light microscope
  • Embodiment 240 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is malate salt Form II.
  • Embodiment 241 The malate salt Form II of embodiment 240, characterized by an XRPD pattern further comprising one or more peaks selected from 8.2, 12.4, 14.7, 15.8, and 18.3 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 242 The malate salt Form II of embodiment 241, characterized by an XRPD pattern further comprising one or more peaks selected from 4.0, 15.6, 16.4, 17.0, and 19.1 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 243 The malate salt Form II of embodiment 241 or 242, characterized by an XRPD pattern further comprising one or more peaks selected from 21.5, 22.2, 22.9, 24.4, and 26.2 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 244 The malate salt Form II of embodiment 240, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 61.
  • XRPD X-ray powder diffraction
  • Embodiment 245. The malate salt Form II, according to any one of embodiments 240 to 244, characterized by a differential scanning calorimetry thermogram (DSC) comprising an endotherm peak at about 180 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 246 The malate salt Form II, according to any one of embodiments 240 to 244, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 62.
  • Embodiment 247 The malate salt Form II, according to any one of embodiments 240 to 246, characterized by about 0.5% weight loss upon heating from about 95 °C to about 170 °C, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment 248 The malate salt Form II, according to any one of embodiments 240 to 246, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 62.
  • TGA thermal gravimetric analysis
  • Embodiment 249. The malate salt Form II, according to any one of embodiments 240 to 248, characterized by a weight gain of about 1.8 % after undergoing a dynamic vapor sorption cycle from about 0 % relative humidity (RH) to about 90 % RH at 25 °C.
  • Embodiment 250 The malate salt Form II, according to any one of embodiments 240 to 248, characterized by a dynamic vapor sorption profile substantially as shown in FIG. 63.
  • Embodiment 251 The malate salt Form II, according to any one of embodiments 240 to 250, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 64.
  • PLM polarized light microscope
  • Embodiment 252 The crystalline form of embodiment 1 or embodiment 2, wherein the crystalline form is succinate salt Form I.
  • Embodiment 253 The succinate salt Form I of embodiment 252, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.5, 12.8, 15.0, 18.8, and 19.9 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment 254 The succinate salt Form I of embodiment 253, characterized by an XRPD pattern further comprising one or more peaks selected from 8.5, 10.7, 12.1, 15.9, and 18.5 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment 256 The succinate salt Form I of embodiment 252, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 65.
  • Embodiment 257 The succinate salt Form I, according to any one of embodiments 252 to 256, characterized by a differential scanning calorimetry thermogram (DSC) comprising an endotherm peak at about 136 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 258 The succinate salt Form I, according to any one of embodiments 252 to 256, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 66.
  • DSC differential scanning calorimetry thermogram
  • Embodiment 259. The succinate salt Form I, according to any one of embodiments 252 to 258, characterized by about 2.8% weight loss upon heating from about 85 °C to about 145 °C, as measured by thermal gravimetric analysis (TGA).
  • Embodiment 260 The succinate salt Form I, according to any one of embodiments 252 to 258, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 66.
  • TGA thermal gravimetric analysis
  • Embodiment 26 The succinate salt Form I, according to any one of embodiments 252 to 260, characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 67.
  • PLM polarized light microscope
  • Embodiment 262 A pharmaceutical composition comprising a crystalline form according to any one of embodiments 1 to 261 and at least one pharmaceutically acceptable excipient.
  • Embodiment 263 A solid state form of Compound 1 or a salt thereof, wherein the solid state form comprises at least 50 wt.% of a particular crystalline form, wherein the particular crystalline form is according to any one of embodiments 1 to 261.
  • Embodiment 264 The solid state form of embodiment 263, wherein the solid state form comprises at least 60 wt.% of the particular crystalline form.
  • Embodiment 265. The solid state form of embodiment 263, wherein the solid state form comprises at least 70 wt.% of the particular crystalline form.
  • Embodiment 266 The solid state form of embodiment 263, wherein the solid state form comprises at least 80 wt.% of the particular crystalline form.
  • Embodiment 267 The solid state form of embodiment 263, wherein the solid state form comprises at least 90 wt.% of the particular crystalline form.
  • Embodiment 268 The solid state form of embodiment 263, wherein the solid state form comprises at least 95 wt.% of the particular crystalline form.
  • Embodiment 269. The solid state form of embodiment 263, wherein the solid state form comprises at least 99 wt.% of the particular crystalline form.
  • Embodiment 270 The solid state form of any one of embodiments 263 to 269, wherein the particular crystalline form is HC1 salt Form I.
  • Embodiment 27 The solid state form of any one of embodiments 263 to 269, wherein the particular crystalline form is free base Form I.
  • Embodiment 272 A pharmaceutical composition comprising a solid state form of any one of embodiments 263 to 269, and at least one pharmaceutically acceptable excipient.
  • Embodiment 27 A pharmaceutical composition prepared by combining a solid state form of any one of embodiments 263 to 269 with at least one pharmaceutically acceptable excipient.
  • Embodiment 274 A method of inhibiting PARG in vivo in a patient, the method comprising administering to the patient an effective amount of a crystalline form of any one of embodiments 1 to 261.
  • Embodiment 275 A method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a crystalline form of any one of embodiments 1 to 261.
  • Embodiment 276 A method of treating a cancer resistant to one or more platins or one or more PARP inhibitors in a patient in need thereof, the method comprising administering to the patient an effective amount of a crystalline form of any one of embodiments 1 to 261.
  • Embodiment 277 A method of treating and/or preventing a homologous recombinant deficient (HRD) cancer in a patient comprising administering to the patient a therapeutically effective amount of a crystalline form of any one of embodiments 1 to 261.
  • HRD homologous recombinant deficient
  • Embodiment 278 The method of embodiment 277, wherein the patient is in recognized need of such treatment.
  • Embodiment 279. A method of treating and/or preventing a cancer in a patient, where the cancer is characterized by a reduction or absence of BRCA1 and/or BRCA2 gene expression, the absence or mutation of BRCA1 and/or BRCA2 genes, or reduced function of BRCA1 and/or BRCA2 proteins, comprising administering to the patient a therapeutically effective amount of a crystalline form of any one of embodiments 1 to 261.
  • Embodiment 280 The method of embodiment 279, wherein the patient is in recognized need of such treatment.
  • Embodiment 28 The crystalline form as defined in any one of embodiments 1 to 261 for use in the treatment of cancer.
  • Embodiment 282 Use of a crystalline form as defined in any one of embodiments 1 to 261 in the manufacture of a medicament for treating cancer.
  • Embodiment 283 The method of any one of embodiments 276 to 280 or the use of embodiments 281 or 282, wherein the cancer is breast cancer, ovarian cancer, gastric cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, or endometrial cancer.
  • Embodiment Al A crystalline form of Compound 1 (Compound 1), or a salt thereof.
  • Embodiment A2 The crystalline form of Embodiment Al, wherein the crystalline form is a single crystalline form substantially free of other crystalline or amorphous forms.
  • Embodiment A3 The crystalline form of Embodiment Al or Embodiment A2, wherein the crystalline form is HC1 salt Form I.
  • Embodiment A4 The crystalline form of Embodiment A3, wherein the crystalline form is a single crystalline form substantially free of other crystalline or amorphous forms.
  • Embodiment A5. The HC1 salt Form I, according to Embodiment A3 or A4, characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more peaks selected from 11.7, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4, and 19.9 degrees 26 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment A6 The HC1 salt Form I, according to Embodiment A3 or A4, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.7, 13.2,
  • Embodiment A7 The HC1 salt Form I, according to Embodiment A3 or A4, characterized by an XRPD pattern comprising peaks at 7.0, 11.7, 12.2, 13.2, 13.7, 15.3, 17.2,
  • Embodiment A8 The HC1 salt Form I, according to any one of Embodiments A3 to A7, wherein the XRPD pattern further comprises one or more peaks selected from 20.6, 20.9, 21.2, 21.7, 22.3, 24.3, 25.0, 25.3, 25.6, 26.1, 28.9 degrees 20 ( ⁇ 0.2 degrees 20).
  • Embodiment A10 The HC1 salt Form I according to Embodiment A3 or A4, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 13.2, 13.7,
  • Embodiment A12 The HC1 salt Form I, according to Embodiment A3 or A4, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 7.
  • XRPD X-ray powder diffraction
  • Embodiment A13 The HC1 salt Form I, according to any one of Embodiments A3 to Al 2, characterized by a differential scanning calorimetry thermogram (DSC) comprising no endotherm prior to decomposition.
  • Embodiment A14 The HC1 salt Form I, according to any one of Embodiments A3 to Al 2, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 8.
  • Embodiment A15 The HC1 salt Form I, according to any one of Embodiments A3 to A14, characterized by no weight loss upon heating prior to decomposition, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment A16 The HC1 salt Form I, according to any one of Embodiments A3 to A14, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 8.
  • TGA thermal gravimetric analysis
  • Embodiment A17 The HC1 salt Form I, according to any one of Embodiments A3 to A16, characterized by a weight gain of about 0.5 % after undergoing a dynamic vapor sorption cycle from about 0% relative humidity (RH) to about 90% RH at 25 °C.
  • Embodiment A18 The HC1 salt Form I, according to any one of Embodiments A3 to A16, characterized by a dynamic vapor sorption profile substantially as shown in FIG. 9.
  • Embodiment A19 The crystalline form of Embodiment Al or A2, wherein the crystalline form is free base Form I.
  • Embodiment A20 The crystalline form of Embodiment A19, wherein the crystalline form is a single crystalline form substantially free of other crystalline or amorphous forms.
  • Embodiment A21 The free base Form I of Embodiments A19 or A20, characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more peaks selected from 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4, and 19.7 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment A22 The free base Form I of Embodiment A19 or A20, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 9.0, 16.4, 18.0, 18.3, and 19.4 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment A25 The free base Form I according to Embodiment A19 or A20, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 9.0, 16.4, 18.3, 23.5, and 24.6 degrees 20 ( ⁇ 0.2 degrees 20).
  • XRPD X-ray powder diffraction
  • Embodiment A27 The free base Form I of Embodiment Al 9 or A20, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 1.
  • XRPD X-ray powder diffraction
  • Embodiment A28 The free base Form I, according to any one of Embodiments A19 to A27, characterized by a differential scanning calorimetry thermogram (DSC) comprising an endothermic peak at about 200 °C.
  • DSC differential scanning calorimetry thermogram
  • Embodiment A29 The free base Form I, according to any one of Embodiments A19 to A27, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 2.
  • DSC differential scanning calorimetry thermogram
  • Embodiment A30 The free base Form I, according to any one of Embodiments A19 to A29, characterized by no weight loss upon heating prior to decomposition, as measured by thermal gravimetric analysis (TGA).
  • TGA thermal gravimetric analysis
  • Embodiment A31 The free base Form I, according to any one of Embodiments A19 to A29, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 2.
  • TGA thermal gravimetric analysis
  • Embodiment A32 A pharmaceutical composition comprising a crystalline form according to any one of Embodiments Al to A31 and at least one pharmaceutically acceptable excipient.
  • Embodiment A33 A pharmaceutical composition prepared by combining a crystalline form according to any one of Embodiments Al to A31 and at least one pharmaceutically acceptable excipient.
  • Embodiment A34 A solid state form of Compound 1 or a salt thereof, wherein the solid state form comprises at least 50 wt.% of a particular crystalline form, at least 60 wt.% of a particular crystalline form, at least 70 wt.% of a particular crystalline form, at least 80 wt.% of a particular crystalline form, at least 90 wt.% of a particular crystalline form, at least 95 wt.% of a particular crystalline form, or at least 99 wt.% of a particular crystalline form, wherein the particular crystalline form is according to any one of Embodiments Al to A31.
  • Embodiment A35 The solid state form of Embodiment A34, wherein the particular crystalline form is HC1 salt Form I.
  • Embodiment A36 The solid state form of Embodiment A34, wherein the particular crystalline form is free base Form I.
  • Embodiment A37 A pharmaceutical composition comprising a solid state form of any one of Embodiments A34 to A36, and at least one pharmaceutically acceptable excipient.
  • Embodiment A38 A pharmaceutical composition prepared by combining a solid state form of any one of Embodiments A34 to A36 with at least one pharmaceutically acceptable excipient.
  • Embodiment A39 A method of inhibiting PARG in vivo in a patient, the method comprising administering to the patient an effective amount of a crystalline form of any one of Embodiments Al to A31, or a pharmaceutical composition of any one of Embodiments A32, A33, A37 and A38.
  • Embodiment A40 A method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a crystalline form of any one of Embodiments Al to A31, or a pharmaceutical composition of any one of Embodiments A32, A33, A37 and A38.
  • Embodiment A41 A method of treating a cancer resistant to one or more platins or one or more PARP inhibitors in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a crystalline form of any one of Embodiments Al to A31, or a pharmaceutical composition of any one of Embodiments A32, A33, A37 and A38.
  • Embodiment A42 A method of treating a cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a crystalline form of any one of Embodiments Al to A31, or a pharmaceutical composition of any one of Embodiments A32, A33, A37 and A38.
  • Embodiment A43 A method of treating and/or preventing a homologous recombinant deficient (HRD) cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a crystalline form of any one of Embodiments Al to A31, or a pharmaceutical composition of any one of Embodiments A32, A33, A37 and A38.
  • HRD homologous recombinant deficient
  • Embodiment A44 A method of treating and/or preventing a cancer in a patient in need thereof, where the cancer is characterized by a reduction or absence of BRCA1 and/or BRCA2 gene expression, the absence or mutation of BRCA1 and/or BRCA2 genes, or reduced function of BRCA1 and/or BRCA2 proteins, the method comprising administering to the patient a therapeutically effective amount of a crystalline form of any one of Embodiments Al to A31, or a pharmaceutical composition of any one of Embodiments A32, A33, A37 and A38.
  • Embodiment A45 The crystalline form as defined in any one of Embodiments Al to A31, or a pharmaceutical composition of any one of Embodiments A32, A33, A37 and A38, for use in the treatment of cancer.
  • Embodiment A46 Use of a crystalline form as defined in any one of Embodiments Al to A31, or a pharmaceutical composition of any one of Embodiments A32, A33, A37 and A38, in the manufacture of a medicament for the treatment of cancer.
  • Embodiment A47 The method of any one of Embodiments A41 to A44, or the use of Embodiment A45 or A46, wherein the cancer is breast cancer, ovarian cancer, gastric cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, head and neck cancer, or endometrial cancer.
  • reaction mixture was diluted with water (500 mL) and extracted with EtOAc (2 x 300 mL), the combined organic phases were washed with brine solution (200 mL), dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to get crude product as an oil.
  • the crude material was purified by column chromatography using silica gel (100-200) and eluted with 20% EtOAc/Hexane as a gradient. The product was eluted with a gradient of 30% EtOAc/Hexane.
  • Step 3 Preparation of 2-(difluoromethyl)-5-(4-fluoro-6-iodo-lH-indazol-l-yl)-l,3,4- thiadiazole (Int 5)
  • Step 5 Preparation of l-(5-(difluoromethyl)-l,3»4-thiadiazol-2-yl)-4-fluoro-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonaniide (Int 7)
  • the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2x30 mL). The combined organic layer was washed with brine solution (20 tnL), dried over anhydrous sodium sulphate, filtered and the filterate was concentrated under reduced pressure to obtain crude product.
  • the crude product was purified by column chromatography using silica gel (100-200) and eluted with 5 to 50% EtOAc/hexane as a gradient. The product was eluted at 20% EtOAc/hexane.
  • Step 6 Preparation of tert-butyl (2S,6S)-4-(l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)- 6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-4-yl)-2,6-dimethylpiperazine-l- carboxylate (Int 8) [0834] To a stirred solution of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-fluoro-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide (Int 7) (80 mg, 0.19 mmol) in DMSO (dimethyl sulfoxide) (2 mL) were added tert-butyl (2S,6S)-2,6-dimethylpiperazine-l- carboxylate (85 mg, 0.39 mmol,
  • Step 7 Preparation of l-(5-(difluoromethyl)-l,3,4-thiadiazoI-2-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide (Compound 1)
  • Example 1 The solid prepared in Example 1 was characterized and assigned as the free base Form I (anhydrate) with 0.4% residual acetonitrile as detected by NMR (data not shown).
  • a slurry study was performed using Compound 1 as prepared in Example 1.
  • About 15-25 mg of Compound 1 was weighed into a sample vial and 0.2-0.5 mL of a solvent (water, EtOH, isopropyl alcohol, MTBE, toluene, n-heptane, cyclohexane, EtOAc, MeCN, isopropyl acetate, acetone, MEK, or MeOH) was added to make a suspension, respectively. All suspensions were stirred at RT for 3 days and 50 °C for 1 day. Then, the solids were filtered and the filter cakes were analyzed by XRPD. The resulting solids were all Form I, and no new form was obtained.
  • a solvent water, EtOH, isopropyl alcohol, MTBE, toluene
  • XRPD diffractograms were collected with an X-ray diffractometer. The sample was prepared on a zero-background silicon wafer by gently pressing onto the flat surface. The parameters of XRPD diffraction are given in the table below.
  • FIG. 1 A plot of the XRPD is shown in FIG. 1, and Table 1, below, summarizes selected peaks observed in the XRPD plot.
  • DSC analysis was performed with a TA Instrument. About 1-3 mg of a sample was placed into an aluminum pan with pin-hole and heated with the parameters in the table below. The data were analyzed using TRIOS.
  • DSC analysis determined that the melting point onset and peak at about 199 °C and 200 °C, respectively.
  • a plot of the DSC thermogram is shown in FIG. 2 (lower trace).
  • TGA analysis was performed using a TA Instrument. About 1-5 mg of a sample was loaded onto a pre-tared aluminum pan and heated with the parameters in the table below. The data were analyzed using TRIOS.
  • the TGA analysis determined that free base Form I of Compound 1 exhibits no weight loss upon heating prior to decomposition.
  • a plot of the TGA thermogram is shown in FIG. 2 (upper trace).
  • DSC Differential scanning calorimetry

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Abstract

L'invention concerne des formes cristallines d'un inhibiteur de PARG ayant la formule du composé 1. L'invention concerne également des compositions pharmaceutiques et des méthodes de traitement à base des formes cristallines du composé 1, décrites dans la description.
PCT/US2024/047591 2023-09-20 2024-09-20 Inhibiteur de parg Pending WO2025064745A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130053383A1 (en) * 2010-05-07 2013-02-28 Glaxosmithkline Llc Indazoles
US20220389003A1 (en) * 2019-09-20 2022-12-08 Ideaya Biosciences, Inc. 4-substituted indole and indazole sulfonamido derivatives as parg inhibitors
US20230303556A1 (en) * 2022-03-23 2023-09-28 Ideaya Biosciences, Inc. Piperazine substituted indazole compounds as inhibitors of parg
WO2024211506A1 (fr) * 2023-04-05 2024-10-10 Ideaya Biosciences, Inc. Polythérapie comprenant un inhibiteur de parg et un inhibiteur de topoisomérase pour le traitement du cancer

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130053383A1 (en) * 2010-05-07 2013-02-28 Glaxosmithkline Llc Indazoles
US20220389003A1 (en) * 2019-09-20 2022-12-08 Ideaya Biosciences, Inc. 4-substituted indole and indazole sulfonamido derivatives as parg inhibitors
US20230303556A1 (en) * 2022-03-23 2023-09-28 Ideaya Biosciences, Inc. Piperazine substituted indazole compounds as inhibitors of parg
WO2024211506A1 (fr) * 2023-04-05 2024-10-10 Ideaya Biosciences, Inc. Polythérapie comprenant un inhibiteur de parg et un inhibiteur de topoisomérase pour le traitement du cancer

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