WO2020210669A1 - Crystalline forms of (s)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine and methods of making - Google Patents

Crystalline forms of (s)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine and methods of making Download PDF

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Publication number
WO2020210669A1
WO2020210669A1 PCT/US2020/027724 US2020027724W WO2020210669A1 WO 2020210669 A1 WO2020210669 A1 WO 2020210669A1 US 2020027724 W US2020027724 W US 2020027724W WO 2020210669 A1 WO2020210669 A1 WO 2020210669A1
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WIPO (PCT)
Prior art keywords
compound
crystalline form
ray powder
signal
powder diffractogram
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Ceased
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PCT/US2020/027724
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English (en)
French (fr)
Inventor
Joshua D. WAETZIG
Brenton MAR
Brian HEINRICH
Gordon Wilkie
Lauren MACEACHERN
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Blueprint Medicines Corp
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Blueprint Medicines Corp
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Priority to LTEPPCT/US2020/027724T priority Critical patent/LT3856341T/lt
Priority to PL20722936.0T priority patent/PL3856341T3/pl
Priority to RS20231131A priority patent/RS64881B1/sr
Priority to EP20722936.0A priority patent/EP3856341B1/en
Priority to SM20230447T priority patent/SMT202300447T1/it
Priority to HRP20231533TT priority patent/HRP20231533T1/hr
Priority to SI202030328T priority patent/SI3856341T1/sl
Priority to CN202080042782.9A priority patent/CN113966334B/zh
Priority to CA3136707A priority patent/CA3136707A1/en
Priority to EP23195076.7A priority patent/EP4302761A3/en
Priority to FIEP20722936.0T priority patent/FI3856341T3/fi
Application filed by Blueprint Medicines Corp filed Critical Blueprint Medicines Corp
Priority to JP2021560265A priority patent/JP7728178B2/ja
Priority to DK20722936.0T priority patent/DK3856341T3/da
Priority to ES20722936T priority patent/ES2966512T3/es
Publication of WO2020210669A1 publication Critical patent/WO2020210669A1/en
Priority to US17/153,727 priority patent/US12060354B2/en
Priority to IL287148A priority patent/IL287148A/en
Anticipated expiration legal-status Critical
Priority to US18/077,466 priority patent/US11964980B2/en
Priority to US18/077,431 priority patent/US12252494B2/en
Priority to US18/543,793 priority patent/US11999744B2/en
Priority to US18/800,215 priority patent/US20260116883A1/en
Priority to IL324301A priority patent/IL324301A/en
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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

  • compositions comprising the same, methods of using the same, and processes for making the Compound (I), including its crystalline forms.
  • the crystalline forms of Compound (I) may be selective inhibitors of KIT, including exon 17 mutant and/or PDGFRa exon 18 mutant proteins.
  • the enzyme KIT (also called CD117) is a receptor tyrosine kinase expressed on a wide variety of cell types.
  • the KIT receptor protein belongs to the class III receptor tyrosine kinase (RTK) family that also includes the structurally related proteins PDGFRa (platelet- derived growth factor receptor A), PDGFRb, FLT3 (FMS-like tyrosine kinase 3), and CSF1R (colony-stimulating factor 1 receptor).
  • RTK receptor tyrosine kinase
  • the KIT molecule contains a long extracellular domain, a transmembrane segment, and an intracellular portion.
  • the ligand for KIT is stem cell factor (SCF).
  • stem cell factor binds to and activates KIT by inducing dimerization, autophosphorylation, and initiation of downstream signaling.
  • somatic activating mutations in KIT drive ligand-independent constitutive activity.
  • KIT mutations generally occur in the DNA encoding the juxtumembrane domain (exon 11). KIT mutations also occur, with less frequency, in exons 7, 8, 9, 13, 14, 17, and 18. Mutations make KIT function independent of activation by SCF, leading to a high cell division rate and possibly genomic instability. Mutant KIT has been implicated in the pathogenesis of several disorders and conditions, e.g., mastocytosis, gastrointestinal stromal tumors (GIST), acute myeloid leukemia (AML), melanoma, and seminoma.
  • GIST gastrointestinal stromal tumors
  • AML acute myeloid leukemia
  • melanoma melanoma
  • the structurally related platelet-derived growth factor receptors are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family.
  • PDGF subunits -a and -b regulate cell proliferation, cellular differentiation, cell growth, and cellular development.
  • Alterations in PDGF subunit -a and -b are associated with many diseases, including some cancers.
  • an exon 18 PDGFRa D842V mutation has been found in a distinct subset of GIST, typically from the stomach.
  • the D842V mutation is also associated with tyrosine kinase inhibitor resistance.
  • exon 18 mutations such as PDGFRa D842I and PDGFRa D842Y are associated with ligand- independent, constitutive activation of PDGFRa.
  • gain of function mutations such as, e.g., PDGFRa D842I, D842V, and D842Y
  • PDGFRa D842I, D842V, and D842Y gain of function mutations that confer ligand-independent constitutive activation of PDGFRa signaling have been identified as drivers of disease.
  • Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing may inhibit KIT and/or PDGFRa and be useful in the treatment of mast cell disorders such as mastocytosis, and disorders and conditions associated with oncogenic KIT and PDGFRa alterations.
  • Compound (I) is disclosed in Example 7 of WO 2015/057873 and has the following structure:
  • Crystalline forms occur where the same composition of matter crystallizes in different lattice arrangements, resulting in different thermodynamic properties and stabilities specific to each crystalline form. Each unique crystal form is known as a “polymorph.” Crystalline forms may also include different solvates ( e.g ., hydrates) of the same compound.
  • polymorphs of a given substance may differ from each other with respect to at least one physical, chemical, and/or pharmaceutical property, such as solubility, dissociation, true density, dissolution, melting point, crystal habit or morphology, compaction behavior, particle size, flow properties, and/or solid state stability.
  • the solid state form of a bioactive compound often determines its ease of preparation, ease of isolation, hygroscopicity, stability, solubility, storage stability, ease of formulation, rate of dissolution in gastrointestinal fluids, and in vivo bioavailability. For example, if an unstable crystalline form is used during large-scale manufacturing, crystal morphology may change during manufacture and/or storage, resulting in quality control problems and formulation irregularities. Unstable crystalline forms may affect the
  • any change to the solid state of a bioactive compound that improves its physical or chemical stability may impart a significant advantage over less stable forms of the same compound.
  • substantially pure crystalline forms are free from reaction impurities, starting materials, reagents, side products, unwanted solvents and/or other processing impurities arising from the preparation and/or isolation and/or purification of the particular crystalline form.
  • novel crystalline forms which are useful for treating mast cell disorders associated with mutant/oncogenic KIT and PDGFRA, including mastocytosis, and disorders and conditions associated with mutant/oncogenic KIT and PDGFRA alterations, e.g., Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing.
  • Compound (I) pharmaceutically acceptable salts thereof, and solvates of any of the foregoing, compositions comprising the same, and methods of using and making the same.
  • the crystalline forms of Compound (I) for pharmaceutical use are substantially free of impurities.
  • the novel crystalline forms disclosed herein have properties that are useful for large-scale manufacturing, pharmaceutical formulation, and/or storage. In some
  • novel crystalline forms disclosed herein consist of one crystalline form.
  • the crystalline forms are substantially pure. Also disclosed herein are novel methods of making Compound (I).
  • a pharmaceutical composition comprising: a pharmaceutically acceptable excipient; and at least one crystalline form which is chosen from crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing.
  • the at least one crystalline form is crystalline Form A of Compound (I).
  • the at least one crystalline form is crystalline Form B of Compound (I).
  • the at least one crystalline form is crystalline Form C of Compound (I).
  • the at least one crystalline form is crystalline Form O of Compound (I).
  • the at least one crystalline form is crystalline Form T of a tosylate salt of Compound (I).
  • the at least one crystalline form is crystalline Form Tr of a tartrate salt of Compound (I).
  • the at least one crystalline form is crystalline Form H of a hydrochloride salt of Compound (I).
  • Some embodiments of the disclosure relate to methods of treating a patient in need of a KIT or PDGFRa inhibitor by administering a therapeutically effective amount of at least one crystalline form chosen from crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing.
  • the at least one crystalline form is crystalline Form A of Compound (I).
  • the at least one crystalline form is crystalline Form B of Compound (I).
  • the at least one crystalline form is crystalline Form C of Compound (I).
  • the at least one crystalline form is crystalline Form O of Compound (I). In some embodiments, the at least one crystalline form is crystalline Form T of a tosylate salt of Compound (I). In some embodiments, the at least one crystalline form is crystalline Form Tr of a tartrate salt of Compound (I). In some embodiments, the at least one crystalline form is crystalline Form H of a hydrochloride salt of Compound (I). [0016] In some embodiments, the patient in need of a KIT or PDGFRa inhibitor is suffering from a disorder or condition associated with at least one oncogenic KIT and/or PDGFRA alteration.
  • the patient in need of a KIT or PDGFRa inhibitor is suffering from PDGFRA exon 18 positive unresectable or metastatic GIST.
  • the at least one oncogenic KIT and/or PDGFRA alteration is a genetic mutation in Exon 18 of PDGFRA.
  • the at least one oncogenic KIT and/or PDGFRa alteration is a D842V mutation in PDGFRA protein.
  • the at least one oncogenic KIT and/or PDGFRa alteration is a D842I mutation in PDGFRA protein.
  • the at least one oncogenic KIT and/or PDGFRa alteration is a D842Y mutation in PDGFRA protein.
  • the at least one oncogenic KIT and/or PDGFRa alteration is a non-D842 alteration in Exon 18 of PDGFRa.
  • the at least one oncogenic KIT and/or PDGFRa alteration is an indel in PDGFRA protein.
  • the at least one oncogenic KIT and/or PDGFRa alteration is D842-H845 in PDGFRA protein.
  • the at least one oncogenic KIT and/or PDGFRa alteration is DI842-843V in PDGFRA protein.
  • the at least one oncogenic KIT and/or PDGFRA alteration is a genetic mutation in Exon 17 of KIT.
  • the at least one oncogenic KIT and/or PDGFRa alteration is d557-558 in KIT protein. In some embodiments, the at least one oncogenic KIT and/or PDGFRa alteration is V560G in KIT protein. In some embodiments, the at least one oncogenic KIT and/or
  • PDGFRa alteration is V560G/D816V in KIT protein. In some embodiments, the at least one oncogenic KIT and/or PDGFRa alteration is V560G/N822K in KIT protein. In some embodiments, the at least one oncogenic KIT and/or PDGFRa alteration is a D816 mutation in KIT protein. In some embodiments, the at least one oncogenic KIT and/or PDGFRa alteration is a D816V mutation in KIT protein. In some embodiments, the at least one oncogenic KIT and/or PDGFRa alteration is D816E in KIT protein.
  • the at least one oncogenic KIT and/or PDGFRa alteration is D816F in KIT protein. In some embodiments, the at least one oncogenic KIT and/or PDGFRa alteration is D816H in KIT protein. In some embodiments, the at least one oncogenic KIT and/or PDGFRa alteration is D816I in KIT protein. In some embodiments, the at least one oncogenic KIT and/or PDGFRa alteration is D816Y in KIT protein. In some embodiments, the at least one oncogenic KIT and/or PDGFRa alteration is D820E in KIT protein.
  • the at least one oncogenic KIT and/or PDGFRa alteration is D820Y in KIT protein. In some embodiments, the at least one oncogenic KIT and/or PDGFRa alteration is Y823D in KIT protein. In some embodiments, the disorder or condition associated with at least one oncogenic KIT and/or PDGFRA alteration is gastrointestinal stromal tumor (GIST). In some embodiments, the patient is refractory to treatment with imatinib. In some embodiments, the patient has been treated with at least 3 prior lines of therapy. In some embodiments, the patient is refractory to treatment with imatinib, sunitinib, and/or regorafenib.
  • GIST gastrointestinal stromal tumor
  • the patient has unresectable GIST. In some embodiments, the patient has metastatic GIST. In some embodiments, the disorder or condition associated with at least one oncogenic KIT and/or PDGFRA alteration is acute myeloid leukemia.
  • the disorder or condition associated with at least one mutant/oncogenic KIT and/or PDGFRA alteration is mastocytosis.
  • the mastocytosis is chosen from cutaneous mastocytosis (CM) and systemic mastocytosis (SM).
  • the systemic mastocytosis is chosen from indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), and advanced systemic mastocytosis (AdvSM).
  • AdvSM includes aggressive systemic mastocytosis (ASM), SM with associated hematologic non-mast cell lineage disease (SM-AHNMD), and mast cell leukemia (MCL).
  • the systemic mastocytosis is indolent systemic mastocytosis (ISM). In some embodiments, the systemic mastocytosis is advanced systemic mastocytosis (AdvSM). In some embodiments, the systemic mastocytosis is smoldering systemic mastocytosis (SSM). In some embodiments, the systemic mastocytosis is aggressive systemic mastocytosis (ASM). In some embodiments, the systemic mastocytosis is SM with associated hematologic non-mast cell lineage disease (SM-AHNMD). In some embodiments, the systemic mastocytosis is mast cell leukemia (MCL).
  • ISM indolent systemic mastocytosis
  • AdvSM advanced systemic mastocytosis
  • SSM smoldering systemic mastocytosis
  • ASM aggressive systemic mastocytosis
  • the systemic mastocytosis is SM with associated hematologic non-mast cell lineage disease (SM-AHNM
  • ISM mastocytosis
  • SSM systemic mastocytosis
  • composition provides dosing regimens of
  • Compound (I) for the treatment of ISM and SSM More specifically, the disclosure provides methods for treating ISM and SSM in patients identified as having moderate-to-severe symptoms based on a minimum mean Total Symptom Score (TSS) as accessed by the Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-ASF) by administering Compound (I) at a once daily dose of 10 to 100 mg.
  • TSS Total Symptom Score
  • ISM-ASF Indolent Systemic Mastocytosis-Symptom Assessment Form
  • the FDA approved dose for Compound (I) (AYVAKITTM or avapritinib) for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations is 300 mg orally QD.
  • a Phase 2 clinical trial is currently evaluating the efficacy and safety of Compound (I) doses at 200-300 mg orally QD in patients with advanced systemic mastocytosis (AdvSM).
  • 25 mg of Compound (I) dosed once daily in patients with ISM or SSM shows improvement across all three aspects of its clinical profile, including reduction in mast cell burden, improvement of disease symptoms, and improvement in quality of life.
  • 25 mg of Compound (I) dosed once daily has a statistically significant reduction in ISM-SAF TSS and each symptom in the total domain score at 16 weeks.
  • the 25 mg dose provided similar mean improvements in TSS as the higher doses of 50 mg and 100 mg and better tolerability.
  • the 25 mg QD dose shows significant reduction in blood KIT D816V allele fraction.
  • 25 mg of Compound (I) dosed once daily in patients has a favorable safety profile in patients with ISM. For example, 95% of patients remain on the clinical study, with no discontinuations for adverse effects (AEs). No grade 33 AEs occurred in the 25 mg once daily cohort. Patients have
  • QoL quality of life
  • Some embodiments of the disclosure are directed to said methods, wherein the at least one crystalline form is crystalline Form T of a tosylate salt of Compound (I). Some embodiments of the disclosure are directed to said methods, wherein the at least one crystalline form is crystalline Form Tr of a tartrate salt of Compound (I). Some embodiments of the disclosure are directed to said methods, wherein the at least one crystalline form is crystalline Form H of a hydrochloride salt of Compound (I).
  • FIG. 1 is a schematic showing the interrelation of four crystalline forms, as well as non-limiting examples of how to prepare the crystalline forms. As indicated in FIG. 1, crystalline Form A, crystalline Form B, and crystalline Form O of Compound (I) are all anhydrous.
  • FIG. 2 shows an X-ray powder diffractogram for crystalline Form A of
  • Compound (I) referred to as crystalline Form A herein, showing degrees 2q (2-theta) on the X-axis and relative intensity on the Y-axis.
  • FIG. 3 shows a differential scanning calorimetry (DSC) thermogram for crystalline Form A of Compound (I) and a thermogravimetric analysis (TGA) thermal curve for crystalline Form A of Compound (I) recrystallized from acetone:water.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • FIG. 4 shows an X-ray powder diffractogram for crystalline Form B of
  • Compound (I) referred to as crystalline Form B herein, showing degrees 2q (2-theta) on the X-axis and relative intensity on the Y-axis.
  • FIG. 5 shows a DSC thermogram for the crystalline Form B of Compound (I).
  • FIG. 6 shows an X-ray powder diffractogram for crystalline Form C of
  • Compound (I) referred to as crystalline Form C herein, showing degrees 2q (2-theta) on the X-axis and relative intensity on the Y-axis.
  • FIG. 7 shows an X-ray powder diffractogram for crystalline Form O of
  • Compound (I) referred to as crystalline Form O herein, showing degrees 2q (2-theta) on the X-axis and relative intensity on the Y-axis.
  • FIG. 8 shows an X-ray powder diffractogram for crystalline Form T of a tosylate salt of Compound (I), referred to as crystalline Form T herein, showing degrees 2q (2-theta) on the X-axis and relative intensity on the Y-axis.
  • FIG. 9 shows an X-ray powder diffractogram for crystalline Form Tr of a tartrate salt of Compound (I), referred to as crystalline Form Tr herein, showing degrees 2q (2-theta) on the X-axis and relative intensity on the Y-axis.
  • FIG. 10 shows an X-ray powder diffractogram for crystalline Form H of a hydrochloride salt of Compound (I), referred to as crystalline Form H herein, showing degrees 2q (2-theta) on the X-axis and relative intensity on the Y-axis.
  • FIG. 11 shows the maximal percentage change in sum of tumor diameters from baseline in patients with PDGFRA D842V mutant GIST treated with Compound (I).
  • FIG. 12 shows bar graphs representing the effect of 25 mg once daily
  • Compound (I) 50 mg once daily Compound (I), 100 mg once daily Compound (I) and placebo on the KIT D816V allele burden in ISM patients. All Compound (I) dose cohorts showed significant decreases in KIT D816V allele burden.
  • FIG. 13 shows significant reductions in serum tryptase, mast cell burden and KIT D816V allele burden in ISM patients treated with 25 mg once daily dose compared to patients treated with placebo.
  • FIG. 14A shows ISM-SAF Total Symptom Score reduction from base line (the dotted line) in patients administered 25 mg once daily Compound (I). The top line represents placebo, the bottom line represents Compound (I) 25 mg once daily dose.
  • FIG. 14B shows ISM-SAF Total Symptom Score reduction from base line (the dotted line) in patients administered 50 mg once daily Compound (I). The top line represents placebo, the bottom line represents Compound (I) 50 mg once daily dose.
  • FIG. 14C shows ISM-SAF Total Symptom Score reduction from base line (the dotted line) in patients administered 100 mg once daily Compound (I). The top line represents placebo, the bottom line represents Compound (I) 100 mg once daily dose.
  • Compound (I) was developed to selectively target KIT D816V and other KIT exon 17 mutations.
  • Compound (I) is amorphous.
  • Compound (I) is crystalline.
  • Compound (I) is a mixture of crystalline forms.
  • Compound (I) is approved by the FDA for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations at 400 mg once a day (QD).
  • Compound (I) has also demonstrated a potent and selective activity in vitro against KIT D816V, robust growth inhibition in a tyrosine kinase inhibitor (TKI)-resistant mastocytoma model in vivo, and tolerability at active doses in toxicology and safety pharmacology studies.
  • TKI tyrosine kinase inhibitor
  • An ongoing Phase 1 study of Compound (I) in patients with AdvSM is evaluating safety and preliminary efficacy.
  • the recommended Phase 2 dose was identified as 300 mg once a day, and an expansion cohort of the study is further evaluating efficacy and safety of this dose in a larger cohort of patients, as well as validating the AdvSM Symptom Assessment Form (AdvSM-SAF) that has been developed to assess the impact of Compound (I) on symptom improvement in patients with AdvSM. Based on emerging safety and efficacy data in patients treated at 300 mg QD, an additional cohort of patients treated at 200 mg QD was added.
  • AdvSM-SAF AdvSM Symptom Assessment Form
  • the term“pharmaceutically acceptable salt” refers to a non-toxic salt form of a compound of this disclosure.
  • Compound (I) of this disclosure include those derived from suitable inorganic and organic acids and bases.
  • Pharmaceutically acceptable salts are well known in the art. Suitable pharmaceutically acceptable salts are, e.g., those disclosed in Berge, S.M., et al. J. Pharma. Sci. 66:1-19 (1977).
  • Non-limiting examples of pharmaceutically acceptable salts disclosed in that article include: acetate; benzenesulfonate; benzoate; bicarbonate; bitartrate; bromide; calcium edetate; camsylate; carbonate; chloride; citrate; dihydrochloride; edetate; edisylate; estolate; esylate; fumarate; gluceptate; gluconate; glutamate; glycollylarsanilate;
  • hexylresorcinate hydrabamine; hydrobromide; hydrochloride; hydroxynaphthoate; iodide; isethionate; lactate; lactobionate; malate; maleate; mandelate; mesylate; methylbromide; methylnitrate; methylsulfate; mucate; napsylate; nitrate; pamoate (embonate); pantothenate; phosphate/diphosphate; polygalacturonate; salicylate; stearate; subacetate; succinate; sulfate; tannate; tartrate; teociate; triethiodide; benzathine; chloroprocaine; choline; diethanolamine; ethylenediamine; meglumine; procaine; aluminum; calcium; lithium; magnesium; potassium; sodium; and zinc.
  • Non-limiting examples of pharmaceutically acceptable salts derived from appropriate acids include: salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; and salts formed by using other methods used in the art, such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid
  • salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid
  • salts formed by using other methods used in the art such as ion exchange.
  • compositions include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate,
  • Non- limiting examples of pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl) 4 salts.
  • alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium.
  • pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • pharmaceutically acceptable salts include besylate and glucosamine salts.
  • the term“ambient conditions” means room temperature, open air condition, and uncontrolled humidity condition.
  • the term“room temperature” or“ambient temperature” means a temperature ranging from 15 °C to 30 °C.
  • the terms“polymorph,”“crystal form,”“crystalline form,”“solid state form,” and“Form” interchangeably refer to a solid having a particular molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • DFS dynamic vapor sorption
  • TGA thermogravimetric analysis
  • the terms“crystalline Form [X] of Compound (I),”“crystalline Form [Y] of a [pharmaceutically acceptable] salt of Compound (I), and“crystalline Form [Z] of Compound (I) [solvate]” refer to unique crystalline forms that can be identified and distinguished from each other by at least one characterization technique including, e.g., X-ray powder diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and/or thermogravimetric analysis (TGA).
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • DVS dynamic vapor sorption
  • TGA thermogravimetric analysis
  • the novel crystalline forms are characterized by an X-ray powder
  • diffractogram having at least one signal at at least one specified two-theta value (o 2q).
  • the term“solvate” refers to a crystalline form of a molecule, atom, and/or ion further comprising at least one molecule of a solvent or solvents incorporated into the crystalline lattice structure in stoichiometric or nonstoichiometric amounts.
  • the solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement.
  • a solvate with a nonstoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate.
  • solvates may occur as dimers or oligomers comprising more than one molecule.
  • the solvent is water, the solvate is referred to herein as a“hydrate.”
  • XRPD refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded at ambient conditions in transmission or reflection geometry using a diffractometer.
  • an X-ray powder diffractogram refers to an experimentally obtained pattern plotting signal positions (on the abscissa) versus signal intensities (on the ordinate).
  • an X-ray powder diffractogram may include at least one broad signal.
  • an X-ray powder diffractogram may include at least one signal, each identified by its angular value as measured in degrees 2q (° 2q), depicted on the abscissa of an X-ray powder diffractogram, which may be expressed as“a signal at ... degrees two- theta,”“a signal at [a] two-theta value(s) of . ..” and/or“a signal at at least ... two-theta value(s) chosen from . ...”
  • the term“X-ray powder diffractogram having a signal at ... two- theta values” refers to an XRPD pattern that contains X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (o 2q).
  • the term“signal” refers to a point in the XRPD pattern where the intensity as measured in counts is at a local maximum.
  • At least one signal in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye.
  • some art- recognized methods are capable of and suitable for determining whether a signal exists in a pattern, such as, e.g., Rietveld refinement.
  • the terms“a signal at ... degrees two-theta,”“a signal at [a] two- theta value[] of ...,” and“a signal at at least ... two-theta value(s) chosen from . ...” refer to X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (o 2q).
  • the repeatability of the angular values is in the range of ⁇ 0.2° 2q, i.e., the angular value can be at the recited angular value + 0.2 degrees two-theta, the angular value - 0.2 degrees two-theta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value -0.2 degrees two-theta).
  • the angular value can be at the recited angular value + 0.2 degrees two-theta, the angular value - 0.2 degrees two-theta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value -0.2 degrees two-theta).
  • signal intensities refer to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect the relative signal intensities include, e.g., sample thickness and preferred orientation (e.g., the crystalline particles are not distributed randomly).
  • amorphous refers to a solid material having no long range order in the position of its molecules.
  • an amorphous material is a solid material having no sharp signal(s) in its X-ray power diffractogram (i.e., is not crystalline as determined by XRPD).
  • Amorphous refers to a solid form that is not crystalline. Instead, at least one broad signal (e.g., at least one halo) may appear in its diffractogram. Broad signals are characteristic of an amorphous solid.
  • an X-ray powder diffractogram is“substantially similar to that in [a particular] Figure” when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two diffractograms are the same ⁇ 0.2 °2q.
  • determining“substantial similarity” one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions in XRPD diffractograms even for the same crystalline form.
  • a crystalline form is“substantially pure” when it accounts for an amount by weight equal to or greater than 90% of the sum of all solid form(s) in a sample as determined by a method in accordance with the art, such as quantitative XRPD.
  • the solid form is“substantially pure” when it accounts for an amount by weight equal to or greater than 95% of the sum of all solid form(s) in a sample.
  • the solid form is“substantially pure” when it accounts for an amount by weight equal to or greater than 98% of the sum of all solid form(s) in a sample.
  • the solid form is“substantially pure” when it accounts for an amount by weight equal to or greater than 99% of the sum of all solid form(s) in a sample.
  • the solid form is“substantially pure” when it accounts for an amount by weight equal to or greater than 98.0% of the sum of all solid organic form(s) in a sample.
  • “solid organic form(s)” excludes water, elementals, solvents, and Compound (I)’s enantiomer.
  • the“enantiomer” of Compound (I) is
  • the solid form is“substantially pure” when it has
  • the solid form is“substantially pure” when it has no more than 2.0% w/w total impurities. In some embodiments, the solid form is“substantially pure” when it has not more than 0.15% w/w of each known unspecified impurity.
  • Known unspecified impurities include, e.g., impurity (I-A):
  • the solid form is“substantially pure” when it has not more than 0.55 area / area of Compound (E). In some embodiments, the solid form is“substantially pure” when it has not more than 0.15% w/w of each known unspecified impurity and not more than 0.10% w/w of any other individual impurity. In some embodiments, the solid form is“substantially pure” when it has not more than 0.15% w/w of each known unspecified impurity and not more than 0.10% w/w of any other individual impurity, and not more than 0.55 area/area of Compound (E).
  • the solid form is“substantially pure” when it is essentially free of solvent, e.g., the solid form has not more than 3000 ppm methanol, not more than 5000 ppm 2-propanol, not more than 600 ppm dichloromethane, not more than 720 ppm tetrahydrofuran, not more than 620 ppm 2-methyltetrahydrofuran, not more than 5000 ppm acetone, not more than 5000 ppm heptane, not more than 5000 ppm methyl tert-butyl ether, not more than 890 ppm toluene, or not more than 380 ppm 1,4-dioxane.
  • N,N-diisopropylethylamine is a tertiary amine which may be used in the last step of the processing step of Compound (I).
  • DIPEA diisopropylethylamine
  • the solid form is“substantially pure” when it is essentially free of DIPEA. In some embodiments, the solid form is“substantially pure” when the solid form has not more than 1000 ppm of DIPEA.
  • the solid form is“substantially pure” when it is 97.0% to 103.0% w/w solvent-free, anhydrous basis (calculation includes correction for water, residual solvents and DIPEA content) by HPLC.
  • HPLC retention time must be ⁇ 2% of that of the standard.
  • HPLC analysis may be performed, e.g., as described below: First generation HPLC method:
  • a“selective KIT inhibitor” or a“selective PDGFRa inhibitor” refers to a compound or a pharmaceutically acceptable salt thereof or a solvate of any of the foregoing that selectively inhibits a KIT protein kinase or PDGFRa protein kinase over another protein kinase and exhibits at least a 2-fold selectivity for a KIT protein kinase or a PDGFRa protein kinase over another kinase.
  • a selective KIT inhibitor or a selective PDGFRA inhibitor exhibits at least a 10-fold selectivity; at least a 15-fold selectivity; at least a 20-fold selectivity; at least a 30-fold selectivity; at least a 40-fold selectivity; at least a 50-fold selectivity; at least a 60-fold selectivity; at least a 70-fold selectivity; at least a 80-fold selectivity; at least a 90-fold selectivity; at least 100-fold, at least 125-fold, at least 150-fold, at least 175-fold, or at least 200-fold selectivity for a KIT protein kinase or a PDGFRa kinase over another kinase.
  • a selective KIT inhibitor or a selective PDGFRa inhibitor exhibits at least 150-fold selectivity over another kinase, e.g., VEGFR2 (vascular endothelial growth factor receptor 2), SRC (Non-receptor protein tyrosine kinase), and FLT3 (Fms-Like Tyrosine kinase 3).
  • selectivity for a KIT protein kinase or a PDGFRa protein kinase over another kinase is measured in a cellular assay (e.g., a cellular assay).
  • selectivity for a KIT protein kinase or a PDGFRa protein kinase over another kinase is measured in a biochemical assay (e.g., a biochemical assay).
  • a therapeutically effective amount of a compound disclosed herein refers to an amount of the compound that will elicit a biological or medical response in a subject, e.g., reduction or inhibition of enzyme or protein activity, or ameliorate symptoms, alleviate conditions, or slow or delay disease progression.
  • a therapeutically effective amount refers to the amount of the compound that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, and/or ameliorate a disorder or condition (i) mediated by KIT and/or PDGRFA, or (ii) associated with KIT and/or PDGFRA activity, or (iii) characterized by activity (normal or abnormal) of KIT and/or PDGFRA; or (2) reduce or inhibit the activity of KIT and/or PDGFRa protein kinase.
  • a therapeutically effective amount refers to the amount of the compound that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, at least partially reduces or inhibits the activity of KIT and/or
  • PDGFRa protein kinase The therapeutically effective amount will depend on the purpose of the treatment and will be ascertainable by one of ordinary skill in the art (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).
  • the term“inhibit,”“inhibition,” or‘inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term“patient” or“subject” refers to an organism to be treated by the methods of the present disclosure.
  • Non-limiting example organisms include mammals, e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like.
  • the organism is a human.
  • the patient to be treated has ISM or SSM with moderate-to-severe symptoms that cannot be adequately controlled with approved symptom-directed therapies.
  • the term“treat,”“treating,” or“treatment,” when used in connection with a disorder or condition includes any effect, e.g., lessening, reducing, modulating, ameliorating, and/or eliminating, that results in the improvement of the disorder or condition. Improvements in or lessening the severity of any symptom of the disorder or condition can be readily assessed according to standard methods and techniques known in the art.
  • treatment comprises a reduction of mast cell burden.
  • objective measures of mast cell burden include serum tryptase, bone marrow mast cell numbers, skin mast cell infiltrates, and KIT D816V mutant allele burden in blood.
  • objective measures of mast cell burden include serum tryptase, bone marrow mast cell numbers, and KIT D816V mutant allele burden in blood.
  • treatment comprises a reduction of systemic mastocytosis symptoms.
  • Systemic mastocytosis symptoms include, but are not limited to, pruritus, flushing, GI cramping, diarrhea, anaphylaxis (especially to bee venom), bone pain, osteoporosis, and urticarial pigmentosa.
  • an ISM-SAF patient reported outcome (PRO) instrument as defined herein is used to assess symptom improvement.
  • the patient completes the ISM-SAF once a day prior to receiving treatment and the patient also completes the ISM-SAF once a day while on treatment.
  • the patient completes the ISM-SAF for a period of time, e.g., four weeks, beginning at the time of informed consent, during which time best-supportive care (BSC) medications are optimized and stabilized.
  • a period of time e.g., four weeks
  • BSC time best-supportive care
  • ISM-SAF once a day while screening procedures are completed to assess study eligibility.
  • baseline symptoms are collected for a period of time, e.g., 14 days, immediately preceding study entry. These data are used as a Baseline Total Symptom Score (TSS).
  • TSS Baseline Total Symptom Score
  • the ISM-SAF is completed by the patient once a day through completion the study, e.g., through Part 1 and Part 2, and through Week 52 in Part 3.
  • the primary endpoint for Part 2 of the study is mean change in ISM-SAF TSS from Baseline to Week 12.
  • treatment improves the number of episodes of anaphylaxis.
  • an“episode of anaphalaxis” is an episode of anaphylaxis treated with epinephrine.
  • treatment improves quality of life (QoL) as measured by one or more questionnaires.
  • QoL questionnaires include the MC- QoL, the PGIS, the SF-12, the PGIC, and the EQ-5D-EL.
  • the MC-QoL is a disease-specific QoL tool developed specifically for use in patients with ISM and CM (Siebenhaar, F. et al., Allergy 71(6):869-77 (2016)).
  • the MC-QoL contains 27 items assessing four domains:
  • the PGIS is a single-item scale that assesses a patient’s perception of disease symptoms at a point in time.
  • the PGIS has been widely used to evaluate a patient’s overall sense of whether a treatment has been beneficial.
  • the SF-12 was developed for the Medical Outcomes Study, a multiyear study of patients with chronic conditions. The instrument was designed to reduce respondent burden, while achieving minimum standards of precision for purposes of group comparisons involving multiple health dimensions.
  • the questionnaire measures health and well-being using 8 health domains from the patient’s perspective.
  • the recall period is four weeks.
  • the PGIC is a single-item scale that assesses a patient’s perception of change in disease symptoms at a point in time.
  • the EQ-5D- 5L is a standardized instrument for measuring generic health status. It is made up of two components: health state description and evaluation. Health status is measured in terms of five dimensions (5D): mobility; self-care; usual activities; pain/discomfort; and
  • treatment improves bone density. Bone density is measured by a dual-energy x-ray absorptiometry scan assessing both lumbar spine and hip. In some embodiments, treatment does not affect bone density.
  • SD stable disease
  • PFS progression free survival
  • SM systemic mastocytosis
  • MCs clonal disorder of mast cells
  • BM bone marrow
  • GI gastrointestinal
  • WHO World Health Organization
  • SM indolent SM
  • SSM smoldering SM
  • ASM aggressive SM
  • MCL MC leukemia
  • ISM is associated with a normal or near-normal life-expectancy and the prognosis of SSM is intermediate (Lim, K.H. et al., Blood 113(23):5727-36 (2009)).
  • the major criterion for SM is the multifocal accumulation and clustering of MCs in the BM or other extracutaneous organs.
  • ISM is defined by the presence of less than two B-findings per WHO criteria and no C-findings; SSM is defined by the presence of two or more B-findings and no C-findings (Valent, P. et al, Blood 129(11):1420-27 (2017)).
  • the B-findings include: 1. Tryptase >200 ng/ml and bone marrow infiltration >30%, 2. Presence of hepatomegaly or splenomegaly without hypersplenism or liver dysfunction, 3.
  • ISM myelodysplastic syndrome
  • MDS myelodysplastic syndrome
  • MPN myeloproliferative neoplasms
  • ISM is the most common category of SM. Patients with ISM have aberrant mast cell collections in their bone marrow but have no evidence for another hematologic disease or tissue dysfunction. Mast cells in aspirate smears are usually ⁇ 5%. Patients with ISM have a comparable life expectancy to general population but can be symptomatic with various mast cell mediator release symptoms. Risk of progression to an advanced variant is less than 5%. SSM is characterized by a high burden of mast cells but no evidence of an overt hematologic disorder or tissue dysfunction. Patients with SSM are thought to have a higher risk of progression to a more advanced category. Both ISM and SSM are referred to as non-advanced SM.
  • neoplastic MCs display a mutation at the D816 position in exon 17 of KIT, which results in ligand- independent activation of KIT kinase activity. Wild-type MCs require KIT activity for their differentiation and survival and, therefore, constitutive activation of KIT through D816V mutation is thought to be a pathogenic driver for SM (Chabot, B. et al., Nature 335(6185):88- 9 (1988)).
  • KIT D816V mutations are found in 90% to 98% of patients with SM, with rare KIT D816Y, D816F, and D816H variants identified (Garcia-Montero, A.C., et al., Blood 108(7):2366-72 (2006); Valent, P., Am J Cancer Res. 3(2):159-72 (2013); Verstovsek, S., Eur J Haematol. 90(2):89-98 (2013)). Based on these findings, KIT D816V is considered a major therapeutic target in SM (Valent et al, 2017) and several agents targeting this mutation have been studied.
  • ISM and SSM are characterized by severe symptoms associated with MC mediator release, including pruritus, flushing, GI cramping, diarrhea, anaphylaxis (especially to bee venom), bone pain, and osteoporosis (Gulen, T. et al., J Intern Med. 279(3):211-28 (2016)). These symptoms can be severely debilitating, having a negative impact on quality of life (Hermine, O. et al, Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: Additional efficacy analyses from the randomized, placebo-controlled, phase 3 study, EHA Abstract 709 (2017); Jennings, S., et al, J Allergy Clin Immunol.
  • CM cosmetically debilitating cutaneous mastocytosis
  • Nonspecific treatments have been employed to control MC mediator-related symptoms with varying degrees of efficacy; none impact MC burden in tissues. These treatments include H1 and H2 blockers, proton-pump inhibitors, osteoclast inhibitors, leukotriene inhibitors, corticosteroids, cromolyn sodium, and the anti-IgE antibody omalizumab. Recently, several KIT-targeting tyrosine kinase inhibitors (TKIs) have been studied in patients with ISM and SSM.
  • TKIs KIT-targeting tyrosine kinase inhibitors
  • TKI therapies have demonstrated that symptom improvement, and in some cases, reduction in measures of MC burden, can be achieved in patients with ISM and SSM
  • none of the available agents specifically target the KIT D816V driver mutation in this disease, and to date, no TKI agent, nor any other agent, has been approved to treat ISM and SSM. Therefore, there remains an unmet medical need in patients with moderate-to-severe symptoms who do not adequately respond to existing symptomatic treatments.
  • the“Indolent Systemic Mastocytosis-Symptom Assessment Form” or“ISM-SAF” is employed for the daily patient reported outcome (PRO) assessment on e.g., an eDiary.
  • the ISM-SAF is a 12-item PRO developed specifically to assess symptoms in patients with ISM and SSM. Though primarily developed for evaluating treatment efficacy hypotheses, the ISM-SAF can also be used to screen participants into (or out of) clinical studies based on a minimum level of sign and symptom severity. Eleven items shown in the table below are graded on an 11-point scale (0 to 10, none to maximum severity), and 1 item (diarrhea) also assesses frequency.
  • the ISM-SAF generates scores for each item, for the domains of skin/Skin Symptom Score (SSS), GI/Gastrointestinal Symptom Score (GSS), and nonspecific symptoms, and a Total Symptom Score (TSS).
  • the TSS is the addition of all symptoms together.
  • TSS is items 1-10 and 12.
  • GSS is items 2-3 and 12.
  • SSS is items 4-6.
  • the patient completes the ISM-SAF daily for 4 weeks beginning at the time of informed consent, during which time BSC medications are optimized and stabilized. Once 4 weeks of data have been collected, the ISM-SAF is completed daily for an additional 2 weeks (14 days) to determine patient eligibility based on the ISM-SAF symptom threshold.
  • the patient with ISM or SSM has moderate-to-severe symptoms characterized by a minimum TTS.
  • the patient with ISM or SSM has moderate- to-severe symptoms characterized by a minimum TTS of 3 28 as assessed using the ISM- SAF.
  • the minimum TTS is >27, >26, >25, >24, >23, >22, >21, >20.
  • the patient with ISM or SSM with moderate-to-severe symptoms has a minimum TSS of >28 and 3 1 symptom in skin or GI domains of the ISM-SAF at baseline.
  • baseline is the 14-day period before cycle 1 day 1 (C1D1).
  • the patient is not experiencing an acute flare of symptoms beyond their typical baseline symptoms.
  • the patient has failed to achieve symptom control for 1 or more baseline symptoms, as determined by the investigator, with at least 2 of the following symptomatic therapies administered at optimal (approved) dose and for a minimum of 4 weeks (28 days) before starting the ISM-SAF for determination of eligibility: H1 blockers, H2 blockers, proton-pump inhibitors, leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab.
  • the patient has a baseline serum tryptase of ⁇ 20 ng/mL.
  • the patient has a baseline serum tryptase of >20 ng/mL.
  • the patient has cutaneous
  • CM mastocytosis
  • the patient does not have CM.
  • the diagnosis of CM requires the presence of clinical and histopathologic findings of abnormal mast cell in- filtration of the dermis with no evidence of systemic mast cell infiltration either in the bone marrow or other extracutaneous organs.
  • CM is further subdivided into 3 different subvariants: urticaria pigmentosa/ maculopapular cutaneous mastocytosis (MPCM), diffuse CM, and mastocytoma of the skin.
  • the patient with ISM or SSM has KIT D816V mutation.
  • the KIT D816V mutation can be detected by a high sensitivity assay such as a droplet digital polymerase chain reaction (ddPCR) assay with a limit of detection (LOD) of 0.022% mutant allele frequency (MAF).
  • ddPCR droplet digital polymerase chain reaction
  • LOD limit of detection
  • MAF mutant allele frequency
  • an“adverse event” or“AE” is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related.
  • An AE also referred to as an adverse experience
  • An AE can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, without any judgement about causality.
  • An AE can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.
  • the terms“about” and“approximately,” when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, include the value of a specified dose, amount, or weight percent or a range of the dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent.
  • the crystalline forms of Compound (I) are substantially pure. These may be inhibitors of KIT and/or PDGFRa protein kinase and in some embodiments are selective inhibitors of KIT and/or PDGFRa protein kinase.
  • KIT and/or PDGFRa inhibitors are useful in the treatment of disorders and conditions associated with oncogenic KIT and PDGFRA alterations, e.g., mastocytosis, gastrointestinal stromal tumors (GIST), acute myeloid leukemia (AML), melanoma, seminoma, intracranial germ cell tumors, and mediastinal B- cell lymphoma.
  • the present disclosure provides crystalline Form A of Compound (I):
  • crystalline Form A is more stable at ambient temperature than the other crystalline forms disclosed herein. Moreover, crystalline Form A has been shown to possess better physical and chemical stability properties for formulating as compared to the other crystalline forms identified herein. Crystalline Form A also provides advantages in its ease of isolation. Crystalline Form A has good thermodynamic stability as shown by its DSC.
  • FIG. 2 shows an X-ray powder diffractogram of crystalline Form A of
  • FIG. 3 shows a DSC thermogram of crystalline Form A of Compound (I).
  • crystalline Form A of Compound (I) is characterized by a DSC thermogram having an endothermic event with a signal at a temperature ranging from 194 °C to 195 oC.
  • crystalline Form A of Compound (I) is characterized by DSC
  • thermogram having an endothermic event with an onset temperature of 193 °C.
  • crystalline Form A of Compound (I) is characterized by DSC thermogram having an endothermic event with an onset temperature of 190 °C, 191 °C, or 192 °C.
  • crystalline Form A of Compound (I) is characterized by a DSC thermogram substantially similar to that in FIG. 3.
  • FIG. 3 also shows a TGA thermal curve for crystalline Form A of Compound (I) recrystallized from a mixture of acetone and water.
  • TGA thermal curve for crystalline Form A of Compound (I) recrystallized from a mixture of acetone and water.
  • crystalline Form A of Compound (I) is a free-flowing, crystalline white to off-white to yellow solid. In some embodiments, crystalline Form A of Compound (I) is anhydrous polymorph. In some embodiments, the water content of crystalline Form A of Compound (I) is below 1.0% water. In some embodiments, the water content of crystalline Form A of Compound (I) is not more than 0.04%. In some
  • water content levels are ⁇ 0.01% - 0.07%.
  • crystalline Form A of Compound (I) appear to be needles and/or sheet- or plate-like solids.
  • crystalline Form A of Compound (I) is characterized by a weight change of 0.42% in a dynamic vapor sorption (DVS) experiment, while varying the relative humidity from 2-95% RH at 25 oC.
  • crystalline Form A of Compound (I) is characterized by a weight change of 0.29% in a dynamic vapor sorption (DVS) experiment, while varying the relative humidity from 2-95% RH at 40 oC.
  • crystalline Form A of Compound (I) is characterized by a weight change of 0.20% in a dynamic vapor sorption (DVS) experiment, while varying the relative humidity from 70-95% RH at 40 oC.
  • crystalline Form A of Compound (I) is non-hygroscopic as determined by dynamic vapor sorption (DVS) analysis. In some embodiments, crystalline Form A of Compound (I) uptakes up to 0.44% moisture by weight when exposed to 40 oC and up to 95% relative humidity.
  • crystalline Form A of Compound (I) is characterized by solubility of 0.03 mg/mL in fasted state simulated intestinal fluid (FaSSIF). In some embodiments, crystalline Form A of Compound (I) is characterized by solubility of 2.11 mg/mL in fasted state simulated gastric fluid.
  • crystalline Form A of Compound (I) is characterized by solubility of 0.03 mg/mL in fasted state simulated intestinal fluid (FaSSIF) at 37 °C. In some embodiments, crystalline Form A of Compound (I) is characterized by solubility of 2.11 mg/mL in fasted state simulated gastric fluid at 37 °C.
  • crystalline Form A of Compound (I) has a particle size distribution (PSD), wherein D10 is not less than (NLT) 1 ⁇ m, D50 is 5-105 ⁇ m, e.g., in some embodiments, D50 is 8-80 ⁇ m; and D90 is not more than (NMT) 500 ⁇ m, e.g., in some embodiments, D90 is NMT 300 ⁇ m.
  • D10 is the diameter at which 10% of the sample’s mass is not less than 1 ⁇ m.
  • D50 is the mass-median-diameter (MMD).
  • MMD is the average particle diameter by mass.
  • the average particle diameter by mass i.e., D50 or MMD
  • D90 is the diameter at which 90% of the sample’s mass is not more than 500 ⁇ m.
  • the PSD is NLT 1 ⁇ m (D10) and NMT 500 ⁇ m (D90).
  • Particle size distribution may be analyzed using a laser diffraction system, e.g., Malvern
  • Mastersizer 3000 equipped with a wet dispersion unit.
  • the dispersant is 0.5% Span 85 in hexanes and the sample is 125 mg crystalline Form A of Compound (I) in 50 mL 0.5% Span 85 in hexanes.
  • particle size and/or particle size distribution has an effect on tablet dissolution.
  • crystalline Form A of Compound (I) is in substantially pure form. In some embodiments, crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. In some embodiments, crystalline Form A of
  • Compound (I) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation with signals
  • crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 11.5 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 15.4 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.7 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 18.1 ⁇ 0.2 degrees two-theta.
  • crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 20.0 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form A of Compound (I) is characterized by an X- ray powder diffractogram having a signal at 21.6 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 23.1 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 23.9 ⁇ 0.2 degrees two-theta.
  • crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 25.9 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 30.7 ⁇ 0.2 degrees two- theta.
  • crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at two-theta values of 11.5 ⁇ 0.2, 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 18.1 ⁇ 0.2, 20.0 ⁇ 0.2, 21.6 ⁇ 0.2, 23.1 ⁇ 0.2, 23.9 ⁇ 0.2, 25.9 ⁇ 0.2, and 30.7 ⁇ 0.2.
  • crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 11.5 ⁇ 0.2, 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 18.1 ⁇ 0.2, 20.0 ⁇ 0.2, 21.6 ⁇ 0.2, 23.1 ⁇ 0.2, 23.9 ⁇ 0.2, 25.9 ⁇ 0.2, and 30.7 ⁇ 0.2.
  • crystalline Form A of Compound (I) is
  • X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 11.5 ⁇ 0.2, 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 18.1 ⁇ 0.2, 20.0 ⁇ 0.2, 21.6 ⁇ 0.2, 23.1 ⁇ 0.2, 23.9 ⁇ 0.2, 25.9 ⁇ 0.2, and 30.7 ⁇ 0.2.
  • crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 11.5 ⁇ 0.2, 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 18.1 ⁇ 0.2, 20.0 ⁇ 0.2, 21.6 ⁇ 0.2, 23.1 ⁇ 0.2, 23.9 ⁇ 0.2, 25.9 ⁇ 0.2, and 30.7 ⁇ 0.2.
  • crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 11.5 ⁇ 0.2, 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 18.1 ⁇ 0.2, 20.0 ⁇ 0.2, 21.6 ⁇ 0.2, 23.1 ⁇ 0.2, 23.9 ⁇ 0.2, 25.9 ⁇ 0.2, and 30.7 ⁇ 0.2.
  • crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 11.5 ⁇ 0.2, 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 18.1 ⁇ 0.2, 20.0 ⁇ 0.2, 21.6 ⁇ 0.2, 23.1 ⁇ 0.2, 23.9 ⁇ 0.2, 25.9 ⁇ 0.2, and 30.7 ⁇ 0.2.
  • crystalline Form A of Compound (I) is characterized by an X- ray powder diffractogram having a signal at at least three two-theta values chosen from 11.5 ⁇ 0.2, 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 18.1 ⁇ 0.2, 20.0 ⁇ 0.2, 21.6 ⁇ 0.2, 23.1 ⁇ 0.2, 23.9 ⁇ 0.2, 25.9 ⁇ 0.2, and 30.7 ⁇ 0.2.
  • crystalline Form A of Compound (I) is
  • X-ray powder diffractogram having a signal at at least two two-theta values chosen from 11.5 ⁇ 0.2, 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 18.1 ⁇ 0.2, 20.0 ⁇ 0.2, 21.6 ⁇ 0.2, 23.1 ⁇ 0.2, 23.9 ⁇ 0.2, 25.9 ⁇ 0.2, and 30.7 ⁇ 0.2.
  • crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 11.5 ⁇ 0.2, 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 18.1 ⁇ 0.2, 20.0 ⁇ 0.2, 21.6 ⁇ 0.2, 23.1 ⁇ 0.2, 23.9 ⁇ 0.2, 25.9 ⁇ 0.2, and 30.7 ⁇ 0.2.
  • crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 11.5 ⁇ 0.2, 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 20.0 ⁇ 0.2, and 21.6 ⁇ 0.2.
  • crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 11.5 ⁇ 0.2, 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 20.0 ⁇ 0.2, and 21.6 ⁇ 0.2.
  • crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 11.5 ⁇ 0.2, 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 20.0 ⁇ 0.2, and 21.6 ⁇ 0.2.
  • crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having a signal at two-theta values of 11.5 ⁇ 0.2, 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 20.0 ⁇ 0.2, and 21.6 ⁇ 0.2.
  • crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 2.
  • crystalline Form A of Compound (I) is characterized by a 13 C NMR (CDCl 3 , 100 MHz) pattern having a signal at the following d (expressed as ppm): 32.1, 39.2, 43.5, 45.5, 55.6, 101.3, 115.2, 115.5, 116.0, 116.5, 117.9, 127.0, 127.7, 131.1, 137.1, 144.4, 146.7, 154.6, 156.3, 160.4, and 161.7.
  • the present disclosure provides a process for preparing crystalline Form A of Compound (I).
  • the process for preparing crystalline Form A of Compound (I) is a recrystallization process.
  • the recrystallization process removes impurities.
  • the recrystallization process removes residual N,N-diisopropylethylamine.
  • the process for preparing crystalline Form A of Compound (I) is a recrystallization process.
  • the recrystallization process removes impurities.
  • the recrystallization process removes residual N,N-diisopropylethylamine.
  • recrystallization process comprises acetone and water.
  • the present disclosure provides crystalline Form A of Compound (I) prepared by a process comprising: dissolving Compound (I) in acetone and water to obtain a suspension; heating the suspension to obtain a solution; and cooling the solution, such as by lowering the temperature.
  • the ratio of acetone to water is 85:15.
  • the suspension is heated to a temperature ranging from 40 °C to 50 °C.
  • the process further comprises stirring the heated suspension. In some embodiments, the process further comprises stirring the heated suspension at a temperature ranging from 40 °C to 50 °C. In some embodiments, the heated suspension is stirred. In some embodiments, the heated suspension is stirred for fifteen minutes. In some embodiments, the heated suspension is stirred at a temperature ranging from 40 °C to 50 °C. In some embodiments, the heated suspension is stirred for fifteen minutes at a temperature ranging from 40 °C to 50 °C.
  • the process further comprises polish filtering the stirred suspension. In some embodiments, the process further comprises polish filtering the stirred suspension at a temperature ranging from 40 °C to 50 °C. [00109] In some embodiments, the process further comprises atmospherically distilling the polish filtered suspension. In some embodiments, the process further comprises
  • cooling the solution comprises lowering the temperature. In some embodiments, cooling the solution comprises lowering the temperature to a temperature ranging from 45 °C to 55 °C. In some embodiments, cooling the solution comprises lowering the temperature over fifteen minutes. In some embodiments, cooling the solution comprises lowering the temperature to a temperature ranging from 45 °C to 55 °C over fifteen minutes.
  • the present disclosure provides a process for preparing crystalline Form A of Compound (I) and also provides crystalline Form A of Compound (I) prepared by a process comprising: slurrying crystalline Form C of Compound (I) in acetone at an elevated temperature.
  • the elevated temperature is at least 30 °C.
  • the present disclosure provides a process for preparing crystalline Form A of Compound (I) and also provides crystalline Form A of Compound (I) prepared by a process comprising: heating crystalline Form O of Compound (I) to an elevated temperature; and slurrying in at least one solvent.
  • the elevated temperature is 186 °C.
  • the at least one solvent is acetone.
  • the at least one solvent comprises acetone and water.
  • the present disclosure provides a process for preparing crystalline Form A of Compound (I) and also provides crystalline Form A of Compound (I) prepared by a process comprising: slurrying crystalline Form B of Compound (I) in at least one solvent at an elevated temperature.
  • the at least one solvent is acetone.
  • the elevated temperature is ranging from 25 °C to 50 °C.
  • any of the above processes for preparing crystalline Form A of Compound (I) may further comprise purifying crystalline Form A by dissolving crystalline Form A in a mixture of acetone and water and/or by slurring in isopropanol.
  • the isopropanol slurry is obtained by taking the crystalline solid up in isopropanol and heating and then cooling the resulting mixture.
  • the crystalline solid is isolated by filtration, washed with isopropanol, and dried.
  • the present disclosure provides a process for preparing a substantially pure crystalline Form A of Compound (I). Crystalline Form B of Compound (I)
  • the present disclosure provides crystalline Form B of Compound (I):
  • FIG. 4 shows an X-ray powder diffractogram for crystalline Form B of Compound (I) at ambient conditions.
  • FIG. 5 shows a DSC thermogram for crystalline Form B of Compound (I).
  • crystalline Form B of Compound (I) is characterized by a DSC thermogram having an endothermic event with a signal at a temperature ranging from 210 oC to 211 oC.
  • crystalline Form B of Compound (I) is characterized by a DSC thermogram having an endothermic event with an onset temperature of 207 °C.
  • crystalline Form B of Compound (I) is characterized by a DSC thermogram substantially similar to that in FIG. 5.
  • crystalline Form B of Compound (I) is in substantially pure form.
  • crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation.
  • Compound (I) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation with signals substantially similar to those recited in Table 2.
  • crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 4.1 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 9.7 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 11.2 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 13.8 ⁇ 0.2 degrees two-theta.
  • crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.4 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form B of Compound (I) is characterized by an X- ray powder diffractogram having a signal at 17.0 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 19.6 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 20.6 ⁇ 0.2 degrees two-theta.
  • crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 21.0 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 22.4 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form B of Compound (I) is characterized by an X- ray powder diffractogram having a signal at 23.1 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 23.8 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 29.0 ⁇ 0.2 degrees two-theta.
  • crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at two-theta values of 4.1 ⁇ 0.2, 9.7 ⁇ 0.2,
  • Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 4.1 + 0.2, 9.7 + 0.2, 11.2 + 0.2, 13.8 + 0.2, 16.4 + 0.2,
  • crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from
  • crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 4.1 + 0.2, 9.7 + 0.2, 11.2 + 0.2,
  • crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 4.1 + 0.2, 9.7 + 0.2, 11.2 + 0.2, 13.8 + 0.2, 16.4 + 0.2, 17.0 + 0.2,
  • crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 4.1 + 0.2,
  • crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 4.1 + 0.2, 9.7 + 0.2, 11.2 + 0.2, 13.8 + 0.2, 16.4 ⁇ 0.2, 17.0 ⁇ 0.2, 19.6 ⁇ 0.2, 20.6 ⁇ 0.2, 21.0 ⁇ 0.2, 22.4 ⁇ 0.2, 23.1 ⁇ 0.2, 23.8 ⁇ 0.2, and 29.0 ⁇ 0.2.
  • crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 4.1 ⁇ 0.2, 9.7 ⁇ 0.2, 11.2 ⁇ 0.2, 13.8 ⁇ 0.2, 16.4 ⁇ 0.2, 17.0 ⁇ 0.2, 19.6 ⁇ 0.2, 20.6 ⁇ 0.2, 21.0 ⁇ 0.2, 22.4 ⁇ 0.2, 23.1 ⁇ 0.2, 23.8 ⁇ 0.2, and 29.0 ⁇ 0.2.
  • crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 4.1 ⁇ 0.2, 9.7 ⁇ 0.2, 11.2 ⁇ 0.2, 13.8 ⁇ 0.2, 16.4 ⁇ 0.2, 17.0 ⁇ 0.2, 19.6 ⁇ 0.2, 20.6 ⁇ 0.2, 21.0 ⁇ 0.2, 22.4 ⁇ 0.2, 23.1 ⁇ 0.2, 23.8 ⁇ 0.2, and 29.0 ⁇ 0.2.
  • crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 4.1 ⁇ 0.2, 16.4 ⁇ 0.2, 17.0 ⁇ 0.2, 19.6 ⁇ 0.2, and 20.6 ⁇ 0.2.
  • crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 4.1 ⁇ 0.2, 16.4 ⁇ 0.2, 17.0 ⁇ 0.2, 19.6 ⁇ 0.2, and 20.6 ⁇ 0.2.
  • crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 4.1 ⁇ 0.2, 16.4 ⁇ 0.2, 17.0 ⁇ 0.2, 19.6 ⁇ 0.2, and 20.6 ⁇ 0.2.
  • crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram having a signal at two-theta values of 4.1 ⁇ 0.2, 16.4 ⁇ 0.2, 17.0 ⁇ 0.2, 19.6 ⁇ 0.2, and 20.6 ⁇ 0.2.
  • crystalline Form B of Compound (I) is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 4.
  • crystalline Form B of Compound (I) is characterized by a 13 C NMR (CDCl 3 , 100 MHz) pattern having a signal at at least one d value (expressed as ppm) chosen from 32.1, 39.2, 43.5, 45.5, 55.6, 101.3, 115.2, 115.5, 116.0, 116.5, 117.9, 127.0, 127.7, 131.1, 137.1, 144.4, 146.7, 154.6, 156.3, 160.4, and 161.7.
  • the present disclosure provides a process for preparing crystalline Form B of Compound (I). In some embodiments, the present disclosure provides crystalline Form B of Compound (I) prepared by a process comprising: heating
  • Compound (I) for a time at an elevated temperature is at an elevated temperature; and cooling to room temperature.
  • the time is ten minutes.
  • the elevated temperature is 195 °C.
  • the process further comprises isolating crystalline Form B of Compound (I) by filtration.
  • the present disclosure provides a process for preparing crystalline Form B of Compound (I) and also provides crystalline Form B of Compound (I) prepared by a process comprising: heating crystalline Form A of Compound (I) for a time at an elevated temperature; and cooling to room temperature. In some embodiments, the time is thirty minutes. In some embodiments, the elevated temperature is 195 °C.
  • the present disclosure provides a process for preparing crystalline Form B of Compound (I) and also provides crystalline Form B of Compound (I) prepared by a process comprising: prolonged heating of crystalline Form A of Compound (I) at 195 °C.
  • the process further comprises isolating crystalline Form B of Compound (I) by filtration. Crystalline Form C of Compound (I)
  • the present disclosure provides crystalline Form C of Compound (I):
  • Crystalline Form C is a hydrate of Compound (I).
  • FIG. 6 shows an X-ray powder diffractogram for crystalline Form C of
  • crystalline Form C of Compound (I) are rod-like crystals. In some embodiments, crystalline Form C of Compound (I) is characterized by irregular morphology.
  • crystalline Form C of Compound (I) is characterized by a weight change of 2.90% in a dynamic vapor sorption experiment, while varying the relative humidity from 2-95% RH at 25 oC. In some embodiments, crystalline Form C of Compound (I) is characterized by a weight change of 1.76% in a dynamic vapor sorption experiment, while varying the relative humidity from 2-10% RH at 25 oC.
  • crystalline Form C of Compound (I) is characterized by a weight change of 2.99% in a dynamic vapor sorption experiment, while varying the relative humidity from 2-95% RH at 40 oC. In some embodiments, crystalline Form C of
  • Compound (I) is characterized by a weight change of 1.93% in a dynamic vapor sorption experiment, while varying the relative humidity from 2-10% RH at 40 oC.
  • crystalline Form C of Compound (I) is characterized by solubility of 0.03 mg/mL in fasted state simulated intestinal fluid. In some embodiments, crystalline Form C of Compound (I) is characterized by solubility of 2.72 mg/mL in fasted state simulated gastric fluid. In some embodiments, crystalline Form C of Compound (I) is characterized by solubility of 0.03 mg/mL in fasted state simulated intestinal fluid at 37 °C. In some embodiments, crystalline Form C of Compound (I) is characterized by solubility of 2.72 mg/mL in fasted state simulated gastric fluid at 37 °C.
  • crystalline Form C of Compound (I) is in substantially pure form. In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. In some embodiments, crystalline Form C of
  • Compound (I) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation with signals substantially similar to those recited in Table 3.
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 5.3 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 9.4 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 10.4 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 13.9 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.1 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 17.4 ⁇ 0.2 degrees two-theta.
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 22.8 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 22.8 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 24.8 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 25.8 ⁇ 0.2 degrees two-theta.
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at two-theta values of 5.3 ⁇ 0.2, 9.4 ⁇ 0.2,
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 5.3 ⁇ 0.2, 9.4 ⁇ 0.2, 10.4 ⁇ 0.2, 12.0 ⁇ 0.2, 13.9 ⁇ 0.2, 16.1 ⁇ 0.2, 17.4 ⁇ 0.2, 22.8 ⁇ 0.2, 24.0 ⁇ 0.2, 24.8 ⁇ 0.2, and 25.8 ⁇ 0.2.
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 5.3 ⁇ 0.2, 9.4 ⁇ 0.2, 10.4 ⁇ 0.2, 12.0 ⁇ 0.2, 13.9 ⁇ 0.2, 16.1 ⁇ 0.2, 17.4 ⁇ 0.2, 22.8 ⁇ 0.2, 24.0 ⁇ 0.2, 24.8 ⁇ 0.2, and 25.8 ⁇ 0.2.
  • Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 5.3 ⁇ 0.2, 9.4 ⁇ 0.2, 10.4 ⁇ 0.2, 12.0 ⁇ 0.2, 13.9 ⁇ 0.2,
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 5.3 ⁇ 0.2, 9.4 ⁇ 0.2,
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 5.3 ⁇ 0.2, 9.4 ⁇ 0.2, 10.4 ⁇ 0.2, 12.0 ⁇ 0.2, 13.9 ⁇ 0.2, 16.1 ⁇ 0.2, 17.4 ⁇ 0.2, 22.8 ⁇ 0.2, 24.0 ⁇ 0.2, 24.8 ⁇ 0.2, and 25.8 ⁇ 0.2.
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 5.3 ⁇ 0.2, 9.4 ⁇ 0.2, 10.4 ⁇ 0.2, 12.0 ⁇ 0.2, 13.9 ⁇ 0.2, 16.1 ⁇ 0.2, 17.4 ⁇ 0.2, 22.8 ⁇ 0.2, 24.0 ⁇ 0.2, 24.8 ⁇ 0.2, and 25.8 ⁇ 0.2.
  • Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 5.3 ⁇ 0.2, 9.4 ⁇ 0.2, 10.4 ⁇ 0.2, 12.0 ⁇ 0.2, 13.9 ⁇ 0.2,
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.3 ⁇ 0.2,
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 5.3 ⁇ 0.2, 9.4 ⁇ 0.2, 10.4 ⁇ 0.2, 12.0 ⁇ 0.2, 13.9 ⁇ 0.2, 16.1 ⁇ 0.2,
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 5.3 ⁇ 0.2, 9.4 ⁇ 0.2, 10.4 ⁇ 0.2, 12.0 ⁇ 0.2, 13.9 ⁇ 0.2, 16.1 ⁇ 0.2, 17.4 ⁇ 0.2, 22.8 ⁇ 0.2, 24.0 ⁇ 0.2, 24.8 ⁇ 0.2, and
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.3 + 0.2, 9.4 + 0.2, 10.4 + 0.2, 12.0 + 0.2, and 16.1 + 0.2.
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 5.3 + 0.2, 9.4 + 0.2, 10.4 + 0.2, 12.0 + 0.2, and
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 5.3 ⁇ 0.2, 9.4 ⁇ 0.2, 10.4 ⁇ 0.2, 12.0 ⁇ 0.2, and 16.1 ⁇ 0.2.
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram having a signal at two-theta values of 5.3 ⁇ 0.2, 9.4 ⁇ 0.2, 10.4 ⁇ 0.2, 12.0 ⁇ 0.2, and 16.1 ⁇ 0.2.
  • crystalline Form C of Compound (I) is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 6.
  • crystalline Form C of Compound (I) is characterized by a 13 C NMR (CDCl 3 , 100 MHz) pattern having a signal at at least one d value (expressed as ppm) chosen from 32.1, 39.2, 43.5, 45.5, 55.6, 101.3, 115.2, 115.5, 116.0, 116.5, 117.9, 127.0, 127.7, 131.1, 137.1, 144.4, 146.7, 154.6, 156.3, 160.4, and 161.7.
  • the present disclosure provides a process for preparing crystalline Form C of Compound (I) and also provides crystalline Form C of Compound (I) prepared by a process comprising: slurrying Compound (I) in methanol or a 1:1 mixture of tetrahydrofuran:water.
  • the process further comprises isolating the crystalline Form C of Compound (I) by filtration. Crystalline Form O of Compound (I)
  • the present disclosure provides crystalline Form O of Compound (I):
  • FIG. 7 shows an X-ray powder diffractogram for crystalline Form O of
  • crystalline Form O of Compound (I) is characterized by a DSC thermogram having an endothermic event with an onset temperature of 182 °C.
  • crystalline Form O of Compound (I) is in substantially pure form. In some embodiments, crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. In some embodiments, crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation with signals substantially similar to those recited in Table 4.
  • crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 7.2 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 10.8 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 12.3 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at
  • crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 14.7 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.1 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 19.0 ⁇ 0.2 degrees two-theta.
  • crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 20.4 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 20.4 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at
  • crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at two-theta values of 7.2 ⁇ 0.2, 10.8 ⁇ 0.2,
  • crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 7.2 ⁇ 0.2,
  • crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from
  • crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from
  • crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from
  • crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from
  • crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from
  • crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from
  • crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 7.2 ⁇ 0.2, 10.8 ⁇ 0.2, 12.3 ⁇ 0.2, 14.5 ⁇ 0.2, 14.7 ⁇ 0.2, 16.1 ⁇ 0.2, 19.0 ⁇ 0.2, 20.4 ⁇ 0.2, and 23.7 ⁇ 0.2.
  • crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 7.2 ⁇ 0.2, 12.3 ⁇ 0.2, 14.7 ⁇ 0.2, 16.1 ⁇ 0.2, and 23.7 ⁇ 0.2.
  • crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 7.2 ⁇ 0.2, 12.3 ⁇ 0.2, 14.7 ⁇ 0.2, 16.1 ⁇ 0.2, and 23.7 ⁇ 0.2.
  • crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 7.2 ⁇ 0.2, 12.3 ⁇ 0.2, 14.7 ⁇ 0.2, 16.1 ⁇ 0.2, and 23.7 ⁇ 0.2.
  • crystalline Form O of Compound (I) is characterized by an X-ray powder diffractogram having a signal at two-theta values of 7.2 ⁇ 0.2, 12.3 ⁇ 0.2, 14.7 ⁇ 0.2, 16.1 ⁇ 0.2, and 23.7 ⁇ 0.2.
  • crystalline Form O of Compound (I) is characterized by a 13 C NMR (CDCl 3 , 100 MHz) pattern having a signal at at least one d value (expressed as ppm) chosen from 32.1, 39.2, 43.5, 45.5, 55.6, 101.3, 115.2, 115.5, 116.0, 116.5, 117.9, 127.0, 127.7, 131.1, 137.1, 144.4, 146.7, 154.6, 156.3, 160.4, and 161.7.
  • the present disclosure provides a process for preparing crystalline Form O of Compound (I) and also provides crystalline Form O of Compound (I) prepared by a process comprising: stagnant cooling of Compound (I) in tetrahydrofuran. In some embodiments, the process comprises stagnant cooling of Compound (I) in
  • the process further comprises collecting the crystalline Form O of Compound (I) by filtration.
  • the present disclosure provides a process for preparing crystalline Form O of Compound (I) and also provides crystalline Form O of Compound (I) prepared by a process comprising: stagnant cooling of crystalline Form A of Compound (I) in tetrahydrofuran.
  • the process comprises stagnant cooling of crystalline Form A of Compound (I) in tetrahydrofuran from room temperature to -20 °C.
  • the process further comprises collecting the crystalline Form O of
  • the present disclosure provides crystalline Form T of a tosylate salt of Compound (I):
  • FIG. 8 shows an X-ray powder diffractogram for crystalline Form T of a tosylate salt of Compound (I) at ambient conditions.
  • crystalline Form T of a tosylate salt of Compound (I) is a mono-tosylate salt of Compound (I), i.e., Form T comprises Compound (I) and tosylate in a 1:1 ratio.
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by a DSC thermogram having an endothermic event with an onset temperature of at 175 °C, an endothermic event with an onset temperature of 189 °C, and/or an endothermic event with an onset temperature of 207 °C.- In some embodiments, crystalline Form T of a tosylate salt of Compound (I) is characterized by a DSC thermogram having an endothermic event with a signal at 183 °C, an endothermic event with a signal at 193 °C, and/or an endothermic event with a signal at 213 °C.
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by a DSC thermogram having an endothermic event with an onset temperature of 175 °C and a signal at 183 °C, an endothermic event with an onset temperature of 189 °C and a signal at 193 °C, and/or an endothermic event with an onset temperature of 207 °C and a signal at 213 °C.
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by solubility of 0.08 mg/mL in fasted state simulated intestinal fluid. In some embodiments, crystalline Form T of a tosylate salt of Compound (I) is characterized by solubility of 1.88 mg/mL in fasted state simulated gastric fluid. In some embodiments, crystalline Form T of a tosylate salt of Compound (I) is characterized by solubility of 0.08 mg/mL in fasted state simulated intestinal fluid at 37 °C. In some embodiments, crystalline Form T of a tosylate salt of Compound (I) is characterized by solubility of 1.88 mg/mL in fasted state simulated gastric fluid at 37 °C.
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by solubility of 0.34 mg/mL in water.
  • crystalline Form T of a tosylate salt of Compound (I) is in substantially pure form. In some embodiments, crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. In some embodiments, crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation with signals substantially similar to those recited in Table 5.
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 5.9 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 6.1 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 9.6 ⁇ 0.2 degrees two- theta.
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 11.7 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.0 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 19.2 ⁇ 0.2 degrees two- theta.
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 20.8 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 21.2 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 22.0 ⁇ 0.2 degrees two- theta.
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 24.1 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 24.5 ⁇ 0.2 degrees two- theta.
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at two-theta values of 5.9 ⁇ 0.2, 6.1 ⁇ 0.2, 9.6 ⁇ 0.2, 11.7 ⁇ 0.2, 16.0 ⁇ 0.2, 19.2 ⁇ 0.2, 20.8 ⁇ 0.2, 21.2 ⁇ 0.2,
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 5.9 ⁇ 0.2, 6.1 ⁇ 0.2, 9.6 ⁇ 0.2, 11.7 ⁇ 0.2, 16.0 ⁇ 0.2,
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X- ray powder diffractogram having a signal at at least seven two-theta values chosen from
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 5.9 ⁇ 0.2, 6.1 ⁇ 0.2, 9.6 ⁇ 0.2, 11.7 ⁇ 0.2, 16.0 ⁇ 0.2,
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X- ray powder diffractogram having a signal at at least five two-theta values chosen from
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 5.9 ⁇ 0.2, 6.1 ⁇ 0.2, 9.6 ⁇ 0.2, 11.7 ⁇ 0.2, 16.0 ⁇ 0.2,
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X- ray powder diffractogram having a signal at at least three two-theta values chosen from
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 5.9 ⁇ 0.2, 6.1 ⁇ 0.2, 9.6 ⁇ 0.2, 11.7 ⁇ 0.2, 16.0 ⁇ 0.2,
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X- ray powder diffractogram having a signal at at least one two-theta value chosen from
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.9 ⁇ 0.2, 11.7 ⁇ 0.2, 16.0 ⁇ 0.2, 22.0 ⁇ 0.2, and 24.5 ⁇ 0.2.
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 5.9 ⁇ 0.2, 11.7 ⁇ 0.2, 16.0 ⁇ 0.2, 22.0 ⁇ 0.2, and 24.5 ⁇ 0.2.
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at two-theta values of 5.9 ⁇ 0.2, 11.7 ⁇ 0.2, 16.0 ⁇ 0.2, 22.0 ⁇ 0.2, and 24.5 ⁇ 0.2.
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 8.
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by a C NMR (DMSO-d6,, 500 MHz) pattern having a signal at at least one d value (expressed as ppm) chosen from 20.7, 26.7, 38.5, 39.0, 40.0, 42.8, 44.9, 58.0, 102.2, 114.3, 115.5, 115.6, 115.8, 118.0, 123.6, 125.4, 127.6, 128.3, 128.4, 136.3, 137.7, 137.8, 145.2, 145.8, 153.2, 156.5, 160.1, 160.7, and 162.6.
  • a C NMR DMSO-d6,, 500 MHz
  • the present disclosure provides a process for preparing a crystalline Form T of a tosylate salt of Compound (I) and also provides crystalline Form T of a tosylate salt of Compound (I) prepared by a process comprising: adding Compound (I) and toluenesulfonic acid to a mixture of 2-propanol (IP A) and water; stirring at an elevated temperature; and reducing the temperature.
  • 1.1 equivalents of toluenesulfonic acid is added.
  • the volumetric ratio of IP A to water in the mixture is 95:5.
  • stirring occurs at 600 rpm.
  • the elevated temperature is a temperature ranging from 48 °C to 50 °C.
  • reducing the temperature comprises transferring the solution to a hot plate at a temperature ranging from 35 °C to 40 °C.
  • the present disclosure provides crystalline Form Tr of a tartrate salt of Compound (I):
  • FIG. 9 shows an X-ray powder diffractogram for crystalline Form Tr of a tartrate salt of Compound (I) at ambient conditions.
  • crystalline Form Tr of a tartrate salt of Compound (I) is a mono-tartrate salt, e.g., Form Tr comprises Compound (I) and tosylate in a 1:1 ratio.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by a DSC onset at 144.5 °C, followed by an exothermic event
  • the endotherm coincides with a mass loss of 4.5 wt.% by TGA.
  • crystalline Form Tr of a tartrate salt of Compound (I) is further characterized by a DSC thermogram having an endothermic event with an onset temperature of 145 °C, an exothermic event with an onset temperature of 159 °C, an endothermic event with an onset temperature of 205 °C, an endothermic event with an onset temperature of 237 °C, and/or an exothermic event with an onset temperature of 254 °C.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by a DSC thermogram having an endothermic event with a signal at 156 °C, an exothermic event with a signal at 163 °C, an endothermic event with a signal at 213 °C, an endothermic event with a signal at 243 °C, and/or an exothermic event with a signal at 257 °C.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by a DSC thermogram having an endothermic event with an onset temperature of 145 °C and a signal temperature of 156 °C, an exothermic event with an onset temperature of 159 °C and a signal temperature of 163 °C, an endothermic event with an onset temperature of 205 °C and a signal temperature of 213 °C, an endothermic event with an onset temperature of 237 °C and a signal temperature of 243 °C, and/or an exothermic event with an onset temperature of 254 °C and a signal temperature of 257 °C.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by solubility of 0.27 mg/mL in fasted state simulated intestinal fluid.
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by solubility of 4.79 mg/mL in fasted state simulated gastric fluid.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by solubility of 0.27 mg/mL in fasted state simulated intestinal fluid at 37 °C.
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by solubility of 4.79 mg/mL in fasted state simulated gastric fluid at 37 °C.
  • crystalline Form T of a tosylate salt of Compound (I) is characterized by solubility of 0.84 mg/mL in water.
  • the crystalline Form Tr of a tartrate salt of Compound (I) is characterized by a weight change of 4.4% in a dynamic vapor sorption experiment, while varying the relative humidity from 2-95% RH at room temperature. In some embodiments, the crystalline Form Tr of a tartrate salt of Compound (I) is characterized by a weight change of 2.95% to 3% in a dynamic vapor sorption experiment, while varying the relative humidity from 2-30% RH at room temperature.
  • crystalline Form Tr of a tartrate salt of Compound (I) is in substantially pure form.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation with signals substantially similar to those recited in Table 6.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 6.3 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 10.6 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 11.1 ⁇ 0.2 degrees two- theta.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 12.5 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 13.3 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 13.7 ⁇ 0.2 degrees two- theta.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 14.2 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 14.9 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 16.2 ⁇ 0.2 degrees two- theta.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 19.0 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 22.5 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 24.1 ⁇ 0.2 degrees two- theta. In some embodiments, crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 27.9 ⁇ 0.2 degrees two- theta.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at two-theta values of 6.3 ⁇ 0.2, 10.6 ⁇ 0.2, 11.1 ⁇ 0.2, 12.5 ⁇ 0.2, 13.3 ⁇ 0.2, 13.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.9 ⁇ 0.2, 16.2 ⁇ 0.2, 19.0 ⁇ 0.2, 22.5 ⁇ 0.2, 24.1 ⁇ 0.2, and 27.9 ⁇ 0.2.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 6.3 ⁇ 0.2, 10.6 ⁇ 0.2, 11.1 ⁇ 0.2, 12.5 ⁇ 0.2, 13.3 ⁇ 0.2, 13.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.9 ⁇ 0.2, 16.2 ⁇ 0.2, 19.0 ⁇ 0.2, 22.5 ⁇ 0.2, 24.1 ⁇ 0.2, and 27.9 ⁇ 0.2.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 6.3 ⁇ 0.2, 10.6 ⁇ 0.2, 11.1 ⁇ 0.2, 12.5 ⁇ 0.2, 13.3 ⁇ 0.2, 13.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.9 ⁇ 0.2, 16.2 ⁇ 0.2, 19.0 ⁇ 0.2, 22.5 ⁇ 0.2, 24.1 ⁇ 0.2, and 27.9 ⁇ 0.2.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 6.3 ⁇ 0.2, 10.6 ⁇ 0.2, 11.1 ⁇ 0.2, 12.5 ⁇ 0.2, 13.3 ⁇ 0.2, 13.7 ⁇ 0.2, 14.2 ⁇ 0.2, 14.9 ⁇ 0.2, 16.2 ⁇ 0.2, 19.0 ⁇ 0.2, 22.5 ⁇ 0.2, 24.1 ⁇ 0.2, and 27.9 ⁇ 0.2.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 6.3 ⁇ 0.2, 10.6 ⁇ 0.2, 11.1 ⁇ 0.2, 12.5 ⁇ 0.2, 13.3 ⁇ 0.2, 13.7 ⁇ 0.2,
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X- ray powder diffractogram having a signal at at least four two-theta values chosen from
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 6.3 + 0.2,
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 6.3 + 0.2, 10.6 + 0.2, 11.1 + 0.2,
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 6.3 + 0.2, 10.6 + 0.2, 11.1 + 0.2, 12.5 + 0.2, 13.3 + 0.2,
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 6.3 + 0.2, 10.6 + 0.2, 12.5 + 0.2, 13.3 + 0.2, 13.7 + 0.2, 22.5 + 0.2, and
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 6.3 + 0.2, 10.6 + 0.2, 12.5 + 0.2, 13.3 + 0.2, 13.7 + 0.2, 22.5 + 0.2, and
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 6.3 + 0.2, 10.6 + 0.2, 12.5 + 0.2, 13.3 + 0.2, 13.7 + 0.2, 22.5 + 0.2, and
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at two-theta values of 6.3 + 0.2, 10.6 + 0.2, 12.5 + 0.2, 13.3 + 0.2, 13.7 + 0.2, 22.5 + 0.2, and 27.9 + 0.2.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 9.
  • crystalline Form Tr of a tartrate salt of Compound (I) is characterized by a 13 C NMR (DMSO-d 6 , 500 MHz) pattern having a signal at at least one d value (expressed as ppm) chosen from 28.5, 38.2, 42.9, 43.0, 44.7, 44.8, 44.9, 56.7, 71.8, 101.6, 114.3, 115.3, 115.5, 115.6, 115.8, 118.0, 127.5, 128.2, 128.3, 136.4, 141.2, 146.5, 153.7, 156.3, 160.0, 160.2, 162.1, and 173.9.
  • the present disclosure provides crystalline Form Tr of a tartrate salt of Compound (I) prepared by a process comprising: adding Compound (I) and tartaric acid to a tetrafluoroethylene, ethanol, and water mixture; stirring; evaporating with gentle stirring; adding acetone and heating to an elevated temperature; and decreasing the temperature.
  • the present disclosure provides crystalline Form H of a hydrochloride salt of Compound (I):
  • FIG. 10 shows an X-ray powder diffractogram for crystalline Form H of a hydrochloride salt of Compound (I) at ambient conditions.
  • Compound (I) is a mono-hydrochloride salt, e.g., Form H comprises Compound (I) and hydrochloride in a 1:1 ratio.
  • Compound (I) is characterized by a TGA thermal curve having an endotherm at 156 °C followed by a recrystallization event, which is associated with 3.3-3.9 wt.% mass loss.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by a DSC thermogram having an endothermic event with an onset temperature of 156 °C, an exothermic event with an onset temperature of 173 °C, and/or an endothermic event with an onset temperature of 210 °C.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by a DSC thermogram having an endothermic event with a signal at 165 °C, an exothermic event with a signal at 176 °C, and/or an endothermic event with a signal at 215 °C.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by a DSC thermogram having an endothermic event with an onset temperature of 156 °C and a peak temperature of 165 °C, an exothermic event with an onset temperature of 173 °C and a peak temperature of 176 °C, and/or an endothermic event with an onset temperature of 210 °C and a peak temperature of 215 °C.
  • Compound (I) is characterized by solubility of 0.10 mg/mL in fasted state simulated intestinal fluid.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by solubility of 4.18 mg/mL in fasted state simulated gastric fluid.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by solubility of 0.10 mg/mL in fasted state simulated intestinal fluid at 37 °C.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by solubility of 4.18 mg/mL in fasted state simulated gastric fluid at 37 °C.
  • Compound (I) is characterized by solubility of 2.86 mg/mL in water.
  • Compound (I) is characterized by a weight change of 15% in a dynamic vapor sorption experiment, while varying the relative humidity (RH) from 2-95% RH at room temperature.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by a weight change of 10.8% in a dynamic vapor sorption experiment, while varying the relative humidity from 80-95% RH at room temperature.
  • Compound (I) is in substantially pure form.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation with signals substantially similar to those recited in Table 7. Table 7.
  • Compound (I) is characterized by an X-ray powder diffractogram having a signal at 4.8 ⁇ 0.2 degrees two-theta.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 8.1 ⁇ 0.2 degrees two-theta.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 8.5 ⁇ 0.2 degrees two-theta.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 9.6 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 9.6 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 20.7 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 21.5 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 23.3 ⁇ 0.2 degrees two-theta.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 23.7 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 24.1 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at 27.6 ⁇ 0.2 degrees two-theta.
  • Compound (I) is characterized by an X-ray powder diffractogram having a signal at two-theta values of 4.8 ⁇ 0.2, 8.1 ⁇ 0.2, 8.5 ⁇ 0.2, 9.6 ⁇ 0.2, 11.1 ⁇ 0.2, 20.7 ⁇ 0.2, 21.5 ⁇ 0.2,
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 4.8 ⁇ 0.2, 8.1 ⁇ 0.2, 8.5 ⁇ 0.2, 9.6 ⁇ 0.2, 11.1 ⁇ 0.2, 20.7 ⁇ 0.2, 21.5 ⁇ 0.2, 23.3 ⁇ 0.2, 23.7 ⁇ 0.2, 24.1 ⁇ 0.2, and 27.6 ⁇ 0.2.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 4.8 ⁇ 0.2, 8.1 ⁇ 0.2, 8.5 ⁇ 0.2, 9.6 ⁇ 0.2, 11.1 ⁇ 0.2, 20.7 ⁇ 0.2,
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 4.8 ⁇ 0.2, 8.1 ⁇ 0.2, 8.5 ⁇ 0.2, 9.6 ⁇ 0.2, 11.1 ⁇ 0.2, 20.7 ⁇ 0.2, 21.5 ⁇ 0.2, 23.3 ⁇ 0.2, 23.7 ⁇ 0.2, 24.1 ⁇ 0.2, and 27.6 ⁇ 0.2.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 4.8 ⁇ 0.2, 8.1 ⁇ 0.2, 8.5 ⁇ 0.2, 9.6 ⁇ 0.2, 11.1 ⁇ 0.2, 20.7 ⁇ 0.2, 21.5 ⁇ 0.2, 23.3 ⁇ 0.2, 23.7 ⁇ 0.2, 24.1 ⁇ 0.2, and 27.6 ⁇ 0.2.
  • an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 4.8 ⁇ 0.2, 8.1 ⁇ 0.2, 8.5 ⁇ 0.2, 9.6 ⁇ 0.2, 11.1 ⁇ 0.2, 20.7 ⁇ 0.2, 21.5 ⁇ 0.2, 23.3 ⁇ 0.2, 23.7 ⁇ 0.2, 24.1 ⁇ 0.2, and 27.6 ⁇ 0.2.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 4.8 ⁇ 0.2, 8.1 ⁇ 0.2, 8.5 ⁇ 0.2, 9.6 ⁇ 0.2, 11.1 ⁇ 0.2, 20.7 ⁇ 0.2, 21.5 ⁇ 0.2, 23.3 ⁇ 0.2, 23.7 ⁇ 0.2, 24.1 ⁇ 0.2, and 27.6 ⁇ 0.2.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 4.8 ⁇ 0.2, 8.1 ⁇ 0.2, 8.5 ⁇ 0.2, 9.6 ⁇ 0.2, 11.1 ⁇ 0.2, 20.7 ⁇ 0.2, 21.5 ⁇ 0.2, 23.3 ⁇ 0.2, 23.7 ⁇ 0.2, 24.1 ⁇ 0.2, and 27.6 ⁇ 0.2.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 4.8 ⁇ 0.2, 8.1 ⁇ 0.2, 8.5 ⁇ 0.2, 9.6 ⁇ 0.2, 11.1 ⁇ 0.2, 20.7 ⁇ 0.2,
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 4.8 ⁇ 0.2, 8.1 ⁇ 0.2, 8.5 ⁇ 0.2, 9.6 ⁇ 0.2, 11.1 ⁇ 0.2, 20.7 ⁇ 0.2, 21.5 ⁇ 0.2, 23.3 ⁇ 0.2, 23.7 ⁇ 0.2, 24.1 ⁇ 0.2, and 27.6 ⁇ 0.2.
  • Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 4.8 ⁇ 0.2, 8.1 ⁇ 0.2, 11.1 ⁇ 0.2, 20.7 ⁇ 0.2, and 23.7 ⁇ 0.2.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 4.8 ⁇ 0.2, 8.1 ⁇ 0.2, 11.1 ⁇ 0.2, 20.7 ⁇ 0.2, and 23.7 ⁇ 0.2.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 4.8 ⁇ 0.2, 8.1 ⁇ 0.2, 11.1 ⁇ 0.2, 20.7 ⁇ 0.2, and 23.7 ⁇ 0.2.
  • crystalline Form H of a hydrochloride salt of Compound (I) is characterized by an X-ray powder diffractogram having a signal at two-theta values of 4.8 ⁇ 0.2, 8.1 ⁇ 0.2, 11.1 ⁇ 0.2,
  • Compound (I) is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 10.
  • Compound (I) is characterized by a 13 C NMR (DMSO-d 6 , 500 MHz) pattern having a signal at at least one d value (expressed as ppm) chosen from 26.7, 42.8, 44.9, 58.0, 102.2, 114.3, 115.3, 115.5, 115.6, 115.8, 118.0, 123.9, 127.6, 128.5, 136.4, 138.1, 138.2, 145.7, 153.2, 156.6, 160.0, 160.6, and 162.5.
  • d value expressed as ppm
  • the present disclosure provides a process for preparing crystalline Form H of a hydrochloride salt of Compound (I) and also provides crystalline Form H of a hydrochloride salt of Compound (I) prepared by a process comprising: adding Compound (I) to a concentrated hydrochloride solution in ethanol; adding tetrafluoroethylene (TFE); and stirring at an elevated temperature.
  • TFE tetrafluoroethylene
  • 1.1 equivalents of a concentrated HCl solution in ethanol is used.
  • the elevated temperature ranges from 35 °C to 40 °C.
  • stirring at an elevated temperature occurs for thirty minutes at 340 rpm.
  • a spatula is used to break up gumming after fifteen minutes of stirring at 340 rpm.
  • additional TFE is added after stirring at an elevated temperature. In some embodiments, more stirring occurs at room temperature after adding additional TFE.
  • the present disclosure provides a process for preparing crystalline Form H of a hydrochloride salt of Compound (I) and also provides crystalline Form H of a hydrochloride salt of Compound (I) prepared by a process comprising slurrying Compound (I) in fasted state simulated gastric fluid at 37° C.
  • the present disclosure provides a method of preparing (S)- 1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4- yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine (Compound (I))
  • the present disclosure provides a process of preparing Compound (I) comprising the step of converting a compound of Formula (VI):
  • the compound of Formula (III) is diastereomerically pure.
  • the desired diastereomer has the S configuration at the carbon center.
  • the compound of Formula (III) is substantially free of the undesired diastereomers (C) and (D):
  • the amount of (C) and (D) is not more than 0.4% w/w (measured by HPLC). In some embodiments, the diastereomeric purity is >97% de
  • the diastereomic purity is >98% de. In some embodiments, the diastereomeric purity is >98.5% de. In some embodiments, the diastereomeric purity is >99% de. In some embodiments, the diastereomeric purity is >99.5% de. In some embodiments, the diastereomeric purity is >99.6% de. In some embodiments, the diastereomeric purity is >99.7% de. In some embodiments, the diastereomeric purity is >99.8%.
  • X 2 is chosen from a carbamate protecting group, benzyl, tetrahydropyranyl, acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide.
  • X 2 is benzyl.
  • X 2 is tetrahydropyranyl.
  • X 2 is acetamide.
  • X 2 is trifluoroacetamide.
  • X 2 is triphenylmethylamine.
  • X 2 is benzylideneamine. In some embodiments, X 2 is p-toluenesulfonamide. In some embodiments, X2 is a carbamate protecting group. In some embodiments, the carbamate protecting group is tert-butyl carbamate, 9-fluorenylmethyl carbamate, and benzyl carbamate. In some embodiments, X 2 is tert-butyl carbamate. In some embodiments, X 2 is 9- fluorenylmethyl carbamate. In some embodiments, X 2 is benzyl carbamate.
  • the present disclosure provides a process of preparing a compound of Formula (III) in a diastereomerically pure form, such as, e.g., compound 7. It has been discovered that the diastereomeric purity of a compound of Formula (III) is important to ensuring the purity of the final Compound (I).
  • the process of preparing a compound of Formula (III) in a diastereomerically pure form involves trituration.
  • the trituration solvent in the step of triturating a compound of Formula (VI) comprises n- heptane and methanol.
  • the process of preparing a compound of Formula III in a diasteromerically pure form involves recrystallization. In some
  • the recrystallization solvent is isopropanol. In some embodiments, the recrystallization solvent is a mixture of ethyl acetate and heptane.
  • the present disclosure provides processes of preparing (S)- 1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4- yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine (Compound (I)):
  • X 1 is a halogen or activated phenol. In some embodiments, X 1 is a halogen. In some embodiments, X 1 is F, Cl, Br, or I. In some embodiments, X 1 is F. In some embodiments, X1 is Cl. In some embodiments, X1 is Br. In some embodiments, X1 is I. In some embodiments, X 1 is activated phenol. In some embodiments, X 1 is tosylate or mesylate.
  • (S)-1-(2-(4l 2 -piperazin-1-yl)pyrimidin-5-yl)-1-(4- fluorophenyl)ethan-1-amine (2) is a free base.
  • the salt of (S)-1-(2- (4l 2 -piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine (2) is a hydrochloride salt or trifluoroacetic acid salt.
  • the salt of (S)-1-(2-(4l 2 -piperazin-1- yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine (2) is a hydrochloride salt.
  • the hydrochloride salt of (S)-1-(2-(4l 2 -piperazin-1-yl)pyrimidin-5-yl)-1-(4- fluorophenyl)ethan-1-amine (II) is (S)-1-(2-(4l 2 -piperazin-1-yl)pyrimidin-5-yl)-1-(4- fluorophenyl)ethan-1-amine 3.5 HCl (2A).
  • the salt of (S)-1-(2-(4l 2 - piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine (2) is a trifluoroacetic acid salt.
  • the 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazine (3) prepared by
  • B(OR) 2 is chosen from:
  • B(OR) 2 is catecholborane. In some embodiments, B(OR)2 is pinacolborane. In some embodiments, B(OR)2 is chosen from boronic acids. In some embodiments, the boronic acid is e.g., isopropylboronic acid, methylboronic acid, or BF3boronic acid. In some embodiments, B(OR) 2 is B(OH) 2 .
  • step (b) is performed in the presence of a palladium catalyst.
  • the palladium catalyst is a Pd(0) or Pd(II) catalyst.
  • the palladium catalyst is a Pd(0) catalyst.
  • the palladium catalyst is a Pd(II) catalyst.
  • the palladium catalyst is PdCl 2 (dtbpf), PdCl 2 (dppf), or Pd(OAc 2 ).
  • the palladium catalyst is PdCl 2 (dtbpf).
  • the palladium catalyst is PdCl 2 (dppf).
  • the palladium catalyst is Pd(OAc 2 ).
  • step (c) is performed in the presence of a base.
  • the base is N,N-diisopropylethylamine, triethylamine, or 1,8- diazabicyclo[5.4.0]undec-7-ene.
  • the base is N,N- diisopropylethylamine.
  • the base is triethylamine.
  • the base is 1,8-diazabicyclo[5.4.0]undec-7-ene.
  • step (c) is performed in the presence of a chlorinating sulfur and phosphorous reagent.
  • the chlorinating sulfur and phosphorous reagent is chosen from phosphorous oxychloride, phosphorous pentachloride, sulfuryl chloride, and trichloromethansulfonyl chloride.
  • the chlorinating sulfur and phosphorous reagent is phosphorous oxychloride.
  • the chlorinating sulfur and phosphorous reagent is phosphorous pentachloride.
  • the chlorinating sulfur and phosphorous reagent is chosen from sulfuryl chloride.
  • the chlorinating sulfur and phosphorous reagent is trichloromethansulfonyl chloride.
  • X 2 is chosen from a carbamate protecting group, benzyl, tetrahydropyranyl, acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide.
  • X 2 is benzyl.
  • X 2 is tetrahydropyranyl.
  • X 2 is acetamide.
  • X 2 is trifluoroacetamide.
  • X 2 is triphenylmethylamine.
  • X 2 is benzylideneamine.
  • X 2 is p-toluenesulfonamide. In some embodiments, X 2 is a carbamate protecting group. In some embodiments, the carbamate protecting group is tert-butyl carbamate, 9-fluorenylmethyl carbamate, and benzyl carbamate. In some embodiments, X 2 is tert-butyl carbamate. In some embodiments, X 2 is 9- fluorenylmethyl carbamate. In some embodiments, X 2 is benzyl carbamate.
  • the pharmaceutically acceptable salt is a hydrochloride salt of (S)-1-(2-(4l 2 -piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine (2).
  • the pharmaceutically acceptable salt is (S)-1-(2-(4l 2 -piperazin-1-yl)pyrimidin- 5-yl)-1-(4-fluorophenyl)ethan-1-amine 3.5 HCl (2A):
  • the pharmaceutically acceptable salt (S)-1-(2-(4l 2 - piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine 3.5 HCl (2A) is not isolated.
  • step (d) is performed in the presence of a first acid.
  • the first acid is a strong acid.
  • the first acid is HCl, TFA, or H 2 SO 4 .
  • the first acid is HCl.
  • the first acid is TFA.
  • the first acid is H 2 SO 4 .
  • the first acid is a Lewis acid.
  • step (d) is performed in the presence of iodine. In some embodiments, step (d) is performed under thermolytic conditions.
  • Some embodiments of the present disclosure comprise:
  • step (e) is performed in the presence of a catalyst.
  • the catalyst is titanium isopropoxide, titanium ethoxide, titanium butoxide, or titanium tetrachloride.
  • the catalyst is titanium
  • step (e) is performed in the presence of (S)-2-methylpropane-2-sulfinamide or (S)-p-toluenesulfinamide. In some embodiments, step (e) is performed in the presence of (S)-2-methylpropane-2- sulfinamide. In some embodiments, step (e) is performed in the presence of (S)-p- toluenesulfinamide.
  • Some embodiments of the present disclosure comprise:
  • step (f) is performed in the presence of a Grignard reagent, alkyl halide, or alkyl metal. In some embodiments, step (f) is performed in the presence of a Grignard reagent. In some embodiments, the Grignard reagent is
  • the Grignard reagent is methylmagnesium bromide.
  • the Grignard reagent is methylmagnesium chloride. In some embodiments, the Grignard reagent is methylmagnesium iodide. In some embodiments, step (f) is performed in the presence of an alkyl halide. In some embodiments, step (f) is performed in the presence of an alkyl metal. In some embodiments, step (f) is performed in the presence of 2-methyl tetrahydrofuran.
  • Some embodiments of the present disclosure comprise:
  • the trituration solvent in step (g) comprises n-heptane and methanol.
  • Some embodiments of the present disclosure comprise:
  • the recrystallization solvent in step (g) comprises isopropanol. In some embodiments, the recrystallization solvent in step (g) comprises heptane and ethyl acetate. [00227] Some embodiments of the present disclosure comprise:
  • step (h) is performed in the presence of an
  • step (h) is performed in the presence of an organolithium reagent.
  • the organolithium reagent is n-butyllithium, n-hexyllithium, or cyclohexyllithium. In some embodiments, the
  • organolithium reagent is n-butyllithium. In some embodiments, the organolithium reagent is n-hexyllithium. In some embodiments, the organolithium reagent is cyclohexyllithium. In some embodiments, step (h) is performed in the presence of magnesium powder. [00229] In some embodiments, the present disclosure provides a method of preparing a compound
  • X 2 is chosen from a carbamate protecting group, benzyl, tetrahydropyranyl, acetamide, trifluoroacetamide, triphenylmethylamine,
  • X 2 is benzyl. In some embodiments, X 2 is tetrahydropyranyl. In some embodiments, X 2 is acetamide. In some embodiments, X 2 is trifluoroacetamide. In some embodiments, X 2 is triphenylmethylamine. In some embodiments, X 2 is benzylideneamine. In some embodiments, X 2 is p- toluenesulfonamide. In some embodiments, X 2 is a carbamate protecting group.
  • the carbamate protecting group is tert-butyl carbamate, 9-fluorenylmethyl carbamate, and benzyl carbamate.
  • X 2 is tert-butyl carbamate.
  • X 2 is 9-fluorenylmethyl carbamate.
  • X 2 is benzyl carbamate.
  • the trituration solvent in the step of triturating a compound of Formula (VI) comprises n-heptane and methanol or the recrystallization solvent in the step of recrystallizing a compound of Formula (VI) is isopropanol or heptane/ethyl acetate.
  • the disclosure provides a process for purifying Compound (I) to remove its undesired enantiomer (Compound (E)).
  • Compound (I) can be crystalline, a mixture of crystalline forms or non-crystalline e.g., an amorphous solid.
  • the disclosure provides a process for the preparation of Compound (I) comprising forming a salt of
  • the organic solvent is THF.
  • the solvent mixture is THF and water.
  • the ratio of the solvent mixture is 20 volumes THF to water.
  • the process further comprises recrystallizing Compound (I) in acetone and water as described herein. Indications
  • Crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing described herein can be useful for treating conditions associated with aberrant KIT activity, in humans or non-humans.
  • Activating mutations in KIT are found in multiple indications, including systemic mastocytosis, gastrointestinal stromal tumors (GIST), acute myeloid leukemia (AML), melanoma, seminoma, intercranial germ cell tumors, and mediastinal B-cell lymphoma.
  • Mastocytosis refers to a group of disorders characterized by excessive mast cell accumulation in one tissue, or in multiple tissues. Mastocytosis is subdivided into two groups of disorders: (1) cutaneous mastocytosis (CM) describes forms that are limited to the skin; and (2) systemic mastocytosis (SM) describes forms in which mast cells infiltrate
  • SM is further subdivided into five forms: indolent (ISM), smoldering (SSM), aggressive (ASM), SM with associated hemotologic non-mast cell lineage disease (SM- AHNMD), and mast cell leukemia (MCL).
  • ISM indolent
  • SSM smoldering
  • ASM aggressive
  • SM- AHNMD SM with associated hemotologic non-mast cell lineage disease
  • MCL mast cell leukemia
  • Adv-SM refers to ASM, SM-AHNMD, and MCL.
  • non-advanced systemic mastocytosis refers to ISM and SSM.
  • Diagnosis of systemic mastocytosis is based in part on histological and cytological studies of bone marrow showing infiltration by mast cells of frequently atypical morphology, which frequently abnormally express non-mast cell markers (CD25 and/or CD2). Diagnosis of SM is confirmed when bone marrow mast cell infiltration occurs in the context of one of the following: (1) abnormal mast cell morphology (spindle-shaped cells); (2) elevated level of serum tryptase above 20 ng/mL; or (3) the presence of the activating KIT D816V mutation.
  • Activating mutations at the D816 position are found in most mastocytosis cases (90%-98%), with the most common mutations being D816V, D816H, and D816Y.
  • the D816V mutation is found in the activation loop of the kinase domain and leads to constitutive activation of KIT kinase.
  • ISM and SSM There are no approved treatments for ISM and SSM; symptoms are managed with symptom-directed therapies, such as antihistamines. Thus, there is a need for safe, effective treatments for ISM and SSM. Furthermore, since ISM and SSM patients have lower disease burden than AdvSM patients and are expected to remain on treatment for long periods of time, there is a need for low doses, if efficacious.
  • Crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing may also be useful to treat GIST, e.g., PDGFRa-exon 18 mutant driven GIST, PDGFRa-exon 18 D842 driven GIST (e.g., PDGFRa-D842I driven GIST, PDGFRa-D842V driven GIST, or PDGFRa-D842Y driven GIST), PDGFRa-exon 18 mutant non-D842 driven GIST (e.g., PDGFRa-D842-H845 driven GIST, PDGFRa-DI842- 843V driven GIST), regardless of prior therapy.
  • GIST e.g., PDGFRa-exon 18 mutant driven GIST, PDGFRa-exon 18 D842 driven GIST (e.g., PDGFRa-D842I driven GIST, PDGFRa-D842V driven GIST, or PDGFRa-D842Y driven
  • KIT V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog
  • PDGFRa highly related protein platelet- derived growth factor receptor alpha
  • the currently approved agents for the treatment of GIST after imatinib are multikinase inhibitors, e.g., sunitinib, regorafenib, and midostaurin. In many cases, these multikinase inhibitors only weakly inhibit imatinib resistant mutants. Additionally, multikinase inhibitors may be of limited therapeutic value due to a more complex safety profile and a small therapeutic window. Thus, there is a need for therapeutic agents to treat GIST patients who are resistant to imatinib.
  • multikinase inhibitors e.g., sunitinib, regorafenib, and midostaurin. In many cases, these multikinase inhibitors only weakly inhibit imatinib resistant mutants. Additionally, multikinase inhibitors may be of limited therapeutic value due to a more complex safety profile and a small therapeutic window. Thus, there is a need for therapeutic agents to treat GIST patients who are resistant to imatinib.
  • PDGFRa tyrosine kinase activity There is also a subset of GIST patients with a D842I mutation in PDGFRa; this subgroup of GIST patients can be stratified by identifying this mutation. The compounds described herein, due to their selective activity against PDGFRa D842I, may be useful in treating these patients. Furthermore, there is a subset of GIST patients with a D842Y mutation in PDGFRa; this subgroup of GIST patients can be stratified by identifying this mutation. The compounds described herein, due to their selective activity against PDGFRa D842Y, may be useful in treating these patients.
  • PDGFRa may be useful in treating these patients.
  • Crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing described herein may also be useful in treating AML.
  • AML patients also harbor KIT mutations, with the majority of KIT mutations occurring at the D816 position.
  • KIT myelodysplastic syndrome
  • MDS myelodysplastic syndrome
  • NKTCL nasal NK/T-cell lymphoma
  • CMML chronic myelomonocytic leukemia
  • Crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing disclosed herein may be used to treat conditions associated with the KIT genetic mutations in Exon 9, Exon 11, Exon 13, Exon 14, Exon 17, and/or Exon 18. The crystalline forms may also be used to treat conditions associated with wild-type KIT. Crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing herein may be used as agents to treat the conditions described herein, or they may be used in combination with other therapeutic agents, including, without limitation, imatinib, sunitinib and regorafenib. Other agents include the compounds described in WO 2014/039714 and WO 2014/100620.
  • Crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing described herein can be active against at least one KIT mutation in exon 11, 11/17 and exon 17 (e.g., d557-558, V560G, V560G/D816V,
  • crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing herein can be active against at least one KIT mutation exon 11, 11/17 and 17 mutants (d557-558, V560G, V560G/D816V, V560G/N822K, D816E, D816F, D816H, D816I, D816V, D816Y, D820E, D820Y and Y823D.
  • the crystalline forms can be administered in combination with an agent that is (a) active against other activating mutations of KIT, such as Exon 9 and 11 mutations, but (b) not active against the Exon 17 mutations.
  • agents include imatinib, sunitinib, and regorafenib.
  • the combination of at least one crystalline form chosen from crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing, and the agent will thus inhibit Exon 17 mutant KIT, as well as inhibiting Exon 9/11 mutant KIT.
  • the at least one crystalline form and the agent can be co-administered or administered in an alternating regimen.
  • the Exon 17 mutant KIT inhibitor can be administered alone for a period of time; then the Exon 9/11 mutant KIT inhibitor can be administered alone for a period of time following. This cycle may then be repeated. It is believed that such a regimen could slow the development of resistance to the Exon 17 mutant KIT inhibitor and/or the Exon 9/11 mutant KIT inhibitor.
  • the at least one crystalline form chosen from crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing described herein that can be selective for Exon 17 KIT mutations can be administered with at least one agent active against Exon 9/11 mutations in combination with a third agent that covers mutations that are missed with the two-way combo.
  • the combination of the three agents could inhibit a spectrum of KIT mutations, as well as wild-type KIT in some instances.
  • the agents could be administered simultaneously or in an alternating regimen. They can be administered one at a time, or two agents can be administered together for a period of time; then the third agent can be administered alone for a following period of time. It is believed that such a regimen could slow the development of resistance to the mutant KIT inhibitors.
  • the at least one crystalline form chosen from crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing may be used as alone or in combination with imatinib, sunitinib, and/or regorafenib.
  • the at least one crystalline form chosen from crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing may be used in conjunction with other treatment modalities such as, for example, surgery or radiation therapy. Dosing
  • the effective dose for any particular patient or subject will depend upon a variety of factors including: the disorder being treated and the severity of the disorder; the specific pharmaceutical composition employed; the age, body weight, general health, sex and diet of the patient or subject; the time of administration, route of administration, the duration of the treatment; and like factors well known in the medical arts.
  • a therapeutically effective amount of at least one crystalline form chosen from crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing is administered to a patient in need thereof.
  • a therapeutically effective amount of at least one crystalline form chosen from crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing is administered to a patient in need thereof once daily.
  • the therapeutically effective amount of the at least one crystalline form administered to the patient once daily is an amount ranging from 25 mg to 400 mg (e.g., 25 mg, 30 mg, 40, mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, or 400 mg) of a crystalline form of Compound (I) (e.g., crystalline Form A of Compound (I), crystalline Form B of
  • Compound (I), or crystalline Form O of Compound (I)) or the weight equivalent of a crystalline form of a pharmaceutically acceptable salt thereof e.g., crystalline Form T of a tosylate salt of Compound (I), crystalline Form Tr of a tartrate salt of Compound (I), or crystalline Form H of a hydrochloride salt of Compound (I)
  • a pharmaceutically acceptable salt thereof e.g., crystalline Form T of a tosylate salt of Compound (I), crystalline Form Tr of a tartrate salt of Compound (I), or crystalline Form H of a hydrochloride salt of Compound (I)
  • the weight equivalent of a crystalline form of a solvate of Compound (I) or a pharmaceutically acceptable salt thereof e.g., crystalline Form C of Compound (I)
  • the disclosure provides improved methods for treating Adv SM in patients in need thereof by administering crystalline forms of Compound (I) and/or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of the at least one crystalline form administered to the patient once daily is an amount ranging from 200 mg to 300 mg (e.g., 200 mg, 225 mg, 250 mg, or 300 mg) of a crystalline form of Compound (I) (e.g., crystalline Form A of Compound (I), crystalline Form B of
  • the patient is suffering from advanced systemic mastocytosis (e.g., ASM, SM-AHN, or MCL) and the
  • therapeutically effective amount of crystalline Form A of Compound (I) is 200 mg to 300 mg administered once daily.
  • the patient is suffering from advanced systemic mastocytosis (e.g., ASM, SM-AHN, or MCL) and the therapeutically effective amount of crystalline Form A of Compound (I) is 200 mg administered once daily.
  • the patient is suffering from advanced systemic mastocytosis (e.g., ASM, SM- AHN, or MCL) and the therapeutically effective amount of crystalline Form A of Compound (I) is 300 mg administered once daily.
  • the disclosure provides improved methods for treating GIST in patients in need thereof by administering crystalline forms of Compound (I) and/or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of the at least one crystalline form administered to the patient once daily is an amount ranging from 300 mg to 400 mg (e.g., 325 mg, 350 mg, 375 mg, or 400 mg) of a crystalline form of Compound (I) (e.g., crystalline Form A of Compound (I), crystalline Form B of Compound (I), or crystalline Form O of Compound (I)) or the weight equivalent of a crystalline form of a pharmaceutically acceptable salt thereof (e.g., crystalline Form T of a tosylate salt of Compound (I), crystalline Form Tr of a tartrate salt of Compound (I), or crystalline Form H of a hydrochloride salt of Compound (I)) or the weight equivalent of a crystalline form of a solvate of Compound (I) or a pharmaceutically acceptable salt
  • the patient is suffering from gastrointestinal stromal tumor and the therapeutically effective amount of crystalline Form A of Compound (I) is 300 mg to 400 mg administered once daily. In some embodiments, the patient is suffering from GIST and the therapeutically effective amount of crystalline Form A of Compound (I) is 300 mg administered once daily. In some embodiments, the patient is suffering from GIST and the therapeutically effective amount of crystalline Form A of Compound (I) is 400 mg administered once daily. If 300 mg once daily of crystalline Form A of Compound (I) is well-tolerated by the patient, the dose can be increased to 400 mg once daily.
  • the dose can be increased to 400 mg once daily.
  • the disclosure provides improved methods for treating indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM) in patients in need thereof by administering Compound (I) and/or a pharmaceutically acceptable salt thereof.
  • ISM indolent systemic mastocytosis
  • SSM smoldering systemic mastocytosis
  • the disclosure provides safe and effective dosing regimens of Compound (I) that can be used for long-term treatment.
  • the ISM or SSM patient in need thereof has moderate-to-severe symptoms.
  • 25 mg of Compound (I) dosed once daily in patients with ISM or SSM shows improvement across all three aspects of its clinical profile, including reduction in mast cell burden, improvement of disease symptoms, and improvement in quality of life.
  • 25 mg of Compound (I) dosed once daily has a statistically significant reduction in ISM-SAF TSS and each symptom in the total domain score at 16 weeks.
  • the 25 mg dose provided similar mean improvements in TSS as the higher doses of 50 mg and 100 mg and better tolerability.
  • the 25 mg QD dose shows significant reduction in blood KIT D816V allele fraction.
  • 25 mg of Compound (I) dosed once daily in patients has a favorable safety profile in patients with ISM. For example, 95% of patients remain on the clinical study, with no
  • AEs adverse effects
  • QoL quality of life
  • the therapeutically effective amount of the at least one crystalline form administered to the patient once daily is an amount ranging from 25 mg to 100 mg (e.g., 25, 50, or 100 mg) of a crystalline form of
  • Compound (I) e.g., crystalline Form A of Compound (I), crystalline Form B of
  • Compound (I), or crystalline Form O of Compound (I)) or the weight equivalent of a crystalline form of a pharmaceutically acceptable salt thereof e.g., crystalline Form T of a tosylate salt of Compound (I), crystalline Form Tr of a tartrate salt of Compound (I), or crystalline Form H of a hydrochloride salt of Compound (I)
  • a pharmaceutically acceptable salt thereof e.g., crystalline Form T of a tosylate salt of Compound (I), crystalline Form Tr of a tartrate salt of Compound (I), or crystalline Form H of a hydrochloride salt of Compound (I)
  • the weight equivalent of a crystalline form of a solvate of Compound (I) or a pharmaceutically acceptable salt thereof e.g., crystalline Form C of Compound (I)
  • the patient is suffering from indolent or smoldering systemic mastocytosis and the therapeutically effective amount of crystalline Form A of Compound (I) is 25 mg to 100 mg administered once daily. In some embodiments, the patient is suffering from indolent or smoldering systemic mastocytosis and the therapeutically effective amount of crystalline Form A of Compound (I) is 25 mg administered once daily. In some embodiments, the patient is suffering from indolent or smoldering systemic mastocytosis and the therapeutically effective amount of crystalline Form A of Compound (I) is 50 mg administered once daily. In some embodiments, the patient is suffering from indolent or smoldering systemic mastocytosis and the therapeutically effective amount of crystalline Form A of Compound (I) is 100 mg administered once daily.
  • the disclosure provides a method of treating indolent systemic mastocytosis (ISM) or smoldering systemic mastocytosis (SSM) comprising administering to a patient in need thereof an amount of 10 mg to 100 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 10 mg to 100 mg of Compound (I), once a day.
  • the patient in need thereof is administered an amount of 10 mg to 100 mg of Compound (I) once a day.
  • the patient in need thereof is administered an amount of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg of Compound (I) (or a pharmaceutically acceptable salt thereof in an amount equivalent to 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg of Compound (I)) once a day.
  • the amount is from 10 mg to 25 mg once a day.
  • the amount is from 10 mg to 50 mg once a day. In some embodiments, the amount is from 10 mg to 75 mg once a day. In some embodiments, the amount is from 10 mg to 100 mg once a day. In some embodiments, the amount is from 25 mg to 50 mg once a day. In some embodiments, the amount is from 25 mg to 100 mg once a day. In some embodiments, the amount is from 50 mg to 100 mg once a day. In some embodiments, the amount is from 75 mg to 100 mg once a day. In some embodiments, the amount is 10 mg once a day. In some embodiments, the amount is 15 mg once a day. In some embodiments, the amount is 20 mg once a day.
  • the amount is 25 mg once a day. In some embodiments, the amount is 30 mg once a day. In some embodiments, the amount is 35 mg once a day. In some embodiments, the amount is 35 mg once a day. In some embodiments, the amount is 40 mg once a day. In some embodiments, the amount is 45 mg once a day. In some embodiments, the amount is 50 mg once a day. In some embodiments, the amount is 55 mg once a day. In some embodiments, the amount is 60 mg once a day. In some embodiments, the amount is 65 mg once a day. In some embodiments, the amount is 70 mg once a day. In some embodiments, the amount is 75 mg once a day.
  • the amount is 80 mg once a day. In some embodiments, the amount is 85 mg once a day. In some embodiments, the amount is 90 mg once a day. In some embodiments, the amount is 95 mg once a day. In some embodiments, the amount is 100 mg once a day.
  • the at least one crystalline form chosen from crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing disclosed herein is administered orally. In some embodiments, the at least one crystalline form chosen from crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing disclosed herein is administered until disease progression, unacceptable toxicity, or individual choice.
  • compositions that incorporate one or more pharmaceutically acceptable excipients and are suitable for administration to human subjets.
  • these pharmaceutical compositions will be a pharmaceutical product, such as, for example, a solid oral dosage form, such as tablets and/or capsules.
  • the crystalline form of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)piperazin-yl)pyrimidin-5-yl)ethan-1-amine may not be detectable in any sufficient amount.
  • the crystalline form may not be detectable where a crystalline API is contacted with one or more pharmaceutically acceptable excipients in the presence of a solvent, such as, for example, water, in an amount sufficient to promote dissolution of the API, e.g., such that its crystalline character is lost and therefore is absent in the final pharmaceutical product.
  • a solvent such as, for example, water
  • crystalline (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl- 1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-yl)pyrimidin-5-yl)ethan-1-amine may be used in a process to prepare a pharmaceutical composition that, for example, involves spray drying or wet granulation. Where the process involves spray drying or wet granulation, little to no crystalline form will likely be detected in the resulting pharmaceutical
  • the present disclosure provides a pharmaceutical composition consisting of at least one crystalline form chosen from crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing.
  • the present disclosure provides a pharmaceutical composition comprising at least one crystalline form chosen from crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing.
  • crystalline Form A of Compound (I) crystalline Form B of
  • Compound (I), crystalline Form C of Compound (I), crystalline Form O of Compound (I), crystalline Form T of a tosylate salt of Compound (I), crystalline Form Tr of a tartrate salt of Compound (I), and/or crystalline Form H of a hydrochloride salt of Compound (I) may be formulated in a pharmaceutical composition for administration in any convenient way for use in human or veterinary medicine.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one crystalline form chosen from crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing and at least one additional pharmaceutically acceptable excipient.
  • pharmaceutically acceptable excipient refers to a pharmaceutically acceptable material, composition, and/or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each excipient must be“pharmaceutically acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient. Except insofar as any conventional pharmaceutically acceptable excipient is incompatible with Compound (I) and/or crystalline forms of
  • Some non-limiting examples of materials which may serve as pharmaceutically acceptable excipients include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate;
  • agar (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution;
  • compositions disclosed herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir.
  • parenteral includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques.
  • the compositions of the disclosure are administered orally, intraperitoneally, or intravenously.
  • Sterile injectable forms of the pharmaceutical compositions of this disclosure may be aqueous or oleaginous suspension.
  • suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxy ethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as
  • carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants, such as Tween, Spans, and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions disclosed herein may also be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, or solutions.
  • aqueous suspensions are required for oral use, the active ingredient is typically combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may also be added.
  • compositions disclosed herein may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non- irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non- irritating excipient include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.
  • compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in at least one excipient.
  • Excipients for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water.
  • pharmaceutical compositions disclosed herein can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in at least one pharmaceutically acceptable excipient.
  • Suitable excipients include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • compositions of this disclosure may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising: at least one pharmaceutically acceptable excipient; and at least one crystalline form chosen from crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing.
  • compositions disclosed herein comprise an intragranular portion and an extragranular portion.
  • the pharmaceutical compositions disclosed herein comprise at least one filler, at least one disintegrant, and at least one lubricant.
  • an“extragranular filler,”“extragranular disintegrant,” or “extragranular lubricant” refers to a filler, disintegrant, or lubricant, respectively, that comprises an extragranular portion of a pharmaceutical composition.
  • Fillers suitable for the pharmaceutical compositions disclosed herein are compatible with the other ingredients of the pharmaceutical compositions, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical compositions.
  • suitable fillers include celluloses, modified celluloses, (e.g. sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose), cellulose acetate, microcrystalline cellulose, calcium phosphates, dibasic calcium phosphate, starches (e.g. corn starch, potato starch), sugars (e.g., mannitol, lactose, sucrose, or the like), or any combination thereof.
  • the filler is microcrystalline cellulose.
  • the pharmaceutical composition comprises at least one extragranular filler in an amount of 15 wt % to 20 wt% (e.g., 15 wt%, 15.5 wt%, 16 wt%, 16.5 wt%, 17%, 17.5 wt%, 18 wt%, 18.5 wt%, 19 wt%, 19.5 wt%, or 20 wt%) by weight of the pharmaceutical composition.
  • the pharmaceutical composition comprises 15 wt % to 20 wt% (e.g., 15 wt%, 15.5 wt%, 16 wt%, 16.5 wt%, 17%, 17.5 wt%, 18 wt%, 18.5 wt%, 19 wt%, 19.5 wt%, or 20 wt%) extragranular
  • microcrystalline cellulose for example MCC Avicel PH-200, by weight of the
  • the pharmaceutical composition comprises 17 wt% extragranular microcrystalline cellulose, for example MCC Avicel PH- 200, by weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises 17 wt% extragranular Avicel PH-200, by weight of the
  • Disintegrants suitable for the pharmaceutical compositions disclosed herein can enhance the dispersal of the pharmaceutical compositions and are compatible with the other ingredients of the pharmaceutical compositions, i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical compositions.
  • suitable disintegrants include croscarmellose sodium, sodium starch glycolate, crospovidone, or any combination thereof.
  • the disintegrant is croscarmellose sodium.
  • the disintegrant is Ac-Di-Sol.
  • the pharmaceutical compositions disclosed herein comprise extragranular disintegrant in an amount of 2 wt% to 3 wt% (e.g., 2 wt%, 2.1 wt%, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3 wt%) by weight of the pharmaceutical composition.
  • 2 wt% to 3 wt% e.g., 2 wt%, 2.1 wt%, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3 wt%
  • the pharmaceutical compositions comprise 2 wt% to 3 wt% (e.g., 2 wt%, 2.1 wt%, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3 wt%) extragranular croscarmellose sodium, e.g., Ac-Di-Sol, by weight of the pharmaceutical composition.
  • the pharmaceutical compositions comprise 2.5 wt% extragranular croscarmellose sodium, e.g., Ac-Di-Sol, by weight of the pharmaceutical composition.
  • the pharmaceutical compositions comprise 2.5 wt% extragranular Ac-Di- Sol by weight of the pharmaceutical composition.
  • the pharmaceutical compositions disclosed herein comprise a lubricant.
  • a lubricant can prevent adhesion of a mixture component to a surface (e.g., a surface of a mixing bowl, a granulation roll, a compression die, and/or punch).
  • a lubricant can also reduce interparticle friction within the granulate and improve the compression and ejection of compressed pharmaceutical compositions from a granulator and/or die press.
  • a suitable lubricant for the pharmaceutical compositions disclosed herein is compatible with the other ingredients of the pharmaceutical compositions, i.e., they do not substantially reduce the solubility, the hardness, or the biological activity of the
  • suitable lubricants include magnesium stearate, sodium stearyl fumarate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil, or any combination thereof.
  • the lubricant is magnesium stearate.
  • compositions comprise an
  • extragranular lubricant in an amount of 0.25 wt% to 1 wt% (e.g., 0.25 wt%, 0.3 wt%, 0.35 wt%, 0.4 wt%, 0.45 wt%, 0.5 wt%, 0.55 wt%, 0.6 wt%, 0.65 wt%, 0.7 wt%, 0.75 wt%, 0.8 wt%, 0.85 wt%, 0.9 wt%, 0.95 wt%, 1 wt%) by weight of the pharmaceutical
  • the pharmaceutical compositions comprise 0.25 wt% to 1 wt% (e.g., 0.25 wt%, 0.3 wt%, 0.35 wt%, 0.4 wt%, 0.45 wt%, 0.5 wt%, 0.55 wt%, 0.6 wt%, 0.65 wt%, 0.7 wt%, 0.75 wt%, 0.8 wt%, 0.85 wt%, 0.9 wt%, 0.95 wt%, 1 wt%) extragranular magnesium stearate, by weight of the pharmaceutical composition.
  • 0.25 wt% to 1 wt% e.g., 0.25 wt%, 0.3 wt%, 0.35 wt%, 0.4 wt%, 0.45 wt%, 0.5 wt%, 0.55 wt%, 0.6 wt%, 0.65 wt%, 0.7 wt%, 0.75 wt%, 0.8 wt%, 0.
  • the pharmaceutical compositions disclosed herein are in the form of a tablet.
  • Tablets disclosed herein can be produced by compacting or compressing an admixture or composition, for example, powder or granules, under pressure to form a stable three-dimensional shape.
  • a“tablet” refers to a compressed
  • pharmaceutical dosage unit forms any shape or size, whether coated or uncoated.
  • tablets disclosed herein comprise an intragranular portion and an extragranular portion.
  • methods of preparing the tablets disclosed herein comprise: (a) mixing at least one crystalline form chosen from crystalline forms of
  • Steps (a), (b), and (c) may occur in any order. Any suitable methods known in the art for granulation and compression of pharmaceutical compositions can be used.
  • Binders suitable for the pharmaceutical compositions e.g., tablets, disclosed herein can enhance the cohesion and/or tensile strength of the pharmaceutical compositions, e.g., tablets, and are compatible with the other ingredients of the pharmaceutical
  • compositions i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical compositions.
  • suitable binders include copovidone, dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose, and modified cellulose (e.g., hydroxymethyl cellulose).
  • the binder is copovidone.
  • the binder is Kollidon VA 64 Fine.
  • the methods disclosed herein further comprise coating the tablet.
  • Tablets disclosed herein can be coated with a film coating, waxed, and optionally labeled with a logo, other image and/or text using a suitable ink.
  • suitable film coatings and inks are compatible with the other ingredients of the tablets, e.g., they do not substantially reduce the solubility, the chemical stability, the physical stability, the hardness, or the biological activity of the tablets.
  • tablets disclosed herein are coated with a film.
  • the film comprises at least one colorant and/or pigment.
  • the film is Opadry II.
  • tablets disclosed herein can be coated with a film coating, e.g., Opadry II, and optionally labeled with a logo, other image and/or text using a suitable ink.
  • a film coating e.g., Opadry II
  • the at least one crystalline form chosen from crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing is in the form of particles.
  • tablets described herein comprise granules comprising 30- 50 wt% particles of at least one crystalline form of Compound (I) or an equivalent amount of particles of a pharmaceutically acceptable salt thereof or a solvate of any of the foregoing, 30-35 wt% of at least one first filler; 2.5-7.5 wt % of at least one binder; 2-3 wt% of at least one first disintegrant; and 0.25-1 wt% of at least one first lubricant.
  • the granules comprise the intragranular portion of a tablet disclosed herein.
  • the tablet comprises particles of at least one crystalline form of Compound (I) having an average diameter of 10 to 150 microns.
  • the tablet comprises particles of at least one crystalline form of Compound (I) having an average diameter of 15, 56, 108, or 147 microns.
  • the tablet comprises crystalline Form A of Compound (I), crystalline Form B of Compound (I), and/or crystalline Form O of Compound (I)) or the weight equivalent of at least one crystalline form of a pharmaceutically acceptable salt thereof (e.g., crystalline Form T of a tosylate salt of Compound (I), crystalline Form Tr of a tartrate salt of Compound (I), and/or crystalline Form H of a hydrochloride salt of Compound (I)) or the weight equivalent of at least one crystalline form of a solvate of Compound (I) or a pharmaceutically acceptable salt thereof (e.g., crystalline Form C of Compound (I)).
  • a pharmaceutically acceptable salt thereof e.g., crystalline Form T of a tosylate salt of Compound (I), crystalline Form Tr of a tartrate salt of Compound (I), and/
  • articles such as“a,”“an,” and“the” may mean at least one than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include“or” between at least one members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
  • the disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
  • the disclosure encompasses all variations, combinations, and permutations in which at least one limitation, element, clause, and descriptive term from at least one of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include at least one limitation found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should be understood that, in general, where the disclosure, or aspects of the disclosure, is/are referred to as comprising particular elements and/or features, embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and/or features.
  • Optical Microscopy was performed using a Zeiss AxioScope A1 equipped with 2.5X, 10X, and 40X objectives and polarizer. Images were captured through a built-in Axiocam 105 digital camera and processed using ZEN 2 (blue edition) software provided by Zeiss.
  • DVS Dynamic Vapor Sorption (DVS) was performed using a DVS Intrinsic 1. The sample was loaded into a sample pan and suspended from a microbalance. A typical sample mass for DVS measurement was 25 mg. Nitrogen gas bubbled through distilled water provided the desired relative humidity. A typical measurement comprised the following steps:
  • the pass criteria was less than 0.002% change
  • the pass criteria was less than 0.002% change
  • the pass criteria was less than 0.002% change
  • Thermal Analysis Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were done using a Mettler Toledo TGA/DSC3+. Samples were weighed in aluminum hermetic pans with pin-holes. The parameters used are shown below.
  • Karl Fisher Titration Karl Fischer titration for water determination was done using a 785 DMP Titrino and 703 Ti Stand equipped with 6.0338.100 double platinum wire electrodes. Samples were dissolved in HPLC grade or anhydrous methanol and titrated with Hydranal-Composite 5. A typical sample mass for the measurement was 0.03 g to 0.10 g. Hydranal 1 wt.% water standard was used for calibration.
  • Chloride Content by Ion-Selective Electrode Chloride content of samples was determined by a titration method with ion- selective electrode. Titration was carried out using an Accumet AB250 pH/ISE benchtop meter (Fisher Scientific) coupled with an Accumet combination chloride electrode. Microsoft Excel software was used to determine the inflection point of the titration curve.
  • NMR Proton and carbon NMR analyses were performed on a Bruker Avance 500 MHz spectrometer. Alternatively, proton NMR was performed on a Bruker Avance 300 MHz spectrometer. Solids were dissolved in 0.75 mL deuterated solvent in a 4 mL vial and transferred to an NMR tube (Wilmad 5mm thin wall 8” 200 MHz, 506-PP-8). Typical parameters for NMR on a Bruker Avance 300 MHz or 500 MHz spectrometer are listed below.
  • XRPD X-ray powder diffraction was done using a Rigaku MiniFlex 600. Samples were prepared on Si zero-return wafers. Typical scans were obtained from 2q of 4 to 30 degrees, with step size 0.05 degrees over five minutes with 40 kV and 15 mA. High resolution scans were obtained from 2q of 4 to 40 degrees, with step size 0.05 degrees over thirty minutes with 40 kV and 15 mA. Typical parameters for XRPD are listed below.
  • Example 1 Preparation of Crystalline Form A of Compound (I)
  • Crystalline Form A of Compound (I) was analyzed by optical microscopy, XRPD, 13 C NMR, DVS, DSC, and TGA.
  • XRPD data for crystalline Form A of Compound (I) are in Table 1.
  • An X-ray powder diffractogram for crystalline Form A of Compound (I) is shown in FIG. 2.
  • a DSC thermogram and TGA thermal curve for crystalline Form A of Compound (I) are shown in FIG. 3.
  • Crystalline Form C was prepared by slurrying Compound (I) in methanol or 1:1 THF:water. The resulting solid was isolated by filtration.
  • Crystalline Form C of Compound (I) was analyzed by optical microscopy, XRPD, 13 C NMR, DVS, DSC, and TGA.
  • XRPD data for crystalline Form C of Compound (I) are in Table 3.
  • An X-ray powder diffractogram for crystalline Form C of Compound (I) is shown in FIG. 6.
  • Crystalline Form O was prepared by stagnant cooling of Compound (I) in THF from room temperature to -20 °C. The resulting solid was isolated by filtration.
  • Crystalline Form O of Compound (I) was analyzed by optical microscopy, XRPD, 13 C NMR, DSC, and TGA.
  • XRPD data for crystalline Form O of Compound (I) are in Table 4.
  • An X-ray powder diffractogram for crystalline Form O of Compound (I) is shown in FIG. 7.
  • the vial was transferred to a hot plate at 35 °C to 40 °C after 10 minutes and left to stir (340 rpm) for an hour before being left to stir at room temperature (340 rpm) for 1 hour.
  • the sample was filtered, washed twice with 2 vol. (2 x 339 ⁇ L) IPA:H 2 O (95:5 vol), and placed under active vacuum at 50 °C to dry. 170.6 mg of salt was collected.
  • Crystalline Form T of a tosylate salt of Compound (I) was analyzed by optical microscopy, XRPD, 13 C NMR, DSC, TGA, and Karl Fisher (KF) titration for water content. Water content for the crystalline Form T of a tosylate salt of Compound (I) was 1.7 wt. %.
  • XRPD data for crystalline Form T of a tosylate salt of Compound (I) are in Table 5.
  • An X- ray powder diffractogram for crystalline Form T of Compound (I) is shown in FIG. 8. [00325]
  • Example 6 Preparation of Crystalline Form Tr of Tartrate Salt of Compound (I)
  • Crystalline Form Tr of a tartrate salt of Compound (I) was analyzed by optical microscopy, XRPD, 13 C NMR, DVS, DSC, TGA, and Karl Fisher (KF) titration for water content. Water content for the crystalline Form Tr of a tartrate salt of Compound (I) was 6.4 wt. %.
  • XRPD data for crystalline Form Tr of a tartrate salt of Compound (I) are in Table 6.
  • An X-ray powder diffractogram for crystalline Form Tr of a tartrate salt of Compound (I) is shown in FIG. 9.
  • Crystalline Form H of a hydrochloride salt of Compound (I) was analyzed by optical microscopy, XRPD, 13 C NMR, DVS, DSC, TGA, and Karl Fisher (KF) titration for water content. Water content for the crystalline Form Tr of a tartrate salt of Compound (I) was 3.9 wt. %.
  • XRPD data for crystalline Form H of a hydrochloride salt of Compound (I) are in Table 7.
  • An X-ray powder diffractogram for crystalline Form Tr of a tartrate salt of Compound (I) is shown in FIG. 10.
  • Example 8 Solubility in Water and Simulated Fluids
  • Solubility of crystalline Form A and a mixture of crystalline Form A and crystalline Form C was measured in fasted simulated intestinal fluid (FaSSIF), fasted simulated gastric fluid (FaSSGF), and water at 37 °C. Thin slurries were stirred overnight and then supernatant was collected for HPLC analysis. The solubility in FaSSIF for crystalline Form A and the mixture of crystalline Form A and crystalline Form C was 0.03 mg/mL. Solubility was higher in FaSSGF for crystalline Form A and the mixture of crystalline Form A and crystalline Form C at 2.11 mg/mL and 2.72 mg/mL, respectively.
  • Solubility of crystalline Form H of a hydrochloride salt of Compound (I), crystalline Form Tr of a tartrate salt of Compound (I), and crystalline Form T of a tosylate salt of Compound (I) was measured in fasted state simulated intestinal fluid (FaSSIF), fasted state simulated gastric fluid (FaSSGF), and water at 37 °C. About 1.5 mL solution was stirred at 37 °C. The salt was then added incrementally until a thin slurry was formed, followed by stirring overnight. The solids were allowed to settle, and the pH of the supernatant was taken. Supernatant was recovered for injection to HPLC and solids were recovered for XRPD.
  • FaSSIF fasted state simulated intestinal fluid
  • FaSSGF fasted state simulated gastric fluid
  • Solubility was determined based on interpolation from a calibration curve prepared using freebase. A linear fit gave an R 2 of 0.999.
  • Solubility of crystalline Form H and crystalline Form Tr were higher in both FaSSIF and water compared to freebase. Solubility in FaSSGF was also higher, but further dilution of samples was necessary. Solubility of crystalline Form Tr was greater than crystalline Form H in FaSSIF (0.27 vs 0.10 mg/mL). Crystalline Form Tr gummed in FaSSIF.
  • Step e Preparation of tert-Butyl (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4- fluorophenyl)methyl)- pyrimidin-2-yl)piperazine-1-carboxylate
  • the mixture was agitated for 2 to 3 hours and filtered through Celite to clarify. Additional brine wash (8.0 mL, 2 vol.) was added and the phases separated. The organic phase was distilled in vacuum and chased with 2-MeTHF (40 mL, 10 vol.) three times.
  • Step f Preparation of tert-Butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4- fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate
  • Step g Purification of tert-Butyl-4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4- fluorophenyl)-ethyl)pyrimidin-2-yl)piperazine-1-carboxylate
  • Step b Preparation of 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol
  • the mixture was degassed followed by K 3 PO 4 (23.7 g, 6.0 eq) in water (7.5 mL, 3 vol.). Finally, the reaction mixture was heated to 100 °C for 12 hours. The reaction mixture was cooled to 20 °C and water (25 mL, 10 vol.) was added and the mixture agitated at 20 °C for 20 minutes. The mixture was clarified by filtration with washing of the filter with water (2.5 mL, 1 vol.). The filtrate was heated to 57 °C and 6 M HCl (12.5 mL, 5 vol.) was added. The resulting slurry was cooled to 3 °C over 3.5 hours and agitated for 2 hours at this temperature.
  • Step c Preparation of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine
  • the solid was filtered and washed with water (1 vol.) and toluene (1 vol.). The filtered solid was reslurried in DCM (28 mL, 7 vol.) at 22 °C. The product solution was mixed with activated charcoal (5%). After charcoal filtration, the solution was concentrated to 2.4 vol. Heptane (7 vol.) was added and the mixture was concentrated to 2.4 volumes. More heptane was added and the mixture was concentrated to 7 volumes and stirred at 0-5 °C overnight.
  • tert-Butyl-4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)- ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (4.0 g, 1 eq.) was mixed with methanol (25.2 mL, 7.5 vol.) and 4 M HCl in dioxane (10.0 mL, 6.0 eq.). The reaction was heated to 40 °C for 1 hour. After reaction completion was reached, the mixture was cooled to 22 °C and charged with MTBE (34 mL, 10 vol.) over 30 minutes.
  • Step a Preparation of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine (Compound (I))
  • Step e Preparation of tert-Butyl (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4- fluorophenyl)methyl)- pyrimidin-2-yl)piperazine-1-carboxylate
  • titanium(IV)isopropoxide (18.42 g, 1.25 eq.) was added and the reaction agitated at 50-60 °C for 1 hour. The reaction was then distilled to remove 80 mL while charging additional toluene (80 mL) at 40-60 °C. The reaction mixture was cooled to 20-30 °C and then added to a monosodium citrate solution (80 mL, 30%-w/w citric acid at pH 3-4). The mixture was agitated for 1.5 hours at 45-55 °C and then the phases separated. The organic phase was washed with potassium bicarbonate (40 mL, 25%-w/w aqueous) and the organic phase distilled to remove 40 mL.
  • potassium bicarbonate 40 mL, 25%-w/w aqueous
  • the product solution was diluted with tetrahydrofuran (30 mL) before being used in the next step directly as a solution (approx. 15% w/w of tert-Butyl (S,Z)- 4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)- pyrimidin-2-yl)piperazine-1- carboxylate).
  • Step f Preparation of tert-Butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4- fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate by isolation
  • Methyl magnesium chloride (27.8 g, 22%-w/w in THF, 2.0 eq.) was added to the tert-butyl (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2- yl)piperazine-1-carboxylate reaction solution in toluene/THF (120 g corresponding to 20 g input material) at 10 °C over 2 to 3 hours. The reaction mixture was allowed to agitate for 1.5 hours to reach reaction completion. The reaction mixture was quenched by the addition of methanol (40 mL) followed by water (10 mL).
  • the mixture was distilled to remove 100-110 mL distillate and then washed with ammonium chloride (80 mL, 20% w/w in water).
  • the organic phase was washed with water (80 mL), diluted with toluene (60 mL), and distilled to remove 60-80 mL distillate.
  • tert-Butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4- fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (10.0 g) was dissolved in isopropanol (100 mL) and heated to 40-60 °C, then passed through a clarifying filter with washing/rinsing with isopropanol (20 mL). The resulting solution was vacuum distilled at 40- 60 °C to remove 60-70 mL distillate.
  • the mixture was diluted with water (45 mL) at 50-60 °C and then cooled to 40 °C, at which time it was seeded with 25-50 mg. The mixture was further cooled to 20-25 °C and water (20 mL) was added. The solids were isolated by filtration, washed with isopropropanol/water mixture (1:1, 20 mL) and then slurry washed with isopropanol/water (1:2, 30 mL).
  • the mixture was cooled to 80-90 °C before it was quenched onto a mixture of K 2 HPO 4 (2.4 g, 0.20 eq.) in 50 mL of deionized water and THF (50 mL) over 25 minutes. During the quench at 40-60 °C, the pH was held between pH 7 and pH 9 by addition of KOH ( ⁇ 62 g, 50% aqueous, ⁇ 8 eq.). The obtained solution was then heated to 50-60 °C and stirring was continued for 30 minutes before the phases separated. The organic phase was washed twice at 50 °C with 45 mL of deionized water. After phase separation, the organic phase was vacuum distilled to 4 volumes at 60 °C. The product precipitated as a yellow solid.
  • Step a Preparation of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine (Compound (I))
  • tert-Butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4- fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (7) (9.0 g) was heated to 45-55 °C in acetonitrile (40 mL) with hydrochloric acid (33%, 8.14 g, 4.1 eq.) for 1 hour to afford tert-Butyl-4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)-ethyl)pyrimidin-2- yl)piperazine-1-carboxylate (2).
  • Step e Preparation of tert-Butyl (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4- fluorophenyl)methyl)- pyrimidin-2-yl)piperazine-1-carboxylate
  • MeMgCl 22.5% in THF, 0.5 eq.
  • Methanol (0.26 vol.) was added at -10 ⁇ 5 °C.
  • the temperature increased to 21 °C.
  • Toluene (4 vol.) was then added.
  • HCl was added at 1.2 °C and the resulting suspension was stirred at room temperature overnight.
  • the suspension was heated to 45 °C to give a biphasic solution.
  • the organic phase was separated from aqueous layer and concentrated. AcOEt (2 vol.) was added and the solution was filtrated under a pad of silica gel (50 g).
  • the silica pad was eluted with ethyl acetate (6 ⁇ 3.6 vol.), and fractions were mixed and concentrated until 1.65 volumes.
  • the suspension of tert-Butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4- fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate was heated (69 °C) to give a solution.
  • Heptane (2.6 vol.) was added and the precipitate was stirred for 30 minutes at 30-40 °C and then cooled to 5 °C. The yellow precipitate was filtrated and washed with heptane (2 ⁇ 1 vol.).
  • reaction mixture was again degassed and heated to 100 ⁇ 2 °C. After reaching reaction completion, 10 volumes of water were added and the suspension agitated at 50 °C for 1 hours. At 21 °C, the addition of HCl (6 N) adjusted the mixture to pH 6.51. Cooling to -10 °C for 1 hour was followed by filtration with washing of the filter cake with 3.6 volumes of water. The solids were triturated with 5 volumes of IPAc, followed by filtration. Additional trituration in 5 volumes of IPAc was again followed by filtration. A third trituration in 5 volumes of IPAc, was followed by filtration and a final trituration in 5 volumes of water.
  • Step a Preparation of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine (Compound (I))
  • Example 12 Phase 1 Dose Escalation and Expansion Study of Compound (I) in Advanced GIST
  • the dose escalation part of the trial was open to patients with refractory solid tumors or unresectable GIST; however, only GIST patients were enrolled.
  • Patients with unresectable GIST who had one or more measurable target lesion per modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST 1.1) were eligible for the dose expansion, which included three cohorts: patients with PDGFRA D842V-mutant GIST regardless of prior therapy; patients who progressed following imatinib and one or more other kinase inhibitors; and patients who received only imatinib.
  • escalation/expansion study were safety and tolerability of Compound (I) administered orally once daily and overall response rate (ORR) for each expansion cohort. Part 1 followed a 3+3 dose-escalation design, starting at 30 mg and continuing until the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) below the MTD was determined.
  • MTD maximum tolerated dose
  • R2D recommended phase 2 dose
  • Intrapatient dose escalation was permitted, and additional accrual was allowed to dose levels previously determined tolerable.
  • the part 1 MTD was used to initiate the part 2 expansion.
  • Treatment with Compound (I) was continued until precluded by toxicity, noncompliance, withdrawal of consent, physician decision, progressive disease, death, or closure of the study.
  • the MTD defined as the highest dose level with £ 1 cycle 1 dose limiting toxicity in six patients, was determined from all part 1 patients who completed cycle 1 and received at least 75% of their prescribed doses or experienced a dose limiting toxicity (DLT) (dose-determining population).
  • the efficacy population included patients who received at least one dose of Compound (I) enrolled in part 1 or part 2 with PDGFRa D842V- mutant GIST who had one or more target lesions and at least one post-baseline disease assessment by central radiology.
  • a sample size of 31 patients allowed testing the null hypothesis of overall response rate £ 10% versus the alternative hypothesis of objective response rate 3 35% with 90% power, assuming a 2-sided type I error rate of 0.05.
  • Kaplan-Meier methods were used to estimate duration of response, PFS and OS, including the median with 95% confidence intervals. Estimated duration of response, PFS, and OS rates at 3-, 6-, and 12-months were also calculated.
  • Efficacy There were 56 response-evaluable patients with PDGFRA D842V- mutant GIST across all dose levels. Confirmed responses per central radiology mRECIST 1.1 assessments were seen in 88% (95% CI: 75.9.94.8) of patients (complete response: 5/56 [8.9%], partial response: 44/56 [78.6%], and stable disease 7/56 (12.5%) (FIG. 11, Table 9).
  • ISM-SAF ISM Symptom Assessment Form
  • ISM-SAF data was collected for an additional 14 days to determine eligibility based on symptom severity i.e., to identify ISM and SSM patients having moderate-to-severe symptoms. Patients not meeting the symptom severity threshold were deemed screen failures and were not eligible for study participation.
  • BM Bone marrow
  • CM cutaneous mastocytosis
  • Additional procedures include: magnetic resonance imaging/computed tomography scan of the brain; bone densitometry; serum tryptase, KIT D816 mutation testing; routine laboratory testing; ECG; and physical examination. All procedures are completed within a 6- week period before the final 14-day collection of baseline ISM-SAF symptoms is initiated.
  • Part 1 of the study approximately 40 patients were randomly assigned to 1 of 3 doses of Compound (I) or to placebo. Each dose-level cohort and placebo group in Part 1 was composed of 10 patients. The 3 dose levels of Compound (I) were tested in parallel: 25, 50, and 100 mg. Patients, study staff, and the Sponsor were blinded to treatment assignment.
  • Compound (I) was administered orally, once a day in continuous 28-day cycles. Patients were assessed weekly for the first 4 weeks, then every 4 weeks (until the RP2D was determined) for safety, laboratory monitoring, and quality of life (QoL) assessments.
  • PK pharmacokinetic
  • the RP2D was determined based on the efficacy, safety, and PK at each dose level.
  • the primary evaluation of efficacy was the symptom improvement using the ISM-SAF.
  • the primary criterion for selection of the RP2D was the dose of Compound (I) that produces the maximum reduction in total symptom score (TSS), as assessed using the ISM-SAF at Week 12 compared with Baseline (Day -14 to Day -1).
  • TSS total symptom score
  • TSS Intent to Treat
  • C4D1 TSS Baseline TSS
  • Baseline TSS was considered as missing for the patient.
  • C4D1 TSS was considered as missing for the patient.
  • Part 2 The screening procedure described above for Part 1 is used for Part 2.
  • Part 2 of the study approximately 72 patients are enrolled. Patients are randomly assigned to receive Compound (I) at the RP2D + BSC or matching placebo + BSC. Patients assigned to placebo in Part 2 receive Compound (I), once they roll over into Part 3. Patients, study staff, and the Sponsor are blinded to treatment assignment.
  • Compound (I) and placebo dosing are administered orally, once a day in continuous 28-day cycles.
  • Compound (I) is administered orally, once a day at 25 mg.
  • Patients are assessed weekly for the first 4 weeks, then every 4 weeks through Week 12 for safety, laboratory monitoring, and QoL assessments. Sparse PK sampling is performed in all patients.
  • the ISM-SAF is completed once a day. After completion of 12 weeks of treatment and the ISM-SAF through Week 12 Day 7, BM and skin biopsy are repeated for MC quantification by the Central Pathology Laboratory and skin photographs are taken in patients with baseline CM.
  • Week 12 assessments are completed, patients roll over into the Part 3 long-term extension. After all patients roll over into Part 3, the primary endpoint of mean change in ISM-SAF TSS from Baseline to Week 12 and other efficacy endpoints is analyzed.
  • the primary efficacy endpoint for Part 2 is the mean change in ISM-SAF TSS from baseline to cycle 4 day 1 (C4D1).
  • the analysis of mean change in TSS will use the intent-to-treat population primarily and will be performed in the per-protocol population as a sensitivity analysis.
  • Mean change in TSS will be calculated as the arithmetic average of the change in TSS in each treatment group.
  • a 2-sample t-test will be used to compare Compound (I) and placebo.
  • CM mastocytosis
  • Week 12 study assessments for BM and skin biopsies from Part 1 and Part 2 may serve as baseline assessments for Part 3.
  • Assessments performed at the final study visits in Part 1 and Part 2 may serve as baseline assessments for Part 3, if obtained within the preceding 4 weeks. Any procedures required at Part 3 baseline and not performed within 4 weeks of Part 3 Day 1 in Part 1 or Part 2 are performed on Day 1 of Part 3.
  • Patients who choose not to continue on Compound (I) will have an end-of-treatment visit 14 days after last dose of study treatment. Patients may continue on Compound (I) until unacceptable toxicity, death, or patient withdrawal for a maximum of 5 years.
  • Part 1 patients received treatment for 12 weeks, then patients continued on assigned therapy and were dosed until the RP2D of 25 mg QD was determined. In Part 2, patients receive treatment for up to 12 weeks. In Part 3, patients receive treatment for up to 5 years, inclusive of Part 1 and Part 2.
  • Part 1 the minimum duration of patient participation was approximately 26 weeks. In Part 2, the minimum duration of patient participation is approximately
  • Part 1 the expected enrollment period was approximately 6 months and the expected duration of this part of the study was approximately 15 months.
  • the expected enrollment period is approximately 9 months and the expected duration of this part of the study is approximately 18 months.
  • the expected duration of Part 3 is approximately 5 years (inclusive of Part 1 and Part 2).
  • Part 1 of the PIONEER trial was designed to determine the RP2D by evaluating three doses of Compound (I) (25 mg, 50 mg and 100 mg QD) versus placebo. Key eligibility criteria include adults with ISM confirmed by central pathology review of bone marrow biopsy (according to WHO criteria) and moderate-to-severe symptom burden despite best supportive care medicines. Overall, 39 patients were enrolled in Part 1 across four concurrent cohorts, consisting of 10 patients each in the Compound (I) dose cohorts and nine patients in the placebo cohort.
  • ISM-SAF Intra-reported outcomes data were collected using the ISM-SAF, which was designed with input from disease experts, patients and regulatory authorities as a clinical benefit measure to support registration.
  • the ISM-SAF assesses symptoms across the skin domain (spots, itching and flushing) and gastrointestinal domain (abdominal pain, diarrhea and nausea), as well as other key symptoms impacting patients with ISM (brain fog, headache, dizziness, bone pain and fatigue). All results are as of a data cutoff date of December 27, 2019.
  • Compound (I) demonstrated clinically meaningful benefits across all measures of mast cell burden, patient-reported symptoms and quality of life. The consistency of results shown across multiple measures of disease support the broad potential of Compound (I) in ISM.
  • Compound (I) showed clinically meaningful reductions in the ISM-SAF TSS, as well as the gastrointestinal domain, skin domain and each individual symptom tested.
  • MC-QoL Mastocytosis Quality of Life
  • Compound (I) showed a favorable safety profile supporting chronic dosing in ISM.
  • No patients treated with Compound (I) in the 25 mg QD dose cohort had serious AEs, Grade 3 or higher AEs, or dose modifications.
  • In the placebo cohort two patients (22 percent) had at least one Grade 3 AE and two patients (22 percent) had dose modifications due to AEs. All doses of Compound (I) were well-tolerated, and no patients discontinued treatment due to AEs as of the data cutoff date.

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PCT/US2020/027724 2019-04-12 2020-04-10 Crystalline forms of (s)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine and methods of making Ceased WO2020210669A1 (en)

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DK20722936.0T DK3856341T3 (da) 2019-04-12 2020-04-10 Krystallinske former af (s)-1-(4-fluorphenyl)-1-(2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amin og fremgangsmåder til fremstilling deraf
JP2021560265A JP7728178B2 (ja) 2019-04-12 2020-04-10 （ｓ）－１－（４－フルオロフェニル）－１－（２－（４－（６－（１－メチル－１ｈ－ピラゾール－４－イル）ピロロ［２，１－ｆ］［１、２，４］トリアジン－４－イル）ピペラジニル）－ピリミジン－５－イル）エタン－１－アミンの結晶形態及び製造方法
RS20231131A RS64881B1 (sr) 2019-04-12 2020-04-10 Kristalini oblici (s)-1-(4-fluorofenil)-1-(2-(4-(6-(1-metil-1h-pirazol-4-il)pirolo[2,1-f][1,2,4]triazin-4-il)piperazinil)-pirimidin-5-il)etan-1-amin i načini pripreme
EP20722936.0A EP3856341B1 (en) 2019-04-12 2020-04-10 Crystalline forms of (s)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine and methods of making
SM20230447T SMT202300447T1 (it) 2019-04-12 2020-04-10 Forme cristalline di (s)-1-(4-fluorofenil)-1-(2-(4-(6-(1-metil-1h-pirazol-4-yl)pirrolo[2,1-f][1,2,4]triazin-4-il)piperazinil)-pirimidin-5-il)etan-1-ammina e metodi di produzione
HRP20231533TT HRP20231533T1 (hr) 2019-04-12 2020-04-10 Kristalni oblici od (s)-1-(4-fluorofenil)-1-(2-(4-(6-(1-metil-1h-pirazol-4-il)pirolo[2,1-f][1,2,4 ]triazin-4-il)piperazinil)-pirimidin-5-il)etan-1-amina i postupci priprave
SI202030328T SI3856341T1 (sl) 2019-04-12 2020-04-10 Kristalinične oblike (s)-1-(4-fluorofenila)-1-(2-(4-(6-(1-metil-1h- pirazola-4-il)pirolo(2,1-f)(1,2,4)triazin-4-il)piperazinil)-pirimidin- 5-il)etan-1-amin in postopki izdelave
PL20722936.0T PL3856341T3 (pl) 2019-04-12 2020-04-10 Postaci krystaliczne (s)-1-(4-fluorofenylo)-1-(2-(4-(6-(1-metylo-1h-pirazol-4-ilo)pirolo[2,1-f][1,2,4]triazyn-4-ylo)piperazynylo)-pirymidyn-5-ylo)etano-1-aminy i sposoby wytwarzania
CA3136707A CA3136707A1 (en) 2019-04-12 2020-04-10 Crystalline forms of (s)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine and methods of making
EP23195076.7A EP4302761A3 (en) 2019-04-12 2020-04-10 Crystalline forms of (s)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine and methods of making
FIEP20722936.0T FI3856341T3 (fi) 2019-04-12 2020-04-10 (s)-1-(4-fluorifenyyli)-1-(2-(4-(6-(1-metyyli-1h-pyratsol-4-yyli)pyrrolo[2,1-f][1,2,4]triatsin-4-yyli)piperatsinyyli)pyrimidin-5-yyli)etaani-1-amiinin kidemuotoja ja valmistusmenetelmiä
LTEPPCT/US2020/027724T LT3856341T (lt) 2019-04-12 2020-04-10 (s)-1-(4-fluorfenil)-1-(2-(4-(6-(1-metil-1h-pirazol-4-il)pirolo[2,1-f] [1,2,4]triazin-4-il)piperazinil)-pirimidin-5-il)etan-1-amino kristalinės formos ir gamybos būdai
ES20722936T ES2966512T3 (es) 2019-04-12 2020-04-10 Formas cristalinas de (S)-1-(4-fluorofenil)-1-(2-(4-(6-(1-metil-1H-pirazol-4-il)pirrolo[2,1-f][1,2,4]triazin-4-il)piperazinil)-pirimidin-5-il)etan-1-amina y métodos de elaboración
CN202080042782.9A CN113966334B (zh) 2019-04-12 2020-04-10 化合物(i)的晶体形式
US17/153,727 US12060354B2 (en) 2019-04-12 2021-01-20 Crystalline forms of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine and methods of making
IL287148A IL287148A (en) 2019-04-12 2021-10-10 Crystalline forms of (s)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine and methods of making
US18/077,466 US11964980B2 (en) 2019-04-12 2022-12-08 Crystalline forms of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine and methods of making
US18/077,431 US12252494B2 (en) 2019-04-12 2022-12-08 Dosing regimens of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine for treatment of indolent systemic mastocytosis
US18/543,793 US11999744B2 (en) 2019-04-12 2023-12-18 Crystalline forms of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine and methods of making
US18/800,215 US20260116883A1 (en) 2019-04-12 2024-08-12 Crystalline forms of (s)-1-(4-fluorophenyl)-1-(2-(4-(6-(1- methyl-1h-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine and methods of making
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