Crystalline form and preparation method 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

Abstract

Compound (I) Pharmaceutically acceptable salts and crystalline forms of any of the foregoing solvates are disclosed. Pharmaceutical compositions containing them, methods of using them to treat disorders and conditions associated with oncogenic KIT and PDGFRA alterations, and methods for making Compound (I) and its crystalline forms are also disclosed.

Description

Related Applications

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 62 / 990,269, filed March 16, 2020, U.S. Provisional Application No. 62 / 844,575, filed May 7, 2019, and U.S. Provisional Application No. 62 / 833,527, filed April 12, 2019. The entire contents of each of the foregoing applications are incorporated herein by reference. [Technical Field]

[0002] Disclosed herein are 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)piperazin-yl)pyrimidin-5-yl)ethan-1-amine (Compound (I)), its pharmaceutically acceptable salts, and solvates of any of the aforementioned compositions comprising the same, methods of using the same, and processes for producing Compound (I) comprising the crystalline form. The crystalline form of Compound (I) may be a selective inhibitor of KIT, including exon 17 mutant and / or PDGFRα exon 18 mutant proteins. [Background technology]

[0003] The enzyme KIT (also known as CD117) is a receptor tyrosine kinase expressed in various cell types. The KIT receptor protein belongs to the class III receptor tyrosine kinase (RTK) family, which also includes the structurally related proteins PDGFRα (platelet-derived growth factor receptor A), PDGFRβ, FLT3 (FMS-like tyrosine kinase 3), and CSF1R (colony-stimulating factor 1 receptor). The KIT molecule contains a long extracellular domain, a transmembrane segment, and an intracellular portion. The ligand for KIT is stem cell factor (SCF). Normally, SCF binds and activates KIT by inducing dimerization, autophosphorylation, and initiation of downstream signaling. However, in some tumor types, somatic activating mutations in KIT promote ligand-independent constitutive activity.

[0004] KIT mutations generally occur in the DNA encoding the juxtamembrane domain (exon 11). KIT mutations also occur less frequently in exons 7, 8, 9, 13, 14, 17, and 18. Mutations can cause KIT to function independently of SCF activation, leading to increased cell division rates and genomic instability. Mutant KIT has been implicated in the pathogenesis of several disorders and conditions, including mastocytosis, gastrointestinal stromal tumors (GISTs), acute myeloid leukemia (AML), melanoma, and seminoma.

[0005] The structurally related platelet-derived growth factor receptor (PDGFR) is a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor (PDGF) family. PDGF subunits α and β regulate cell proliferation, differentiation, growth, and development. Alterations (e.g., mutations) in PDGF subunits α and β are associated with many diseases, including some cancers. For example, the exon 18 PDGFRα D842V mutation has been found in a distinct subset of gastrointestinal stromal tumors (GISTs), usually in the stomach. The D842V mutation is also associated with tyrosine kinase inhibitor resistance. Furthermore, other exon 18 mutations, such as PDGFRα D842I and PDGFRα D842Y, are associated with ligand-independent constitutive activation of PDGFRα. In GISTs, functional mutations that confer ligand-independent constitutive activation of PDGFRα signaling (e.g., PDGFRα D842I, D842V, and D842Y) have been identified as disease drivers.

[0006] Compound (I), its pharmaceutically acceptable salts, and solvates of any of the foregoing can inhibit KIT and / or PDGFRα and may be useful in treating mast cell disorders, such as mastocytosis, and disorders and conditions associated with oncogenic KIT and PDGFRα alterations. Compound (I) is disclosed in Example 7 of WO 2015 / 057873 and has the following structure: [ka]

[0007] The procedure described in WO 2015 / 057873 for preparing Compound (I) uses chiral supercritical fluid chromatography (SFC) to separate the enantiomers in the final step. Chromatographic separation is generally undesirable for large-scale manufacturing processes. Furthermore, trace impurities can be present in Compound (I) obtained by the procedure described in WO 2015 / 057873. 1 1 H NMR.

[0008] Crystalline forms of biologically active compounds, such as Compound (I), its pharmaceutically acceptable salts, and solvates of any of the foregoing, are of interest in the pharmaceutical industry, where crystalline forms may be desirable or even necessary for drug development. Crystalline forms arise when substances of the same composition crystallize with different lattice arrangements, resulting in different thermodynamic properties and stability characteristics specific to each crystalline form. Each unique crystalline form is known as a "polymorph." Crystalline forms may also include different solvates (e.g., hydrates) of the same compound. Although polymorphs of a given substance have the same chemical composition, they may differ from each other with respect to at least one physical, chemical, and / or pharmaceutical property, such as solubility, dissociation, true density, dissociation, melting point, crystal habit or shape, compaction behavior, particle size, flow properties, and / or solid-state stability.

[0009] The solid form of a biologically active compound often determines its ease of preparation, ease of isolation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and in vivo bioavailability. For example, if an unstable crystalline form is used during large-scale manufacturing, the crystalline form may change during manufacturing and / or storage, resulting in quality control issues and formulation irregularities. An unstable crystalline form may affect the development of pharmaceuticals for human use. Therefore, any changes to the solid state of a biologically active compound that improve its physical or chemical stability may be significantly advantageous over a less stable form of the same compound.

[0010] Furthermore, it is important that the crystalline form used as the active pharmaceutical ingredient (API) in a therapeutic composition be substantially pure. Specifically, a substantially pure crystalline form is free of reaction impurities, starting materials, reagents, by-products, unwanted solvents, and / or other processing impurities resulting from the preparation and / or isolation and / or purification of the particular crystalline form.

[0011] It remains impossible to predict whether a particular compound, salt, or hydrate of a compound will form crystalline forms, how many different crystalline forms will exist, whether such crystalline forms will be suitable for commercial use in pharmaceutical compositions, or which crystalline form(s) will exhibit desirable properties. Because different crystalline forms may have different properties, reproducible processes, including large-scale manufacturing processes, for producing substantially pure crystalline forms, i.e., not a mixture of forms, are desirable for biologically active compounds intended for use in pharmaceutical products.

[0012] Thus, there is a need for novel crystalline forms, e.g., Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing, that are useful for treating mast cell disorders associated with mutant / oncogenic KIT and PDGFRA, including mastocytosis, and disorders and conditions associated with alterations in mutant / oncogenic KIT and PDGFRA. Summary of the Invention

[0013] Disclosed herein are novel crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing, compositions containing the same, and methods of using and preparing the same. Importantly, crystalline forms of Compound (I) for pharmaceutical use are substantially free of impurities. In some embodiments, the novel crystalline forms disclosed herein have properties useful for large-scale manufacture, formulation, and / or storage. In some embodiments, the novel crystalline forms disclosed herein consist of a single crystalline form. The crystalline form is substantially pure. Also disclosed herein are novel methods for making Compound (I).

[0014] Some embodiments of the present disclosure relate to pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one crystalline form selected from the crystalline forms of Compound (I), a pharmaceutically acceptable salt thereof, and any of the foregoing solvates. In some embodiments, at least one crystalline form is crystalline form A of Compound (I). In some embodiments, at least one crystalline form is crystalline form B of Compound (I). In some embodiments, at least one crystalline form is crystalline form C of Compound (I). In some embodiments, at least one crystalline form is crystalline form O of Compound (I). In some embodiments, at least one crystalline form is crystalline form T of the tosylate salt of Compound (I). In some embodiments, at least one crystalline form is crystalline form Tr of the tartrate salt of Compound (I). In some embodiments, at least one crystalline form is crystalline form H of the hydrochloride salt of Compound (I).

[0015] Some embodiments of the present disclosure relate to methods of treating a patient in need of a KIT or PDGFRα inhibitor by administering a therapeutically effective amount of at least one crystalline form selected from the crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and any of the foregoing solvates. In some embodiments, at least one crystalline form is crystalline form A of Compound (I). In some embodiments, at least one crystalline form is crystalline form B of Compound (I). In some embodiments, at least one crystalline form is crystalline form C of Compound (I). In some embodiments, at least one crystalline form is crystalline form O of Compound (I). In some embodiments, at least one crystalline form is crystalline form T of the tosylate salt of Compound (I). In some embodiments, at least one crystalline form is crystalline form Tr of the tartrate salt of Compound (I). In some embodiments, at least one crystalline form is crystalline form H of the hydrochloride salt of Compound (I).

[0016] In some embodiments, a patient in need of a KIT or PDGFRα inhibitor suffers from a disorder or condition associated with at least one oncogenic KIT and / or PDGFRA alteration. In some embodiments, a patient in need of a KIT or PDGFRα inhibitor suffers from PDGFRA exon 18-positive unresectable or metastatic GIST. In some embodiments, the at least one oncogenic KIT and / or PDGFRA alteration is a genetic mutation in exon 18 of PDGFRA. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is a D842V mutation in the PDGFRA protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is a D842I mutation in the PDGFRA protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is a D842Y mutation in the PDGFRA protein.

[0017] In some embodiments, at least one oncogenic KIT and / or PDGFRα alteration is a non-D842 alteration in exon 18 of PDGFRα. In some embodiments, at least one oncogenic KIT and / or PDGFRα alteration is an indel in the PDGFRA protein. In some embodiments, at least one oncogenic KIT and / or PDGFRα alteration is D842-H845 in the PDGFRA protein. In some embodiments, at least one oncogenic KIT and / or PDGFRα alteration is D1842-843V in the PDGFRA protein. In some embodiments, at least one oncogenic KIT and / or PDGFRA alteration is a genetic mutation in exon 17 of KIT. In some embodiments, at least one oncogenic KIT and / or PDGFRα alteration is D557-558 in the KIT protein. In some embodiments, at least one oncogenic KIT and / or PDGFRα alteration is V560G in the KIT protein. In some embodiments, at least one oncogenic KIT and / or PDGFRα alteration is V560G / D816V in the KIT protein. In some embodiments, at least one oncogenic KIT and / or PDGFRα alteration is V560G / N822K in the KIT protein. In some embodiments, at least one oncogenic KIT and / or PDGFRα alteration is a D816 mutation in the KIT protein. In some embodiments, at least one oncogenic KIT and / or PDGFRα alteration is a D816V mutation in the KIT protein. In some embodiments, at least one oncogenic KIT and / or PDGFRα alteration is D816E in the KIT protein. In some embodiments, at least one oncogenic KIT and / or PDGFRα alteration is D816F in the KIT protein. In some embodiments, at least one oncogenic KIT and / or PDGFRα alteration is D816H in the KIT protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is D816I in the KIT protein.In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is D816Y in the KIT protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is D820E in the KIT protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is D820Y in the KIT protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is Y823D in the KIT protein. In some embodiments, the disorder or condition associated with at least one oncogenic KIT and / or PDGFRα alteration is gastrointestinal stromal tumor (GIST). In some embodiments, the patient is refractory to treatment with imatinib. In some embodiments, the patient has undergone at least three prior therapies. In some embodiments, the patient is refractory to treatment with imatinib, sunitinib, and / or regorafenib. In some embodiments, 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.

[0018] In some embodiments, the disorder or condition associated with at least one mutant / oncogenic KIT and / or PDGFRA alteration is mastocytosis. In some embodiments, the mastocytosis is selected from cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In some embodiments, the systemic mastocytosis is selected from indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), and advanced systemic mastocytosis (AdvSM). AdvSM includes aggressive systemic mastocytosis (ASM), SM associated with hematopoietic non-mast cell lineage disease (SM-AHNMD), and mast cell leukemia (MCL). In some embodiments, 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 associated with hematopoietic non-mast cell lineage disease (SM-AHNMD). In some embodiments, the systemic mastocytosis is mast cell leukemia (MCL).

[0019] Disclosed herein are improved methods for treating indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM) in patients with Compound (I). In some embodiments, the disclosure provides Compound (I) dosing regimens 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 assessed by the Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-ASF), by administering Compound (I) at a dose of 10 to 100 mg once daily.

[0020] There are no approved treatments for ISM and SSM. Symptoms are managed with symptom-directed treatments, such as antihistamines. Therefore, safe and effective treatments for ISM and SSM are needed. Furthermore, patients with ISM and SSM have a lower disease burden than those with AdvSM and are expected to remain on treatment for longer periods, so if effective, lower doses are required.

[0021] The FDA-approved dose of Compound (I) (AYVAKIT™ or avapritinib) for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including the PDGFRA D842V mutation, is 300 mg orally QD. A Phase 2 clinical trial is currently evaluating the efficacy and safety of Compound (I) at doses of 200-300 mg orally QD in patients with advanced systemic mastocytosis (AdvSM). According to the latest clinical trial results shown in the Examples provided herein, Compound (I) administered at 25 mg once daily to patients with ISM or SSM has now been shown to demonstrate improvements across all three aspects of its clinical profile, including reduced mast cell burden, improved disease symptoms, and improved quality of life. Specifically, Compound (I) administered at 25 mg once daily resulted in statistically significant reductions in the ISM-SAF TSS total domain score and each symptom at 16 weeks. Surprisingly, the 25 mg dose produced similar mean improvements in TSS as the higher doses of 50 mg and 100 mg, and was better tolerated. For example, the 25 mg QD dose showed a significant reduction in the blood KIT D816V allele fraction, similar to the 50 mg QD and 100 mg QD doses. Furthermore, 25 mg of Compound (I) administered once daily to patients with ISM had a favorable safety profile. For example, 95% of patients continued in the clinical trial, with no discontinuation due to adverse events (AEs). No grade 3 or higher AEs occurred in the 25 mg once-daily cohort. Patients experienced improved quality of life (QoL), as measured by the MC-QoL global score and all domain scores at 16 weeks.

[0022] Also disclosed herein are methods for preparing at least one crystalline form selected from the crystalline forms of Compound (I), its pharmaceutically acceptable salts, and any of the foregoing solvates. Some embodiments of the present disclosure relate to the method, wherein at least one crystalline form is crystalline form A of Compound (I). Some embodiments of the present disclosure relate to the method, wherein at least one crystalline form is crystalline form B of Compound (I). Some embodiments of the present disclosure relate to the method, wherein at least one crystalline form is crystalline form C of Compound (I). Some embodiments of the present disclosure relate to the method, wherein at least one crystalline form is crystalline form O of Compound (I). Some embodiments of the present disclosure relate to the method, wherein at least one crystalline form is crystalline form T of the tosylate salt of Compound (I). Some embodiments of the present disclosure relate to the method, wherein at least one crystalline form is crystalline form Tr of the tartrate salt of Compound (I). Some embodiments of the present disclosure relate to the method, wherein at least one crystalline form is crystalline form H of the hydrochloride salt of Compound (I). [Brief explanation of the drawings]

[0023] [Figure 1] Figure 1 is a schematic diagram illustrating the interrelationship of the four crystalline forms and non-limiting examples of methods for preparing the crystalline forms. As shown in Figure 1, crystalline Form A, crystalline Form B, and crystalline Form O of Compound (I) are all anhydrous. [Figure 2] FIG. 2 shows the powder X-ray diffraction pattern of crystalline Form A of Compound (I), herein referred to as crystalline Form A, with degrees 2θ (2-theta) on the X-axis and relative intensity on the Y-axis. [Figure 3] FIG. 3 shows a differential scanning calorimetry (DSC) thermogram of crystalline Form A of Compound (I) and a thermogravimetric analysis (TGA) heat curve for crystalline Form A of Compound (I) recrystallized from acetone:water. [Figure 4] FIG. 4 shows the powder X-ray diffraction pattern of crystalline form B of Compound (I), herein referred to as crystalline form B, with degrees 2θ (2-theta) on the X-axis and relative intensity on the Y-axis. [Figure 5]FIG. 5 shows the DSC thermogram of crystalline form B of Compound (I). [Figure 6] FIG. 6 shows the powder X-ray diffraction pattern of crystalline form C of Compound (I), herein referred to as crystalline form C, with degrees 2θ (2-theta) on the X-axis and relative intensity on the Y-axis. [Figure 7] FIG. 7 shows the powder X-ray diffraction pattern for crystalline form O of Compound (I), herein referred to as crystalline form O, with degrees 2θ (2-theta) on the X-axis and relative intensity on the Y-axis. [Figure 8] FIG. 8 shows the powder X-ray diffraction pattern for crystalline Form T of the tosylate salt of Compound (I), herein referred to as crystalline Form T, with degrees 2θ (2-theta) on the X-axis and relative intensity on the Y-axis. [Figure 9] FIG. 9 shows the powder X-ray diffraction pattern for crystalline Form Tr of the tartrate salt of Compound (I), herein referred to as Crystalline Form Tr, with degrees 2θ (2-theta) on the X-axis and relative intensity on the Y-axis. [Figure 10] FIG. 10 shows the powder X-ray diffraction pattern for crystalline Form H of the hydrochloride salt of Compound (I), herein referred to as crystalline Form H, with degrees 2θ (2-theta) on the X-axis and relative intensity on the Y-axis. [Figure 11] FIG. 11 shows the maximum percentage change in sum of tumor diameters from baseline in patients with PDGFRA D842V mutant GIST treated with Compound (I). [Figure 12] 12 shows a bar graph depicting the effect of Compound (I) 25 mg once daily, Compound (I) 50 mg once daily, Compound (I) 100 mg once daily, and placebo on KIT D816V allele burden in ISM patients. All Compound (I) dose cohorts showed a significant reduction in KIT D816V allele burden. [Figure 13] FIG. 13 shows significant decreases in serum tryptase, mast cell burden, and KIT D816V allele burden in ISM patients treated with a 25 mg once daily dose compared to placebo-treated patients. [Figure 14A]Figure 14A shows the reduction in ISM-SAF total symptom score from baseline (dotted line) in patients receiving 25 mg of Compound (I) once daily. The top line represents placebo, and the bottom line represents the 25 mg once daily dose of Compound (I). [Figure 14B] Figure 14B shows the reduction in ISM-SAF total symptom score from baseline (dotted line) in patients receiving 50 mg of Compound (I) once daily. The top line represents placebo, and the bottom line represents the 50 mg once daily dose of Compound (I). [Figure 14C] Figure 14C shows the reduction in ISM-SAF total symptom score from baseline (dotted line) in patients receiving 100 mg of Compound (I) once daily. The top line represents placebo, and the bottom line represents the 100 mg once daily dose of Compound (I). DETAILED DESCRIPTION OF THE INVENTION

[0024] Compound (I) was developed to selectively target KIT D816V and other KIT exon 17 mutations. In some embodiments, Compound (I) is amorphous. In some embodiments, Compound (I) is crystalline. In some embodiments, Compound (I) is a mixture of crystalline forms. Compound (I) has been approved by the FDA at 400 mg once daily (QD) for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a PDGFRA exon 18 mutation, including the PDGFRA D842V mutation. Compound (I) has also demonstrated potent and selective activity against KIT D816V in vitro, potent growth inhibition in a tyrosine kinase inhibitor (TKI)-resistant mast cell tumor model in vivo, and tolerability at active doses in toxicology and safety pharmacology studies. An ongoing Phase 1 trial of Compound (I) in patients with AdvSM (Explorer / NCT02561988) is evaluating safety and preliminary efficacy. The recommended phase 2 dose (RP2D) was identified as 300 mg once daily, and an expansion cohort of the study was conducted to further evaluate the efficacy and safety of this dose in a larger patient cohort, as well as to validate the AdvSM Symptom Assessment Form (AdvSM-SAF), which was developed to assess the impact of Compound (I) on symptom improvement in AdvSM patients. Based on emerging safety and efficacy data in patients treated with 300 mg QD, an additional cohort of patients treated with 200 mg QD was added.

[0025] As used herein, the term "pharmaceutically acceptable salt" refers to a non-toxic salt form of the compound of the present disclosure. Pharmaceutically acceptable salts of Compound (I) of the present 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, for example, those disclosed in Berge, SM, et al. J. Pharma. Sci. 66:1-19 (1977). Non-limiting examples of pharmaceutically acceptable salts disclosed in the article include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, edetate calcium salt, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, Maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucilage, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, acetate, succinate, sulfate, tannate, tartrate, teosylate, triethiodide, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.

[0026] Non-limiting examples of pharmaceutically acceptable salts derived from appropriate acids include salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, or perchloric acids, salts formed with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, and salts formed by using other methods used in the art, such as ion exchange. Additional non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glyceroate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, and the like. Non-limiting examples of pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1-4 (Alkyl) 4 salts are included. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0027] As used herein, the term "ambient conditions" refers to room temperature, outdoor conditions, and uncontrolled humidity conditions. As used herein, the term "room temperature" or "ambient temperature" refers to a temperature in the range of 15°C to 30°C.

[0028] As used herein, the terms "polymorph," "crystal form," "solid form," and "form" interchangeably refer to solids having a particular molecular packing arrangement within a crystal lattice. Crystalline forms can be identified and distinguished from one another by at least one characterization technique, including, for example, powder X-ray diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and / or thermogravimetric analysis (TGA). Thus, as used herein, 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 one another by at least one characterization technique, including, for example, powder X-ray diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and / or thermogravimetric analysis (TGA). In some embodiments, the novel crystalline forms are characterized by a powder X-ray diffraction pattern having at least one signal at at least one designated two-theta value (°2θ).

[0029] As used herein, the term "solvate" refers to a crystalline form of a molecule, atom, and / or ion that further comprises at least one molecule of a solvent(s) incorporated into the crystal lattice structure, in a stoichiometric or non-stoichiometric amount. The solvent molecules in a solvate may exist in an ordered and / or disordered arrangement. For example, a solvate containing a non-stoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate. Alternatively, the solvate may occur as a dimer or oligomer containing multiple molecules. When the solvent is water, the solvate is referred to herein as a "hydrate."

[0030] As used herein, the term "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.

[0031] As used herein, the terms "powder X-ray diffractogram," "powder X-ray diffraction pattern," and "XRPD pattern" refer to an experimentally obtained pattern that plots signal position (abscissa) versus signal intensity (ordinate). For amorphous materials, the powder X-ray diffractogram can include at least one broad signal. For crystalline materials, the powder X-ray diffractogram can include at least one signal, each signal identified by an angle value measured in degrees 2θ (°2θ), depicted on the abscissa of the powder X-ray diffractogram and expressed as "signal at ⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ degrees 2-theta," "signal at [one] 2-theta value of ⋅⋅⋅⋅⋅," and / or "signal at at least ⋅ ...

[0032] As used herein, the term "powder X-ray diffractogram with signals at degrees 2-theta values" refers to an XRPD pattern containing the positions of X-ray reflections measured and observed in an X-ray powder diffraction experiment (degrees 2θ).

[0033] As used herein, the term "signal" refers to a point in an XRPD pattern where the intensity, measured in counts, is at a maximum. Those skilled in the art will recognize that at least one signal in an XRPD pattern may overlap and may not be apparent to the naked eye, for example. Those skilled in the art will recognize that some art-recognized methods are capable of and suitable for determining whether a signal is present in a pattern, such as Rietveld refinement.

[0034] As used herein, the terms "signal at . . . degrees 2-theta," "signal at a 2-theta value of . . .," and "signal at a degree 2-theta value selected from . . .," refer to the X-ray reflection positions measured and observed in a powder X-ray diffraction experiment (degrees 2-theta). In some embodiments, the reproducibility of angle values ​​is in the range of ±0.2 degrees 2-theta, i.e., the angle value can be the stated angle value +0.2 degrees 2-theta, the angle value -0.2 degrees 2-theta, or any value between these two endpoints (angle value +0.2 degrees 2-theta and angle value -0.2 degrees 2-theta). Those skilled in the art are well aware that there can be variability in the measurement of powder X-ray diffraction signal values. Thus, those skilled in the art will understand that there can be variability of up to ±0.2 degrees 2-theta in signal values ​​for the same signal in different samples. As used herein, the term "signal intensity" refers to the relative signal intensity within a given powder X-ray diffractogram. Factors that can affect relative signal intensities include, for example, sample thickness and preferred orientation (eg, crystalline grains are not randomly distributed).

[0035] As used herein, the term "amorphous" refers to a solid material that does not have long-range order in the position of its molecules. For example, an amorphous material is a solid material that does not have sharp signals in its power X-ray diffraction pattern (i.e., is not crystalline as determined by XRPD). Amorphous refers to a solid that is not crystalline. Instead, at least one broad signal (e.g., at least one halo) may appear in its diffraction pattern. A broad signal is characteristic of an amorphous solid.

[0036] As used herein, a powder X-ray diffractogram is "substantially similar to that of a [particular] diagram" if at least 90%, e.g., at least 95%, at least 98%, or at least 99% of the signals in the two powder diffractograms are the same ±0.2 degrees 2θ. In determining "substantial similarity," one skilled in the art will understand that even with the same crystalline form, there may be variations in intensity and / or signal positions in XRPD diffractograms. Thus, one skilled in the art will understand that signal maxima (degrees two-theta (°2θ)) in an XRPD diffractogram generally mean the reported value ±0.2 degrees 2θ, with the values ​​being the art-recognized variations noted above.

[0037] As used herein, a crystalline form is "substantially pure" if it accounts for 90% or more by weight of the sum of all solid form(s) in a sample, as determined by art-based methods such as quantitative XRPD. In some embodiments, a solid form is "substantially pure" if it accounts for 95% or more by weight of the sum of all solid form(s) in a sample. In some embodiments, a solid form is "substantially pure" if it accounts for 98% or more by weight of the sum of all solid form(s) in a sample. In some embodiments, a solid form is "substantially pure" if it accounts for 99% or more by weight of the sum of all solid form(s) in a sample.

[0038] In some embodiments, a solid form is "substantially pure" if it accounts for 98.0% or more by weight of the sum of all solid organic form(s) in a sample. As used herein, "solid organic form(s)" excludes water, elements, solvents, and enantiomers of Compound (I). As used herein, an "enantiomer" of Compound (I) is Compound (E), which has the following chemical structure: [ka]

[0039] In some embodiments, a solid form is "substantially pure" if it has ≦0.8% w / w, ≦0.7% w / w, ≦0.6% w / w, ≦0.55% w / w of its undesired enantiomer (compound (E)).

[0040] In some embodiments, a solid form is "substantially pure" if it has 2.0% w / w or less total impurities. In some embodiments, a solid form is "substantially pure" if it has 0.15% w / w or less of each known unspecified impurity. Known unspecified impurities include, for example, impurity (IA), [ka] and impurities (IB) [ka] Includes:

[0041] In some embodiments, a solid form is "substantially pure" if it has no more than 0.55 area / area of ​​Compound (E). In some embodiments, a solid form is "substantially pure" if it has no more than 0.15% w / w of each known unspecified impurity and no more than 0.10% w / w of other individual impurities. In some embodiments, a solid form is "substantially pure" if it has no more than 0.15% w / w of each known unspecified impurity and no more than 0.10% w / w of other individual impurities, and no more than 0.55 area / area of ​​Compound (E).

[0042] In some embodiments, a solid form is "substantially pure" if it is primarily free of solvent, e.g., if the solid form is primarily free of 3000 ppm or less of methanol, 5000 ppm or less of 2-propanol, 600 ppm or less of dichloromethane, 720 ppm or less of tetrahydrofuran, 620 ppm or less of 2-methyltetrahydrofuran, 5000 ppm or less of acetone, 5000 ppm or less of heptane, 5000 ppm or less of methyl tert-butyl ether, 890 ppm or less of toluene, or 380 ppm or less of 1,4-dioxane.

[0043] In some embodiments, N,N-diisopropylethylamine (DIPEA) is a tertiary amine that may be used in the final step of processing Compound (I). In some embodiments, a solid form is "substantially pure" if it is essentially free of DIPEA. In some embodiments, a solid form is "substantially pure" if it has 1000 ppm or less of DIPEA.

[0044] In some embodiments, a solid form is "substantially pure" when it is 97.0% to 103.0% w / w by HPLC on a solvent-free, anhydrous basis (calculation includes correction for water, residual solvent, and DIPEA content). The HPLC retention time should be ±2% of the standard. HPLC analysis can be performed, for example, as described below. [Table 1] [Table 2]

[0045] As used herein, a "selective KIT inhibitor" or a "selective PDGFRα inhibitor" refers to a compound, or a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing, that selectively inhibits KIT protein kinase or PDGFRα protein kinase over another protein kinase and exhibits at least 2-fold selectivity for KIT protein kinase or PDGFRα protein kinase over another kinase. For example, a selective KIT inhibitor or a selective PDGFRA inhibitor may exhibit at least 10-fold selectivity, at least 15-fold selectivity, at least 20-fold selectivity, at least 30-fold selectivity, at least 40-fold selectivity, at least 50-fold selectivity, at least 60-fold selectivity, at least 70-fold selectivity, at least 80-fold selectivity, at least 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 KIT protein kinase or PDGFRα kinase over another kinase. In some embodiments, the selective KIT inhibitor or selective PDGFRα 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). In some embodiments, selectivity for KIT protein kinase or PDGFRα protein kinase over another kinase is measured in a cellular assay (e.g., a cellular assay). In some embodiments, selectivity for KIT protein kinase or PDGFRα protein kinase over another kinase is measured in a biochemical assay (e.g., a biochemical assay).

[0046] As used herein, a "therapeutically effective amount" of a compound disclosed herein refers to an amount of compound that elicits a biological or medical response in a subject, e.g., reduces or inhibits enzyme or protein activity, or ameliorates symptoms, alleviates a condition, or slows or delays the progression of a disease. In some embodiments, a "therapeutically effective amount" refers to an amount of compound that, when administered to a subject, is effective to (1) at least partially reduce, inhibit, and / or ameliorate a disorder or condition (i) due to KIT and / or PDGFRA, or (ii) associated with KIT and / or PDGFRA activity, or (iii) characterized by KIT and / or PDGFRA activity (normal or abnormal), or (2) reduce or inhibit the activity of KIT and / or PDGFRα protein kinase. In some embodiments, a "therapeutically effective amount" refers to an amount of compound that, when administered to a cell, tissue, non-cellular biological material, or culture medium, at least partially reduces or inhibits the activity of KIT and / or PDGFRα protein kinase. The therapeutically effective amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0047] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer 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.

[0048] As used herein, the term "patient" or "subject" refers to an organism treated by the methods of the present disclosure. Non-limiting exemplary organisms include mammals, such as murines, simians, equines, bovines, porcines, canines, felines, etc. In some embodiments, the organism is a human. In some embodiments, the patient being treated has ISM or SSM with moderate to severe symptoms that cannot be adequately controlled with approved symptom-directed therapies.

[0049] As used herein, the terms "treat," "treating," or "treatment," when used in reference to a disorder or condition, include any effect that results in an improvement of the disorder or condition, including, for example, alleviation, reduction, modulation, amelioration, and / or elimination. Improvement in the symptoms or reduction in severity of a disorder or condition can be readily assessed according to standard methods and techniques known in the art.

[0050] In some embodiments, treating comprises reducing mast cell burden. In some embodiments, objective measures of mast cell burden comprise serum tryptase, bone marrow mast cell count, skin mast cell infiltration, and blood KIT D816V mutant allele load. In some embodiments, objective measures of mast cell burden comprise serum tryptase, bone marrow mast cell count, and blood KIT D816V mutant allele load.

[0051] In some embodiments, treatment involves alleviating symptoms of systemic mastocytosis. Symptoms of systemic mastocytosis include, but are not limited to, pruritus, flushing, gastrointestinal cramps, diarrhea, anaphylaxis (especially bee venom), bone pain, osteoporosis, and urticaria pigmentosa. In some embodiments, an ISM-SAF patient-reported outcome (PRO) instrument, as defined herein, is used to assess symptomatic improvement. In some embodiments, a patient completes an ISM-SAF once daily before receiving treatment, and the patient also completes an ISM-SAF once daily during treatment. For example, a patient completes an ISM-SAF for a period of, e.g., four weeks, beginning at the time of informed consent, during which best-supportive care (BSC) interventions are optimized and stabilized. Once a period of data, e.g., four weeks, has been collected, an ISM-SAF is completed once daily for an additional period, e.g., two weeks (14 days), and patient eligibility is determined based on ISM-SAF symptom thresholds. Patients who meet the ISM-SAF threshold for eligibility then complete the ISM-SAF once daily while completing screening procedures to assess study eligibility.

[0052] Once all screening procedures are completed, baseline symptoms are collected over a period of time, for example, 14 days immediately prior to the start of the study. These data are used as the baseline total symptom score (TSS). The ISM-SAF is completed by patients once daily throughout the completion of the study, for example, through week 52 in Part 1 and Part 2, and Part 3. In some embodiments, the primary endpoint of Part 2 of the study is the mean change in ISM-SAF TSS from baseline to Week 12. In some embodiments, treatment improves the number of anaphylactic episodes. In some embodiments, an "anaphylactic episode" is an anaphylactic episode treated with epinephrine.

[0053] In some embodiments, treatment improves quality of life (QoL) as measured by one or more questionnaires. Non-limiting examples of QoL questionnaires include the MC-QoL, PGIS, SF-12, PGIC, and EQ-5D-EL. The MC-QoL is a disease-specific QoL tool developed specifically for patients with ISM and CM (Siebenhaar, F. et al., Allergy 71(6):869-77(2016)). The MC-QoL includes 27 items assessing four domains: symptoms, emotions, social life / functioning, and skin. Items are rated on a 5-point scale with a 2-week recall period. The PGIS is a single-item measure that assesses a patient's awareness of their disease symptoms at a given point in time. The PGIS has been widely used to assess a patient's overall sense of whether treatment has been beneficial. The SF-12 is a multi-year study of patients with chronic diseases, the Medical Outcomes Assessment and Clinical Trials (MCI), and the EQ-5D-EL. The instrument was developed for the EQ-5D-5L study. The instrument was designed to reduce respondent burden while achieving minimum standards of precision for group comparisons involving multiple health dimensions. The questionnaire measures health and well-being using eight health domains from the patient's perspective. The recall period is 4 weeks. The PGIC is a single-item measure assessing patients' perceptions of change in disease symptoms at a given point in time. The EQ-5D-5L is a standardized instrument for measuring general health status. It consists of two components: a description and an assessment of health status. Health status is measured using terms for five dimensions (5D): mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Respondents self-assess the level of severity of each dimension using a 5-point scale. The recall period is "same day" (Whynes, DK, Health Qual Life Outcomes 6:94 (2008)).

[0054] In some embodiments, the treatment improves bone density. Bone density is measured by a dual-energy x-ray absorptiometry scan evaluating both the lumbar spine and hip joints. In some embodiments, the treatment does not affect bone density.

[0055] As used herein, "SD" means unchanged.

[0056] As used herein, "CR" means complete response.

[0057] As used herein, "PFS" means progression-free survival.

[0058] The term "systemic mastocytosis" or "SM" refers to a clonal disorder of mast cells (MCs) characterized by increased MC burden and increased release of MC mediators, with focal and / or diffuse infiltration of neoplastic MCs in the skin, bone marrow (BM), spleen, liver, gastrointestinal (GI) tract, and other organs. All patients have BM involvement. The World Health Organization (WHO) has established criteria for the diagnosis and classification of SM. In the recently proposed WHO update (Valent, P. et al., Blood 129(11):1420-27(2017)), SM is subdivided into indolent SM (ISM), smoldering SM (SSM), SM associated with hematological tumors of non-MC lineage (SM-AHN), aggressive SM (ASM), and MC leukemia (MCL). The latter three subclassifications are associated with shorter overall survival and are grouped together as advanced SM (AdvSM). Advanced SM is associated with a poor prognosis, with a median overall survival of 3.5 years for ASM, 2 years for SM-AHN, and less than 6 months for MCL. ISM is associated with a normal or near-normal life expectancy, while SSM has an intermediate prognosis (Lim, K. et al., Blood 113(23):5727-36(2009)). The primary criterion for SM is multifocal accumulation and clustering of MCs in the BM or other extracutaneous organs. Minor criteria confirm the clonality of the disease and include abnormal MC morphology (spindle), expression of CD2 and / or CD25 on MCs, expression of an activating mutation at codon 816 of the V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) exon 17 (usually D816V), and a serum tryptase level >20 ng / mL. Advanced SM is characterized by the presence of organ damage due to MC infiltration (C findings), whereas ISM and SSM are not associated with organ dysfunction.

[0059] ISM is defined by the presence of fewer than two B findings and the absence of C findings per the WHO criteria, while SSM is defined by the presence of two or more B findings and the absence of C findings ((Valent, P. et al, Blood 129(11):1420-27(2017)). B findings include: 1. tryptase >200ng / ml and bone marrow infiltration >30%, 2. hepatomegaly or splenomegaly without hypersplenism or liver dysfunction, and 3. mild dysplastic changes or hypercellular bone marrow that do not fit the WHO classification of another hematologic disorder, such as myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN). ISM is the most common classification of SM. Patients with ISM have abnormal mast cell populations in the bone marrow but do not have another hematopoietic disorder or There are no signs of tissue dysfunction. Mast cells are usually less than 5% in aspirate smears. Patients with ISM have a life expectancy comparable to the general population, but may have various mast cell mediator release symptoms. The risk of progression to the advanced variant is less than 5%. SSM is characterized by a high mast cell burden but no obvious signs of hematologic disease or tissue dysfunction. Patients with SSM are considered at high risk of progressing to more advanced stages. Both ISM and SSM are referred to as non-progressive SM.

[0060] In all subtypes of SM and in most patients with this disease, neoplastic MCs exhibit mutations at D816 in exon 17 of KIT, resulting in ligand-independent activation of KIT kinase activity. Because wild-type MCs require KIT activity for their differentiation and survival, constitutive activation of KIT by the D816V mutation is therefore thought to be the pathogenic driver of SM. (Chabot, B. et al., Nature 335(6185):88-9(1988)). Specifically, the KIT D816V mutation is found in 90%–98% of patients with SM, and rare KIT D816Y, D816F, and D816H variants have been identified (Garcia-Montero, AC, 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 primary therapeutic target for SM (Valent et al., 2017), and several drugs targeting this mutation have been investigated.

[0061] ISM and SSM are characterized by severe symptoms associated with the release of MC mediators, including itching, flushing, gastrointestinal spasms, diarrhea, anaphylaxis (especially with wasp venom), bone pain, and osteoporosis (Gulen, T. et al., J Intern Med. 279(3):211-28(2016)). These symptoms can be severely debilitating and negatively impact 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. 2(1):70-76(2014); Siebenhaar, F. et al., Allergy 71(6):869-77(2016); Van Anrooij, B. et al,Midostaurin(PKC412)in Indolent Systemic Mastocytosis:A Phase 2 Trial.2016;Pp.Poster Presentation Abstract: P303: European Hematology Association(EHA)).

[0062] Patients are also frequently affected by cosmetically debilitating cutaneous mastocytosis (CM), most often accompanied by urticaria pigmentosa, which impacts quality of life. Abnormal MCs are seen in skin and BM biopsies, but the MC burden is low and there is no evidence of significant cytopenias or other organ dysfunction due to these infiltrates. Nonspecific treatments have been employed to control MC mediator-related symptoms with varying degrees of effectiveness, but none affect the tissue MC burden. These treatments include H1 and H2 blockers, proton pump inhibitors, osteoclast inhibitors, leukotriene inhibitors, corticosteroids, sodium cromoglycate, and the anti-IgE antibody omalizumab. Recently, several KIT-targeted tyrosine kinase inhibitors (TKIs) have been studied in patients with ISM and SSM. Although several TKI therapies have shown that symptomatic improvement and, in some cases, reductions in measured MC burden can be achieved in patients with ISM and SSM, none of the available drugs specifically target the KIT D816V driver mutation in this disease, and to date, no TKI or other drugs have been approved to treat ISM and SSM. Thus, there remains a medical need for patients with moderate to severe symptoms who do not adequately respond to existing symptomatic treatments.

[0063] As used herein, the "Indolent Systemic Mastocytosis - Symptom Assessment Form" or "ISM-SAF" (ISPOR Europe 2019, Copenhagen, Denmark, 2-6 Nov 2019) is used for daily patient-reported outcome (PRO) assessment, e.g., in eDiary. The ISM-SAF is a 12-item PRO specifically developed to assess symptoms in patients with ISM and SSM. While the ISM-SAF was primarily developed to evaluate hypotheses of treatment efficacy, it can also be used to screen participants into (or out of) clinical studies based on a minimum level of sign and symptom severity. The 11 items shown in the table below are rated on an 11-point scale (0-10, none to maximal severity), and one item (diarrhea) assesses frequency. [Table 3]

[0064] The ISM-SAF generates scores for each item in the following domains: Skin / Skin Symptom Score (SSS), GI / Gastrointestinal Symptom Score (GSS), Nonspecific Symptoms, and Total Symptom Score (TSS). The TSS is the sum of all symptoms. In one embodiment, the TSS is items 1-10 and 12. In one embodiment, the GSS is items 2-3 and 12. In one embodiment, the SSS is items 4-6. In one embodiment, patients complete the ISM-SAF daily for 4 weeks, beginning at the time of informed consent, during which time BSC interventions 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 ISM-SAF symptom thresholds. Patients who meet the ISM-SAF threshold for eligibility complete the ISM-SAF daily while completing screening procedures to assess study eligibility. Once all screening procedures are completed, baseline symptoms are collected for 14 days immediately prior to study initiation. These data will be used as the baseline TSS.

[0065] In one aspect, a patient with ISM or SSM has moderate to severe symptoms characterized by a minimal TTS. In one aspect, a patient with ISM or SSM exhibits moderate to severe symptoms characterized by a minimal TTS of 28 or greater when assessed using the ISM-SAF. In one aspect, the minimal TTS is ≧ 27, ≧ 26, ≧ twenty five, ≧ twenty four, ≧ twenty three, ≧ twenty two, ≧ twenty one, ≧20. In one embodiment, patients with ISM or SSM with moderate to severe symptoms have a minimum TSS of greater than 28 on the ISM-SAF at baseline and one or more symptoms in the skin or GI domain. In one embodiment, baseline is a 14-day period prior to Cycle 1 Day 1 (C1D1). In one embodiment, the patient has not experienced an acute flare of symptoms beyond typical baseline symptoms. In one embodiment, the patient has failed to achieve symptom control for one or more baseline symptoms with at least two of the following symptomatic therapies (H1 blockers, H2 blockers, proton pump inhibitors, leukotriene inhibitors, sodium cromoglycate, corticosteroids, or omalizumab) administered at optimal (approved) doses, as determined by the investigator, for a minimum of 4 weeks (28 days) prior to starting the ISM-SAF to determine eligibility. In one embodiment, the patient has a baseline serum tryptase of less than 20 ng / mL. In one embodiment, the patient has a baseline serum tryptase of greater than or equal to 20 ng / mL. In one embodiment, the patient has cutaneous mastocytosis (CM). In one embodiment, the patient does not have CM. A diagnosis of CM requires the presence of clinical and histopathological findings of abnormal mast cell infiltration of the dermis in the absence of signs of systemic mast cell infiltration in either bone marrow or other extradermal organs. CM is further subdivided into three distinct subvariants: pigmented urticaria / maculopapular cutaneous mastocytosis (MPCM), diffuse CM, and cutaneous mastocytoma.

[0066] In one embodiment, a patient with ISM or SSM has a KIT D816V mutation, which can be detected by a highly sensitive assay such as a droplet digital polymerase chain reaction (ddPCR) assay with a limit of detection (LOD) of 0.022% mutant allele frequency (MAF).

[0067] As used herein, 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 called an adverse event) can be an untoward and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease that is temporarily associated with the use of the drug, without any determination of causality. AEs can result 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 overdose.

[0068] As used herein, the terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, include the value of the particular dose, amount, or weight percent or range of doses that would be 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.

[0069] As noted above, described herein are novel crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing. In some embodiments, the crystalline forms of Compound (I) are substantially pure. They may be inhibitors of KIT and / or PDGFRα protein kinase, and in some embodiments, are selective inhibitors of KIT and / or PDGFRα protein kinase. KIT and / or PDGFRα inhibitors are useful for treating disorders and conditions associated with oncogenic KIT and PDGFRA alterations, such as mastocytosis, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), melanoma, seminoma, intracranial germ cell tumor, and mediastinal B-cell lymphoma.

[0070] Crystalline Form A of Compound (I) In some embodiments, the present disclosure provides crystalline Form A of Compound (I). [ka]

[0071] Among the different crystalline forms of Compound (I) identified, crystalline form A is more stable at ambient temperature than the other crystalline forms disclosed herein. Furthermore, crystalline form A has been shown to have better physical and chemical stability properties for formulation compared to the other crystalline forms identified herein. Crystalline form A also offers the advantage of being easily separated. Crystalline form A has excellent thermodynamic stability as shown by DSC.

[0072] FIG. 2 shows the powder X-ray diffraction diagram of crystalline Form A of Compound (I) at ambient conditions.

[0073] 3 shows a DSC thermogram of crystalline form A of Compound (I). In some embodiments, 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° C. In some embodiments, crystalline form A of Compound (I) is characterized by a DSC thermogram having an endothermic event with an onset temperature of 193° C. In some embodiments, crystalline form A of Compound (I) is characterized by a DSC thermogram having an endothermic event with an onset temperature of 190° C., 191° C., or 192° C.

[0074] In some embodiments, crystalline Form A of Compound (I) is characterized by a DSC thermogram substantially similar to that of FIG.

[0075] 3 also shows the TGA thermal curve of crystalline Form A of Compound (I) recrystallized from a mixture of acetone and water. For crystalline Form A of Compound (I), the mass loss demonstrated by TGA varies depending on the recrystallization conditions.

[0076] In some embodiments, crystalline Form A of Compound (I) is a free-flowing, crystalline white, off-white, or yellow solid. In some embodiments, crystalline Form A of Compound (I) is an anhydrous polymorph. In some embodiments, crystalline Form A of Compound (I) has a water content of less than 1.0% water. In some embodiments, crystalline Form A of Compound (I) has a water content of 0.04% or less. In some embodiments, the water content level is <0.01% to 0.07%. In some embodiments, crystalline Form A of Compound (I) appears as a needle-shaped and / or sheet-like or plate-like solid.

[0077] In some embodiments, crystalline Form A of Compound (I) is characterized by a weight change of 0.42% in a dynamic water vapor sorption (DVS) experiment at 25° C. while varying the relative humidity from 2 to 95% RH.

[0078] In some embodiments, crystalline Form A of Compound (I) is characterized by a weight change of 0.29% in a dynamic water vapor sorption (DVS) experiment at 40° C. while varying the relative humidity from 2 to 95% RH.

[0079] In some embodiments, crystalline Form A of Compound (I) is characterized by a weight change of 0.20% in a dynamic water vapor sorption (DVS) experiment at 40° C. while varying the relative humidity from 70 to 95% RH.

[0080] In some embodiments, 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) picks up up to 0.44% water by weight when exposed to 40° C. and up to 95% relative humidity.

[0081] In some embodiments, crystalline Form A of Compound (I) is characterized by a solubility of 0.03 mg / mL in fasting simulated intestinal fluid (FaSSIF). In some embodiments, crystalline Form A of Compound (I) is characterized by a solubility of 2.11 mg / mL in fasting simulated gastric fluid.

[0082] In some embodiments, crystalline Form A of Compound (I) is characterized by a solubility of 0.03 mg / mL in fasting simulated intestinal fluid (FaSSIF) at 37° C. In some embodiments, crystalline Form A of Compound (I) is characterized by a solubility of 2.11 mg / mL in fasting simulated gastric fluid at 37° C.

[0083] In some embodiments, crystalline Form A of Compound (I) has a particle size distribution (PSD) in which D10 is 1 μm or more (NLT), D50 is 5-105 μm, e.g., in some embodiments, D50 is 8-80 μm, and D90 is 500 μm or less (NMT), e.g., in some embodiments, D90 is NMT 300 μm. As used herein, D10 is the diameter at which 10% of the mass of a sample is 1 μm or more. As used herein, D50 is the mass median diameter (MMD). As used herein, MMD is the mean particle diameter by mass. In some embodiments, the mean particle diameter by mass (i.e., D50 or MMD) is 5-105 μm. As used herein, D90 is the diameter at which 90% of the mass of a sample is 500 μm or less. In some embodiments, the PSD is NLT 1 μm (D10) and NMT 500 μm (D90). The particle size distribution (PSD) can be analyzed using a laser diffraction system, such as a Malvern Mastersizer 3000 equipped with a wet dispersion unit. The dispersant is 0.5% Span 85 in hexane, and the sample is 125 mg of crystalline Form A of Compound (I) in 50 mL of 0.5% Span 85 in hexane.

[0084] In some embodiments, particle size and / or particle size distribution affects tablet dissolution.

[0085] In some embodiments, crystalline Form A of Compound (I) is in a substantially pure form. In some embodiments, crystalline Form A of Compound (I) is characterized by a powder X-ray diffractogram produced by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation. In some embodiments, crystalline Form A of Compound (I) is characterized by a powder X-ray diffractogram produced by powder X-ray diffractometry using an incident beam of Cu Kα radiation having signals substantially similar to those set forth in Table 1. [Table 4]

[0086] In some embodiments, crystalline form A of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 11.5±0.2 degrees two-theta. In some embodiments, crystalline form A of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 15.4±0.2 degrees two-theta. In some embodiments, crystalline form A of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 16.7±0.2 degrees two-theta. In some embodiments, crystalline form A of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 18.1±0.2 degrees two-theta. In some embodiments, crystalline form A of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 20.0±0.2 degrees two-theta. In some embodiments, crystalline form A of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 21.6±0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 23.1±0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 23.9±0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 25.9±0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 30.7±0.2 degrees two-theta.

[0087] In some embodiments, crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having signals at 2-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. In some embodiments, crystalline Form A of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least eight 2-theta values ​​selected 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. In some embodiments, crystalline Form A of Compound (I) is characterized by a powder X-ray diffraction pattern having signals at at least seven 2-theta values ​​selected 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. In some embodiments, crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least six 2-theta values ​​selected 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. In some embodiments, crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least five 2-theta values ​​selected 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. In some embodiments, crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least four 2-theta values ​​selected 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.In some embodiments, crystalline Form A of Compound (I) is characterized by a powder X-ray diffraction pattern having signals at at least three 2-theta values ​​selected 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. In some embodiments, crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2-theta values ​​selected 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. In some embodiments, crystalline Form A of Compound (I) is characterized by a powder X-ray diffraction pattern having a signal at at least one 2-theta value selected 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.

[0088] In some embodiments, crystalline Form A of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least three 2-theta values ​​selected from 11.5±0.2, 15.4±0.2, 16.7±0.2, 20.0±0.2, and 21.6±0.2. In some embodiments, crystalline Form A of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least two 2-theta values ​​selected from 11.5±0.2, 15.4±0.2, 16.7±0.2, 20.0±0.2, and 21.6±0.2. In some embodiments, crystalline Form A of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least one 2-theta value selected from 11.5±0.2, 15.4±0.2, 16.7±0.2, 20.0±0.2, and 21.6±0.2. In some embodiments, crystalline Form A of Compound (I) is characterized by a powder X-ray diffraction pattern having signals at 2-theta values ​​of 11.5±0.2, 15.4±0.2, 16.7±0.2, 20.0±0.2, and 21.6±0.2.

[0089] In some embodiments, crystalline Form A of Compound (I) is characterized by a powder X-ray diffraction pattern substantially similar to that of FIG.

[0090] In some embodiments, crystalline Form A of Compound (I) has signals at the following δ (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. 13 Characterized by C NMR (CDCl3, 100 MHz) pattern.

[0091] In some embodiments, the disclosure provides a process for preparing crystalline Form A of Compound (I). In some embodiments, the process for preparing crystalline Form A of Compound (I) is a recrystallization process. In some embodiments, the recrystallization process removes impurities. In some embodiments, the recrystallization process removes residual N,N-diisopropylethylamine. In some embodiments, the recrystallization process includes acetone and water. In some embodiments, the disclosure provides crystalline Form A of Compound (I) prepared by a process including 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 reducing the temperature.

[0092] In some embodiments, the ratio of acetone to water is 85:15.

[0093] In some embodiments, the suspension is heated to a temperature in the range of 40°C to 50°C.

[0094] In some embodiments, 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 15 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 15 minutes at a temperature ranging from 40°C to 50°C.

[0095] In some embodiments, the process further comprises polish filtering the stirred suspension. In some embodiments, the process further comprises polish filtering the stirred suspension at a temperature in the range of 40°C to 50°C.

[0096] In some embodiments, the process further comprises atmospheric distillation of the polish-filtered suspension. In some embodiments, the process further comprises atmospheric distillation of the polish-filtered suspension at a temperature in the range of 55°C to 65°C.

[0097] In some embodiments, cooling the solution comprises lowering the temperature. In some embodiments, cooling the solution comprises lowering the temperature to a temperature in the range of 45°C to 55°C. In some embodiments, cooling the solution comprises lowering the temperature over 15 minutes. In some embodiments, cooling the solution comprises lowering the temperature to a temperature in the range of 45°C to 55°C over 15 minutes.

[0098] In some embodiments, 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. In some embodiments, the elevated temperature is at least 30° C.

[0099] In some embodiments, the present disclosure provides a process for preparing crystalline form A of Compound (I), and 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 at least one solvent. In some embodiments, the elevated temperature is 186° C. In some embodiments, the at least one solvent is acetone. In some embodiments, the at least one solvent comprises acetone and water.

[0100] In some embodiments, 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. In some embodiments, the at least one solvent is acetone. In some embodiments, the elevated temperature is in the range of 25°C to 50°C.

[0101] In some embodiments, any of the above processes for preparing crystalline Form A of Compound (I) may further comprise purifying crystalline Form A by dissolving it in a mixture of acetone and water and / or by slurrying it in isopropanol. In some embodiments, the isopropanol slurry is obtained by dissolving the crystalline solid in isopropanol, heating, and then cooling the resulting mixture. In some embodiments, the crystalline solid is isolated by filtration, washed with isopropanol, and dried.

[0102] In some embodiments, the present disclosure provides processes for preparing substantially pure crystalline Form A of Compound (I).

[0103] Crystalline form B of compound (I) In some embodiments, the present disclosure provides crystalline Form B of Compound (I). [ka]

[0104] FIG. 4 shows the powder X-ray diffraction diagram of crystalline form B of Compound (I) at ambient conditions.

[0105] 5 shows a DSC thermogram of crystalline form B of Compound (I). In some embodiments, 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° C. to 211° C. In some embodiments, crystalline form B of Compound (I) is characterized by a DSC thermogram having an endothermic event with an onset temperature of 207° C. In some embodiments, crystalline form B of Compound (I) is characterized by a DSC thermogram substantially similar to that of FIG. 5.

[0106] In some embodiments, crystalline Form B of Compound (I) is in a substantially pure form. In some embodiments, crystalline Form B of Compound (I) is characterized by a powder X-ray diffractogram produced by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation. In some embodiments, crystalline Form B of Compound (I) is characterized by a powder X-ray diffractogram produced by powder X-ray diffractometry using an incident beam of Cu Kα radiation having signals substantially similar to those set forth in Table 2. [Table 5]

[0107] In some embodiments, crystalline form B of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 4.1±0.2 degrees two-theta. In some embodiments, crystalline form B of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 9.7±0.2 degrees two-theta. In some embodiments, crystalline form B of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 11.2±0.2 degrees two-theta. In some embodiments, crystalline form B of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 13.8±0.2 degrees two-theta. In some embodiments, crystalline form B of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 16.4±0.2 degrees two-theta. In some embodiments, crystalline form B of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 17.0±0.2 degrees two-theta. In some embodiments, crystalline form B of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 19.6±0.2 degrees two-theta. In some embodiments, crystalline form B of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 20.6±0.2 degrees two-theta. In some embodiments, crystalline form B of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 21.0±0.2 degrees two-theta. In some embodiments, crystalline form B of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 22.4±0.2 degrees two-theta. In some embodiments, crystalline form B of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 23.1±0.2 degrees two-theta. In some embodiments, crystalline form B of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 23.8±0.2 degrees two-theta. In some embodiments, crystalline form B of Compound (I) is characterized by a powder X-ray diffraction pattern having a signal at 29.0±0.2 degrees two-theta.

[0108] In some embodiments, crystalline Form B of Compound (I) is characterized by a powder X-ray diffraction pattern having signals at 2-theta values ​​of 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. In some embodiments, crystalline Form B of Compound (I) is characterized by a powder X-ray diffraction pattern having signals at at least eight 2-theta values ​​selected 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. In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least seven 2-theta values ​​selected 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. In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least six 2-theta values ​​selected 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. In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least five 2-theta values ​​selected 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.In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least four 2-theta values ​​selected 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. In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least three 2-theta values ​​selected 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. In some embodiments, crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2-theta values ​​selected 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. In some embodiments, crystalline Form B of Compound (I) is characterized by a powder X-ray diffraction pattern having a signal at at least one 2-theta value selected 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.

[0109] In some embodiments, crystalline form B of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least three 2-theta values ​​selected from 4.1±0.2, 16.4±0.2, 17.0±0.2, 19.6±0.2, and 20.6±0.2. In some embodiments, crystalline form B of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least two 2-theta values ​​selected from 4.1±0.2, 16.4±0.2, 17.0±0.2, 19.6±0.2, and 20.6±0.2. In some embodiments, crystalline form B of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least one 2-theta value selected from 4.1±0.2, 16.4±0.2, 17.0±0.2, 19.6±0.2, and 20.6±0.2. In some embodiments, crystalline Form B of Compound (I) is characterized by a powder X-ray diffraction pattern having signals at 2-theta values ​​of 4.1±0.2, 16.4±0.2, 17.0±0.2, 19.6±0.2, and 20.6±0.2.

[0110] In some embodiments, crystalline Form B of Compound (I) is characterized by a powder X-ray diffraction pattern substantially similar to that of FIG.

[0111] In some embodiments, crystalline Form B of Compound (I) has a signal at at least one δ value (expressed as ppm) selected 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. 13 Characterized by C NMR (CDCl3, 100 MHz) pattern.

[0112] In some embodiments, 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) at an elevated temperature for a period of time and cooling to room temperature. In some embodiments, the period of time is 10 minutes. In some embodiments, the elevated temperature is 195°C.

[0113] In some embodiments, the process further comprises isolating crystalline Form B of Compound (I) by filtration.

[0114] In some embodiments, 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) at an elevated temperature for a period of time and cooling to room temperature. In some embodiments, the period of time is 30 minutes. In some embodiments, the elevated temperature is 195°C.

[0115] In some embodiments, 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) at 195° C. for an extended period of time.

[0116] In some embodiments, the process further comprises isolating crystalline Form B of Compound (I) by filtration.

[0117] Crystalline form C of compound (I) In some embodiments, the present disclosure provides crystalline Form C of Compound (I). [ka]

[0118] Crystalline form C is a hydrate of compound (I).

[0119] FIG. 6 shows the powder X-ray diffraction diagram of crystalline Form C of Compound (I) at ambient conditions.

[0120] In some embodiments, crystalline Form C of Compound (I) is a rod-shaped crystal. In some embodiments, crystalline Form C of Compound (I) is characterized by an irregular morphology.

[0121] In some embodiments, crystalline Form C of Compound (I) is characterized by a weight change of 2.90% in a dynamic water vapor sorption experiment at 25° C. while varying the relative humidity from 2 to 95% RH. In some embodiments, crystalline Form C of Compound (I) is characterized by a weight change of 1.76% in a dynamic water vapor sorption experiment at 25° C. while varying the relative humidity from 2 to 10% RH.

[0122] In some embodiments, crystalline Form C of Compound (I) is characterized by a weight change of 2.99% in a dynamic water vapor sorption experiment at 40° C. and varying relative humidity from 2 to 95% RH. In some embodiments, crystalline Form C of Compound (I) is characterized by a weight change of 1.93% in a dynamic water vapor sorption experiment at 40° C. and varying relative humidity from 2 to 10% RH.

[0124] In some embodiments, crystalline Form C of Compound (I) is a substantially pure form. In some embodiments, crystalline Form C of Compound (I) is characterized by a powder X-ray diffractogram produced by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation. In some embodiments, crystalline Form C of Compound (I) is characterized by a powder X-ray diffractogram produced by powder X-ray diffractometry using an incident beam of Cu Kα radiation having signals substantially similar to those set forth in Table 3. [Table 6]

[0125] In some embodiments, crystalline form C of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 5.3±0.2 degrees two-theta. In some embodiments, crystalline form C of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 9.4±0.2 degrees two-theta. In some embodiments, crystalline form C of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 10.4±0.2 degrees two-theta. In some embodiments, crystalline form C of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 12.0±0.2 degrees two-theta. In some embodiments, crystalline form C of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 13.9±0.2 degrees two-theta. In some embodiments, crystalline form C of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 16.1±0.2 degrees two-theta. In some embodiments, crystalline form C of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 17.4±0.2 degrees two-theta. In some embodiments, crystalline form C of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 22.8±0.2 degrees two-theta. In some embodiments, crystalline form C of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 24.0±0.2 degrees two-theta. In some embodiments, crystalline form C of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 24.8±0.2 degrees two-theta. In some embodiments, crystalline form C of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 25.8±0.2 degrees two-theta.

[0126] In some embodiments, crystalline Form C of Compound (I) is characterized by a powder X-ray diffraction pattern having signals at 2-theta values ​​of 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. In some embodiments, crystalline Form C of Compound (I) is characterized by a powder X-ray diffraction pattern having signals at at least eight 2-theta values ​​selected 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. In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least seven 2-theta values ​​selected 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. In some embodiments, crystalline Form C of Compound (I) is characterized by a powder X-ray diffraction pattern having signals at at least six 2-theta values ​​selected 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. In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least five 2-theta values ​​selected 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.In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least four 2-theta values ​​selected 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. In some embodiments, crystalline Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least three 2-theta values ​​selected 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. In some embodiments, crystalline Form C of Compound (I) is characterized by a powder X-ray diffraction pattern having signals at at least two 2-theta values ​​selected 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. In some embodiments, crystalline Form C of Compound (I) is characterized by a powder X-ray diffraction pattern having a signal at at least one 2-theta value selected 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.

[0127] In some embodiments, crystalline Form C of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least three 2-theta values ​​selected from 5.3±0.2, 9.4±0.2, 10.4±0.2, 12.0±0.2, and 16.1±0.2. In some embodiments, crystalline Form C of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least two 2-theta values ​​selected from 5.3±0.2, 9.4±0.2, 10.4±0.2, 12.0±0.2, and 16.1±0.2. In some embodiments, crystalline Form C of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least one 2-theta value selected from 5.3±0.2, 9.4±0.2, 10.4±0.2, 12.0±0.2, and 16.1±0.2. In some embodiments, crystalline Form C of Compound (I) is characterized by a powder X-ray diffraction pattern having signals at 2-theta values ​​of 5.3±0.2, 9.4±0.2, 10.4±0.2, 12.0±0.2, and 16.1±0.2.

[0128] In some embodiments, crystalline Form C of Compound (I) is characterized by a powder X-ray diffraction pattern substantially similar to that of FIG.

[0129] In some embodiments, crystalline Form C of Compound (I) has a signal at at least one δ value (expressed as ppm) selected 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. 13 Characterized by C NMR (CDCl3, 100 MHz) pattern.

[0130] In some embodiments, the present disclosure provides a process for preparing crystalline Form C of Compound (I), and provides crystalline Form C of Compound (I) prepared by a process comprising slurrying Compound (I) in a 1:1 mixture of methanol or tetrahydrofuran:water. In some methods, the process further comprises isolating crystalline Form C of Compound (I) by filtration.

[0131] Crystalline form O of compound (I) In some embodiments, the present disclosure provides crystalline form O of Compound (I). [ka]

[0132] FIG. 7 shows the powder X-ray diffraction diagram of crystalline form O of Compound (I) at ambient conditions.

[0133] In some embodiments, crystalline form O of Compound (I) is characterized by a DSC thermogram having an endothermic event with an onset temperature of 182°C.

[0134] In some embodiments, crystalline Form O of Compound (I) is a substantially pure form. In some embodiments, crystalline Form O of Compound (I) is characterized by a powder X-ray diffractogram produced by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation. In some embodiments, crystalline Form O of Compound (I) is characterized by a powder X-ray diffractogram produced by powder X-ray diffractometry using an incident beam of Cu Kα radiation having signals substantially similar to those set forth in Table 4. [Table 7]

[0135] In some embodiments, crystalline form O of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 7.2±0.2 degrees two-theta. In some embodiments, crystalline form O of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 10.8±0.2 degrees two-theta. In some embodiments, crystalline form O of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 12.3±0.2 degrees two-theta. In some embodiments, crystalline form O of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 14.5±0.2 degrees two-theta. In some embodiments, crystalline form O of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 14.7±0.2 degrees two-theta. In some embodiments, crystalline form O of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 16.1±0.2 degrees two-theta. In some embodiments, crystalline form O of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 19.0±0.2 degrees two-theta. In some embodiments, crystalline form O of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 20.4±0.2 degrees two-theta. In some embodiments, crystalline form O of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 23.7±0.2 degrees two-theta.

[0136] In some embodiments, crystalline form O of Compound (I) is characterized by an X-ray powder diffractogram having signals at 2-theta values ​​of 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. In some embodiments, crystalline form O of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least eight 2-theta values ​​selected 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. In some embodiments, crystalline form O of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least seven 2-theta values ​​selected 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. In some embodiments, crystalline form O of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least six 2-theta values ​​selected 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. In some embodiments, crystalline form O of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least five 2-theta values ​​selected 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. In some embodiments, crystalline form O of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least four 2-theta values ​​selected 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.In some embodiments, crystalline form O of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected 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. In some embodiments, crystalline form O of Compound (I) is characterized by an X-ray powder diffractogram having signals at at least two 2-theta values ​​selected 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. In some embodiments, crystalline form O of Compound (I) is characterized by a powder X-ray diffraction pattern having a signal at at least one 2-theta value selected 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.

[0137] In some embodiments, crystalline form O of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least three 2-theta values ​​selected from 7.2±0.2, 12.3±0.2, 14.7±0.2, 16.1±0.2, and 23.7±0.2. In some embodiments, crystalline form O of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least two 2-theta values ​​selected from 7.2±0.2, 12.3±0.2, 14.7±0.2, 16.1±0.2, and 23.7±0.2. In some embodiments, crystalline form O of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least one 2-theta value selected from 7.2±0.2, 12.3±0.2, 14.7±0.2, 16.1±0.2, and 23.7±0.2. In some embodiments, crystalline form O of Compound (I) is characterized by a powder X-ray diffraction pattern having signals at 2-theta values ​​of 7.2±0.2, 12.3±0.2, 14.7±0.2, 16.1±0.2, and 23.7±0.2.

[0138] In some embodiments, crystalline form O of Compound (I) has a signal at at least one δ value (expressed as ppm) selected 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. 13 Characterized by C NMR (CDCl3, 100 MHz) pattern.

[0139] In some embodiments, the present disclosure provides a process for preparing crystalline form O of Compound (I), and 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 tetrahydrofuran from room temperature to −20° C. In some embodiments, the process further comprises recovering crystalline form O of Compound (I) by filtration.

[0140] In some embodiments, the present disclosure provides a process for preparing crystalline form O of Compound (I), and provides crystalline form O of Compound (I) prepared by a process comprising stagnant cooling of crystalline form A of Compound (I) in tetrahydrofuran. In some embodiments, the process comprises stagnant cooling of crystalline form A of Compound (I) in tetrahydrofuran from room temperature to −20° C. In some embodiments, the process further comprises recovering crystalline form O of Compound (I) by filtration.

[0141] Crystalline Form T of the tosylate salt of Compound (I) In some embodiments, the present disclosure provides crystalline Form T of the tosylate salt of Compound (I). [ka]

[0142] FIG. 8 shows the powder X-ray diffraction diagram of crystalline form T of the tosylate salt of Compound (I) at ambient conditions.

[0143] In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is a mono-tosylate salt of Compound (I), i.e., Form T contains Compound (I) and citrate in a 1:1 ratio.

[0144] In some embodiments, crystalline form T of the tosylate salt of Compound (I) is characterized by a DSC thermogram having an endothermic event with an onset temperature of 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 the 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. In some embodiments, crystalline form T of the 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.

[0145] In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by a solubility of 0.08 mg / mL in fasted simulated intestinal fluid. In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by a solubility of 1.88 mg / mL in fasted simulated gastric fluid. In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by a solubility of 0.08 mg / mL in fasted simulated intestinal fluid at 37° C. In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by a solubility of 1.88 mg / mL in fasted simulated gastric fluid at 37° C.

[0146] In some embodiments, crystalline form T of the tosylate salt of Compound (I) is characterized by a solubility in water of 0.34 mg / mL.

[0147] In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is a substantially pure form. In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffractogram produced by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation. In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffractogram produced by powder X-ray diffractometry using an incident beam of Cu Kα radiation having signals substantially similar to those set forth in Table 5. [Table 8]

[0148] In some embodiments, crystalline form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 5.9±0.2 degrees two-theta. In some embodiments, crystalline form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 6.1±0.2 degrees two-theta. In some embodiments, crystalline form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 9.6±0.2 degrees two-theta. In some embodiments, crystalline form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 11.7±0.2 degrees two-theta. In some embodiments, crystalline form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 16.0±0.2 degrees two-theta. In some embodiments, crystalline form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 19.2±0.2 degrees two-theta. In some embodiments, crystalline form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 20.8±0.2 degrees two-theta. In some embodiments, crystalline form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 21.2±0.2 degrees two-theta. In some embodiments, crystalline form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 22.0±0.2 degrees two-theta. In some embodiments, crystalline form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 24.1±0.2 degrees two-theta. In some embodiments, crystalline form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 24.5±0.2 degrees two-theta.

[0149] In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at 2-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, 22.0±0.2, 24.1±0.2, and 24.5±0.2. In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least eight 2-theta values ​​selected from 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, 22.0±0.2, 24.1±0.2, and 24.5±0.2. In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least seven 2-theta values ​​selected from 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, 22.0±0.2, 24.1±0.2, and 24.5±0.2. In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least six 2-theta values ​​selected from 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, 22.0±0.2, 24.1±0.2, and 24.5±0.2. In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least five 2-theta values ​​selected from 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, 22.0±0.2, 24.1±0.2, and 24.5±0.2.In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least four 2-theta values ​​selected from 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, 22.0±0.2, 24.1±0.2, and 24.5±0.2. In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least three 2-theta values ​​selected from 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, 22.0±0.2, 24.1±0.2, and 24.5±0.2. In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2-theta values ​​selected from 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, 22.0±0.2, 24.1±0.2, and 24.5±0.2. In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least one 2-theta value selected from 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, 22.0±0.2, 24.1±0.2, and 24.5±0.2.

[0150] In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least three 2-theta values ​​selected from 5.9±0.2, 11.7±0.2, 16.0±0.2, 22.0±0.2, and 24.5±0.2. In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least two 2-theta values ​​selected from 5.9±0.2, 11.7±0.2, 16.0±0.2, 22.0±0.2, and 24.5±0.2. In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least one 2-theta value selected from 5.9±0.2, 11.7±0.2, 16.0±0.2, 22.0±0.2, and 24.5±0.2. In some embodiments, crystalline form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffraction pattern having signals at 2-theta values ​​of 5.9±0.2, 11.7±0.2, 16.0±0.2, 22.0±0.2, and 24.5±0.2.

[0151] In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by a powder X-ray diffraction pattern substantially similar to that of FIG.

[0152] In some embodiments, crystalline Form T of the tosylate salt of Compound (I) has a signal at at least one δ value (expressed as ppm) selected 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. 13 Characterized by C NMR (DMSO-d6, 500 MHz) pattern.

[0153] In some embodiments, the present disclosure provides a process for preparing crystalline form T of the tosylate salt of Compound (I), and provides crystalline form T of the tosylate salt of Compound (I) prepared by a process comprising adding Compound (I) and toluenesulfonic acid to a mixture of 2-propanol (IPA) and water, stirring at an elevated temperature, and reducing the temperature.

[0154] In some embodiments, 1.1 equivalents of toluenesulfonic acid are added. In some embodiments, the volume ratio of IPA to water in the mixture is 95:5. In some embodiments, stirring is at 600 rpm. In some embodiments, the elevated temperature is a temperature in the range of 48°C to 50°C. In some embodiments, lowering the temperature includes transferring the solution to a hot plate at a temperature in the range of 35°C to 40°C.

[0155] Crystalline form Tr of the tartrate salt of compound (I) In some embodiments, the present disclosure provides crystalline Form Tr of the tartrate salt of Compound (I). [ka]

[0156] FIG. 9 shows the powder X-ray diffraction diagram of crystalline form Tr of the tartrate salt of Compound (I) at ambient conditions.

[0157] In some embodiments, crystalline Form Tr of the tartrate salt of Compound (I) is a mono-tartrate salt, e.g., Form Tr comprises Compound (I) and tosylate in a 1:1 ratio.

[0158] In some embodiments, crystalline Form Tr of the tartrate salt of Compound (I) is characterized by a DSC onset at 144.5° C., followed by an exothermic event (recrystallization) at 158.8° C. In some embodiments, the endotherm coincides with a mass loss of 4.5 wt % by TGA.

[0159] In some embodiments, 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. In some embodiments, 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. In some embodiments, crystalline Form Tr of the 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 at a temperature of 156°C, an exothermic event with an onset temperature of 159°C and a signal at a temperature of 163°C, an endothermic event with an onset temperature of 205°C and a signal at a temperature of 213°C, an endothermic event with an onset temperature of 237°C and a signal at a temperature of 243°C, and / or an exothermic event with an onset temperature of 254°C and a signal at a temperature of 257°C.

[0160] In some embodiments, crystalline Form Tr of the tartrate salt of Compound (I) is characterized by a solubility of 0.27 mg / mL in fasted simulated intestinal fluid. In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by a solubility of 4.79 mg / mL in fasted simulated gastric fluid. In some embodiments, crystalline Form Tr of the tartrate salt of Compound (I) is characterized by a solubility of 0.27 mg / mL in fasted simulated intestinal fluid at 37° C. In some embodiments, crystalline Form T of the tosylate salt of Compound (I) is characterized by a solubility of 4.79 mg / mL in fasted simulated gastric fluid at 37° C.

[0161] In some embodiments, crystalline form T of the tosylate salt of Compound (I) is characterized by a solubility in water of 0.84 mg / mL.

[0162] In some embodiments, the tartaric acid crystalline Form Tr of Compound (I) is characterized by a weight change of 4.4% in a dynamic water vapor sorption experiment at room temperature with relative humidity varying from 2 to 95% RH. In some embodiments, the tartaric acid crystalline Form Tr of Compound (I) is characterized by a weight change of 2.95% to 3% in a dynamic water vapor sorption experiment at room temperature with relative humidity varying from 2 to 30% RH.

[0163] In some embodiments, crystalline Form Tr of the tartrate salt of Compound (I) is in a substantially pure form. In some embodiments, crystalline Form Tr of the tartrate salt of Compound (I) is characterized by a powder X-ray diffractogram produced by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation. In some embodiments, crystalline Form Tr of the tartrate salt of Compound (I) is characterized by a powder X-ray diffractogram produced by powder X-ray diffractometry using an incident beam of Cu Kα radiation having signals substantially similar to those set forth in Table 6. [Table 9]

[0164] In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 6.3±0.2 degrees two-theta. In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 10.6±0.2 degrees two-theta. In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 11.1±0.2 degrees two-theta. In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 12.5±0.2 degrees two-theta. In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 13.3±0.2 degrees two-theta. In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 13.7±0.2 degrees two-theta. In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 14.2±0.2 degrees two-theta. In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 14.9±0.2 degrees two-theta. In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 16.2±0.2 degrees two-theta. In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 19.0±0.2 degrees two-theta. In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 22.5±0.2 degrees two-theta. In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 24.1±0.2 degrees two-theta. In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by a powder X-ray diffraction pattern having a signal at 27.9±0.2 degrees two-theta.

[0165] In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by a powder X-ray diffraction pattern having signals at 2-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. In some embodiments, crystalline Form Tr of the tartrate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least eight 2-theta values ​​selected 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. In some embodiments, crystalline Form Tr of the tartrate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least seven 2-theta values ​​selected 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. In some embodiments, crystalline Form Tr of the tartrate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least six 2-theta values ​​selected 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. In some embodiments, crystalline Form Tr of the tartrate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least five 2-theta values ​​selected 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.In some embodiments, crystalline Form Tr of the tartrate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least four 2-theta values ​​selected 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. In some embodiments, crystalline Form Tr of the tartrate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least three 2-theta values ​​selected 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. In some embodiments, crystalline Form Tr of the tartrate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2-theta values ​​selected 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. In some embodiments, crystalline Form Tr of the tartrate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least one 2-theta value selected 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.

[0166] In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least three 2-theta values ​​selected 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 27.9±0.2. In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2-theta values ​​selected 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 27.9±0.2. In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least one 2-theta value selected 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 27.9±0.2. In some embodiments, crystalline form Tr of the tartrate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at 2-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.

[0167] In some embodiments, crystalline Form Tr of the tartrate salt of Compound (I) is characterized by a powder X-ray diffraction pattern substantially similar to that of FIG.

[0168] In some embodiments, the crystalline form Tr of the tartrate salt of Compound (I) has at least one crystalline form selected 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. Has a signal at δ values ​​(expressed as ppm) 13 Characterized by C NMR (DMSO-d6, 500 MHz) pattern.

[0169] In some embodiments, the present disclosure provides crystalline Form Tr of the tartrate salt of Compound (I), prepared by a process comprising adding Compound (I) and tartaric acid to a mixture of tetrafluoroethylene, ethanol, and water, stirring, evaporating with gentle stirring, adding acetone, heating to an elevated temperature, and reducing the temperature.

[0170] Crystalline Form H of the hydrochloride salt of Compound (I) In some embodiments, the present disclosure provides crystalline Form H of the hydrochloride salt of Compound (I). [ka]

[0171] FIG. 10 shows the powder X-ray diffraction diagram of crystalline form H of the hydrochloride salt of Compound (I) at ambient conditions.

[0172] In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is a mono-hydrochloride salt, eg, Form H comprises Compound (I) and hydrochloric acid in a 1:1 ratio.

[0173] In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a TGA thermogram having an endotherm at 156°C followed by a recrystallization event associated with a mass loss of 3.3-3.9% by weight. In some embodiments, crystalline Form H of the 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. In some embodiments, crystalline Form H of the 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. In some embodiments, crystalline Form H of the 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.

[0174] In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a solubility of 0.10 mg / mL in fasted simulated intestinal fluid. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a solubility of 4.18 mg / mL in fasted simulated gastric fluid. In some embodiments, at 37° C., crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a solubility of 0.10 mg / mL in fasted simulated intestinal fluid. In some embodiments, at 37° C., crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a solubility of 4.18 mg / mL in fasted simulated gastric fluid.

[0175] In some embodiments, crystalline form H of the hydrochloride salt of Compound (I) is characterized by a solubility in water of 2.86 mg / mL.

[0176] In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a 15% weight change in a dynamic vapor sorption experiment over a relative humidity (RH) range of 2-95% RH at room temperature. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a 10.8% weight change in a dynamic vapor sorption experiment over a relative humidity range of 80-95% RH at room temperature.

[0177] In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is a substantially pure form. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffractogram produced by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffractogram produced by powder X-ray diffractometry using an incident beam of Cu Kα radiation having signals substantially similar to those set forth in Table 7. [Table 10]

[0178] In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 4.8±0.2 degrees two-theta. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 8.1±0.2 degrees two-theta. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 8.5±0.2 degrees two-theta. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 9.6±0.2 degrees two-theta. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 11.1±0.2 degrees two-theta. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 20.7±0.2 degrees two-theta. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 21.5±0.2 degrees two-theta. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 23.3±0.2 degrees two-theta. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 23.7±0.2 degrees two-theta. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 24.1±0.2 degrees two-theta. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffractogram having a signal at 27.6±0.2 degrees two-theta.

[0179] In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffraction pattern having signals at 2-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, 23.3±0.2, 23.7±0.2, 24.1±0.2, and 27.6±0.2. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least eight 2-theta values ​​selected 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. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least seven 2-theta values ​​selected 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. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least six 2-theta values ​​selected 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. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least five 2-theta values ​​selected 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.In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least four 2-theta values ​​selected 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. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least three 2-theta values ​​selected 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. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2-theta values ​​selected 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. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least one 2-theta value selected 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.

[0180] In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least three 2-theta values ​​selected from 4.8±0.2, 8.1±0.2, 11.1±0.2, 20.7±0.2, and 23.7±0.2. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least two 2-theta values ​​selected from 4.8±0.2, 8.1±0.2, 11.1±0.2, 20.7±0.2, and 23.7±0.2. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffractogram having signals at at least one 2-theta value selected from 4.8±0.2, 8.1±0.2, 11.1±0.2, 20.7±0.2, and 23.7±0.2. In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffraction pattern having signals at 2-theta values ​​of 4.8±0.2, 8.1±0.2, 11.1±0.2, 20.7±0.2, and 23.7±0.2.

[0181] In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a powder X-ray diffraction pattern substantially similar to that of FIG.

[0182] In some embodiments, crystalline Form H of the hydrochloride salt of Compound (I) has a signal at at least one δ value (expressed as ppm) selected 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. 13 Characterized by C NMR (DMSO-d6, 500 MHz) pattern.

[0183] In some embodiments, the present disclosure provides a process for preparing crystalline Form H of the hydrochloride salt of Compound (I), and also provides crystalline Form H of the hydrochloride salt of Compound (I) prepared by a process comprising adding Compound (I) to a concentrated hydrochloric acid solution in ethanol, adding tetrafluoroethylene (TFE), and adding at an elevated temperature. In some embodiments, 1.1 equivalents of concentrated HCl solution in ethanol are used. In some embodiments, the elevated temperature is in the range of 35°C to 40°C. In some embodiments, stirring at elevated temperature occurs at 340 rpm for 30 minutes. In some embodiments, a spatula is used to break down the gum after stirring at 340 rpm for 15 minutes. In some embodiments, additional TFE is added after stirring at elevated temperature. In some embodiments, more stirring occurs at room temperature after adding the additional TFE.

[0184] In some embodiments, the present disclosure provides a process for preparing crystalline Form H of the hydrochloride salt of Compound (I), and also provides crystalline Form H of the hydrochloride salt of Compound (I) prepared by a process comprising slurrying Compound (I) in fasted simulated gastric fluid at 37° C.

[0185] Method for preparing compound (I) In some embodiments, the present disclosure provides (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)). [ka] or a pharmaceutically acceptable salt thereof. Scheme 1 [ka]

[0186] In some embodiments, the present disclosure provides a compound of formula (VI): [ka] to the compound of formula (III), [ka] The present invention provides a process for preparing compound (I), comprising the step of converting

[0187] In some embodiments, the compound of formula (III) is diastereomerically pure. The desired diastereomer has the S configuration at the carbon center.

[0188] In some embodiments, the compound of formula (III) is substantially free of undesired diastereomers (C) and (D). [ka]

[0189] In some embodiments, the amount of (C) and (D) is 0.4% w / w or less (as measured by HPLC). In some embodiments, the diastereomeric purity is >97% de (diastereomeric excess). In some embodiments, the diastereomeric 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%.

[0190] In some embodiments, X2 is selected from carbamate protecting groups, benzyl, tetrahydropyranyl, acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. In some embodiments, X2 is benzyl. In some embodiments, X2 is tetrahydropyranyl. In some embodiments, X2 is acetamide. In some embodiments, X2 is trifluoroacetamide. In some embodiments, X2 is triphenylmethylamine. In some embodiments, X2 is benzylideneamine. In some embodiments, X2 is p-toluenesulfonamide. In some embodiments, X2 is a carbamate protecting group. In some embodiments, the carbamate protecting groups are tert-butyl carbamate, 9-fluorenylmethyl carbamate, and benzyl carbamate. In some embodiments, X2 is tert-butyl carbamate. In some embodiments, X2 is 9-fluorenylmethyl carbamate. In some embodiments, X2 is benzyl carbamate.

[0191] The present disclosure provides processes for preparing diastereomerically pure compounds of formula (III), such as compound 7. It has been discovered that the diastereomeric purity of compounds of formula (III) is important for ensuring the purity of the final compound (I). In some embodiments, the process for preparing compounds of formula (III) in diastereomerically pure form involves grinding. In some embodiments, the grinding solvent in the step of grinding compounds of formula (VI) comprises n-heptane and methanol. In some embodiments, the process for preparing compounds of formula III in diastereomerically pure form involves recrystallization. In some embodiments, the recrystallization solvent is isopropanol. In some embodiments, the recrystallization solvent is a mixture of ethyl acetate and heptane.

[0192] In some embodiments, the present disclosure provides (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)). [ka] or a pharmaceutically acceptable salt thereof, (a)(S)-1-(2-(4λ 2 -piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine (2) or its salt [ka] and compounds of formula (I) [ka] This includes reacting

[0193] In some embodiments, X1 is a halogen or an activated phenol. In some embodiments, X1 is a halogen. In some embodiments, X1 is F, Cl, Br, or I. In some embodiments, X1 is F. In some embodiments, X1 is Cl. In some embodiments, X1 is Br. In some embodiments, X1 is I. In some embodiments, X1 is an activated phenol. In some embodiments, X1 is tosylate or mesylate.

[0194] In some embodiments, (S)-1-(2-(4λ 2 In some embodiments, (S)-1-(2-(4λ-piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine (2) is the free base. 2In some embodiments, (S)-1-(2-(4λ-piperazin-1-yl)-pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine (2) is a hydrochloride or trifluoroacetate salt. 2 In some embodiments, the salt of (S)-1-(2-(4λ-piperazin-1-yl)-pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine (2) is the hydrochloride salt. 2 The hydrochloride salt of (S)-1-(2-(4λ-piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine (II) 2 In some embodiments, (S)-1-(2-(4λ-piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine·3.5HCl (2A). 2 -piperazin-1-yl)-pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine (2) is the trifluoroacetate salt.

[0195] In some embodiments, 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine (3) [ka] teeth, (b) 6-bromopyrrolo[2,1-f][1,2,4]triazin-4-ol (4) [ka] and a compound of formula (II) [ka] By reacting forming 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (6); [ka] (c) 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (6), [ka] and converting the compound into 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine (3). [ka]

[0196] In some embodiments, B(OR)2 is Catecholborane, [ka] pinacolborane, [ka] and boronic acids.

[0197] In some embodiments, B(OR)2 is catecholborane. In some embodiments, B(OR)2 is pinacolborane. In some embodiments, B(OR)2 is selected from boronic acids. In some embodiments, the boronic acid is, for example, isopropylboronic acid, methylboronic acid, or BF3boronic acid. In some embodiments, B(OR)2 is B(OH)2.

[0198] In some embodiments, step (b) is carried out in the presence of a palladium catalyst. In some embodiments, the palladium catalyst is a Pd(0) or Pd(II) catalyst. In some embodiments, the palladium catalyst is a Pd(0) catalyst. In some embodiments, the palladium catalyst is a Pd(II) catalyst. In some embodiments, the palladium catalyst is PdCl2(dtbpf), PdCl2(dppf), or Pd(OAc2). In some embodiments, the palladium catalyst is PdCl2(dtbpf). In some embodiments, the palladium catalyst is PdCl2(dppf). In some embodiments, the palladium catalyst is Pd(OAc2).

[0199] In some embodiments, step (c) is carried out in the presence of a base. In some embodiments, the base is N,N-diisopropylethylamine, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene. In some embodiments, the base is N,N-diisopropylethylamine. In some embodiments, the base is triethylamine. In some embodiments, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0200] In some embodiments, step (c) is carried out in the presence of a chlorinated sulfur and phosphorus reagent. In some embodiments, the chlorinated sulfur and phosphorus reagent is selected from phosphorus oxychloride, phosphorus pentachloride, sulfuryl chloride, and trichloromethanesulfonyl chloride. In some embodiments, the chlorinated sulfur and phosphorus reagent is phosphorus oxychloride. In some embodiments, the chlorinated sulfur and phosphorus reagent is phosphorus pentachloride. In some embodiments, the chlorinated sulfur and phosphorus reagent is selected from sulfuryl chloride. In some embodiments, the chlorinated sulfur and phosphorus reagent is trichloromethanesulfonyl chloride.

[0201] In some embodiments, (S)-1-(2-(4λ 2-piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine (2) or a pharmaceutically acceptable salt thereof, [ka] or a pharmaceutically acceptable salt thereof, (d) Formula (III) [ka] The compound (S)-1-(2-(4λ 2 -piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine (2). [ka]

[0202] In some embodiments, X2 is selected from carbamate protecting groups, benzyl, tetrahydropyranyl, acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. In some embodiments, X2 is benzyl. In some embodiments, X2 is tetrahydropyranyl. In some embodiments, X2 is acetamide. In some embodiments, X2 is trifluoroacetamide. In some embodiments, X2 is triphenylmethylamine. In some embodiments, X2 is benzylideneamine. In some embodiments, X2 is p-toluenesulfonamide. In some embodiments, X2 is a carbamate protecting group. In some embodiments, the carbamate protecting groups are tert-butyl carbamate, 9-fluorenylmethyl carbamate, and benzyl carbamate. In some embodiments, X2 is tert-butyl carbamate. In some embodiments, X2 is 9-fluorenylmethyl carbamate. In some embodiments, X2 is benzyl carbamate.

[0203] In some embodiments, the pharmaceutically acceptable salt is (S) 1-(2-(4λ 2 In some embodiments, the pharmaceutically acceptable salt is the hydrochloride salt of (S)-1-(2-(4λ-piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine (2). 2 -piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine·3.5HCl (2A). [ka]

[0204] In some embodiments, the pharmaceutically acceptable salt (S)-1-(2-(4λ 2 (-piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine·3.5HCl (2A) was not isolated.

[0205] In some embodiments, step (d) is performed in the presence of a first acid. In some embodiments, the first acid is a strong acid. In some embodiments, the first acid is HCl, TFA, or H2SO4. In some embodiments, the first acid is HCl. In some embodiments, the first acid is TFA. In some embodiments, the first acid is H2SO4. In some embodiments, the first acid is a Lewis acid. In some embodiments, step (d) is performed in the presence of iodine. In some embodiments, step (d) is performed under pyrolysis conditions.

[0206] Some embodiments of the present disclosure include: (e) reacting a compound of formula (IV) with [ka] converting the compound of formula (V) [ka]

[0207] In some embodiments, step (e) is carried out in the presence of a catalyst. In some embodiments, the catalyst is titanium isopropoxide, titanium ethoxide, titanium butoxide, or titanium tetrachloride. In some embodiments, the catalyst is titanium isopropoxide. In some embodiments, the catalyst is titanium ethoxide. In some embodiments, the catalyst is titanium butoxide. In some embodiments, the catalyst is titanium tetrachloride. In some embodiments, the catalyst is a Lewis acid. In some embodiments, step (e) is carried out in the presence of (S)-2-methylpropane-2-sulfinamide or (S)-p-toluenesulfinamide. In some embodiments, step (e) is carried out in the presence of (S)-2-methylpropane-2-sulfinamide. In some embodiments, step (e) is carried out in the presence of (S)-p-toluenesulfinamide.

[0208] Some embodiments of the present disclosure include: (f) reacting a compound of formula (V) with [ka] converting the compound of formula (VI) [ka]

[0209] In some embodiments, step (f) is carried out in the presence of a Grignard reagent, an alkyl halide, or an alkyl metal. In some embodiments, step (f) is carried out in the presence of a Grignard reagent. In some embodiments, the Grignard reagent is methylmagnesium bromide, methylmagnesium chloride, or methylmagnesium iodide. In some embodiments, the Grignard reagent is methylmagnesium bromide. In some embodiments, the Grignard reagent is methylmagnesium chloride. In some embodiments, the Grignard reagent is methylmagnesium iodide. In some embodiments, step (f) is carried out in the presence of an alkyl halide. In some embodiments, step (f) is carried out in the presence of an alkyl metal. In some embodiments, step (f) is carried out in the presence of 2-methyltetrahydrofuran.

[0210] Some embodiments of the present disclosure include: (g) a compound of formula (VI) [ka] By crushing Compound of formula (III) [ka] This includes obtaining

[0211] In some embodiments, the milling solvent in step (g) comprises n-heptane and methanol.

[0212] Some embodiments of the present disclosure include: (g) recrystallizing the compound of formula (VI); [ka] Compound of formula (III) [ka] This includes obtaining

[0213] In some embodiments, the recrystallization solvent in step (g) comprises isopropanol. In some embodiments, the recrystallization solvent in step (g) comprises heptane and ethyl acetate.

[0214] Some embodiments of the present disclosure include: h) a compound of formula (VII) [ka] and 4-fluoro-N-methoxy-N-methylbenzamide (12), [ka] forming a compound of formula (IV): [ka]

[0215] In some embodiments, step (h) is carried out in the presence of an organolithium reagent or magnesium powder. In some embodiments, step (h) is carried out in the presence of an organolithium reagent. In some embodiments, 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 carried out in the presence of magnesium powder.

[0216] In some embodiments, the present disclosure provides a compound [ka] and a method for preparing by grinding or recrystallizing the compound of formula (VI), [ka] to obtain a compound of formula (III). [ka]

[0217] In some embodiments, X2 is selected from carbamate protecting groups, benzyl, tetrahydropyranyl, acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. In some embodiments, X2 is benzyl. In some embodiments, X2 is tetrahydropyranyl. In some embodiments, X2 is acetamide. In some embodiments, X2 is trifluoroacetamide. In some embodiments, X2 is triphenylmethylamine. In some embodiments, X2 is benzylideneamine. In some embodiments, X2 is p-toluenesulfonamide. In some embodiments, X2 is a carbamate protecting group. In some embodiments, the carbamate protecting groups are tert-butyl carbamate, 9-fluorenylmethyl carbamate, and benzyl carbamate. In some embodiments, X2 is tert-butyl carbamate. In some embodiments, X2 is 9-fluorenylmethyl carbamate. In some embodiments, X2 is benzyl carbamate.

[0218] In some embodiments, the grinding solvent in the step of grinding the compound of Formula (VI) comprises n-heptane and methanol, or the recrystallization solvent in the step of recrystallizing the compound of Formula (VI) is isopropanol or heptane / ethyl acetate.

[0219] The present 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. Specifically, the present disclosure provides a process for the preparation of Compound (I), comprising forming a salt of Compound (I) with D-quinic acid in an organic solvent and crystallizing the salt from the solvent mixture. In some embodiments, the organic solvent is THF. In some embodiments, the solvent mixture is THF and water. In some embodiments, the ratio of the solvent mixture is 20 volumes of THF to water. In some embodiments, the process further comprises recrystallizing Compound (I) in acetone and water, as described herein.

[0220] Indications The crystalline forms of Compound (I), its pharmaceutically acceptable salts, and any of the foregoing solvates described herein may be useful for treating conditions associated with abnormal KIT activity in humans or non-humans. Activating mutations in KIT are found in multiple indications, including systemic mastocytosis, gastrointestinal stromal tumors (GISTs), acute myeloid leukemia (AML), melanoma, seminoma, intercranial germ cell tumors, and mediastinal B-cell lymphoma.

[0221] Mastocytosis refers to a group of disorders characterized by the accumulation of excess mast cells in one or more tissues. Mastocytosis is subdivided into two groups of disorders: (1) cutaneous mastocytosis (CM), which represents a form limited to the skin, and (2) systemic mastocytosis (SM), which represents a form in which mast cells infiltrate extracutaneous organs, with or without skin involvement. Systemic mastocytosis is a rare disease. A cohort study conducted in Denmark estimated the incidence of SM (all subtypes, including patients with cutaneous mastocytosis (CM) without documented systemic involvement) at 0.89 per 100,000 people per year. The prevalence of ISM in the Groningen region of the Netherlands, the main referral area for SM patients, is estimated at 13 / 100,000. Mutations in KIT D816 have been shown in 90%–95% of SM patients.

[0222] SM is further classified into five forms: indolent (ISM), smoldering (SSM), aggressive (ASM), SM associated with hematologic non-mast cell-lineage disease (SM-AHNMD), and mast cell leukemia (MCL). The term "advanced systemic mastocytosis" (Adv-SM) refers to ASM, SM-AHNMD, and MCL. The term "non-advanced systemic mastocytosis" (non-Adv SM) refers to ISM and SSM.

[0223] The diagnosis of systemic mastocytosis is based in part on histologic and cytologic studies of bone marrow, which demonstrate infiltration by mast cells, often of atypical morphology, that frequently abnormally express non-mast cell markers (CD25 and / or CD2). The diagnosis of SM is confirmed when bone marrow mast cell infiltration occurs in one of the following situations: (1) abnormal mast cell morphology (spindle-shaped cells), (2) elevated serum tryptase levels greater than 20 ng / mL, or (3) the presence of the activating KIT D816V mutation.

[0224] Activating mutations at the D816 position are found in most cases of mastocytosis (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 the KIT kinase.

[0225] There are no approved treatments for ISM and SSM, and symptoms are managed with symptom-directed treatments, such as antihistamines. Therefore, safe and effective treatments for ISM and SSM are needed. Furthermore, patients with ISM and SSM have a lower disease burden than those with AdvSM and are expected to remain on treatment for longer periods, so if effective, lower doses are required.

[0226] Compound (I), its pharmaceutically acceptable salts, and crystalline forms of any of the aforementioned solvates are also useful for treating GISTs, e.g., PDGFRα-exon 18 mutant-driven GISTs, PDGFRα-exon 18 D842-driven GISTs (e.g., PDGFRα-D842I-driven GISTs, PDGFRα-D842V-driven GISTs, or PDGFRα-D842Y-driven GISTs), and PDGFRα-exon 18 mutant non-D842-driven GISTs (e.g., PDGFRα-D842-H845-driven GISTs and PDGFRα-DI842-843V-driven GISTs), regardless of prior treatment. Approximately 90% of GIST patients have tumors that are dependent on mutations in either the V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) (75%-80%) or the closely related protein platelet-derived growth factor receptor alpha (PDGFRα) (10%-15%). At the molecular level, the most common sites of oncogenic mutations at diagnosis are the juxtamembrane domain (exon 11 [60%–70%]) and extracellular domain (exon 9 [5%–15%]) relative to the activation loop (exon 18) of KIT and PDGFRα, where the most common activation loop mutation is D842V.

[0227] Complete surgical resection remains the primary treatment for patients with primary GIST. GIST is not considered sensitive to either systemic cytotoxic chemotherapy or radiation therapy. Surgery is effective in approximately 50% of GIST patients. Tumor recurrence is frequent in the remaining patients. First-line treatment with KIT inhibitors, such as imatinib, has also been shown to be sufficient for the initial treatment of GIST. However, resistance to imatinib develops within a few months in GIST patients due to somatic mutations in KIT that significantly reduce imatinib binding affinity. These resistance mutations always occur within the ATP-binding pocket (exons 13 and 14) or activation loop (exons 17 and 18) of the kinase. None of the currently approved therapies for treating GIST are selective targeted agents. Rather, the drugs currently approved for the treatment of GIST after imatinib are multikinase inhibitors, such as sunitinib, regorafenib, and midostaurin. In many cases, these multikinase inhibitors only weakly inhibit imatinib-resistant mutations. Furthermore, multikinase inhibitors may have limited therapeutic value due to their more complicated safety profile and narrow therapeutic window. Therefore, therapeutic agents for treating GIST patients resistant to imatinib are needed.

[0228] There is a subset of patients with unresectable or metastatic GIST who have been treated with at least three lines of therapy, and the compounds described herein may be useful in treating these patients.

[0229] In addition to the use of crystalline forms of compound (I), its pharmaceutically acceptable salts, and any of the aforementioned solvates described herein as drugs in the setting of refractory GIST, the use of a combination of imatinib, sunitinib, and / or regorafenib with at least one crystalline form selected from compound (I), its pharmaceutically acceptable salts, and any of the aforementioned solvate crystalline forms disclosed herein may enable the prevention of the emergence of resistance to exon 17 mutations.

[0230] A subset of GIST patients has alterations in the activation loop of PDGFRα. A subset of GIST patients has point mutations in the activation loop of PDGFRα. A subset of GIST patients has the D842V mutation in PDGFRα, and this subgroup of GIST patients can be stratified by identifying this mutation. This subset of patients is refractory to all currently available tyrosine kinase inhibitors. The compounds described herein may be useful in treating these patients due to their selective activity against PDGFRα D842V.

[0231] Mutation of the aspartic acid (D) residue at position 842 in exon 18 of PDGFRα to isoleucine (I) or tyrosine (Y) results in constitutive activation of PDGFRα tyrosine kinase activity in a ligand-independent manner. A subset of GIST patients also harbors the D842I mutation in PDGFRα, and this subgroup of GIST patients can be stratified by identifying this mutation. The compounds described herein may be useful for treating these patients due to their selective activity against PDGFRα D842I. Furthermore, a subset of GIST patients harbors the D842Y mutation in PDGFRα, and this subgroup of GIST patients can be stratified by identifying this mutation. The compounds described herein may be useful for treating these patients due to their selective activity against PDGFRα D842Y.

[0232] There is a subset of GIST patients with indels in the activation loop of PDGFRα. There is a subset of GIST patients with the D842-H845 alteration in PDGFRα, and this subgroup of GIST patients can be stratified by identifying this alteration. The compounds described herein may be useful in treating these patients due to their selective activity against PDGFRα D842-H845.

[0233] There is a subset of GIST patients who have the DI842-843V alteration in PDGFRα, and this subgroup of GIST patients can be stratified by identifying this alteration. The compounds described herein may be useful in treating these patients due to their selective activity against PDGFRα DI842-843V.

[0234] The crystalline forms of Compound (I), its pharmaceutically acceptable salts, and any of the foregoing solvates described herein may also be useful in treating AML. AML patients also harbor KIT mutations, with the majority of KIT mutations occurring at position D816.

[0235] Furthermore, mutations in KIT are associated with Ewing's sarcoma, DLBCL (diffuse large B-cell lymphoma), embryonal carcinoma, MDS (myelodysplastic syndrome), NKTCL (nasal NK / T-cell lymphoma), CMML (chronic myelomonocytic leukemia), and brain cancer.

[0236] The crystalline forms of Compound (I), its pharmaceutically acceptable salts, and any of the aforementioned solvates disclosed herein can be used to treat conditions associated with KIT gene mutations in exon 9, exon 11, exon 13, exon 14, exon 17, and / or exon 18. The crystalline forms can also be used to treat conditions associated with wild-type KIT. The crystalline forms of Compound (I), its pharmaceutically acceptable salts, and any of the aforementioned solvates disclosed herein can be used as medicaments to treat the conditions described herein, or they can be used in combination with other therapeutic agents, including, but not limited to, imatinib, sunitinib, and regorafenib. Other medicaments include compounds described in WO 2014 / 039714 and WO 2014 / 100620.

[0237] Crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and any of the foregoing solvates described herein are active against at least one KIT mutation in exon 11, 11 / 17, and exon 17 (e.g., d557-558, V560G, V560G / D816V, V560G / N822K, D816E, D816F, D816H, D816I, D816V, D816Y, D816K, D816H, D816A, D816G, D820A, D820E, D802Y, D820G, N822K, N822H, Y823D, and / or A829P), and are less active against wild-type KIT. In some embodiments, crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and any of the foregoing solvates described herein may be active against at least one of KIT mutant exons 11, 11 / 17, and 17 mutants (d557-558, V560G, V560G / D816V, V560G / N822K, D816E, D816F, D816H, D816I, D816V, D816Y, D820E, D820Y, and Y823D).

[0238] The crystalline form can be administered in combination with a drug that is (a) active against other activating mutations of KIT, such as exon 9 and 11 mutations, but (b) not active against exon 17 mutations. Such drugs include imatinib, sunitinib, and regorafenib. A combination of at least one crystalline form selected from the crystalline forms of compound (I), its pharmaceutically acceptable salts, and any of the foregoing solvates, and the drug thus inhibits exon 17 mutant KIT and also inhibits exon 9 / 11 mutant KIT. The at least one crystalline form and the drug can be administered simultaneously or in an alternating regimen. That is, the exon 17 mutant KIT inhibitor can be administered alone for a certain period of time, followed by the exon 9 / 11 mutant KIT inhibitor for a subsequent period of time. This cycle can then be repeated. It is believed that such a regimen can delay the development of resistance to exon 17 mutant KIT inhibitors and / or exon 9 / 11 mutant KIT inhibitors.

[0239] Furthermore, at least one crystalline form selected from the crystalline forms of Compound (I), its pharmaceutically acceptable salts, and any of the aforementioned solvates described herein, which may be selective for exon 17 KIT mutants, can be administered in combination with a third drug that covers mutations missed by the two-way combo, along with at least one drug that is effective against exon 9 / 11 mutations. The three-drug combination may inhibit various KIT mutations, and potentially wild-type KIT. The drugs can be administered simultaneously or in an alternating regimen. They can be administered one at a time, or two drugs can be administered together for a period of time, followed by a third drug alone for a subsequent period of time. It is believed that such a regimen can delay the development of resistance to mutant KIT inhibitors.

[0240] In some embodiments, at least one crystalline form selected from crystalline forms of Compound (I), its pharmaceutically acceptable salts, and any of the foregoing solvates may be used alone or in combination with imatinib, sunitinib, and / or regorafenib.

[0241] In some embodiments, at least one crystalline form selected from the crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing may be used in combination with other treatments, such as, for example, surgery or radiation therapy.

[0242] dose The effective dose for a particular patient or subject may depend on a variety of factors, including the disorder being treated and the severity of the disorder, the particular pharmaceutical composition used, the age, weight, general health, sex and diet of the patient or subject, the time of administration, the route of administration, the duration of treatment, and similar factors well known in the medical arts.

[0243] In some embodiments, a therapeutically effective amount of at least one crystalline form selected from Compound (I), a pharmaceutically acceptable salt thereof, and a crystalline form of any of the foregoing solvates (e.g., crystalline Form A of Compound (I)) is administered to a patient in need thereof. In some embodiments, a therapeutically effective amount of at least one crystalline form selected from Compound (I), a pharmaceutically acceptable salt thereof, and a crystalline form of any of the foregoing solvates (e.g., crystalline Form A of Compound (I)) is administered to a patient in need thereof once daily.

[0244] In some embodiments, a therapeutically effective amount of at least one crystalline form administered to a patient once daily ranges 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 a weight equivalent amount of a crystalline form of a pharmaceutically acceptable salt thereof (e.g., crystalline form T of the tosylate salt of Compound (I), crystalline form Tr of the tartrate salt of Compound (I), or crystalline form H of the hydrochloride salt of Compound (I)) or a weight equivalent amount of a crystalline form of a solvate of Compound (I) or a pharmaceutically acceptable salt thereof (e.g., crystalline form of Compound (I)).

[0245] The present disclosure provides improved methods for treating AdvSM in a patient in need thereof by administering a crystalline form of Compound (I) and / or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of at least one crystalline form administered to a patient once daily is an amount ranging from 200 mg to 300 mg (e.g., 200 mg, 225 mg, 250 mg, 300 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 a weight equivalent amount of a crystalline form of a pharmaceutically acceptable salt thereof (e.g., crystalline Form T of the tosylate salt of Compound (I), crystalline Form Tr of the tartrate salt of Compound (I), or crystalline Form H of the hydrochloride salt of Compound (I)), or a weight equivalent amount of a crystalline form of Compound (I) or a solvate of a pharmaceutically acceptable salt thereof (e.g., crystalline Form C of Compound (I)). In some embodiments, the patient has 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. In some embodiments, the patient has 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. In some embodiments, the patient has 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.

[0246] The present disclosure provides improved methods for treating GIST in patients in need thereof by administering a crystalline form of Compound (I) and / or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of at least one crystalline form administered to a patient once daily is an amount ranging from 300 mg to 400 mg (e.g., 325 mg, 350 mg, 375 mg, 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 a weight equivalent of a pharmaceutically acceptable salt of the crystalline form (e.g., crystalline Form T of the tosylate salt of Compound (I), crystalline Form Tr of the tartrate salt of Compound (I), or crystalline Form H of the hydrochloride salt of Compound (I)), or a weight equivalent of a crystalline form of Compound (I) or a solvate of a pharmaceutically acceptable salt thereof (e.g., crystalline Form C of Compound (I)). In some embodiments, 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 of crystalline Form A of Compound (I) once daily is well tolerated by the patient, the dose can be increased to 400 mg once daily. If 300 mg of crystalline Form A of Compound (I) once daily is well tolerated for at least two consecutive treatment cycles (each 28 days), at least three consecutive treatment cycles (each 28 days), or at least four consecutive treatment cycles (each 28 days), the dose can be increased to 400 mg once daily.

[0247] The present 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. Specifically, the present disclosure provides safe and effective dosing regimens of Compound (I) that can be used for long-term treatment. In one aspect, an ISM or SSM patient in need thereof has moderate to severe symptoms.

[0248] According to a recent clinical study, as shown in Example 12, Compound (I) administered at 25 mg once daily to patients with ISM or SSM demonstrated improvements across all three aspects of its clinical profile, including reduced mast cell burden, improved disease symptoms, and improved quality of life. Specifically, Compound (I) administered at 25 mg once daily demonstrated statistically significant reductions in each symptom of the ISM-SAF TSS and total domain score over 16 weeks. Surprisingly, the 25 mg dose produced similar mean improvements in TSS as the higher doses of 50 mg and 100 mg, and was more tolerable. For example, the 25 mg QD dose demonstrated a significant reduction in the blood KIT D816V allele fraction, similar to the 50 mg QD and 100 mg QD doses. Furthermore, Compound (I) administered at 25 mg once daily to patients with ISM demonstrated a favorable safety profile. For example, 95% of patients continued in the clinical trial, with no discontinuations due to adverse events (AEs). There were no grade 3 or higher AEs in the 25 mg once-daily cohort. Patients experienced improvement in quality of life (QoL) as measured by MC-QoL global score and all domain scores at week 16.

[0249] The present disclosure provides improved methods for treating ISM and SSM in a patient in need thereof by administering a crystalline form of Compound (I) and / or a pharmaceutically acceptable salt thereof. In some embodiments, a therapeutically effective amount of at least one crystalline form administered to a patient once daily is in an amount ranging from 25 mg to 100 mg (e.g., 25, 50, or 100 mg). The therapeutically effective amount of the crystalline form 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 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.

[0250] The present 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 Compound (I) or a pharmaceutically acceptable salt thereof, equivalent to 10 mg to 100 mg of Compound (I), once daily. In some embodiments, a patient in need thereof is administered an amount of Compound (I) of 10 mg to 100 mg once daily. In some embodiments, a patient in need thereof is administered 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 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 daily. In some embodiments, the amount is 10 mg to 25 mg once daily. In some embodiments, the amount is 10 mg to 50 mg once daily. In some embodiments, the amount is 10 mg to 75 mg once daily. In some embodiments, the amount is 10 mg to 100 mg once daily. In some embodiments, the amount is 25 mg to 50 mg once daily. In some embodiments, the amount is 25 mg to 100 mg once daily. In some embodiments, the amount is 50 mg to 100 mg once daily. In some embodiments, the amount is 75 mg to 100 mg once daily. In some embodiments, the amount is 10 mg once daily. In some embodiments, the amount is 15 mg once daily. In some embodiments, the amount is 20 mg once daily. In some embodiments, the amount is 25 mg once daily. In some embodiments, the amount is 30 mg once daily. In some embodiments, the amount is 35 mg once daily. In some embodiments, the amount is 35 mg once daily. In some embodiments, the amount is 40 mg once daily. In some embodiments, the amount is 45 mg once daily. In some embodiments, the amount is 50 mg once daily.In some embodiments, the amount is 55 mg once daily. In some embodiments, the amount is 60 mg once daily. In some embodiments, the amount is 65 mg once daily. In some embodiments, the amount is 70 mg once daily. In some embodiments, the amount is 75 mg once daily. In some embodiments, the amount is 80 mg once daily. In some embodiments, the amount is 85 mg once daily. In some embodiments, the amount is 90 mg once daily. In some embodiments, the amount is 95 mg once daily. In some embodiments, the amount is 100 mg once daily.

[0251] In some embodiments, at least one crystalline form selected from Compound (I), a pharmaceutically acceptable salt thereof, and a crystalline form of any of the foregoing solvates disclosed herein is administered orally. In some embodiments, at least one crystalline form selected from Compound (I), a pharmaceutically acceptable salt thereof, and a crystalline form of any of the foregoing solvates disclosed herein is administered until disease progression, unacceptable toxicity, or individual choice.

[0252] In clinical trials using crystalline form A of Compound (I), adverse reactions were classified into grades 1 to 5 based on severity. Most reported adverse events were grade 1 or 2, indicating that crystalline form A of Compound (I) is well tolerated. Patients receiving crystalline form A of Compound (I) did not experience severe dose-limiting toxicities, such as skin, liver, and cardiovascular toxicities, observed with other tyrosine kinase inhibitors (TKIs). Severe dose-limiting toxicities with other TKIs may be the result of broad-spectrum kinase inhibition.

[0253] Pharmaceutical Composition The crystalline forms described herein are useful as materials for preparing pharmaceutical compositions incorporating an active pharmaceutical ingredient (API) and one or more pharmaceutically acceptable excipients suitable for administration to a human subject. In some embodiments, these pharmaceutical compositions will be pharmaceutical products, such as solid oral dosage forms, such as tablets and / or capsules. In preparing these pharmaceutical compositions, 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. For example, when a crystalline API is contacted with one or more pharmaceutically acceptable excipients in the presence of a solvent, such as water, in an amount sufficient to promote dissolution of the API, such that, for example, crystallization properties are lost and therefore it is not present in the final drug product, the crystalline form may not be detectable.

[0254] In some embodiments, 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 for preparing a pharmaceutical composition that includes, for example, spray drying or wet granulation. When the process involves spray drying or wet granulation, it is likely that little or no crystalline form will be detectable in the resulting pharmaceutical composition.

[0255] In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one crystalline form selected from the crystalline forms of Compound (I), a pharmaceutically acceptable salt thereof, and any of the foregoing solvates.

[0256] In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one crystalline form selected from crystalline forms of Compound (I), a pharmaceutically acceptable salt thereof, and any of the foregoing solvates. For example, 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 the tosylate salt of Compound (I), crystalline Form Tr of the tartrate salt of Compound (I), and / or crystalline Form H of the hydrochloride salt of Compound (I) can be formulated into pharmaceutical compositions for administration in any convenient manner for use in human or veterinary medicine.

[0257] In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one crystalline form selected from the crystalline forms of Compound (I), its pharmaceutically acceptable salts, and any of the foregoing solvates, and at least one additional pharmaceutically acceptable excipient. As used herein, the term "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 harmful to the patient. Except insofar as any conventional pharmaceutically acceptable excipient is incompatible with Compound (I) and / or the crystalline forms of Compound (I), its pharmaceutically acceptable salts, and the foregoing solvates, e.g., by producing any undesirable biological effect or otherwise interacting in a manner that adversely affects the other component(s) of the pharmaceutically acceptable composition, the use of an excipient is intended to be within the scope of the present disclosure.

[0258] Some non-limiting examples of materials that 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, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; and (9) peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, and corn oil. (10) oils such as soybean oil, (11) glycols such as propylene glycol, (12) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, (13) esters such as ethyl oleate and ethyl laurate, (14) buffers such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer, and (21) other non-toxic compatible substances used in the formulation.

[0259] Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C.B. Boylan, 1988-1999, Marcel Dekker, New York, the contents of each of which are incorporated herein by reference, also disclose additional non-limiting examples of pharmaceutically acceptable excipients, as well as known techniques for preparing and using them.

[0260] The pharmaceutical compositions disclosed herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions of the present disclosure are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the pharmaceutical compositions of the present disclosure may be aqueous or oily suspensions. These 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 used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0261] For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for preparing injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, spans, and other emulsifiers or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0262] The pharmaceutical compositions disclosed herein can also be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions.When aqueous suspensions are required for oral use, active ingredients are usually combined with emulsifiers and suspending agents.If necessary, certain sweeteners, flavors, or coloring agents can be added.

[0263] Alternatively, the pharmaceutical compositions disclosed herein can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and melts in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0264] The pharmaceutical compositions of the present disclosure can also be administered topically, especially when the target of treatment includes areas or organs that are easily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. For each of these areas or organs, suitable topical formulations are easily prepared. Topical application to the lower intestinal tract can be carried out in a rectal suppository formulation (see above) or a suitable enema formulation. Topical transdermal patches can also be used.

[0265] For topical application, the pharmaceutical composition may be formulated into a suitable ointment containing the active ingredient suspended or dissolved in at least one excipient.Excipients for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, the pharmaceutical composition disclosed herein may be formulated into a suitable lotion or cream containing the active ingredient 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 ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0266] The pharmaceutical compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0267] In some embodiments, the present disclosure provides pharmaceutical compositions, comprising at least one excipient and at least one crystalline form selected from crystalline forms of Compound (I), a pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing.

[0268] In some embodiments, the pharmaceutical compositions disclosed herein comprise an intragranular portion and an extragranular portion. In some embodiments, the pharmaceutical compositions disclosed herein comprise at least one filler, at least one disintegrant, and at least one lubricant. As used herein, "extragranular filler," "extragranular disintegrant," or "extragranular lubricant" refers to a filler, disintegrant, or lubricant, respectively, that comprises the extragranular portion of the pharmaceutical composition.

[0269] Suitable fillers for the pharmaceutical compositions disclosed herein are compatible with the other components of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, hardness, chemical stability, physical stability, or biological activity of the pharmaceutical composition. Non-limiting examples of suitable fillers include cellulose, modified cellulose (e.g., sodium carboxymethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose), cellulose acetate, microcrystalline cellulose, calcium phosphate, dibasic calcium phosphate, starch (e.g., corn starch, potato starch), sugar (e.g., mannitol, lactose, sucrose, etc.), or any combination thereof. In some embodiments, the filler is microcrystalline cellulose.

[0270] In some embodiments, the pharmaceutical composition comprises at least one extragranular filler in an amount of 15% to 20% by weight (e.g., 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, or 20% by weight) of the pharmaceutical composition. For example, in some embodiments, the pharmaceutical composition comprises 15% to 20% by weight (e.g., 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, or 20% by weight) of the pharmaceutical composition of extragranular microcrystalline cellulose, e.g., MCC Avicel PH-200. In some embodiments, the pharmaceutical composition comprises 17% by weight of the pharmaceutical composition of extragranular microcrystalline cellulose, e.g., MCC Avicel PH-200. In some embodiments, the pharmaceutical composition comprises 17% extragranular Avicel PH-200 by weight of the pharmaceutical composition.

[0271] Disintegrants suitable for the pharmaceutical compositions disclosed herein can enhance dispersion of the pharmaceutical composition and are compatible with other components of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, physical stability, hardness, or biological activity of the pharmaceutical composition. Non-limiting examples of suitable disintegrants include croscarmellose sodium, sodium starch glycolate, crospovidone, or any combination thereof. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is Ac-Di-Sol.

[0272] In some embodiments, the pharmaceutical compositions disclosed herein comprise 2% to 3% by weight (e.g., 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3% by weight) of the pharmaceutical composition of an extragranular disintegrant. For example, in some embodiments, the pharmaceutical composition comprises 2% to 3% by weight (e.g., 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3% by weight) of the pharmaceutical composition of an extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3% by weight of extragranular croscarmellose sodium, e.g., Ac-Di-Sol. In some embodiments, the pharmaceutical composition comprises 2.5% by weight of the pharmaceutical composition of extragranular croscarmellose sodium, e.g., Ac-Di-Sol. In some embodiments, the pharmaceutical composition comprises 2.5% by weight of the pharmaceutical composition of extragranular Ac-Di-Sol.

[0273] In some embodiments, the pharmaceutical compositions disclosed herein comprise a lubricant. Lubricants can prevent adhesion of mixed ingredients to surfaces (e.g., the surface of a mixing bowl, granulation rolls, compression dies, and / or punches). Lubricants can also reduce interparticle friction within granules, improving compaction and ejection of the compacted pharmaceutical composition from the granulator and / or die press. Suitable lubricants for the pharmaceutical compositions disclosed herein are compatible with the other components of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, hardness, or biological activity of the pharmaceutical composition. Non-limiting examples of 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. In some embodiments, the lubricant is magnesium stearate.

[0274] In some embodiments, the pharmaceutical composition comprises 0.25% to 1% by weight of the pharmaceutical composition (e.g., 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1% by weight of a lubricant. In some embodiments, the pharmaceutical composition comprises 0.25% to 1% by weight (e.g., 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1% by weight of the pharmaceutical composition) of extragranular magnesium stearate.

[0275] In some embodiments, the pharmaceutical compositions disclosed herein are in the form of tablets. The tablets disclosed herein can be produced by compressing or pressing a mixture or composition, such as a powder or granules, under pressure to form a stable three-dimensional shape. As used herein, "tablet" refers to a compressed pharmaceutical dosage unit of any shape or size, whether coated or not. In some embodiments, the tablets disclosed herein comprise an intragranular portion and an extragranular portion.

[0276] In some embodiments, the method for preparing tablets disclosed herein includes: (a) mixing at least one crystalline form selected from Compound (I), a pharmaceutically acceptable salt thereof, and any of the aforementioned solvate crystalline forms, at least one first filler, at least one binder, at least one first disintegrant, and at least one first lubricant (granulation mixture); (b) granulating the intragranular mixture (granulation mixture); (c) mixing at least one second filler, at least one second disintegrant, and at least one second lubricant (extragranular mixture); (d) mixing the granular mixture and the extragranular mixture to form a tablet mixture; and (e) compressing the tablet mixture containing the granulation mixture and the extragranular mixture into a tablet. Steps (a), (b), and (c) can be performed in any order. Any suitable method known in the art for granulating and compressing pharmaceutical compositions can be used.

[0277] Suitable binders for the pharmaceutical compositions disclosed herein, e.g., tablets, can enhance the adhesiveness and / or tensile strength of the pharmaceutical composition, e.g., tablets, and are compatible with other components of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, physical stability, hardness, or biological activity of the pharmaceutical composition. Non-limiting examples of suitable binders include copovidone, dibasic calcium phosphate, sucrose, maize (corn) starch, microcrystalline cellulose, and modified cellulose (e.g., hydroxymethylcellulose). In some embodiments, the binder is copovidone. In some embodiments, the binder is Kollidon VA 64 Fine.

[0278] In some embodiments, the methods disclosed herein further comprise coating the tablet. The 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 components of the tablet; for example, they do not substantially reduce the tablet's dissolution, chemical stability, physical stability, hardness, or biological activity.

[0279] In some embodiments, the tablets disclosed herein are coated with a film. In some embodiments, the film comprises at least one colorant and / or pigment. In some embodiments, the film is Opadry II.

[0280] In some embodiments, the tablets disclosed herein may 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.

[0281] In some embodiments, at least one crystalline form selected from the crystalline forms of Compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing is in the form of particles.

[0282] In some embodiments, the tablets described herein comprise granules comprising 30-50% by weight of 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% by weight of at least one first filler, 2.5-7.5% by weight of at least one binder, 2-3% by weight of at least one first disintegrant, and 0.25-1% by weight of at least one first lubricant. In some embodiments, the granules comprise the intragranular portion of the tablets disclosed herein.

[0283] In some embodiments, the tablet comprises particles of at least one crystalline form of Compound (I) having an average diameter of 10 to 150 μm. In some embodiments, the tablet comprises particles of at least one crystalline form of Compound (I) having an average diameter of 15, 56, 108, or 147 μm. In some embodiments, the tablet comprises crystalline Form A of Compound (I), crystalline Form B of Compound (I), and / or crystalline Form O of Compound (I), or a weight equivalent of at least one crystalline form of a pharmaceutically acceptable salt thereof (e.g., crystalline Form T of the tosylate salt of Compound (I), crystalline Form Tr of the tartrate salt of Compound (I), and / or crystalline Form H of the hydrochloride salt of Compound (I)), or a 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)).

[0284] All publications and patents mentioned in this specification are herein incorporated by reference in their entirety, to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

[0285] In the claims, articles such as "a," "an," and "the" may mean at least one unless indicated to the contrary or clear from the context. A claim or description including "or" between at least one member of a group is deemed to be satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a particular product or process, unless specified to the contrary or clear from the context. The present disclosure includes embodiments in which exactly one member of a group is present in, used in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all group members are present in, used in, or otherwise relevant to a given product or process.

[0286] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which at least one limitation, element, clause, and descriptive term from at least one of the enumerated claims is introduced into another claim. For example, a claim that depends on another claim can be modified to include at least one limitation found in any other claim that depends on the same base claim. When elements are presented as lists, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element(s) can be removed from the group. In general, when the present disclosure or aspects of the present disclosure are referred to as including particular elements and / or features, it is understood that embodiments of the present disclosure or aspects of the present disclosure consist of or consist essentially of such elements and / or features. For the sake of brevity, these embodiments are not specifically described in these terms herein. When ranges are specified, endpoints are included. Furthermore, unless otherwise indicated or apparent from the context and understanding of one of ordinary skill in the art, values ​​expressed as ranges can, in different embodiments of the present disclosure, take any specific value or subrange within the stated range, down to one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0287] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein which equivalents are intended to be encompassed by the following claims.

[0288] Example The following examples are intended to be illustrative and are not meant to limit the scope of the disclosure in any way.

[0289] The synthetic schemes listed below are intended to provide general guidance regarding the preparation of compounds of the present disclosure. Those skilled in the art will understand that the preparations shown may be modified and / or optimized using general knowledge of organic chemistry. [Table 11-1] [Table 11-2]

[0290] General method Optical microscopy: Optical microscopy was performed using a Zeiss AxioScope A1 equipped with 2.5X, 10X, and 40X objectives and polarizers. Images were captured with a built-in Axiocam 105 digital camera and processed using ZEN2 (Blue Edition) software provided by Zeiss.

[0291] DVS: Dynamic water vapor sorption (DVS) was performed using the DVS Intrinsic1. Samples were loaded into a sample pan and suspended from a microbalance. Typical sample mass for DVS measurements was 25 mg. Nitrogen gas bubbled through distilled water provided the desired relative humidity. A typical measurement consisted of the following steps: 1. Equilibrate at 50% RH 2. 50% to 2%. (50%, 40%, 30%, 20%, 10%, and 2%) a. Hold at each humidity level for a minimum of 5 minutes and a maximum of 60 minutes. The pass criterion was a change of less than 0.002%. 3. 2%~95% (2%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%) a. Hold at each humidity level for a minimum of 5 minutes and a maximum of 60 minutes. The pass criterion was a change of less than 0.002%. 4. 95%~2% (95%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 2%) a. Hold at each humidity level for a minimum of 5 minutes and a maximum of 60 minutes. The pass criterion was a change of less than 0.002%. 5. 2%~50% (2%, 10%, 20%, 30%, 40%, 50%) a. Hold at each humidity level for a minimum of 5 minutes and a maximum of 60 minutes. The pass criterion was a change of less than 0.002%.

[0292] Thermal analysis: Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed using a Mettler Toledo TGA / DSC3+. Samples were weighed in aluminium hermetically sealed pans with a pinhole. The parameters used were as follows: [Table 12]

[0293] Karl Fischer titration: Karl Fischer titration for water content determination was performed using a 785DMP Titrino and 703Ti Stand equipped with a 6.0338.100 dual platinum wire electrode. Samples were dissolved in HPLC-grade or anhydrous methanol and titrated with Hydranal-Composite 5. Typical sample masses for measurements were 0.03 g to 0.10 g. A 1 wt. % Hydranal water standard was used for calibration.

[0294] Chloride content by ion-selective electrode (ISE): The chloride content of the samples was determined by titration using an ion-selective electrode. Titrations were performed 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 points of the titration curves.

[0295] 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 of deuterated solvent in 4 mL vials and transferred to NMR tubes (Wilmad 5 mm thin-walled 8 inch 200 MHz, 506-PP-8). Typical NMR parameters for the Bruker Avance 300 MHz or 500 MHz spectrometers are listed below. [Table 13]

[0296] XRPD: Powder X-ray diffraction was performed using a Rigaku MiniFlex600. Samples were prepared on Si zero-return wafers. Typical scans were acquired from 4 to 30 degrees 2θ at 40 kV and 15 mA for 5 minutes with a 0.05 degree step size. High-resolution scans were acquired from 4 to 40 degrees 2θ at 40 kV and 15 mA for 30 minutes with a 0.05 degree step size. Typical parameters for XRPD are listed below. [Table 14]

[0297] Example 1: Preparation of crystalline form A of compound (I)

[0298] Compound (I) (10.0 g) was dissolved in acetone (17.4 vol) and deionized water (3.2 vol, final ratio: acetone / water 85 / 15) to obtain a suspension. The suspension was heated to a temperature ranging from 40°C to 50°C and stirred at 40°C to 50°C for 15 minutes. A clear yellow solution was obtained. This was followed by polish filtration at 40°C to 50°C. The filter was washed with acetone / water 85 / 15 (1 vol). The solution was then atmospherically distilled at 55°C to 65°C until a volume of approximately 146 mL was reached (14.6 vol, approximately 74 mL distillate). The solution was cooled to 45°C to 55°C over 15 minutes. Deionized water (10.5 vol) was then added to the solution at 45°C to 55°C over 30 minutes, resulting in a pale yellow suspension. The suspension was cooled to 20°C to 25°C over 2.5 hours and then stirred at 20°C to 25°C for 3 hours. The product was collected by filtration, and the filter cake was washed twice with acetone / water (2 vol each). The wet product was dried under vacuum at 68-72°C to give crystalline Form A of Compound (I) as a pale yellow solid (92% isolated yield).

[0299] Crystalline Form A of Compound (I) was confirmed by optical microscopy, XRPD, 13The compound (I) was analyzed by C NMR, DVS, DSC, and TGA. The XRPD data of crystalline form A of compound (I) is shown in Table 1. The powder X-ray diffraction pattern of crystalline form A of compound (I) is shown in Figure 2. The DSC thermogram and TGA thermal curve of crystalline form A of compound (I) are shown in Figure 3.

[0300] Example 2: Preparation of crystalline form B of compound (I)

[0301] Compound (I) was heated and held at 195° C. for 10 minutes, then cooled to room temperature, and the resulting solid was isolated by filtration.

[0302] Crystalline Form B of Compound (I) was identified by optical microscopy, XRPD, 13 The compound (I) crystalline form B was analyzed by C NMR, DSC, and TGA. The XRPD data of the compound (I) crystalline form B is shown in Table 2. The powder X-ray diffraction pattern of the compound (I) crystalline form B is shown in Figure 4. The DSC thermogram of the compound (I) crystalline form B is shown in Figure 5.

[0303] Example 3: Preparation of crystalline form C of compound (I)

[0304] Crystalline Form C was prepared by slurrying Compound (I) in methanol or 1:1 THF:water. The resulting solid was isolated by filtration.

[0305] Crystalline Form C of Compound (I) was confirmed by optical microscopy, XRPD, 13 The compound (I) was analyzed by C NMR, DVS, DSC, and TGA. The XRPD data of crystalline form C of compound (I) is shown in Table 3. The powder X-ray diffraction pattern of crystalline form C of compound (I) is shown in Figure 6.

[0306] Example 4: Preparation of crystalline form O of compound (I)

[0307] 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.

[0308] The crystalline form O of compound (I) was confirmed by optical microscopy, XRPD,13 The compound (I) was analyzed by C NMR, DSC, and TGA. The XRPD data of crystalline form O of compound (I) is shown in Table 4. The powder X-ray diffraction pattern of crystalline form O of compound (I) is shown in Figure 7.

[0309] Example 5: Preparation of crystalline form T of the tosylate salt of compound (I)

[0310] Compound (I) (169.7 mg) was weighed into a 4 mL vial equipped with a 10 mm stir bar. Toluenesulfonic acid (75.8 mg, 1.1 equiv.) was weighed into the same vial. 20 vol (3.39 mL) of IPA:HO (95:5 vol) was added to the vial. The sample was frozen, vortexed, and then stirred at room temperature for 5 min. The vial was transferred to a hot plate at 48-50 °C and stirred at 600 rpm. The sample went into solution and immediately precipitated as a thick slurry. After 10 min, the vial was transferred to a hot plate at 35-40 °C and stirred at 340 rpm for 1 h, followed by another hour at room temperature (340 rpm). The sample was filtered and washed twice with 2 vol (2 x 339 μL) of IPA:HO (95:5 vol) and placed under active vacuum at 50 °C to dry. 170.6 mg of salt was recovered.

[0311] The crystalline form T of the tosylate salt of Compound (I) was confirmed by optical microscopy, XRPD, 13 The water content was analyzed by C NMR, DSC, TGA, and Karl Fischer (KF) titration. The water content of crystalline Form T of the tosylate salt of Compound (I) was 1.7 wt%. The XRPD data of crystalline Form T of the tosylate salt of Compound (I) are shown in Table 5. The powder X-ray diffraction pattern of crystalline Form T of Compound (I) is shown in Figure 8.

[0312] Example 6: Preparation of Crystalline Form Tr of the Tartrate Salt of Compound (I)

[0313] Compound (I) (145.2 mg) was weighed into a 4 mL vial equipped with a 10 mm stir bar. Tartaric acid (50.3 mg, 1.1 equiv.) was weighed into the same vial. TFE (450 μL) was added. EtOH (250 μL) was also added because the solid did not dissolve. Upon stirring at room temperature, the slurry thinned slightly. Water (200 μL) was added to completely dissolve the solid, and the vial was allowed to stir (350 rpm) at room temperature overnight.

[0314] The next day, the solution was still clear. The cap was removed and the vial was placed on a hot plate at 35-40°C with gentle stirring (300 rpm) to allow for slow evaporation. After 3 hours, all solids had precipitated from solution, and the vial was placed under active vacuum at 50°C for 2 hours. 15 vol (2.18 mL) acetone was added to the vial, and the sample was heated to 45°C and stirred (400 rpm) for 1 hour. The temperature was reduced 5 degrees per hour and the sample was stirred at room temperature overnight. The sample was filtered, washed twice with 2 vol (2 x 290 μL) acetone, and dried under active vacuum at 50°C. 152.1 mg of salt was recovered.

[0315] The crystalline form Tr of the tartrate salt of Compound (I) was determined by optical microscopy, XRPD, 13 The water content was analyzed by C NMR, DVS, DSC, TGA, and Karl Fischer (KF) titration. The water content of crystalline Form Tr of the tartrate salt of Compound (I) was 6.4 wt%. The XRPD data of crystalline Form Tr of the tartrate salt of Compound (I) are shown in Table 6. The powder X-ray diffraction pattern of crystalline Form Tr of the tartrate salt of Compound (I) is shown in Figure 9.

[0316] Example 7: Preparation of crystalline form H of the hydrochloride salt of compound (I)

[0317] Compound (I) (154.0 mg) was weighed into a 4 mL vial equipped with a 10 mm stir bar. 564 μL (1.1 equivalents) of concentrated HCl solution in ethanol (5:95 vol) was added. The sample immediately became gummy, and the solid was slightly yellowish. TFE (450 μL) was added, and the vial was placed on a hot plate at 35°C to 40°C and stirred (340 rpm) for 30 minutes. After 15 minutes, the gum was broken down with a spatula. Since the sample was still gummy after 30 minutes, TFE (100 μL) was added, and the sample was vortexed to produce a flowable white slurry. The vial was transferred to a stir plate at room temperature, and the sample was stirred for an additional 45 minutes. The cap was removed from the vial, and the solution was allowed to slowly evaporate overnight.

[0318] The next morning, the solution was removed and the vial was returned to a 35-40°C hot plate for 2 hours, then placed under active vacuum in a 50°C oven for 2 hours. Once removed, the gummy solid in the vial was broken up with a spatula, and 15 vol (2.31 mL) acetone was added. The vial was placed on a 48°C hot plate and stirred (450 rpm) for 1 hour, then transferred to a room temperature hot plate (340 rpm) for an additional 2 hours. The sample was filtered, washed twice with 2 vol (2 x 308 μL) acetone, and placed under active vacuum at 50°C to dry. 138.4 mg of salt was recovered.

[0319] Crystalline Form H of the hydrochloride salt of Compound (I) was confirmed by optical microscopy, XRPD, 13 The water content was analyzed by C NMR, DVS, DSC, TGA, and Karl Fischer (KF) titration. The water content of crystalline Form Tr of the tartrate salt of Compound (I) was 3.9 wt%. The XRPD data of crystalline Form H of the hydrochloride salt of Compound (I) are shown in Table 7. The powder X-ray diffraction pattern of crystalline Form Tr of the tartrate salt of Compound (I) is shown in Figure 10.

[0320] Example 8: Solubility in Water and Simulated Fluids

[0321] Fasted simulated intestinal fluid (FaSSIF) (pH = 6.57) was prepared by dissolving NaOH pellets (0.105 g), NaH2PO4HO (0.9875 g), and NaCl (1.5475 g) in distilled water (225 mL) and adjusting the pH to 6.57 by adding 1 N NaOH solution and 1 N HCl. Water was then added to a volume of 250 mL to produce a phosphate buffer solution. Biorelevant powder (0.56 g) was dissolved in phosphate buffer (125 mL) and made up to 250 mL using phosphate buffer. The prepared solution was allowed to stand for 2 hours before being used for solubility measurements.

[0322] Fasting simulated gastric fluid (FaSSGF) (pH = 1.67) was prepared by dissolving 0.5 g of NaCl in 225 mL of distilled water. The pH was adjusted to 1.67 using 1 N HCl, and the solution was then made up to 250 mL using distilled water to create a NaCl / HCl solution. 0.015 g of biorelevant powder was dissolved in 125 mL of NaCl / HCl solution, and the solution was then made up to 250 mL using NaCl / HCl. The prepared solution was ready for use.

[0323] Crystalline Forms A and C of Compound (I)

[0324] The solubilities of crystalline form A and the mixture of crystalline form A and crystalline form C were measured in fasted simulated intestinal fluid (FaSSIF), fasted simulated gastric fluid (FaSSGF), and water at 37°C. The thin slurries were stirred overnight, and then the supernatants were 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. The solubilities were high 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. The solubility in water at approximately pH 7 was below the detection limit (BDL) for both crystalline form A and the mixture of crystalline form A and crystalline form C. The solubility data are summarized in Table 8 below.

[0325] Crystalline forms of salts of compound (I)

[0326] The solubilities of crystalline Form H of the hydrochloride salt of Compound (I), crystalline Form Tr of the tartrate salt of Compound (I), and crystalline Form T of the tosylate salt of Compound (I) were measured in fasting simulated intestinal fluid (FaSSIF), fasting simulated gastric fluid (FaSSGF), and water at 37°C. Approximately 1.5 mL of solution was stirred at 37°C. Salt was then added gradually until a thin slurry was formed, followed by stirring overnight. The solids were allowed to settle, and the pH of the supernatant was measured. The supernatant was collected and injected into HPLC, and the solids were collected for XRPD.

[0327] Solubility was determined based on interpolation from a calibration curve generated using the free base. The linear fit had an R of 0.999. 2 obtained.

[0328] The solubilities of crystalline Form H and crystalline Form Tr were higher in both FaSSIF and water compared to the free base. Solubility in FaSSGF was also higher, but further dilution of the sample was required. In FaSSIF, the solubility of crystalline Form Tr was greater than that of crystalline Form H (0.27 vs. 0.10 mg / mL). Crystalline Form Tr was gummed in FaSSIF.

[0329] Solids were collected from the slurries for analysis by XRPD. Crystalline form H was stable when slurried in all solutions. Crystalline form Tr was stable when slurried in water. Crystalline form Tr converted to crystalline form H upon slurrying in FaSSGF. The solubility data are summarized in Table 8 below. [Table 15]

[0330] Example 9: Preparation of Compound (I) 1 Step e: Preparation of tert-butyl (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylate

[0331] tert-Butyl 4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)piperazine-1-carboxylate (4.0 g, 1 eq), (S)-(-)-2-methyl-2-propanesulfinamide (1.88 g, 1.5 eq), Ti(OiPr)4 (4.6 mL, 1.5 eq), LiOH (0.06 g, 0.25 eq), and 2-MeTHF (32.0 mL, 8 vol) were combined and heated to 55 °C. The reaction was held for 3.5 h and then cooled to 23 °C. Brine solution (8.0 mL, 2 vol) was added. The mixture was stirred for 2–3 h and clarified by filtration through Celite. Additional brine washes (8.0 mL, 2 vol) were added, and the phases were separated. The organic phase was evaporated in vacuo and chased three times with 2-MeTHF (40 mL, 10 vol). 2-MeTHF (16 mL, 4 vol) was then added and the mixture was stirred at 22° C. while heptane (48 mL, 12 vol) was added. After 1 hour, the mixture was filtered to isolate the solid product, which was dried under vacuum for 16 hours (75% yield of tert-butyl (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylate).

[0332] Step f: Preparation of tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate 2-MeTHF (32 mL, 8 vol) was added to tert-butyl (S,Z)-4-(5-(((tert-butylsulfinyl)imino)-(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylate (4.0 g solid, 1 eq). The mixture was cooled to -7 °C, and MeMgCl (5.45 mL, 2.0 eq) was added. The mixture was stirred at -7 °C for 2 h. Methanol (4.0 mL, 1 vol) was added below 0 °C. The temperature was raised to 0-5 °C. NHCl solution (24 mL, 6 vol) was added, and the biphasic mixture was stirred at 20 °C. The organic phase was separated from the aqueous layer and then washed with water (12 mL, 2 vol). MeOH (140 mL) was then added, and the mixture was vacuum distilled while 2-MeTHF (250 mL) was added. Vacuum distillation and 2-MeTHF chases were continued three times, culminating in 38.0 g of a 10.5% w / w solution of tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate. The mixture was heated to 52°C and heptane (46 mL, 11.5 vol) was added, followed by seeds (4 mg, 0.1% w / w). After stirring at 52°C for 152 minutes, the mixture was slowly cooled to 22°C. The solid was filtered, washed with heptane (2 x 8 mL), and then dried under vacuum for 16 hours. The crude solid (tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate) (97.8-99.8% de) was purified according to the protocol immediately below.

[0333] Step g: Preparation of tert-butyl-4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)-ethyl)pyrimidin-2-yl)piperazine-1-carboxylate Crude tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)-ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (4.0 g) was suspended in heptane (78 mL, 19.5 vol) and MeOH (2.0 mL, 0.5 vol) and then heated to 57°C. After 2 hours, the mixture was cooled to 22°C and stirred for 1 hour. Filtration with heptane washes (2 x 2 vol) was performed, and the material was dried overnight in vacuo (35% yield of tert-butyl-4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)-ethyl)pyrimidin-2-yl)piperazine-1-carboxylate, >99.8% yield over two steps).

[0334] Step b: Preparation of 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol To a solution of 6-bromopyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (2.50 g, 1 eq) in NMP (15 mL, 6 vol) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.08 g, 2.5 eq). TBAB (0.15 g, 4 mol%), Pd(OAc) (0.026 g, 1 mol%), and DTBPF (0.055 g, 1 mol%) were added. The mixture was degassed and then poured into KPO (23.7 g, 6.0 eq) and water (7.5 mL, 3 vol). Finally, the reaction mixture was heated to 100 °C for 12 h. The reaction mixture was cooled to 20 °C, water (25 mL, 10 vol) was added, and the mixture was stirred at 20 °C for 20 min. The mixture was clarified by filtration, rinsing 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 stirred at this temperature for 2 hours. The product was isolated by filtration and the solid was washed with water (2 x 5 mL) followed by a 1:1 mixture of THF and IPA (2 x 5 mL). The solid was dried to give 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol in 80% yield.

[0335] Step c: Preparation of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine 6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (4.0 g, 1 eq) was suspended in toluene (40 mL, 10 vol) with DIPEA (3.9 mL, 1.2 eq). The mixture was heated to 75°C and POCl3 (3.8 mL, 2.2 eq) was added. The reaction was further heated to 105°C for 16 h. After the reaction was complete, the reaction was cooled to 22°C and K2HPO4 (32.5 g, 10 eq) and water (25.9 mL, 6.5 vol) were added. 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 vol. More heptane was added and the mixture was concentrated to 7 vol and stirred at 0-5 °C overnight. Filtration followed by heptane washing afforded a solid (78% yield of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine).

[0336] Step d: Preparation of (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine hydrochloride 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 mixture was The mixture was heated to 40° C. for 1 hour. After the reaction was complete, the mixture was cooled to 22° C. and MTBE (34 mL, 10 vol) was charged over 30 minutes. The mixture was filtered, washed with MTBE (3×10 mL, 3×3 vol), and dried under vacuum for 15 hours (97.0% yield of (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine hydrochloride).

[0337] 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)) 4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine (3.87 kg, 0.95 eq) was dissolved in DCM (138.1 kg, 20.0 vol), followed by the addition of (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine hydrochloride (7.4 kg, 1.0 eq) and DIPEA (10.0 kg, 4.5 eq). The reaction was heated at reflux for 12 hours. After reaction conversion was reached, the mixture was washed with brine (2 x 13% NaCl, 2 x 10 vol). After concentration to 3.7 volumes at atmospheric pressure, IPA (61.3 kg) was added and the mixture was further concentrated under vacuum to 14.5 volumes. The mixture was stirred below 25°C, then IPA (20.4 kg) was added again. After a further vacuum distillation to 14.5 volumes, another portion of IPA (20.4 kg) was added. The resulting mixture was cooled to 2-8°C and stirred for 1 hour. The solid product was isolated by filtration and washed with IPA (2 x 12.2 kg).

[0338] The crude solid was dissolved in a mixture of acetone (10.8 vol) and water (1.9 vol) at 50°C. Additional water (8.5 vol) was added over 30 minutes and the resulting suspension was cooled to 20°C over 1 hour and stirred at that temperature for 2.5 hours. The resulting solid was isolated by filtration and washed with a water / acetone mixture (1:1, 2 x 2 vol). The solid was dried to give Compound (I) as a solid (77% yield of Compound (I)).

[0339] Example 10: Preparation of Compound (I) 2 Step e: Preparation of tert-butyl (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylate

[0340] tert-Butyl 4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)piperazine-1-carboxylate (20.0 g, 1.0 eq), (S)-(-)-2-methyl-2-propanesulfinamide (9.43 g, 1.5 eq), and LiOH (0.64 g, 0.5 eq) were added to a reaction vessel along with toluene (160 mL). To this mixture, titanium(IV) isopropoxide (18.42 g, 1.25 eq) was added, and the reaction was stirred at 50-60 °C for 1 h. 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 monosodium citrate solution (80 mL, 30% w / w citric acid, pH 3-4). The mixture was stirred at 45-55 °C for 1.5 h, and then the phases were separated. The organic phase was washed with potassium bicarbonate (40 mL, 25% w / w aqueous solution), and 40 mL was removed by distillation. The product solution was diluted with tetrahydrofuran (30 mL) and then used directly in the next step as a solution (approximately 15% w / w tert-butyl (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylate).

[0341] Step f: Preparation by isolation of tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate Methylmagnesium 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 corresponds to 20 g of input material) at 10 °C over 2-3 h. The reaction mixture was stirred for 1.5 h to reach 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 of 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 of distillate. tert-Butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate at 50-60°C was charged with n-heptane (80 mL) and cooled to 42°C, at which point seeds were added (25-50 mg). The solution was held for 30 minutes and then cooled to 0-10°C for 30 minutes. The solid was isolated by filtration and washed with a 1:1 mixture of n-heptane and toluene (30 mL), followed by n-heptane (30 mL). The product was dried to give 9 g (40–45%) of crude tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (96.4–97.2% de).

[0342] Recrystallization of tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate 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, washing / rinsing with isopropanol (20 mL). The resulting solution was vacuum distilled at 40-60 °C to remove 60-70 mL of distillate. The mixture was diluted with water (45 mL) at 50-60 °C and then cooled to 40 °C, at which point it was seeded with 25-50 mg of ethanol. The mixture was further cooled to 20-25 °C, and water (20 mL) was added. The solid was isolated by filtration, washed with an isopropanol / water mixture (1:1, 20 mL), and then slurry washed with isopropanol / water (1:2, 30 mL). Drying afforded 8.5 g (85%) of the product: tert-butyl-4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (>99.8% de).

[0343] Step b: Preparation of 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol 6-Bromopyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (10.0 g) was charged to a reaction vessel, followed by N-methyl-2-pyrrolidone (40 mL). To this mixture was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24.4 g, 2.5 eq), palladium(II) acetate (0.22 g), and 1,1'-bis(di-tert-butylphosphino)ferrocene (0.44 g). The mixture was stirred for 15 minutes. Potassium phosphate (59.66 g in 66 mL of water) was added, and the reaction mixture was heated to 115°C for 2 hours. The reaction mixture was cooled to 80 °C, and N-acetyl-L-cysteine ​​(1.5 g) and Na2EDTA·2H2O (1.5 g) in water (100 mL) were added to the mixture. The resulting mixture was stirred at 45 °C for 1.5 h and then cooled to 20 °C. The organic layer was clarified and diluted with water (100 mL). Hydrochloric acid (10% w / w) was added to adjust the pH to 9.5. The organic solution was then heated to 75 °C and further adjusted to pH 6.9 with hydrochloric acid (10% w / w). The mixture was cooled to 20 °C and held for 1 h. The product was collected by filtration and washed twice with water / isopropanol (20 mL, 8:1 v / v) to give 8.2 g of dried product, 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol.

[0344] Step c: Preparation of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine 6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (15 g), DIPEA (10.36 g, 1.15 eq), toluene (90 mL), and benzyltriethylammonium chloride (3.97 g, 0.25 eq) were mixed. POCl3 (21.37 g, 2.0 eq) was added over 30 min. The mixture was then heated to 100 °C. The mixture was cooled to 80–90 °C and then quenched over 25 min with a mixture of K2HPO4 (2.4 g, 0.20 eq) in 50 mL of deionized water and THF (50 mL). During the quench at 40–60 °C, the pH was maintained between pH 7 and pH 9 by the addition of KOH (∼62 g, 50% aqueous, ∼8 eq). The resulting solution was then heated to 50-60°C, and stirring was continued for 30 minutes, after which the phases were separated. The organic phase was washed twice with 45 mL of deionized water at 50°C. After phase separation, the organic phase was vacuum distilled to 4 volumes at 60°C. The product precipitated as a yellow solid. Heptane (150 mL) was added, and the product was filtered and then washed with heptane (50 mL). After drying under reduced pressure, the product, 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine (12.7 g), was obtained as a yellow powder.

[0345] 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 at 45-55° C. for 1 hour in acetonitrile (40 mL) containing hydrochloric acid (33%, 8.14 g, 4.1 eq) to give tert-butyl-4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)-ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (2).

[0346] The mixture was cooled to 20-35 °C, then N,N-diisopropylethylamine (13.9 g, 6.0 eq) and 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine (4.0 g, 0.95 eq) were added, followed by methyl tert-butyl ether (20 mL) at 45-55 °C. The reaction mixture was stirred at 50-65 °C for 30 min. Water (95 mL) was added slowly over 1 h at 55-65 °C and IPC (pH 7.3-7.7) (adjusted with DIPEA or HCl as needed). The reaction mixture was cooled to 20-30 °C over 1 h and held at that temperature for 1 h. The product was filtered and washed (15 mL ACN displacement followed by 20 mL ACN slurry) to give 6.7 g of crude (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)).

[0347] (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)) (10.0 g) was dissolved in acetone (17.4 vol) and deionized water (3.2 vol, final ratio: acetone / water 85 / 15). The suspension was heated to 43-48 °C and stirred at this temperature for 15 min. A clear yellow solution was obtained. Subsequently, polishing filtration was carried out at 43-48 °C, and the filter was washed with acetone / water 85 / 15 (1 vol). The yellow solution was then atmospherically distilled at 57-62°C until a volume of approximately 146 mL was reached (14.6 volumes, approximately 74 mL distillate, final ratio: acetone / water 76 / 24). The solution was cooled to 48-53°C over 15 minutes. Deionized water (10.5 vol) was then added over 30 minutes at 48-53°C (final ratio: acetone / water 44 / 56). The pale yellow suspension was cooled to 20-25°C over 2.5 hours and stirred at 20-25°C for 3 hours. The product was recovered by filtration, and the filter cake was displacement washed twice with acetone / water 1 / 1 (2 vol each). The wet product was dried at 67-72°C and 35 mbar. Compound (I) was isolated as crystalline Form A as a pale yellow solid (92% of theory).

[0348] Example 11: Preparation of Compound (I) 3 Step e: Preparation of tert-butyl (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylate

[0349] tert-Butyl 4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)piperazine-1-carboxylate (500 g, 1 eq), (S)-(-)-2-methyl-2-propanesulfinamide (1.5 eq), Ti(OiPr)4 (2.0 eq), LiOH (0.5 eq), and toluene (4 L, 8 vol) were mixed and heated to 60 °C under partial vacuum to remove IPA. The reaction was held for 5 h and then cooled to 5-10 °C. Citrate solution (30%, 4 vol) was added. After decanting at 40 °C, a toluene extraction (1 vol) was performed. The combined organic phase was washed with aqueous NaHCO3. The solution of tert-butyl (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylate was used directly in the next step.

[0350] Step f: Preparation of tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate To a reaction solution of tert-butyl (S,Z)-4-(5-(((tert-butylsulfinyl)imino)-(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylate (solid 50 g, 1 equiv.) in toluene was added THF (4.2 vol). At −15° C. to −10° C., MeMgCl (22.5% in THF, 1.5 eq.) was added. The mixture was stirred at −10° C. to −15° C. for 1 h. Additional MeMgCl (22.5% in THF, 0.5 eq.) was added and the mixture was stirred at −10° C. to −15° C. for 5 h. At −10±5° C., methanol (0.26 vol.) was added. The temperature was allowed to rise 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 the aqueous layer and concentrated. AcOEt (2 vol) was added, and the solution was filtered through a pad of silica gel (50 g). The silica pad was eluted with ethyl acetate (6 x 3.6 vol), and the fractions were combined and concentrated to 1.65 vol. A 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 at 30-40 °C for 30 min, then cooled to 5 °C. The yellow precipitate was filtered and washed with heptane (2 x 1 vol). The solid was dried under vacuum (45.4% yield (94.4% de) of crude tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate).

[0351] Recrystallization of tert-butyl-4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)-ethyl)pyrimidin-2-yl)piperazine-1-carboxylate Crude tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate was dissolved in AcOEt (0.6 vol). To this was added heptane (0.3 vol) at reflux. Additional heptane (1.7 vol) was added over 32 minutes, followed by cooling to 20-25 °C overnight. Filtration with heptane washes (2 x 0.5 vol) was performed, and the material was dried overnight in vacuo (tert-butyl-4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)-ethyl)pyrimidin-2-yl)piperazine-1-carboxylate, 88.2% yield of 100% dextran).

[0352] Step b: Preparation of 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol To a solution of 6-bromopyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (50 g, 1 eq) in NMP (6 vol) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.5 eq). The mixture was degassed with nitrogen, and then TBAB (0.04 eq), Pd(OAc) (0.01 eq), and DPPF (0.01 eq) were added. The mixture was degassed again. Water (3 vol) was added in one portion, followed by the addition of KPO (6 eq). Finally, the reaction mixture was degassed again and heated to 100 ± 2 °C. After the reaction was complete, 10 volumes of water were added, and the suspension was stirred at 50 °C for 1 h. At 21 °C, the pH of the mixture was adjusted to 6.51 by the addition of HCl (6 N). After cooling to -10°C for 1 hour, the filter cake was washed with 3.6 volumes of water and filtered. The solid was triturated with 5 volumes of IPAc followed by filtration. Trituration with another 5 volumes of IPAc was followed by filtration again. Trituration with 5 volumes of IPAc was performed a third time, followed by filtration and a final trituration with 5 volumes of water. The solid product was washed with 5 volumes of water and dried under vacuum at 50°C (70% yield of 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol).

[0353] Step c: Preparation of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine 6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (180 g) was suspended in toluene (9.3 vol) with DIPEA (1.2 eq). To this mixture, POCl3 (2.0 eq) was added over 12 minutes at 70-80°C. The suspension was heated to 70-80°C. After the reaction was complete, the reaction mixture was added to a solution of K2HPO4 (13 eq) in water (11 vol) at a temperature below 30°C. The solid was filtered and washed with toluene and water. The filtrate was decanted, and the aqueous layer was extracted with DCM. The filtered solid was reslurried in DCM (10 vol). The organic layer was mixed with activated carbon (5%) and stirred. After charcoal filtration, the solution was concentrated to 2.4 vol. Heptane (7 vol) was added, and the mixture was concentrated to 2.4 vol. Additional heptane was added, and the mixture was concentrated to 7 volumes and stirred overnight at 0–5°C. Filtration followed by a heptane wash gave a crude solid. The wet solid was reslurried in water (7 vol) for 3.5 hours, then filtered and dried under vacuum (82.8% 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine).

[0354] Preparation of (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine hydrochloride tert-Butyl-4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)-ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (50 g, 1 eq) was mixed with ethanol (7.5 vol) and concentrated hydrochloric acid (11.2 M, 5.6 eq). The reaction was heated to reflux. After the reaction was complete, the mixture was concentrated to 5 volumes at atmospheric pressure. Ethanol was added to continue concentration, maintaining the concentration at 5 volumes until the water content was 3% or less. Concentration was stopped at 2 volumes, followed by cooling to 0-5°C over 30 minutes. Filtration and drying under vacuum gave the solid product ((S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine hydrochloride, 92.0% yield.

[0355] 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)) 4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine (5.0 g, 1 eq) was dissolved in DCM (17.6 vol), followed by the addition of (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine hydrochloride (1.05 eq) and butane-2,3-diol (5 wt%). DIPEA (4.5 eq) was added over 5 minutes at a temperature below 30°C. The reaction was heated at reflux for 5.5 hours. After reaching conversion, the mixture was washed with brine (2 x 8.9 vol of 2 x 22% NaCl), and the organic phase was treated with charcoal (10% CPW) for 2 hours. After concentration at atmospheric pressure to 3.7 volumes, IPA (26.8 vol) was added. After further concentration at atmospheric pressure to 18.3 vol, the mixture was cooled to 20-25°C. The mixture was stirred at 20-25°C for 1.5 hours, then filtered and washed with IPA (1.8 vol). The wet solid was dissolved in a mixture of acetone (23.2 vol) and water (4.1 vol) at reflux. Additional water (21.4 vol) was added at 45-55°C, and the resulting suspension was cooled to 15-25°C overnight. After cooling to 0-5°C for 1 hour, the mixture was filtered and washed with water (2 x 3.6 vol) and acetone (3.6 vol) to give compound (I) in 79.5% yield.

[0356] Example 12: Phase 1 dose escalation and expansion study of Compound (I) in advanced GIST Patients: Eligibility criteria for the phase 1 dose-escalation and expansion study included written informed consent, age 18 years or older, Eastern Cooperative Oncology Group performance status 2 or less, and adequate end-stage function. The dose-escalation portion of the study was open to patients with refractory solid tumors or unresectable GIST, but only GIST patients were enrolled. Patients with unresectable GIST with one or more measurable target lesions per modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST 1.1) were eligible for dose expansion in three cohorts: patients with PDGFRA D842V-mutant GIST regardless of prior therapy, patients who progressed after imatinib and one or more other kinase inhibitors, and patients who received imatinib alone.

[0357] Study Design: The primary endpoints of this Phase 1, open-label, dose-escalation / expansion study were the safety and tolerability of Compound (I) administered orally once daily and the overall response rate (ORR) in 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 a recommended Phase 2 dose (RP2D) below the MTD was determined. Intrapatient dose escalation was permitted, with additional increases permitted to dose levels previously determined to be tolerable. The Part 1 MTD was used to initiate Part 2 expansion. Treatment with Compound (I) continued until eliminated by toxicity, noncompliance, consent withdrawal, physician decision, progressive disease, death, or study termination.

[0358] Safety and response assessment: Adverse events were assessed at each visit from the start of study drug administration until 30 days after the last dose of Compound (I) and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. All patients underwent tumor imaging for response assessment by computed tomography (CT) or magnetic resonance imaging (MRI) at screening, every two cycles up to and including cycle 13, and every three months thereafter until progression or discontinuation. Target and non-target lesions were identified and evaluated according to mRECIST 1.1 for GIST by an independent, blinded central radiograph review (BioTelemetry, Inc., Rockville, MD, USA).

[0359] Pharmacokinetics: In Part 1, serial blood samples were collected pre-dose and at multiple time points during Cycle 4. Parameters were calculated from plasma concentration-time data using standard non-compartmental methods.

[0360] Statistical Methods: The MTD, defined as the highest dose level with dose-limiting toxicity in 6 or fewer patients in Cycle 1, was determined from all Part 1 patients who completed Cycle 1, received at least 75% of the prescribed dose, or experienced a dose-limiting toxicity (DLT) (dose-finding population). The efficacy population included patients with PDGFRα D842V-mutant GIST enrolled in Part 1 or Part 2 who received at least one dose of Compound (I), and who underwent central radiology evaluation of one or more target lesions and at least one post-baseline disease assessment. For the primary endpoint of partial or complete response, the sample size of 31 patients allowed 90% power to test the null hypothesis of an overall response rate of ≤10% against the alternative hypothesis of an objective response rate of ≥35%, assuming a two-sided type I error of 0.05. The Kaplan-Meier method was used to estimate duration of response, PFS, and OS, including median and 95% confidence intervals. Estimates of response duration, PFS, and OS rates at 3, 6, and 12 months were also calculated.

[0361] Results: Forty-six patients with PDGFRA-mutant (D842V, n=20; N659K, n=1; D842-H845, n=1; DI842-843V, n=1) or KIT-mutant GIST (n=23) were enrolled in Part 1 between October 2015 and January 2017, with a data cutoff of November 16, 2018. Based on early efficacy observations, enrichment enrollment was limited to patients with PDGFRA D842-mutant GIST. An additional 36 patients with PDGFRA D842V-mutant GIST were enrolled in Part 2, resulting in a total of 56 patients in the efficacy population (PDGFRA D842V-mutant GIST) and 82 patients in the safety population. In the D842V-mutant GIST population, the median age was 64 years, 41% were male, and 69% were white. The majority had metastatic disease (96.4%), at least one target lesion was 5 cm or larger (58.6%), and had prior treatment with one or more kinase inhibitors. Safety and baseline characteristics of the D842V population were generally similar, except for mutation status and median number of prior kinase inhibitors (2 vs. 1). Efficacy results for patients with KIT-mutant GIST will be reported separately.

[0362] Safety Profile: Patients enrolled in Part 1 (n=46) received Compound (I) at doses of 30 to 600 mg once daily. No dose-limiting toxicities were observed in Cycle 1 at doses of 30 to 400 mg per day. Two patients experienced dose-limiting toxicities in Cycle 1 at 600 mg (Patient 1: Grade 2 hypertension, acneiform dermatitis, and memory impairment; Patient 2: Grade 2 hyperbilirubinemia). Both patients experienced temporary dose interruptions and resumed treatment at 400 mg. Compound (I) at 400 mg was considered the maximum tolerated dose and selected as the starting dose for Part 2. The starting dose for Part 2 was subsequently reduced to 300 mg based on data demonstrating a lower incidence of Grade 3 cognitive AEs and a similar frequency of tumor responses when Compound (I) exposure achieved predicted therapeutic levels. Therefore, 300 mg of Compound (I) was considered the recommended Phase 2 dose and selected as the starting dose for the remainder of the study.

[0363] Most treatment-related adverse events were grade 1 or 2. At the 300 mg dose, the most common grade 1 / 2 events were nausea (69%), diarrhea (41%), decreased appetite (38%), and fatigue (38%); these were primarily grade 1 (19, 23%) and resulted in treatment discontinuation in only two patients (2%). Intracranial hemorrhage occurred in two patients. Both events were grade 3, were nonfatal, and resolved. At the 400 mg dose, the most common events were nausea (71%), vomiting (47%), fatigue (47%), and periorbital edema (47%). Grade 3 / 4 events occurred in 47 patients (57%), regardless of dose, with anemia being the most common (30%). Adverse events of particular interest included cognitive effects and intracranial hemorrhage. Cognitive effects occurred in 33 (40%) patients and included memory impairment (n=25, 30%), cognitive impairment (8, 10%), confusional state (7, 9%), and encephalopathy (2, 2%). Cognition improved or resolved after treatment discontinuation.

[0364] A total of 69 (84%) patients required at least one dose reduction or treatment interruption, but the median daily dose intensity of 267 mg for the 84 patients who started at 300 mg remained high.

[0365] Of the 82 patients enrolled, 44 (54%) discontinued treatment. The most common reasons for discontinuation were disease progression (59%) and adverse events (34%), of which 12% were considered related to Compound (I). There were no treatment-related deaths. In the PDGFRA D842V population, 19 / 56 (34%) discontinued treatment. The most common reasons for discontinuation were disease progression (21%) and adverse events (63%), of which 14% were considered related to Compound (I). At the time of data cutoff, 46% of all patients and 66% of the PDGFRA D842V population remained on treatment.

[0366] Efficacy: Across all dose levels, 56 patients with PDGFRA D842V-mutant GIST were evaluable for response. Confirmed responses per median radiological mRECIST 1.1 assessment 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 response: 7 / 56 [12.5%]) (Figure 11, Table 9). The clinical benefit rate (CBR), defined as the proportion of patients achieving a confirmed complete response (CR) or persistent response (PR) lasting at least 16 weeks from the start of treatment, was 95%. Among patients (n=28) who initiated treatment at the recommended 300 mg dose, the overall response rate was higher at 93% (95% CI: 76.5, 99.1). The median duration of response was not reached, with a 12-month response duration of 70%. The median progression-free survival (PFS) was not reached, with progression-free survival rates at 3, 6, and 12 months being 100%, 94%, and 90%, respectively. OS was estimated at 6, 12, and 24 months, respectively, with a median follow-up of 15.9 months (95% CI: 54, 87%). [Table 16]

[0367] Part 1 enrolled three patients with other PDGFRA mutations: one with the exon 14 N659K mutation and two with other exon 18 activation loop mutations (D842-H845, n=1; DI 842-843V, n=1). Both patients with activation loop mutations responded, but the patient with the N659K mutation progressed.

[0368] Example 13: ISM and SSM studies of compound (I) This is a Phase 2, randomized, double-blind, placebo-controlled study comparing the efficacy and safety of Compound (I) plus best supportive care (BSC) with placebo plus BSC in patients with ISM and SSM whose symptoms are not adequately controlled by BSC. The study will be conducted in three parts. In Part 1, the optimal dose of Compound (I) (recommended Phase 2 dose (RP2D)) will be identified in patients with ISM. In Part 2, patients with ISM and SSM will be randomly assigned to the RP2D of Compound (I) identified in Part 1 plus BSC or a matching placebo plus BSC. In Part 3, patients who completed treatment in Part 1 or Part 2 of the study will participate in a long-term extension and will receive Compound (I) at the RP2D plus BSC.

[0369] In Part 1, immediately after informed consent was obtained, SM symptom management was optimized and, if necessary, BSC medication dose and SM symptom management schedule were stabilized over a 4-week period. Data collection on the ISM-SAF (ISM Symptom Assessment Form) began within 5 days of informed consent being obtained. The number of anaphylactic episodes treated with epinephrine and all concomitant medications received for the indicated indication were collected from the time of informed consent.

[0370] Once BSC was optimized (between day -98 and day -71) and the dose was stable for at least 14 days, ISM-SAF data were collected for an additional 14 days to determine eligibility based on symptom severity, i.e., to identify ISM and SSM patients with moderate to severe symptoms. Patients who did not meet the symptom severity threshold were considered screening dropouts and were ineligible for study participation. Patients with moderate to severe symptoms and who met the symptom severity threshold underwent bone marrow (BM) biopsies (archived or new samples obtained within the past 24 weeks) and skin biopsies of lesional and non-lesional skin (patients with cutaneous mastocytosis (CM)) to confirm the SM diagnosis and quantify mast cells (MCs). Patients with CM (maculopapular rash) underwent skin photography. Additional procedures included brain magnetic resonance imaging / computed tomography scans, bone mineral density measurements, serum tryptase and KIT D816 mutation testing, routine laboratory tests, electrocardiograms, and physical examinations. All procedures will be completed within 6 weeks before the start of collection of the last 14 days of baseline ISM-SAF symptoms.

[0371] Once the screening procedures were completed, patients collected ISM-SAF data for an additional 2 weeks (14 days) to establish a baseline score, after which patients who met all eligibility requirements were randomly assigned to treatment and began dosing.

[0372] Part 1 In Part 1 of the study, approximately 40 patients were randomly assigned to one of three doses of Compound (I) or placebo. Each dose level cohort and placebo group in Part 1 consisted of 10 patients. Three dose levels of Compound (I): 25 mg, 50 mg, and 100 mg were tested in parallel. Patients, study staff, and sponsors were blinded to treatment assignments.

[0373] Compound (I) was administered orally once daily for 28 consecutive days. Patients were evaluated weekly for the first 4 weeks and then every 4 weeks (until the RP2D was determined) for safety, laboratory monitoring, and quality of life (QoL) assessments. Intensive pharmacokinetic (PK) sampling was performed in all patients. ISM-SAF was completed once daily. After completing 12 weeks of treatment, BM and skin biopsies were repeated for quantification of MC, and patients' skin was photographed at baseline CM.

[0374] The RP2D was determined based on efficacy, safety, and PK at each dose level. The primary efficacy assessment was symptom improvement using the ISM-SAF. The primary criterion for selecting the RP2D was the dose of Compound (I) that resulted in the greatest reduction in Total Symptom Score (TSS) as assessed using the ISM-SAF at Week 12 compared to baseline (Day 1 vs. Day 14). Other measures of efficacy (e.g., change in serum tryptase) were also considered. Once the Week 12 assessment was completed, patients continued on their assigned treatment and dose until the RP2D was determined. At that time, they rolled over to Part 3 of the study and received the RP2D of Compound (I).

[0375] For each dose level of Compound (I) or placebo, the mean change in TSS was calculated as the arithmetic mean of the change in TSS in the intent-to-treat (ITT) population. Each patient's baseline TSS was defined as the 14-day mean of TSS from C1D-14 to C1D-1. Each patient's TSS on Day 1 of Cycle 4 was defined as the 14-day mean of TSS from C3D15 to C3D28. For each patient, the change in TSS was calculated as follows: (C4D1 TSS - baseline TSS). If a patient missed TSS for more than 7 days between C1D-14 and C1D-1, the baseline TSS was considered unknown for that patient. If a patient missed TSS for more than 7 days between C3D15 and C3D28, the C4D1 TSS was considered unknown for that patient.

[0376] Part 2 The screening procedures for Part 1 described above will be used for Part 2. Approximately 72 patients are enrolled in Part 2 of the study. Patients will be randomly assigned to receive Compound (I) or matching placebo + BSC at RP2D + BSC. Patients assigned to placebo in Part 2 will receive Compound (I) upon rollover to Part 3. Patients, study staff, and sponsors will be blinded to treatment assignment.

[0377] Compound (I) and placebo will be administered orally once daily in 28 consecutive day cycles. Compound (I) will be administered orally at 25 mg once daily. Patients will be evaluated weekly for the first 4 weeks, then every 4 weeks until Week 12 for safety, laboratory monitoring, and QoL assessments. Sparse PK sampling will be performed in all patients. ISM-SAF will be completed once daily. After 12 weeks of treatment and completion of ISM-SAF, 7 days a week throughout the 12 weeks, BM and skin biopsies will be repeated for MC quantification by the Central Pathology Laboratory, and skin photographs will be taken of patients at baseline CM. Upon completion of all Week 12 assessments, patients will roll over to Part 3, the long-term extension. After all patients have rolled over to Part 3, the primary endpoint of mean change in ISM-SAF TSS from baseline to Week 12 and other efficacy endpoints will be analyzed.

[0378] The primary efficacy endpoint for Part 2 is the mean change in ISM-SAF TSS from baseline to Cycle 4 Day 1 (C4D1). Analysis of mean change in TSS will be performed primarily using the intention-to-treat population, with the per-protocol population as a sensitivity analysis. The mean change in TSS will be calculated as the arithmetic mean of the change in TSS for each treatment group. Compound (I) will be compared with placebo using a two-sample t-test.

[0379] Part 3 Patients who complete Part 1 will roll over to Part 3 of the study, where all patients will receive treatment with Compound (I) + BSC at 25 mg QD. Similarly, patients who complete all study assessments at Week 12 of Part 2 will roll over to Part 3 of the study and receive treatment with Compound (I) + BSC at 25 mg QD. All patients will have study visits weekly for 4 weeks, then every 4 weeks for 5 months, and then every 3 months thereafter, for a total of 2 years, starting from Cycle 1 Day 1 (C1D1). Patients still on the study after 2 years will return to the study every 6 months (24 weeks) for a total study period of 5 years, including Parts 1 and 2. The ISM-SAF will be completed daily, and QoL assessments will be performed through Week 52. Patients who develop maculopapular CM (cutaneous mastocytosis) at baseline in Part 1 or Part 2 will have skin photographs taken at baseline in Part 3 (if not obtained within the past 4 weeks of Part 1 or Part 2) and at Weeks 12, 24, 36, and 52. Optional BM and skin biopsies will be repeated at Week 52 for mast cell (MC) quantification by the Central Pathology Laboratory. Week 12 study assessments of 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 past 4 weeks. Procedures required at baseline for Part 3 and not performed in Part 1 or Part 2 within 4 weeks of Day 1 of Part 3 will be performed on Day 1 of Part 3. Patients who elect not to continue Compound (I) will have an end-of-treatment visit 14 days after the last dose of study treatment. Patients may continue Compound (I) for up to 5 years until unacceptable toxicity, death, or patient withdrawal.

[0380] In Part 1, patients received treatment for 12 weeks, then continued their assigned treatment until the RP2D of 25 mg QD was determined. In Part 2, patients received treatment for up to 12 weeks. In Part 3, patients received treatment for up to 5 years, including Parts 1 and 2.

[0381] In Part 1, the minimum duration of patient participation was approximately 26 weeks. In Part 2, the minimum duration of patient participation was approximately 26 weeks. In Part 3, the minimum duration of patient participation was approximately 8 weeks.

[0382] For Part 1, the expected enrollment period was approximately 6 months, and the expected duration of this part of the study was approximately 15 months. For Part 2, the expected enrollment period was approximately 9 months, and the expected duration of this part of the study was approximately 18 months. The expected duration of Part 3 is approximately 5 years (including Parts 1 and 2).

[0383] Part 1 Results Results from the Phase 2 PIONEER study of Compound (I) in patients with indolent systemic mastocytosis (SM) demonstrate significant clinical improvement versus placebo, including significant benefits across all symptoms evaluated. In Part 1 of the PIONEER study, patients treated with 25 mg of Compound (I) once daily (QD) demonstrated improved clinical outcomes from baseline to 16 weeks, demonstrating a mean 31% reduction in the Total Symptom Score (TSS) as measured by the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) and Time-Deepening Activity. Furthermore, patients treated with 25 mg QD demonstrated significant reductions in objective measures of mast cell burden and improved patient-reported quality of life. Compound (I) demonstrated a favorable safety profile supporting chronic administration of ISM, with all adverse events (AEs) reported in the 25 mg QD dose cohort being Grade 1 or 2. Based on complete data from Part 1, 25 mg QD has been selected as the recommended Part 2 dose (RP2D).

[0384] 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 included adults with ISM confirmed by central pathology review of bone marrow biopsy results (per WHO criteria) and moderate to severe symptom burden despite best supportive care medication. Overall, 39 patients were enrolled in Part 1 across four concurrent cohorts, each consisting of 10 patients in a Compound (I) dose cohort and 9 patients in a placebo cohort.

[0385] Patient-reported outcome data were collected using the ISM-SAF, designed with input from disease experts, patients, and regulatory authorities as a measure of clinical benefit to support enrollment. The ISM-SAF assesses symptoms in the cutaneous domain (plaque, pruritus, flushing) and gastrointestinal domain (abdominal pain, diarrhea, nausea), as well as other major symptoms affecting ISM patients (brain fog, headache, dizziness, bone pain, and fatigue). All results are current as of the data cutoff date of December 27, 2019.

[0386] The complete data from Part 1 demonstrate potent clinical activity and a well-tolerated safety profile of Compound (I) at 25 mg QD. Based on these results, 25 mg QD was selected as the optimal dose for further evaluation in the chronic treatment of ISM.

[0387] Baseline patient characteristics

[0388] Patients had a high symptom burden at baseline, with a mean ISM-SAF TSS of 53. Eight patients (21%) had a mean ECOG performance status of 2, reflecting an inability to perform work activities. Patients received a median of 4 best supportive care medications (range, 2-9) at baseline. The median serum tryptase level was 45 μg per liter (the upper limit of normal is 11.4 μg per liter). A high-sensitivity polymerase chain reaction assay of peripheral blood detected the KIT D816V mutation in 37 patients (95%).

[0389] Clinical activity data

[0390] Compound (I) demonstrated clinically meaningful benefits across all measures of mast cell burden, patient-reported symptoms, and quality of life. The consistency of results across multiple measures of disease supports the broad potential of Compound (I) in ISM.

[0391] Patients in the Compound (I) 25 mg QD dose cohort demonstrated significant reductions in mast cell burden based on assessment of serum tryptase, bone marrow mast cells, and KIT D816V allele burden. See Figures 12-13.

[0392] Compound (I) demonstrated clinically meaningful reductions in ISM-SAF TSS, as well as in the gastrointestinal domain, cutaneous domain, and individual symptoms tested. Improvements continued to deepen over 16 weeks and may further decrease with additional patient follow-up. Patients in the 25 mg QD dose cohort of Compound (I) demonstrated a similar reduction in mean symptom burden as the 50 mg QD and 100 mg QD dose cohorts at 16 weeks. See Figures 14A-14C. As of the data cutoff date, 37 patients (95%) remained on study, with a median follow-up of 18 weeks (range: 1-36 weeks). [Table 17]

[0393] At 16 weeks, patients experienced a statistically significant reduction in ISM-SAF TSS (p=0.001), with a mean improvement of approximately 30% across all Compound (I) dose cohorts compared to approximately 3% in the placebo cohort (p=0.001).

[0394] Data from the Mastocytosis Quality of Life (MC-QoL) questionnaire, a commonly used patient-reported outcome tool for mast cell disorders, demonstrated an improvement in quality of life in patients receiving Compound (I), substantiating the clinical benefit observed in the ISM-SAF. At week 16, seven patients in the Compound (I) 25 mg QD cohort and six patients in the placebo cohort completed the MC-QoL questionnaire. Patients in the 25 mg QD dose cohort experienced a mean 34% reduction in total MC-QoL score, with improvements in all four domains assessed (symptoms, social functioning, emotion, and skin). A 7% increase from baseline was observed in the placebo cohort.

[0395] Safety Data

[0396] As shown in the table below, Compound (I) demonstrated a favorable safety profile supporting chronic administration in ISM. Patients treated with Compound (I) in the 25 mg QD dose cohort had no serious AEs, Grade 3 or higher AEs, or dose modifications. In the placebo cohort, two patients (22%) had at least one Grade 3 AE, and two patients (22%) 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. [Table 18] Example 14: Process for purifying compound (I) [ka]

[0397] Purification of compound (I) and its undesired enantiomer (compound (E)) is difficult. For example, recrystallization of compound (I) in acetone and water does not remove compound (E). Several acids had to be investigated to find a process for removing the undesired enantiomer. The studies summarized in Table 10 were each conducted on a 500 mg scale, and D-quinic acid was determined to be the best acid for purifying compound (I). [Table 19]

[0398] Specifically, to a suspension of Compound (I) (25.0 g, 1 equivalent) and 5% Compound (E) in tetrahydrofuran (375 mL) was added D-quinic acid (1.5 equivalents). The suspension was refluxed for 1 hour, water was added (5.5 equivalents), and the mixture was cooled to 15-25°C. The solid was isolated by filtration and washed with tetrahydrofuran (2 x 50 mL). If necessary, the enantiomeric excess can be improved by repeated recrystallization in THF and water.

[0399] The isolated solid quinate salt of Compound (I) was suspended in dichloromethane (250 mL) and water (125 mL) and NaOH (6.0 equiv.) were added. The organic layer was separated and washed with water (2 x 150 mL). Acetone was used to displace the dichloromethane final product in a distillation with a target volume of 5 mL / g of Compound (I). Crude Compound (I) was isolated by filtration free of the undesired enantiomer and recrystallized using acetone and water as described in Example 9 (step a). Compound (I) was isolated in approximately 65% ​​yield with no detectable quinic acid and less than 0.55% w / w of the enantiomer (Compound (E)).

Claims

1. Compound (I) is characterized by a powder X-ray diffraction pattern comprising at least three peaks selected from 11.5±0.2, 15.4±0.2, 16.7±0.2, 20.0±0.2, and 21.6±0.2 in 2θ angles, or alternatively, by a powder X-ray diffraction pattern comprising at least seven peaks selected 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 in 2θ angles. 【Chemical 1】 Crystals.

2. 2. The crystal of compound (I) according to claim 1, characterized by a powder X-ray diffraction pattern comprising at least eight peaks selected 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 in 2θ angles.

3. 2. The crystal of compound (I) according to claim 1, characterized by a powder X-ray diffraction pattern comprising peaks at 2θ angles 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.

4. 2. The crystal of compound (I) according to claim 1, characterized by a powder X-ray diffraction pattern comprising peaks at 2θ angles of 11.5±0.2, 15.4±0.2, 16.7±0.2, 20.0±0.2, and 21.6±0.

2.

5. A crystal of compound (I) according to any one of claims 1 to 4, characterized by a DSC thermogram having an endothermic event with a signal at a temperature in the range of 194°C to 195°C or with an onset temperature of 193°C.

6. A method for preparing the crystals of compound (I) according to any one of claims 1 to 5, comprising dissolving compound (I) in a mixture of acetone and water to obtain a suspension; 【Chemistry 2】 heating the suspension to a temperature in the range of 40°C to 50°C to obtain a solution; and cooling the solution. method.

7. at least one pharmaceutically acceptable excipient; A pharmaceutical composition comprising a crystal of compound (I) according to any one of claims 1 to 5.

8. A pharmaceutical composition comprising a crystal of compound (I) according to any one of claims 1 to 5 for treating mastocytosis.

9. The pharmaceutical composition of claim 8, wherein the mastocytosis is selected from cutaneous mastocytosis (CM) and systemic mastocytosis (SM).

10. 10. The pharmaceutical composition of claim 9, wherein the systemic mastocytosis is selected from indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), and advanced systemic mastocytosis (AdvSM).

11. 11. The pharmaceutical composition of claim 10, wherein the systemic mastocytosis is advanced systemic mastocytosis (AdvSM), and optionally, the crystals of compound (I) are administered once daily in a therapeutically effective amount of 200 mg.

12. 11. The pharmaceutical composition of claim 10, wherein the systemic mastocytosis is indolent systemic mastocytosis (ISM) or smoldering systemic mastocytosis (SSM), and optionally, the crystals of compound (I) are administered once a day in a therapeutically effective amount of 25 mg.

13. A pharmaceutical composition for treating gastrointestinal stromal tumors, comprising the crystal of compound (I) according to any one of claims 1 to 5, wherein optionally the crystal of compound (I) is administered once a day in a therapeutically effective amount of 300 mg.

14. The pharmaceutical composition of claim 13 , wherein the gastrointestinal stromal tumor is characterized by an exon 18 mutation in PDGFRα.

15. A pharmaceutical composition for treating acute myeloid leukemia, comprising a crystal of compound (I) according to any one of claims 1 to 5.

16. A pharmaceutical composition comprising a crystal of compound (I) according to any one of claims 1 to 5 for treating painless systemic mastocytosis.

Images