Crystalline form of compound (I)

Abstract

The crystalline forms of compound (I) are disclosed, as well as pharmaceutically acceptable salts thereof and solvates of any of the foregoing substances. Pharmaceutical compositions comprising these compounds, methods of using them to treat conditions and symptoms associated with oncogenic KIT and PDGFRA alterations, and methods for preparing compound (I) and its crystalline forms are also disclosed.

Description

[0001] This application claims priority to U.S. Provisional Application No. 62 / 990,269, filed on March 16, 2020; U.S. Provisional Application No. 62 / 844,575, filed on May 7, 2019; and U.S. Provisional Application No. 62 / 833,527, filed on April 12, 2019. The entire contents of each of the foregoing applications are incorporated herein by reference.

[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)piperazinyl)pyrimidin-5-yl)ethane-1-amine (Compound (I)), pharmaceutically acceptable salts thereof, and solvates of any of the aforementioned compositions comprising the same, methods of use thereof, and methods for preparing Compound (I), including crystalline forms thereof. The crystalline form of Compound (I) can be a selective inhibitor of KIT, including exon 17 mutants and / or PDGFRα exon 18 mutant proteins.

[0003] The enzyme KIT (also known as CD117) is a receptor tyrosine kinase expressed on a variety of 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 of KIT is stem cell factor (SCF). Typically, stem cell factor (SCF) binds to and activates KIT by inducing dimerization, autophosphorylation and initiation of downstream signaling. However, in several tumor types, somatic activating mutations in KIT drive ligand-independent constitutive activity.

[0004] KIT mutations usually occur in the DNA encoding the juxtamembrane domain (exon 11). KIT mutations also occur at lower frequencies in exons 7, 8, 9, 13, 14, 17, and 18. Mutations render KIT function independent of activation by SCF, leading to high cell division rates and possible genomic instability. Mutant KIT is implicated in the pathogenesis of several disorders and conditions (e.g., mastocytosis, gastrointestinal stromal tumors (GIST), acute myeloid leukemia (AML), melanoma, and seminoma).

[0005] The structurally related platelet-derived growth factor receptor (PDGFR) is a cell surface tyrosine kinase receptor of a member of the platelet-derived growth factor (PDGF) family. PDGF subunits-α and -β regulate cell proliferation, cell differentiation, cell growth and cell development. Changes (e.g., mutations) in PDGF subunits-α and -β are associated with many diseases, including some cancers. For example, exon 18 PDGFRαD842V mutations have been found in different subsets of GIST, usually from the stomach. The D842V mutation is also associated with resistance to tyrosine kinase inhibitors. In addition, other exon 18 mutations (such as PDGFRαD842I and PDGFRαD842Y) are associated with ligand-independent, constitutive activation of PDGFRα. In GIST, an increase in functional mutations (e.g., PDGFRαD842I, D842V, and D842Y) that confer ligand-independent constitutive activation of PDGFRα signaling has been identified as a driver of the disease.

[0006] Compound (I), its pharmaceutically acceptable salts and solvates of any of the foregoing substances can inhibit KIT and / or PDGFRα and can be used to treat mast cell disorders (such as mastocytosis), as well as 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:

[0007]

[0008] The procedure for producing compound (I) described in WO 2015 / 057873 uses chiral supercritical fluid chromatography (SFC) in the last step to separate the enantiomers. In general, chromatographic separation is not desirable for large-scale manufacturing processes. In addition, in the case of compound (I) obtained by the procedure described in WO 2015 / 057873, the enantiomers are separated by a chiral supercritical fluid chromatography (SFC). 1 Trace impurities were observed in H NMR.

[0009] Crystalline forms of biologically active compounds (such as Compound (I)), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing are of interest in the pharmaceutical industry, where crystalline forms may be desirable or even required for drug development. Crystalline forms occur when the same composition of matter crystallizes in different lattice arrangements, resulting in different thermodynamic properties and stability specific to each crystalline form. Each unique crystalline form is referred to 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 one another with respect to at least one physical, chemical, and / or pharmaceutical property (e.g., solubility, dissociation, true density, solubility, melting point, crystal habit or morphology, compaction behavior, particle size, flow properties, and / or solid state stability).

[0010] The solid state form of a biologically active compound generally determines its ease of preparation, ease of separation, 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 in a large-scale manufacturing process, the crystalline form may change during manufacturing and / or storage, resulting in quality control problems and formulation irregularities. Unstable crystalline forms may affect the development of drugs for human use. Therefore, any changes in the solid state of a biologically active compound that improves its physical or chemical stability can confer significant advantages over a less stable form of the same compound.

[0011] Furthermore, it is essential that the crystalline form used as an active pharmaceutical ingredient (API) in a therapeutic composition is substantially pure. Specifically, a substantially pure crystalline form is free of reaction impurities, raw materials, reagents, by-products, unwanted solvents and / or other processing impurities resulting from the preparation and / or isolation and / or purification of a particular crystalline form.

[0012] It is not possible to predict whether a particular compound, salt or hydrate of a compound will form a crystalline form, how many different crystalline forms there will be, whether any such crystalline form will be suitable for commercial use in a pharmaceutical composition, or which crystalline form or forms will exhibit the desired properties. Because different crystalline forms may have different properties, reproducible methods (including large-scale manufacturing methods) for producing substantially pure crystalline forms (i.e., not mixtures of crystalline forms) are also desirable for biologically active compounds intended for use as medicines.

[0013] Therefore, there is a need for new crystalline forms, such as 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 mutant / oncogenic KIT and PDGFRA alterations.

[0014] Disclosed herein are novel crystalline forms of compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing substances, compositions comprising the same, and methods of use and preparation thereof. Importantly, the crystalline forms of compound (I) for pharmaceutical use are substantially free of impurities. In some embodiments, the novel crystalline forms disclosed herein have properties that can be used for large-scale manufacturing, pharmaceutical preparations, and / or storage. In some embodiments, the novel crystalline forms disclosed herein consist of one crystalline form. The crystalline form is substantially pure. Also disclosed herein is a novel method for preparing compound (I).

[0015] Some embodiments of the present disclosure relate to a pharmaceutical composition comprising: a pharmaceutically acceptable excipient; and at least one crystalline form selected from a crystalline form of compound (I), a pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing substances. In some embodiments, the at least one crystalline form is crystalline form A of compound (I). In some embodiments, the at least one crystalline form is crystalline form B of compound (I). In some embodiments, the at least one crystalline form is crystalline form C of compound (I). In some embodiments, the at least one crystalline form is crystalline form O of compound (I). In some embodiments, the at least one crystalline form is crystalline form T of a toluenesulfonate salt of compound (I). In some embodiments, the at least one crystalline form is crystalline form Tr of a tartrate salt of compound (I). In some embodiments, the at least one crystalline form is crystalline form H of a hydrochloride salt of compound (I).

[0016] Some embodiments of the present disclosure relate to a method for treating a patient in need of a KIT or PDGFRα inhibitor by administering a therapeutically effective amount of at least one crystalline form, the at least one crystalline form being selected from a crystalline form of compound (I), a pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing. In some embodiments, the at least one crystalline form is crystalline form A of compound (I). In some embodiments, the at least one crystalline form is crystalline form B of compound (I). In some embodiments, the at least one crystalline form is crystalline form C of compound (I). In some embodiments, the at least one crystalline form is crystalline form O of compound (I). In some embodiments, the at least one crystalline form is crystalline form T of a tosylate salt of compound (I). In some embodiments, the at least one crystalline form is crystalline form Tr of a tartrate salt of compound (I). In some embodiments, the at least one crystalline form is crystalline form H of a hydrochloride salt of compound (I).

[0017] In some embodiments, the patient in need of a KIT or PDGFRα inhibitor has a disorder or condition associated with at least one oncogenic KIT and / or PDGFRA alteration. In some embodiments, the patient in need of a KIT or PDGFRα inhibitor has an unresectable or metastatic GIST that is positive for PDGFRA exon 18. 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.

[0018] In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is a non-D842 alteration in exon 18 of PDGFRα. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is an indel in the PDGFRA protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is D842-H845 in the PDGFRA protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is DI842-843V in the PDGFRA protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRA alteration is a genetic mutation in exon 17 of KIT. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is d557-558 in the KIT protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is V560G in the KIT protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is V560G / D816V in KIT protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is V560G / N822K in KIT protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is a D816 mutation in KIT protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is a D816V mutation in KIT protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is D816E in KIT protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is D816F in KIT protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is D816H in KIT protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is D816I in KIT protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is D816Y in KIT protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is D820E in KIT protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is D820Y in KIT protein. In some embodiments, the at least one oncogenic KIT and / or PDGFRα alteration is Y823D in KIT protein. In some embodiments, the disorder or condition associated with at least one oncogenic KIT and / or PDGFRA alteration is gastrointestinal stromal tumor (GIST). In some embodiments, the patient is refractory to treatment with imatinib.In some embodiments, the patient has been treated with at least 3 prior lines of therapy. In some embodiments, the patient is refractory to treatment with imatinib, sunitinib, and / or regorafenib. 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.

[0019] In some embodiments, the disorder or condition associated with at least one mutant / oncogenic KIT and / or PDGFRA alteration is mastocytosis. In some embodiments, mastocytosis is selected from cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In some embodiments, 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 with related hematological non-mast cell lineage diseases (SM-AHNMD) and mast cell leukemia (MCL). In some embodiments, systemic mastocytosis is indolent systemic mastocytosis (ISM). In some embodiments, systemic mastocytosis is advanced systemic mastocytosis (AdvSM). In some embodiments, systemic mastocytosis is smoldering systemic mastocytosis (SSM). In some embodiments, systemic mastocytosis is aggressive systemic mastocytosis (ASM). In some embodiments, systemic mastocytosis is SM with associated hematological non-mast cell lineage disease (SM-AHNMD). In some embodiments, systemic mastocytosis is mast cell leukemia (MCL).

[0020] Disclosed herein are improved methods for treating indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM) in patients using compound (I). In some embodiments, the disclosure provides a dosing regimen of compound (I) for treating ISM and SSM. More specifically, the disclosure provides a method for treating ISM and SSM in patients who are identified as having moderate to severe symptoms based on the minimum mean total symptom score (TSS) as accessed by the Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-ASF) by administering compound (I) once daily at a dose of 10 to 100 mg.

[0021] There are no approved treatments for ISM and SSM. Symptoms are managed with symptom-directed therapies, such as antihistamines. Therefore, safe, effective treatments for ISM and SSM are needed. In addition, because patients with ISM and SSM have a lower disease burden than patients with AdvSM and are expected to be on treatment long-term, a lower dose (if effective) is desirable.

[0022] Compound (I) (AYVAKIT TM The FDA-approved dose of 250mg or afatinib is 300mg oral QD. A Phase 2 clinical trial is currently evaluating the efficacy and safety of a compound (I) dose of 200-300mg oral QD in patients with advanced systemic mastocytosis (AdvSM). According to the latest clinical studies shown in the embodiments provided herein, it has now been found that a compound (I) of 25mg administered once a day in patients with ISM or SSM shows improvements in all three aspects of its clinical characteristics, including reduction of mast cell load, improvement of symptoms of the disease, and improvement of quality of life. Specifically, a compound (I) of 25mg administered once a day has statistically significant reductions in each symptom in the ISM-SAF TSS and total domain scores at 16 weeks. Surprisingly, the 25mg dose provides a TSS average improvement similar to a higher dose of 50mg and 100mg and better tolerability. For example, similar to a 50mg QD dose and a 100mg QD dose, a 25mg QD dose shows a significant reduction in the blood KIT D816V allele score. In addition, compound (I) administered once daily at 25 mg in patients had a good safety profile in patients with ISM. For example, 95% of patients continued clinical studies without discontinuation due to adverse reactions (AEs). No AEs of grade ≥ 3 occurred in the once daily 25 mg cohort. At week 16, patients' quality of life (QoL) improved as measured by MC-QoL overall and all domain scores.

[0023] Also disclosed herein is a method for preparing at least one crystalline form selected from a crystalline form of compound (I), a pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing substances. Some embodiments of the present disclosure relate to the method, wherein the at least one crystalline form is crystalline form A of compound (I). Some embodiments of the present disclosure relate to the method, wherein the at least one crystalline form is crystalline form B of compound (I). Some embodiments of the present disclosure relate to the method, wherein the at least one crystalline form is crystalline form C of compound (I). Some embodiments of the present disclosure relate to the method, wherein the at least one crystalline form is crystalline form O of compound (I). Some embodiments of the present disclosure relate to the method, wherein the at least one crystalline form is crystalline form T of a tosylate salt of compound (I). Some embodiments of the present disclosure relate to the method, wherein the at least one crystalline form is crystalline form Tr of a tartrate salt of compound (I). Some embodiments of the present disclosure relate to the method, wherein the at least one crystalline form is crystalline form H of a hydrochloride salt of compound (I). BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 Schematic diagram showing the relationship of the four crystalline forms to each other and a non-limiting example of how to prepare the crystalline forms. Figure 1 As shown, the crystalline form A, crystalline form B and crystalline form O of compound (I) are all anhydrous.

[0025] Figure 2 Shown is an X-ray powder diffraction pattern of Form A of Compound (I) (referred to herein as Form A), which shows 2 degrees θ (2-θ) on the X-axis and relative intensity on the Y-axis.

[0026] Figure 3 Shown are a differential scanning calorimetry (DSC) thermogram of Form A of Compound (I), and a thermogravimetric analysis (TGA) thermal curve of Form A of Compound (I) recrystallized from acetone:water.

[0027] Figure 4 Shown is an X-ray powder diffraction pattern of Form B of Compound (I) (referred to herein as Form B), which shows 2 degrees θ (2-θ) on the X-axis and relative intensity on the Y-axis.

[0028] Figure 5 The DSC thermogram of Form B of Compound (I) is shown.

[0029] Figure 6 Shown is an X-ray powder diffraction pattern of Form C of Compound (I) (referred to herein as Form C), which shows 2 degrees θ (2-θ) on the X-axis and relative intensity on the Y-axis.

[0030] Figure 7Shown is an X-ray powder diffraction pattern of Form O of Compound (I) (referred to herein as Form O), which shows 2 degrees θ (2-θ) on the X-axis and relative intensity on the Y-axis.

[0031] Figure 8 Shown is an X-ray powder diffraction pattern of Form T of the tosylate salt of Compound (I) (referred to herein as Form T), which shows 2 degrees θ (2-θ) on the X-axis and relative intensity on the Y-axis.

[0032] Fig. 9 Shown is an X-ray powder diffraction pattern of crystalline form Tr (referred to herein as crystalline form Tr) of a tartrate salt of Compound (I), which shows 2 degrees θ (2-θ) on the X-axis and relative intensity on the Y-axis.

[0033] Fig.10 Shown is an X-ray powder diffraction pattern of Form H of the hydrochloride salt of Compound (I) (referred to herein as Form H), which shows 2 degrees θ (2-θ) on the X-axis and relative intensity on the Y-axis.

[0034] Fig.11 Shown is the maximum percent change from baseline in the sum of tumor diameters for patients with PDGFRA D842V mutant GIST treated with Compound (I).

[0035] Fig.12 A bar graph representing the effect of 25 mg compound (I) once daily, 50 mg compound (I) once daily, 100 mg compound (I) once daily, and placebo on KIT D816V allele burden in ISM patients is shown. All compound (I) dose cohorts showed a significant reduction in KIT D816V allele burden.

[0036] Fig.13 Serum tryptase, mast cell burden, and KIT D816V allele burden were shown to be significantly reduced in ISM patients treated with a once daily 25 mg dose compared to patients treated with placebo.

[0037] Fig.14A Shown is the reduction in ISM-SAF total symptom score from baseline (dashed line) in patients administered 25 mg of Compound (I) once daily. The top line represents placebo and the bottom line represents Compound (I) at a 25 mg dose once daily. Fig. 14B Shown is the reduction in ISM-SAF total symptom score from baseline (dashed line) in patients administered 50 mg of Compound (I) once daily. The top line represents placebo and the bottom line represents a 50 mg dose of Compound (I) once daily. Fig. 14CShown is the reduction in ISM-SAF total symptom score from baseline (dashed line) in patients administered 100 mg of Compound (I) once daily. The top line represents placebo and the bottom line represents Compound (I) at a dose of 100 mg once daily.

[0038] 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) is approved by the FDA for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumors (GIST) containing PDGFRA exon 18 mutations (including PDGFRA D842V mutations) at 400 mg once daily (QD). Compound (I) also exhibits potent and selective activity against KIT D816V in vitro, strong growth inhibition in an in vivo tyrosine kinase inhibitor (TKI)-resistant mastocytoma model, and tolerance to active doses in toxicology and safety pharmacology studies. A Phase 1 study of compound (I) in patients with AdvSM (Explorer / NCT02561988) is evaluating safety and preliminary efficacy. The recommended Phase 2 dose (RP2D) was determined to be 300 mg once daily, and the expansion cohort of the study is further evaluating the efficacy and safety of this dose in a larger patient cohort and validating the AdvSM Symptom Assessment Form (AdvSM-SAF) developed to evaluate the effect of compound (I) on symptom improvement in patients with AdvSM. Based on emerging safety and efficacy data in patients treated with 300 mg QD, an additional patient cohort treated with 200 mg QD was added.

[0039] As used herein, the term "pharmaceutically acceptable salt" refers to a non-toxic salt form of a 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; calcium edetate; camsylate; carbonate; chloride; citrate; dihydrochloride; edetate; edisylate; estolate; esylate; fumarate; gluceptate; gluconate; glutamate; glycollylarsanilate; hexyl raclotamine; hydrabamine; hydrobromide; hydrochloride; hydroxy naphthol salts; iodides; isethionates; lactates; lactobionates; malates; maleates; mandelates; methanesulfonates; methyl bromides; methyl nitrates; methyl sulfates; mucates; naphthylsulfonates; nitrates; embonates; pantothenates; phosphates / diphosphates; polygalacturonates; salicylates; stearates; subacetates; succinates; sulfates; tannates; tartrates; 8-chlorotheophylline salts (teociate); triethyl iodide; benzathine salts; chloroprocaine salts; choline; diethanolamine salts; ethylenediamine salts; methylglucamine; procaine salts; aluminum salts; calcium salts; lithium salts; magnesium salts; potassium salts; sodium salts; and zinc salts.

[0040] Non-limiting examples of pharmaceutically acceptable salts derived from appropriate acids include: salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or perchloric acid; salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; and salts formed by using other methods used in the art, such as ion exchange. Additional non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Non-limiting examples of pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium and magnesium. Other 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 benzenesulfonates and glucosamine salts.

[0041] As used herein, the term "ambient conditions" means room temperature, open air conditions, and uncontrolled humidity conditions. As used herein, the term "room temperature" or "ambient temperature" means a temperature ranging from 15°C to 30°C.

[0042] As used herein, the terms "polymorph", "crystalline form", "crystalline form", "solid state form" and "form" refer interchangeably to a solid having a specific molecular packing arrangement in a crystal lattice. Crystalline forms can be identified and distinguished from one another by at least one characterization technique, including, for example, X-ray powder 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] [solvate] of Compound (I)" refer to unique crystalline forms that can be identified and distinguished from one another by at least one characterization technique, including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS) and / or thermogravimetric analysis (TGA). In some embodiments, the new crystalline form is characterized by an X-ray powder diffraction pattern having at least one signal at at least one specified 2-theta value (° 2-theta).

[0043] As used herein, the term "solvate" refers to a crystalline form of molecules, atoms and / or ions, which further comprises at least one molecule of one or more solvents incorporated into the lattice structure in a stoichiometric or non-stoichiometric amount. The solvent molecules in the solvate can exist in a regular arrangement and / or a disordered arrangement. For example, a solvate with a non-stoichiometric amount of solvent molecules may be caused by a partial loss of the solvent in the solvate. Alternatively, the solvate may appear as a dimer or oligomer comprising more than one molecule. When the solvent is water, the solvate is referred to as a "hydrate" in this article.

[0044] As used herein, the term "XRPD" refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded in transmission or reflection geometry under ambient conditions using a diffractometer.

[0045] As used herein, the terms "X-ray powder diffraction pattern", "X-ray powder diffraction pattern" and "XRPD diagram" refer to an experimentally obtained graph that plots signal position (on the abscissa) versus signal intensity (on the ordinate). For amorphous materials, an X-ray powder diffraction pattern may include at least one broad signal. For crystalline materials, an X-ray powder diffraction pattern may include at least one signal, each signal being identified by its angle value measured in degrees 2θ (°2θ) as depicted on the abscissa of the X-ray powder diffraction pattern, which angle value may be expressed as "a signal at ... degrees 2-θ", "a signal at a [a] 2-θ value of ...", and / or "a signal at at least ... 2-θ values ​​selected from . . . ."

[0046] As used herein, the term "X-ray powder diffraction pattern having signals at ... 2-theta values" refers to an XRPD pattern containing X-ray reflection positions as measured and observed in an X-ray powder diffraction experiment (° 2θ).

[0047] As used herein, the term "signal" refers to a point in an XRPD pattern where the intensity, as measured in counts, is at a local maximum. One of ordinary skill in the art will recognize that at least one signal in an XRPD pattern may overlap and, for example, may not be apparent to the naked eye. One of ordinary skill 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, for example, Rietveld refinement.

[0048] As used herein, the terms "signal at ... degrees 2-θ", "signal at [a] 2-θ value [] of ...", and "signal at at least ... 2-θ values ​​selected from ..." refer to the positions of X-ray reflections as measured and observed in an X-ray powder diffraction experiment (°2θ). In some embodiments, the repeatability of the angle value is within the range of ±0.2°2θ, that is, the angle value can be the listed angle value +0.2 degrees 2-θ, the angle value -0.2 degrees 2-θ, or any value between these two endpoints (angle value +0.2 degrees 2-θ and angle value -0.2 degrees 2-θ). It is well known to those of ordinary skill in the art that there may be variability in the measurement of X-ray powder diffraction signal values. Therefore, for the same signal in different samples, there may be variability in the signal value of up to ±0.2°2θ. As used herein, the term "signal intensity" refers to the relative signal intensity in a given X-ray powder diffraction pattern. Factors that can affect relative signal intensity include, for example, sample thickness and preferred orientation (eg, crystalline particles are not randomly distributed).

[0049] As used herein, the term "amorphous" refers to a solid material that has no long-range order in its molecular positions. For example, an amorphous material is a solid material that has no sharp signals in its X-ray powder diffraction pattern (i.e., not crystalline as determined by XRPD). Amorphous refers to a non-crystalline solid form. Instead, at least one broad signal (e.g., at least one halo) may appear in its diffraction pattern. Broad signals are characteristic of amorphous solids.

[0050] As used herein, an X-ray powder diffraction pattern is "substantially similar to the diffraction pattern in [a particular] pattern" when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in both diffraction patterns are the same ±0.2° 2θ. In determining "substantial similarity," one of ordinary skill in the art will understand that there may be variations in the intensity and / or signal positions in an XRPD diffraction pattern even for the same crystalline form. Thus, one of ordinary skill in the art will understand that a signal maximum in an XRPD diffraction pattern (expressed in degrees 2-θ (°2θ) as referred to herein) generally means that the reported value is ±0.2 degrees 2θ of the reported value, which is the art-recognized variance discussed above.

[0051] As used herein, a crystalline form is "substantially pure" when the crystalline form comprises an amount equal to or greater than 90% by weight of the sum of all solid forms in a sample, as determined by methods according to the art (e.g., quantitative XRPD). In some embodiments, the solid form is "substantially pure" when the solid form comprises an amount equal to or greater than 95% by weight of the sum of all solid forms in a sample. In some embodiments, the solid form is "substantially pure" when the solid form comprises an amount equal to or greater than 98% by weight of the sum of all solid forms in a sample. In some embodiments, the solid form is "substantially pure" when the solid form comprises an amount equal to or greater than 99% by weight of the sum of all solid forms in a sample.

[0052] In some embodiments, the solid form is "substantially pure" when the solid form accounts for an amount equal to or greater than 98% by weight of the sum of all solid organic forms in the sample. As used herein, "solid organic form" 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:

[0053]

[0054] In some embodiments, a solid form is "substantially pure" when it has ≤ 0.8% w / w, ≤ 0.7% w / w, ≤ 0.6% w / w, ≤ 0.55% w / w of its undesired enantiomer (Compound (E)).

[0055] In some embodiments, a solid form is "substantially pure" when it has no more than 2.0% w / w of total impurities. In some embodiments, a solid form is "substantially pure" when it has no more than 0.15% w / w of each known unspecified impurity. Known unspecified impurities include, for example, impurity (IA):

[0056] And impurities (IB):

[0057] In some embodiments, the solid form is "substantially pure" when it has no more than 0.55 area / area of ​​compound (E). In some embodiments, the solid form is "substantially pure" when it has no more than 0.15% w / w of each known unspecified impurity and no more than 0.10% w / w of any other individual impurity. In some embodiments, the solid form is "substantially pure" when it has no more than 0.15% w / w of each known unspecified impurity and no more than 0.10% w / w of any other individual impurity and no more than 0.55 area / area of ​​compound (E).

[0058] In some embodiments, a solid form is "substantially pure" when it is substantially free of solvent (e.g., the solid form has no more than 3000 ppm methanol, no more than 5000 ppm 2-propanol, no more than 600 ppm dichloromethane, no more than 720 ppm tetrahydrofuran, no more than 620 ppm 2-methyltetrahydrofuran, no more than 5000 ppm acetone, no more than 5000 ppm heptane, no more than 5000 ppm methyl tert-butyl ether, no more than 890 ppm toluene, or no more than 380 ppm 1,4-dioxane).

[0059] In some embodiments, N,N-diisopropylethylamine (DIPEA) is a tertiary amine that can be used in the last step of the processing steps of compound (I). In some embodiments, the solid form is "substantially pure" when it is substantially free of DIPEA. In some embodiments, the solid form is "substantially pure" when it has no more than 1000 ppm of DIPEA.

[0060] In some embodiments, a solid form is "substantially pure" when it is 97.0% to 103.0% w / w solvent-free, anhydrous basis (calculation includes correction for water, residual solvents, and DIPEA content) by HPLC. The HPLC retention time must be ±2% of the retention time of the standard. HPLC analysis can be performed, for example, as described below:

[0061] First generation HPLC method:

[0062]

[0063]

[0064] Second generation HPLC

[0065]

[0066]

[0067] As used herein, "selective KIT inhibitor" or "selective PDGFRα inhibitor" refers to a compound 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 relative to another kinase, or a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing. For example, a selective KIT inhibitor or a selective PDGFRA inhibitor exhibits 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 relative to another kinase. In some embodiments, a selective KIT inhibitor or a selective PDGFRα inhibitor exhibits at least 150-fold selectivity relative to 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, the selectivity for KIT protein kinase or PDGFRα protein kinase relative to another kinase is measured in a cellular assay (e.g., a cellular assay). In some embodiments, the selectivity for KIT protein kinase or PDGFRα protein kinase relative to another kinase is measured in a biochemical assay (e.g., a biochemical assay).

[0068] As used herein, a "therapeutically effective amount" of a compound disclosed herein refers to an amount of a compound that will elicit a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity, or an improvement in symptoms, alleviation of a condition, or a slowing or delay of disease progression). In some embodiments, a "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit and / or improve (i) a disorder or condition mediated by KIT and / or PDGRFA, or (ii) associated with KIT and / or PDGFRA activity, or (iii) characterized by the activity (normal or abnormal) of KIT and / or PDGFRA; 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 a compound that, when administered to a cell, or tissue, or non-cellular biological material or 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 determined by one of ordinary skill in the art (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0069] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to a 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.

[0070] As used herein, the term "patient" or "subject" refers to an organism to be treated by the methods of the present disclosure. Non-limiting example organisms include mammals, such as murines, simians, equines, bovines, porcines, canines, felines, etc. In some embodiments, the organism is a human. In some embodiments, the patient to be treated suffers from ISM or SSM with moderate to severe symptoms that are not adequately controlled with approved symptom-directed therapies.

[0071] As used herein, the terms "treat," "treating," or "treatment," when used in conjunction with a disorder or condition, include any effect resulting in improvement of the disorder or condition, such as alleviation, reduction, modulation, improvement, and / or elimination. Improvement of any symptom of a disorder or condition or reduction in its severity can be readily assessed according to standard methods and techniques known in the art.

[0072] In some embodiments, treatment comprises reducing mast cell burden. In some embodiments, objective measures of mast cell burden include serum tryptase, bone marrow mast cell count, skin mast cell infiltration, and KITD816V mutant allele burden in the blood. In some embodiments, objective measures of mast cell burden include serum tryptase, bone marrow mast cell count, and KIT D816V mutant allele burden in the blood.

[0073] In some embodiments, treatment includes reducing systemic mastocytosis symptoms.Systemic mastocytosis symptoms include but are not limited to itching, flushing, GI cramps, diarrhea, allergic reactions (especially bee venom), bone pain, osteoporosis and urticaria pigmentosa. In some embodiments, ISM-SAF patient-reported results (PRO) instruments as defined herein are used to assess symptom improvement. In some embodiments, the patient completes ISM-SAF once a day before receiving treatment, and the patient also completes ISM-SAF once a day during treatment. For example, the patient starts at the time of informed consent, completes ISM-SAF for a period of time (such as four weeks), during which the best supportive care (BSC) medicine is optimized and stable. Once the data for a period of time (such as four weeks) are collected, then ISM-SAF is completed once a day for an additional period of time (such as two weeks (14 days)), and patient qualifications are determined based on ISM-SAF symptom thresholds. Then, the patient who meets the ISM-SAF qualification threshold completes ISM-SAF once a day, while completing screening procedures to assess research qualifications.

[0074] Once all screening procedures are completed, baseline symptoms are collected in a period of time (e.g., 14 days) immediately before the study enters. These data are used as baseline total symptom score (TSS). ISM-SAF is completed by the patient once a day until the study is completed, for example, until Part 1 and Part 2, and until the 52nd week of Part 3. In some embodiments, the primary endpoint of Part 2 of the study is the average change of ISM-SAF TSS from baseline to the 12th week. In some embodiments, treatment improves the number of attacks of allergic reactions. In some embodiments, "the onset of allergic reactions" is the onset of allergic reactions treated with epinephrine.

[0075] In some embodiments, treatment improves quality of life (QoL) as measured by one or more questionnaires. Non-limiting examples of QoL questionnaires include MC-QoL, PGIS, SF-12, PGIC, and EQ-5D-EL. MC-QoL is a disease-specific QoL tool developed for use with patients with ISM and CM ((Siebenhaar, F. et al., Allergy 71(6):869-77(2016)). MC-QoL contains 27 items that assess four domains: symptoms, mood, social life / function, and skin. Items are assessed on a 5-point scale with a recall period of two weeks. PGIS is a single-item scale that assesses a patient's perception of disease symptoms at a certain point in time. PGIS has been widely used to assess a patient's overall feeling that a treatment is beneficial. SF-12 was developed for the Medical Outcomes Study, a multi-year study of patients with chronic diseases. The instrument is designed to reduce respondent burden while achieving minimum accuracy standards for group comparisons involving multiple health dimensions. The questionnaire measures health and well-being from the patient's perspective using eight health domains. The recall period is four weeks. PGIC is a single-item scale that assesses a patient's perception of changes in disease symptoms at a certain point in time. EQ-5D-5L is a standardized instrument for measuring general health status. It consists of two parts: health status description and assessment. Health status is measured based on five dimensions (5D): mobility; self-care; daily activities; pain / discomfort; and anxiety / depression. Respondents self-assess the severity of each dimension using a 5-point scale. The recall period is "today" (Whynes, DK, Health Qual Life Outcomes 6:94 (2008)).

[0076] In some embodiments, treatment improves bone density. Bone density is measured by dual energy x-ray absorptiometry scans that assess both the lumbar spine and hip. In some embodiments, treatment does not affect bone density.

[0077] As used herein, "SD" means stable disease.

[0078] As used herein, "CR" means complete response.

[0079] As used herein, "PFS" means progression-free survival.

[0080] The term "systemic mastocytosis" or "SM" refers to a clonal disorder of mast cells (MCs), characterized by increased MC load, focal and / or diffuse infiltration of neoplastic MCs in the skin, bone marrow (BM), spleen, liver, gastrointestinal (GI) tract, and other organs, and increased release of MC mediators. All patients have BM involvement. The World Health Organization (WHO) has established diagnostic and classification criteria for 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 with non-MC lineage-related hematological tumors (SM-AHN), aggressive SM (ASM), and MC leukemia (MCL). The latter three subclasses are associated with reduced overall survival and are classified as advanced SM (AdvSM). Late stage SM is associated with a poor prognosis, with a median overall survival of 3.5 years for ASM, two years for SM-AHN, and less than six months for MCL. ISM is associated with a normal or near-normal life expectancy, and the prognosis of SSM is moderate (Lim, KH et al., Blood 113(23):5727-36(2009)). The main criteria for SM are multifocal accumulation and aggregation of MC in BM or other extracutaneous organs. Secondary criteria confirm the clonal nature of the disease, including abnormal MC morphology (rotation), expression of CD2 and / or CD25 in MC, expression of activating mutations in codon 816 of V-kit Hardy-Zuckerman 4 feline sarcoma virus oncogene homolog (KIT) exon 17 (usually D816V), and serum tryptase levels>20ng / mL. Late stage SM is characterized by the presence of organ damage (C-discovery) caused by MC infiltration, while ISM and SSM are not associated with organ function damage.

[0081] ISM is defined as the presence of less than two B-findings and no C-findings according to WHO criteria; SSM is defined as the presence of two or more B-findings and no 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, but no hypersplenism or liver dysfunction, 3. Mild dysplastic changes or high cell bone marrow, but not meeting the WHO classification of another blood disorder such as myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPNs). ISM is the most common category of SM. Patients with ISM have an abnormal collection of mast cells in the bone marrow, but no evidence of another blood disease or tissue dysfunction. Mast cells in aspirate smears are usually <5%. The life expectancy of patients with ISM is comparable to that of the general population, but may present with various symptoms of mast cell mediator release. The risk of progression to advanced variants is less than 5%. SSM is characterized by a high mast cell load but no evidence of overt blood disorders or tissue dysfunction. Patients with SSM are considered to be at higher risk of progression to more advanced categories. Both ISM and SSM are referred to as non-advanced SM.

[0082] In all subtypes of SM and in the majority of patients with the disease, neoplastic MCs display a mutation at position D816 in exon 17 of KIT, which results in ligand-independent activation of KIT kinase activity. KIT activity is required for differentiation and survival of wild-type MCs, and thus, constitutive activation of KIT by the D816V mutation is considered a pathogenic driver of SM (Chabot, B. et al., Nature 335(6185):88-9 (1988)). Specifically, KIT D816V mutations were found in 90% to 98% of patients with SM, while rare KIT D816Y, D816F, and D816H variants were 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, KITD816V is considered a major therapeutic target for SM (Valent et al., 2017), and several agents targeting this mutation have been studied.

[0083] ISM and SSM are characterized by severe symptoms associated with MC mediator release, including itching, flushing, GI cramping, diarrhea, allergic reactions (especially to bee venom), bone pain, and osteoporosis (Gulen, T. et al., J Intern Med. 279(3):211-28 (2016)). These symptoms can be severely debilitating and have a negative impact on quality of life (Hermine, O. et al., Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: Additional efficacy analyses from the randomized, placebo-controlled, Phase 3 study, EHA Abstract 709 (2017); Jennings, S. et al., J Allergy Clin Immunol. 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)).

[0084] Patients are also frequently affected by cosmetically debilitating cutaneous mastocytosis (CM), most commonly urticaria pigmentosa, which impacts their quality of life. Abnormal MCs are found in skin and BM biopsies, but the MC burden is low and there is no overt cytopenia or other evidence of organ dysfunction due to these infiltrates. Nonspecific treatments have been used to control symptoms associated with MC mediators, with varying degrees of efficacy; without affecting the MC burden in tissues. 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 tyrosine kinase inhibitors (TKIs) targeting KIT have been studied in patients with ISM and SSM. While some TKI therapies have demonstrated symptomatic improvement and, in some cases, reductions in MC burden measures in patients with ISM and SSM, none of the existing agents specifically targets the KIT D816V driver mutation in this disease, and to date, no TKI agent or any other agent has been approved for the treatment of ISM and SSM. Therefore, there remains an unmet medical need in patients with moderate to severe symptoms who do not respond adequately to existing symptomatic treatments.

[0085] As used herein, the "Indolent Systemic Mastocytosis-Symptom Assessment Form" or "ISM-SAF" (ISPOREurope 2019, Copenhagen Denmark, November 2-6, 2019) is used for daily patient-reported outcomes (PRO) assessments, such as on an electronic diary (eDiary). The ISM-SAF is a 12-item PRO specifically developed to assess the symptoms of patients with ISM and SSM. Although originally developed to assess the efficacy hypothesis of treatment, the ISM-SAF can also be used to screen participants for entry (or exit) clinical studies based on the minimum level of signs and symptom severity. The 11 items shown in the table below are graded on an 11-point scale (0 to 10, none to most severe), and 1 item (diarrhea) also assesses frequency.

[0086]

[0087]

[0088] For the fields of skin / skin symptom score (SSS), GI / gastrointestinal symptom score (GSS) and non-specific symptoms and total symptom score (TSS), ISM-SAF generates scores for each project.TSS is to add all symptoms together.On the one hand, TSS is 1-10 and 12.On the one hand, GSS is 2-3 and 12.On the one hand, SSS is 4-6.On the one hand, patients start at the time of informed consent and complete ISM-SAF daily for 4 weeks, during which BSC drugs are optimized and stable.Once 4 weeks of data have been collected, ISM-SAF is completed daily for another 2 weeks (14 days) to determine patient qualifications based on ISM-SAF symptom thresholds.Patients who meet the ISM-SAF qualification threshold complete ISM-SAF daily, while completing screening procedures to assess study qualifications.Once all screening procedures are completed, baseline symptoms are collected within 14 days immediately before the study enters.These data will be used as baseline TSS.

[0089] On the one hand, the patient with ISM or SSM has moderate to severe symptoms characterized by minimum TTS. On the one hand, the patient with ISM or SSM has moderate to severe symptoms, characterized in that the minimum TTS≥28 as assessed using ISM-SAF. On the one hand, the minimum TTS is ≥27, ≥26, ≥25, ≥24, ≥23, ≥22, ≥21, ≥20. On the one hand, the patient with ISM or SSM with moderate to severe symptoms has a minimum TSS of ≥28 and ≥1 symptom in the skin or GI fields of ISM-SAF at baseline. On the one hand, baseline is the 14-day time period before the 1st day (C1D1) of the 1st cycle. On the one hand, the patient does not experience the acute symptom onset beyond its typical baseline symptoms. On the one hand, the patient failed to achieve symptom control of one or more baseline symptoms as determined by the investigator before starting the ISM-SAF eligibility determination, wherein at least 2 of the following symptomatic treatments are administered at the optimal (approved) dose and last for at least 4 weeks (2 days): H1 blockers, H2 blockers, proton pump inhibitors, leukotriene inhibitors, sodium cromoglycate, corticosteroids or omalizumab. On the one hand, the patient has a baseline serum tryptase of <20ng / mL. On the one hand, the patient has a baseline serum tryptase of ≥20ng / mL. On the one hand, the patient suffers from cutaneous mastocytosis (CM). On the one hand, the patient does not have CM. The diagnosis of CM requires the presence of clinical and histopathological findings of abnormal mast cell infiltration in the dermis, and there is no evidence of systemic mast cell infiltration in the bone marrow or other extracutaneous organs. CM is further subdivided into 3 different sub-variants: urticaria pigmentosa / maculopapular cutaneous mastocytosis (MPCM), diffuse CM and cutaneous mastocytoma.

[0090] In one aspect, the patient with ISM or SSM has a KIT D816V mutation.The KIT D816V mutation 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).

[0091] 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 to be related to the drug. An AE (also called an adverse experience) can be any unfavorable and unexpected sign (e.g., abnormal laboratory findings), symptom, or disease that is temporally associated with the use of a drug, without any judgment of causality. An AE may be caused by any use of a drug (e.g., off-label use, use in combination with another drug) and any route of administration, formulation, or dose (including overdose).

[0092] As used herein, when used in conjunction with a dose, amount, or weight percentage of an ingredient of a composition or dosage form, the terms "about" and "approximately" include the value of the specified dose, amount, or weight percentage, or a range of doses, amounts, or weight percentages 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 percentage.

[0093] As described above, new crystalline forms of compound (I), pharmaceutically acceptable salts thereof, and solvates of any of the foregoing are described herein. In some embodiments, the crystalline form of compound (I) is substantially pure. These may be inhibitors of KIT and / or PDGFRα protein kinases, and in some embodiments, selective inhibitors of KIT and / or PDGFRα protein kinases. KIT and / or PDGFRα inhibitors may be used to treat disorders and conditions associated with oncogenic KIT and PDGFRA changes, such as mastocytosis, gastrointestinal stromal tumors (GIST), acute myeloid leukemia (AML), melanoma, seminoma, intracranial germ cell tumors, and mediastinal B-cell lymphomas.

[0094] Crystalline Form A of Compound (I)

[0095] In some embodiments, the present disclosure provides a crystalline form A of compound (I):

[0096]

[0097] Among the different crystalline forms of Compound (I) identified, Form A is more stable at ambient temperature than other crystalline forms disclosed herein. In addition, Form A has been shown to have better physical and chemical stability properties for formulation than other crystalline forms identified herein. Form A also provides the advantage of easy separation. Form A has good thermodynamic stability, as shown by its DSC.

[0098] Figure 2 Shown is an X-ray powder diffraction pattern of Form A of Compound (I) under ambient conditions.

[0099] Figure 3 The DSC thermogram of Form A of Compound (I) is shown. In some embodiments, 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, 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, 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.

[0100] In some embodiments, the crystalline Form A of Compound (I) is characterized by being substantially similar to Figure 3 DSC thermogram in .

[0101] Figure 3 Also shown is a TGA thermal curve of Form A of Compound (I) recrystallized from a mixture of acetone and water. For Form A of Compound (I), the mass loss demonstrated by TGA varies depending on the recrystallization conditions.

[0102] In some embodiments, the crystalline form A of compound (I) is a free-flowing white crystal to off-white to yellow solid. In some embodiments, the crystalline form A of compound (I) is an anhydrous polymorph. In some embodiments, the water content of the crystalline form A of compound (I) is less than 1.0% water. In some embodiments, the water content of the crystalline form A of compound (I) is no more than 0.04%. In some embodiments, the water content level is <0.01%-0.07%. In some embodiments, the crystalline form A of compound (I) appears to be a needle-shaped and / or flaky or plate-shaped solid.

[0103] In some embodiments, Form A of Compound (I) is characterized by a weight change of 0.42% in a dynamic vapor sorption (DVS) experiment while varying relative humidity from 2-95% RH at 25°C.

[0104] In some embodiments, Form A of Compound (I) is characterized by a weight change of 0.29% in a dynamic vapor sorption (DVS) experiment while varying the relative humidity from 2-95% RH at 40°C.

[0105] In some embodiments, Form A of Compound (I) is characterized by a weight change of 0.20% in a dynamic vapor sorption (DVS) experiment while varying the relative humidity from 70-95% RH at 40°C.

[0106] In some embodiments, the crystalline Form A of Compound (I) is non-hygroscopic as determined by dynamic vapor sorption (DVS) analysis. In some embodiments, the crystalline Form A of Compound (I) absorbs up to 0.44% by weight of water when exposed to 40° C. and up to 95% relative humidity.

[0107] In some embodiments, the crystalline Form A of Compound (I) is characterized by a solubility of 0.03 mg / mL in fasted state simulated intestinal fluid (FaSSIF). In some embodiments, the crystalline Form A of Compound (I) is characterized by a solubility of 2.11 mg / mL in fasted state simulated gastric fluid.

[0108] In some embodiments, Form A of Compound (I) is characterized by a solubility of 0.03 mg / mL in fasting state simulated intestinal fluid (FaSSIF) at 37° C. In some embodiments, Form A of Compound (I) is characterized by a solubility of 2.11 mg / mL in fasting state simulated gastric fluid at 37° C.

[0109] In some embodiments, the crystalline form A of compound (I) has a particle size distribution (PSD) wherein D10 is not less than (NLT) 1 μm, D50 is 5-105 μm, for example, in some embodiments, D50 is 8-80 μm; and D90 is not more than (NMT) 500 μm, for example, in some embodiments, D90 is NMT 300 μm. As used herein, D10 is the diameter at which 10% of the sample mass is not less than 1 μm. As used herein, D50 is the mass median diameter (MMD). As used herein, MMD is the average particle size by mass. In some embodiments, the average particle size by mass (ie, D50 or MMD) is 5-105 μm. As used herein, D90 is the diameter at which 90% of the sample mass is no more than 500 μm. In some embodiments, PSD is NLT 1 μm (D10) and NMT 500 μm (D90). Particle size distribution (PSD) can be analyzed using a laser diffraction system (eg 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 Form A of Compound (I) in 50 mL 0.5% Span 85 in hexane.

[0110] In some embodiments, particle size and / or particle size distribution has an impact on tablet dissolution.

[0111] In some embodiments, the crystalline Form A of Compound (I) is in substantially pure form. In some embodiments, the crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis using an incident beam of Cu Ka radiation. In some embodiments, the crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis using an incident beam of Cu Ka radiation, the signals of which are substantially similar to those described in Table 1.

[0112] Table 1.

[0113]

[0114]

[0115] In some embodiments, the crystalline form A of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 11.5±0.2 degrees 2θ. In some embodiments, the crystalline form A of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 15.4±0.2 degrees 2θ. In some embodiments, the crystalline form A of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 16.7±0.2 degrees 2θ. In some embodiments, the crystalline form A of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 18.1±0.2 degrees 2θ. In some embodiments, the crystalline form A of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 20.0±0.2 degrees 2θ. In some embodiments, the crystalline form A of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 21.6±0.2 degrees 2θ. In some embodiments, the crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 23.1±0.2 degrees 2θ. In some embodiments, the crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 23.9±0.2 degrees 2θ. In some embodiments, the crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 25.9±0.2 degrees 2θ. In some embodiments, the crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 30.7±0.2 degrees 2θ.

[0116] In some embodiments, the crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at 2θ 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, the crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least eight 2θ 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, the crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least seven 2θ 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, the crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least six 2θ 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, the crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least five 2θ 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, the crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least four 2θ 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, Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least three 2θ 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, the crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2θ 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, the crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2θ 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.

[0117] In some embodiments, the crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least three 2θ 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, the crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2θ 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, the crystalline Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least one 2θ 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, Form A of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at 2θ values ​​of 11.5±0.2, 15.4±0.2, 16.7±0.2, 20.0±0.2, and 21.6±0.2.

[0118] In some embodiments, Form A of Compound (I) is characterized by being substantially similar to Figure 2 X-ray powder diffraction pattern of .

[0119] In some embodiments, the crystalline Form A of Compound (I) is characterized by having a signal at the following δ (expressed in ppm): 13 C NMR (CDCl3, 100 MHz) pattern: 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.

[0120] In some embodiments, the present disclosure provides a method for preparing Form A of Compound (I). In some embodiments, the method for preparing Form A of Compound (I) is a recrystallization method. In some embodiments, the recrystallization method removes impurities. In some embodiments, the recrystallization method removes residual N,N-diisopropylethylamine. In some embodiments, the recrystallization method comprises acetone and water. In some embodiments, the present disclosure provides Form A of Compound (I) prepared by a method comprising the following steps: dissolving Compound (I) in acetone and water to obtain a suspension; heating the suspension to obtain a solution; and cooling the solution, such as by lowering the temperature.

[0121] In some embodiments, the ratio of acetone to water is 85:15.

[0122] In some embodiments, the suspension is heated to a temperature in the range of 40°C to 50°C.

[0123] In some embodiments, the method further comprises stirring the heated suspension. In some embodiments, the method further comprises stirring the heated suspension at a temperature ranging from 40°C to 50°C. In some embodiments, the heated suspension is stirred. In some embodiments, the heated suspension is stirred for fifteen minutes. In some embodiments, the heated suspension is stirred at a temperature ranging from 40°C to 50°C. In some embodiments, the heated suspension is stirred for fifteen minutes at a temperature ranging from 40°C to 50°C.

[0124] In some embodiments, the method further comprises polish filtering the stirred suspension. In some embodiments, the method further comprises polish filtering the stirred suspension at a temperature ranging from 40°C to 50°C.

[0125] In some embodiments, the method further comprises atmospheric distillation of the polish filtered suspension. In some embodiments, the method further comprises atmospheric distillation of the polish filtered suspension at a temperature in the range of 55°C to 65°C.

[0126] In some embodiments, cooling the solution comprises reducing the temperature. In some embodiments, cooling the solution comprises reducing the temperature to a temperature in the range of 45°C to 55°C. In some embodiments, cooling the solution comprises reducing the temperature within fifteen minutes. In some embodiments, cooling the solution comprises reducing the temperature to a temperature in the range of 45°C to 55°C within fifteen minutes.

[0127] In some embodiments, the present disclosure provides a method for preparing Form A of Compound (I), and further provides Form A of Compound (I) prepared by a method comprising the steps of slurrying Form C of Compound (I) in acetone at an elevated temperature. In some embodiments, the elevated temperature is at least 30°C.

[0128] In some embodiments, the present disclosure provides a method for preparing Form A of Compound (I), and also provides Form A of Compound (I) prepared by a method comprising the following steps: heating Form O of Compound (I) to an elevated temperature; and slurrying in 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.

[0129] In some embodiments, the present disclosure provides a method for preparing Form A of Compound (I), and also provides Form A of Compound (I) prepared by a method comprising the following steps: slurrying 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.

[0130] In some embodiments, any of the above methods for preparing Form A of Compound (I) may further comprise purifying Form A by dissolving Form A in a mixture of acetone and water and / or by slurrying in isopropanol. In some embodiments, an isopropanol slurry is obtained by absorbing the crystalline solid in isopropanol and heating and then cooling the resulting mixture. In some embodiments, the crystalline solid is isolated by filtration, washed with isopropanol and dried.

[0131] In some embodiments, the present disclosure provides a method for preparing substantially pure crystalline Form A of Compound (I).

[0132] Crystalline Form B of Compound (I)

[0133] In some embodiments, the present disclosure provides Form B of Compound (I):

[0134]

[0135] Figure 4 Shown is an X-ray powder diffraction pattern of Form B of Compound (I) under ambient conditions.

[0136] Figure 5The DSC thermogram of Form B of Compound (I) is shown. In some embodiments, 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, 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, Form B of Compound (I) is characterized by a DSC thermogram substantially similar to Figure 5 DSC thermogram in .

[0137] In some embodiments, the crystalline Form B of Compound (I) is in substantially pure form. In some embodiments, the crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis using an incident beam of Cu Ka radiation. In some embodiments, the crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis using an incident beam of Cu Ka radiation, the signals of which are substantially similar to those described in Table 2.

[0138] Table 2:

[0139]

[0140]

[0141]

[0142] In some embodiments, the crystalline Form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 4.1±0.2 degrees 2θ. In some embodiments, the crystalline Form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 9.7±0.2 degrees 2θ. In some embodiments, the crystalline Form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 11.2±0.2 degrees 2θ. In some embodiments, the crystalline Form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 13.8±0.2 degrees 2θ. In some embodiments, the crystalline Form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 16.4±0.2 degrees 2θ. In some embodiments, the crystalline Form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 17.0±0.2 degrees 2θ. In some embodiments, the crystalline Form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 19.6±0.2 degrees 2θ. In some embodiments, the crystalline Form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 20.6±0.2 degrees 2θ. In some embodiments, the crystalline Form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 21.0±0.2 degrees 2θ. In some embodiments, the crystalline Form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 22.4±0.2 degrees 2θ. In some embodiments, the crystalline Form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 23.1±0.2 degrees 2θ. In some embodiments, the crystalline Form B of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 23.8±0.2 degrees 2θ. In some embodiments, Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 29.0 ± 0.2 degrees 2θ.

[0143] In some embodiments, Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at 2θ 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, Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least eight 2θ 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, Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least seven 2θ 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, Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least six 2θ 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, Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least five 2θ 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, Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least four 2θ 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, Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least three 2θ 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, Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2θ 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, Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least one 2θ 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.

[0144] In some embodiments, the crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least three 2θ 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, the crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2θ 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, the crystalline Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least one 2θ 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, Form B of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at 2θ values ​​of 4.1±0.2, 16.4±0.2, 17.0±0.2, 19.6±0.2, and 20.6±0.2.

[0145] In some embodiments, Form B of Compound (I) is characterized by being substantially similar to Figure 4 X-ray powder diffraction pattern of .

[0146] In some embodiments, Form B of Compound (I) is characterized by having 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 C NMR (CDCl3, 100 MHz) pattern.

[0147] In some embodiments, the present disclosure provides a method for preparing Form B of Compound (I). In some embodiments, the present disclosure provides Form B of Compound (I) prepared by a method comprising the following steps: heating Compound (I) at an elevated temperature for a period of time; and cooling to room temperature. In some embodiments, the time is ten minutes. In some embodiments, the elevated temperature is 195°C.

[0148] In some embodiments, the method further comprises isolating Form B of Compound (I) by filtration.

[0149] In some embodiments, the present disclosure provides a method for preparing Form B of Compound (I), and also provides Form B of Compound (I) prepared by a method comprising the following steps: heating Form A of Compound (I) at an elevated temperature for a period of time; and cooling to room temperature. In some embodiments, the time is thirty minutes. In some embodiments, the elevated temperature is 195°C.

[0150] In some embodiments, the present disclosure provides a method for preparing Form B of Compound (I), and also provides Form B of Compound (I) prepared by a method comprising the steps of prolonged heating Form A of Compound (I) at 195°C.

[0151] In some embodiments, the method further comprises isolating Form B of Compound (I) by filtration.

[0152] Crystalline Form C of Compound (I)

[0153] In some embodiments, the present disclosure provides Form C of Compound (I):

[0154]

[0155] Crystalline Form C is a hydrate of Compound (I).

[0156] Figure 6Shown is an X-ray powder diffraction pattern of Form C of Compound (I) under ambient conditions.

[0157] In some embodiments, the crystalline form C of compound (I) is a rod-shaped crystal. In some embodiments, the crystalline form C of compound (I) is characterized by an irregular morphology.

[0158] In some embodiments, Form C of Compound (I) is characterized by a weight change of 2.90% in a dynamic vapor sorption experiment while the relative humidity is varied from 2-95% RH at 25° C. In some embodiments, Form C of Compound (I) is characterized by a weight change of 1.76% in a dynamic vapor sorption experiment while the relative humidity is varied from 2-10% RH at 25° C.

[0159] In some embodiments, Form C of Compound (I) is characterized by a weight change of 2.99% in a dynamic vapor sorption experiment while the relative humidity is varied from 2-95% RH at 40° C. In some embodiments, Form C of Compound (I) is characterized by a weight change of 1.93% in a dynamic vapor sorption experiment while the relative humidity is varied from 2-10% RH at 40° C.

[0160] In some embodiments, the crystalline form C of compound (I) is characterized by a solubility of 0.03 mg / mL in fasted state simulated intestinal fluid. In some embodiments, the crystalline form C of compound (I) is characterized by a solubility of 2.72 mg / mL in fasted state simulated gastric fluid. In some embodiments, the crystalline form C of compound (I) is characterized by a solubility of 0.03 mg / mL in fasted state simulated intestinal fluid at 37°C. In some embodiments, the crystalline form C of compound (I) is characterized by a solubility of 2.72 mg / mL in fasted state simulated gastric fluid at 37°C.

[0161] In some embodiments, the crystalline Form C of Compound (I) is in substantially pure form. In some embodiments, the crystalline Form C of Compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis using an incident beam of Cu Ka radiation. In some embodiments, the crystalline Form C of Compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis using an incident beam of Cu Ka radiation, the signals of which are substantially similar to those described in Table 3.

[0162] Table 3:

[0163]

[0164]

[0165] In some embodiments, the crystalline Form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 5.3±0.2 degrees 2θ. In some embodiments, the crystalline Form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 9.4±0.2 degrees 2θ. In some embodiments, the crystalline Form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 10.4±0.2 degrees 2θ. In some embodiments, the crystalline Form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 12.0±0.2 degrees 2θ. In some embodiments, the crystalline Form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 13.9±0.2 degrees 2θ. In some embodiments, the crystalline Form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 16.1±0.2 degrees 2θ. In some embodiments, the crystalline Form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 17.4±0.2 degrees 2θ. In some embodiments, the crystalline Form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 22.8±0.2 degrees 2θ. In some embodiments, the crystalline Form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 24.0±0.2 degrees 2θ. In some embodiments, the crystalline Form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 24.8±0.2 degrees 2θ. In some embodiments, the crystalline Form C of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 25.8±0.2 degrees 2θ.

[0166] In some embodiments, Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at 2θ 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, Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least eight 2θ 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, Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least seven 2θ 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, Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least six 2θ 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, Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least five 2θ 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, Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least four 2θ 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, Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least three 2θ 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, Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2θ 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, Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at at least one 2θ 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.

[0167] In some embodiments, the crystalline Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least three 2θ 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, the crystalline Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2θ 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, the crystalline Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least one 2θ 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, Form C of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at 2θ values ​​of 5.3±0.2, 9.4±0.2, 10.4±0.2, 12.0±0.2, and 16.1±0.2.

[0168] In some embodiments, Form C of Compound (I) is characterized by being substantially similar to Figure 6 X-ray powder diffraction pattern of .

[0169] In some embodiments, Form C of Compound (I) is characterized by having 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 C NMR (CDCl3, 100 MHz) pattern.

[0170] In some embodiments, the present disclosure provides a method for preparing Form C of Compound (I), and also provides Form C of Compound (I) prepared by a method comprising the following steps: slurrying Compound (I) in a 1:1 mixture of methanol or tetrahydrofuran: water. In some methods, the method further comprises isolating Form C of Compound (I) by filtration.

[0171] Crystalline Form O of Compound (I)

[0172] In some embodiments, the present disclosure provides a crystalline form O of compound (I):

[0173]

[0174] Figure 7 Shown is an X-ray powder diffraction pattern of Form O of Compound (I) under ambient conditions.

[0175] In some embodiments, Form O of Compound (I) is characterized by a DSC thermogram having an endothermic event with an onset temperature of 182 °C.

[0176] In some embodiments, the crystalline Form O of Compound (I) is in substantially pure form. In some embodiments, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis using an incident beam of Cu Ka radiation. In some embodiments, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis using an incident beam of Cu Ka radiation, the signals of which are substantially similar to those described in Table 4.

[0177] Table 4.

[0178] 2-θ (degrees) 7.17 10.14 10.78 11.37 12.25 14.48 14.68 16.08 17.34 18.95 20.35 21.86 22.71 23.65 25.70 26.96 28.49 29.59 30.46 32.41 34.77 36.37 37.71

[0179] In some embodiments, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 7.2±0.2 degrees 2θ. In some embodiments, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 10.8±0.2 degrees 2θ. In some embodiments, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 12.3±0.2 degrees 2θ. In some embodiments, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 14.5±0.2 degrees 2θ. In some embodiments, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 14.7±0.2 degrees 2θ. In some embodiments, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 16.1±0.2 degrees 2θ. In some embodiments, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 19.0±0.2 degrees 2θ. In some embodiments, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 20.4±0.2 degrees 2θ. In some embodiments, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 23.7±0.2 degrees 2θ.

[0180] In some embodiments, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at 2θ 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, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least eight 2θ 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, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least seven 2θ 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, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least six 2θ 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, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least five 2θ 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, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least four 2θ 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, Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least three 2θ 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, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2θ 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, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2θ 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.

[0181] In some embodiments, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least three 2θ 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, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2θ 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, the crystalline Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least one 2θ 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, Form O of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at 2θ values ​​of 7.2±0.2, 12.3±0.2, 14.7±0.2, 16.1±0.2, and 23.7±0.2.

[0182] In some embodiments, Form O of Compound (I) is characterized by having 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 C NMR (CDCl3, 100 MHz) pattern.

[0183] In some embodiments, the present disclosure provides a method for preparing Form O of Compound (I), and further provides Form O of Compound (I) prepared by a method comprising the following steps: stagnant cooling of Compound (I) in tetrahydrofuran. In some embodiments, the method comprises stagnant cooling of Compound (I) in tetrahydrofuran from room temperature to -20°C. In some embodiments, the method further comprises collecting Form O of Compound (I) by filtration.

[0184] In some embodiments, the present disclosure provides a method for preparing Form O of Compound (I), and further provides Form O of Compound (I) prepared by a method comprising the following steps: stagnant cooling of Form A of Compound (I) in tetrahydrofuran. In some embodiments, the method comprises stagnant cooling of Form A of Compound (I) in tetrahydrofuran from room temperature to -20°C. In some embodiments, the method further comprises collecting Form O of Compound (I) by filtration.

[0185] Crystalline Form T of the Tosylate Salt of Compound (I)

[0186] In some embodiments, the present disclosure provides a crystalline form T of a tosylate salt of Compound (I):

[0187]

[0188] Figure 8 Shown is an X-ray powder diffraction pattern of Form T of the tosylate salt of Compound (I) under ambient conditions.

[0189] In some embodiments, the crystalline Form T of the tosylate salt of Compound (I) is a monotosylate salt of Compound (I), ie, the crystalline Form T comprises Compound (I) and the tosylate salt in a 1:1 ratio.

[0190] In some embodiments, the 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, the 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, the 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 an endothermic event with 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.

[0191] In some embodiments, the crystalline Form T of the tosylate salt of Compound (I) is characterized by a solubility of 0.08 mg / mL in fasting state simulated intestinal fluid. In some embodiments, the crystalline Form T of the tosylate salt of Compound (I) is characterized by a solubility of 1.88 mg / mL in fasting state simulated gastric fluid. In some embodiments, the crystalline Form T of the tosylate salt of Compound (I) is characterized by a solubility of 0.08 mg / mL in fasting state simulated intestinal fluid at 37°C. In some embodiments, the crystalline Form T of the tosylate salt of Compound (I) is characterized by a solubility of 1.88 mg / mL in fasting state simulated gastric fluid at 37°C.

[0192] In some embodiments, Form T of the tosylate salt of Compound (I) is characterized by a solubility in water of 0.34 mg / mL.

[0193] In some embodiments, the crystalline Form T of the tosylate salt of Compound (I) is in substantially pure form. In some embodiments, the crystalline Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis using an incident beam of Cu Ka radiation. In some embodiments, the crystalline Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis using an incident beam of Cu Ka radiation, and its signals are substantially similar to those described in Table 5.

[0194] Table 5.

[0195]

[0196]

[0197] In some embodiments, the crystalline form T of the tosylate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 5.9±0.2 degrees 2θ. In some embodiments, the crystalline form T of the tosylate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 6.1±0.2 degrees 2θ. In some embodiments, the crystalline form T of the tosylate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 9.6±0.2 degrees 2θ. In some embodiments, the crystalline form T of the tosylate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 11.7±0.2 degrees 2θ. In some embodiments, the crystalline form T of the tosylate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 16.0±0.2 degrees 2θ. In some embodiments, the crystalline form T of the tosylate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 19.2±0.2 degrees 2θ. In some embodiments, the crystalline Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 20.8±0.2 degrees 2θ. In some embodiments, the crystalline Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 21.2±0.2 degrees 2θ. In some embodiments, the crystalline Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 22.0±0.2 degrees 2θ. In some embodiments, the crystalline Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 24.1±0.2 degrees 2θ. In some embodiments, the crystalline Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 24.5±0.2 degrees 2θ.

[0198] In some embodiments, Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at 2θ 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, Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least eight 2θ 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, Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least seven 2θ 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, Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least six 2θ 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, Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least five 2θ 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, Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least four 2θ 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, Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least three 2θ 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, Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2θ 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, 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 2θ 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.

[0199] In some embodiments, the 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 2θ 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, the 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 2θ 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, the crystalline Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least one 2θ 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, Form T of the tosylate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at 2θ values ​​of 5.9±0.2, 11.7±0.2, 16.0±0.2, 22.0±0.2, and 24.5±0.2.

[0200] In some embodiments, the crystalline Form T of the tosylate salt of Compound (I) is characterized by being substantially similar to Figure 8 X-ray powder diffraction pattern of .

[0201] In some embodiments, Form T of the tosylate salt of Compound (I) is characterized by having a signal at at least one δ value (expressed in 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 C NMR (DMSO-d6, 500 MHz) pattern.

[0202] In some embodiments, the present disclosure provides a method for preparing the crystalline Form T of the tosylate salt of Compound (I), and also provides the crystalline Form T of the tosylate salt of Compound (I) prepared by a method comprising the steps of: adding Compound (I) and toluenesulfonic acid to a mixture of 2-propanol (IPA) and water; stirring at an elevated temperature; and lowering the temperature.

[0203] 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 occurs at 600 rpm. In some embodiments, the elevated temperature is a temperature ranging from 48°C to 50°C. In some embodiments, lowering the temperature comprises transferring the solution to a hot plate having a temperature ranging from 35°C to 40°C.

[0204] Crystalline form Tr of the tartrate salt of compound (I)

[0205] In some embodiments, the present disclosure provides a crystalline form Tr of a tartrate salt of Compound (I):

[0206]

[0207] Fig. 9 The X-ray powder diffraction pattern of the crystalline form Tr of the tartrate salt of Compound (I) under ambient conditions is shown.

[0208] In some embodiments, the crystalline form Tr of the tartrate salt of Compound (I) is a monotartrate salt, for example, the crystalline form Tr comprises Compound (I) and tosylate in a 1:1 ratio.

[0209] In some embodiments, 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.

[0210] In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is further characterized by having an endothermic event with an onset temperature of 145° C., an endothermic 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 endothermic event with an onset temperature of 254° C. DSC thermogram. In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by having an endothermic event with a signal at 156° C., an endothermic 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 endothermic event with a signal at 257° C. DSC thermogram. In some embodiments, the 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 temperature of 156°C, an endothermic event with an onset temperature of 159°C and a signal temperature of 163°C, an endothermic event with an onset temperature of 205°C and a signal temperature of 213°C, an endothermic event with an onset temperature of 237°C and a signal temperature of 243°C, and / or an endothermic event with an onset temperature of 254°C and a signal temperature of 257°C.

[0211] In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by a solubility of 0.27 mg / mL in fasting state simulated intestinal fluid. In some embodiments, the crystalline form T of the toluenesulfonate salt of compound (I) is characterized by a solubility of 4.79 mg / mL in fasting state simulated gastric fluid. In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by a solubility of 0.27 mg / mL in fasting state simulated intestinal fluid at 37°C. In some embodiments, the crystalline form T of the toluenesulfonate salt of compound (I) is characterized by a solubility of 4.79 mg / mL in fasting state simulated gastric fluid at 37°C.

[0212] In some embodiments, Form T of the tosylate salt of Compound (I) is characterized by a solubility in water of 0.84 mg / mL.

[0213] In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by a weight change of 4.4% in a dynamic vapor sorption experiment while the relative humidity changes from 2-95% RH at room temperature. In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by a weight change of 2.95% to 3% in a dynamic vapor sorption experiment while the relative humidity changes from 2-30% RH at room temperature.

[0214] In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is in substantially pure form. In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation, and its signals are substantially similar to those described in Table 6.

[0215] Table 6

[0216]

[0217]

[0218] In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 6.3±0.2 degrees 2θ. In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 10.6±0.2 degrees 2θ. In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 11.1±0.2 degrees 2θ. In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 12.5±0.2 degrees 2θ. In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 13.3±0.2 degrees 2θ. In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 13.7±0.2 degrees 2θ. In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 14.2±0.2 degrees 2θ. In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 14.9±0.2 degrees 2θ. In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 16.2±0.2 degrees 2θ. In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 19.0±0.2 degrees 2θ. In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 22.5±0.2 degrees 2θ. In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 24.1±0.2 degrees 2θ. In some embodiments, the crystalline Form Tr of the tartrate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 27.9±0.2 degrees 2θ.

[0219] In some embodiments, the crystalline Form Tr of the tartrate salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at 2θ 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, the 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 2θ 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, the 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 2θ 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, the 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 2θ 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, the 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 2θ 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, the 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 2θ 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, the 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 2θ 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, the 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 2θ 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, the 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 2θ 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.

[0220] In some embodiments, the 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 2θ 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, the 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 2θ 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, the 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 2θ 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, the crystalline form Tr of the tartrate salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 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 2θ values.

[0221] In some embodiments, the crystalline form Tr of the tartrate salt of Compound (I) is characterized by being substantially similar to Fig. 9 X-ray powder diffraction pattern of .

[0222] In some embodiments, the crystalline form Tr of the tartrate salt of compound (I) is characterized by having a signal at at least one δ value (expressed as ppm) 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. 13 C NMR (DMSO-d6, 500 MHz) pattern.

[0223] In some embodiments, the present disclosure provides a crystalline form Tr of a tartrate salt of compound (I) prepared by a method comprising the steps of adding compound (I) and tartaric acid to a mixture of tetrafluoroethylene, ethanol and water; stirring; evaporating under gentle stirring; adding acetone and heating to an elevated temperature; and reducing the temperature.

[0224] Crystalline Form H of the hydrochloride salt of Compound (I)

[0225] In some embodiments, the present disclosure provides a crystalline form H of the hydrochloride salt of Compound (I):

[0226]

[0227] Fig.10 Shown is an X-ray powder diffraction pattern of Form H of the hydrochloride salt of Compound (I) under ambient conditions.

[0228] In some embodiments, the crystalline Form H of the hydrochloride salt of Compound (I) is a monohydrochloride salt, for example, the crystalline Form H comprises Compound (I) and the hydrochloride salt in a 1:1 ratio.

[0229] In some embodiments, the crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a TGA thermal curve having an endotherm at 156°C, followed by a recrystallization event, which is associated with a mass loss of 3.3-3.9 wt.%. In some embodiments, the 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 endothermic event with an onset temperature of 173°C, and / or an endothermic event with an onset temperature of 210°C. In some embodiments, the 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 endothermic event with a signal at 176°C, and / or an endothermic event with a signal at 215°C. In some embodiments, 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 endothermic 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.

[0230] In some embodiments, the crystalline Form H of the hydrochloride of Compound (I) is characterized by a solubility of 0.10 mg / mL in fasting state simulated intestinal fluid. In some embodiments, the crystalline Form H of the hydrochloride of Compound (I) is characterized by a solubility of 4.18 mg / mL in fasting state simulated gastric fluid. In some embodiments, the crystalline Form H of the hydrochloride of Compound (I) is characterized by a solubility of 0.10 mg / mL in fasting state simulated intestinal fluid at 37°C. In some embodiments, the crystalline Form H of the hydrochloride of Compound (I) is characterized by a solubility of 4.18 mg / mL in fasting state simulated gastric fluid at 37°C.

[0231] In some embodiments, Form H of the hydrochloride salt of Compound (I) is characterized by a solubility in water of 2.86 mg / mL.

[0232] In some embodiments, the crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a weight change of 15% in a dynamic vapor sorption experiment while the relative humidity (RH) is varied from 2-95% RH at room temperature. In some embodiments, the crystalline Form H of the hydrochloride salt of Compound (I) is characterized by a weight change of 10.8% in a dynamic vapor sorption experiment while the relative humidity is varied from 80-95% RH at room temperature.

[0233] In some embodiments, the crystalline Form H of the hydrochloride salt of Compound (I) is in substantially pure form. In some embodiments, the crystalline Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis using an incident beam of Cu Ka radiation. In some embodiments, the crystalline Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern produced by X-ray powder diffraction analysis using an incident beam of Cu Ka radiation, and its signals are substantially similar to those described in Table 7.

[0234] Table 7.

[0235]

[0236]

[0237] In some embodiments, the crystalline form H of the hydrochloride of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 4.8±0.2 degrees 2θ. In some embodiments, the crystalline form H of the hydrochloride of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 8.1±0.2 degrees 2θ. In some embodiments, the crystalline form H of the hydrochloride of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 8.5±0.2 degrees 2θ. In some embodiments, the crystalline form H of the hydrochloride of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 9.6±0.2 degrees 2θ. In some embodiments, the crystalline form H of the hydrochloride of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 11.1±0.2 degrees 2θ. In some embodiments, the crystalline form H of the hydrochloride of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 20.7±0.2 degrees 2θ. In some embodiments, the crystalline form H of the hydrochloride salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 21.5±0.2 degrees 2θ. In some embodiments, the crystalline form H of the hydrochloride salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 23.3±0.2 degrees 2θ. In some embodiments, the crystalline form H of the hydrochloride salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 23.7±0.2 degrees 2θ. In some embodiments, the crystalline form H of the hydrochloride salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 24.1±0.2 degrees 2θ. In some embodiments, the crystalline form H of the hydrochloride salt of compound (I) is characterized by an X-ray powder diffraction pattern having a signal at 27.6±0.2 degrees 2θ.

[0238] In some embodiments, Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at 2θ 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, Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least eight 2θ 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, Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least seven 2θ 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, Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least six 2θ 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, Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least five 2θ 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, Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least four 2θ 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, Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least three 2θ 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, Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least two 2θ 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, 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 2θ 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.

[0239] In some embodiments, the 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 2θ 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, the 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 2θ 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, the crystalline Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at at least one 2θ 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, Form H of the hydrochloride salt of Compound (I) is characterized by an X-ray powder diffraction pattern having signals at 2θ values ​​of 4.8±0.2, 8.1±0.2, 11.1±0.2, 20.7±0.2, and 23.7±0.2.

[0240] In some embodiments, the crystalline Form H of the hydrochloride salt of Compound (I) is characterized by being substantially similar to Fig.10 X-ray powder diffraction pattern of .

[0241] In some embodiments, Form H of the hydrochloride salt of Compound (I) is characterized by having 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 C NMR (DMSO-d6, 500 MHz) pattern.

[0242] In some embodiments, the present disclosure provides a method for preparing a crystalline form H of the hydrochloride salt of compound (I), and also provides a crystalline form H of the hydrochloride salt of compound (I) prepared by a method comprising the following steps: adding compound (I) to a concentrated hydrochloric acid solution in ethanol; adding tetrafluoroethylene (TFE); and stirring at an elevated temperature. In some embodiments, a solution of 1.1 equivalents of concentrated HCl in ethanol is used. In some embodiments, the elevated temperature range is 35°C to 40°C. In some embodiments, stirring is performed at 340rpm for 30 minutes at an elevated temperature. In some embodiments, after stirring at 340rpm for 15 minutes, a spatula is used to break the jelly. In some embodiments, additional TFE is added after stirring at an elevated temperature. In some embodiments, more stirring is performed at room temperature after adding additional TFE.

[0243] In some embodiments, the present disclosure provides a method for preparing Form H of the hydrochloride salt of Compound (I), and also provides Form H of the hydrochloride salt of Compound (I) prepared by a method comprising the following steps: slurrying Compound (I) in fasting state simulated gastric fluid at 37°C.

[0244] Method for preparing compound (I)

[0245] In some embodiments, the present disclosure provides a method for preparing (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethane-1-amine (Compound (I))

[0246]

[0247] or a pharmaceutically acceptable salt thereof.

[0248] Solution 1

[0249]

[0250] In some embodiments, the present disclosure provides a method for preparing compound (I), comprising treating a compound of formula (VI):

[0251]

[0252] Steps for conversion to compounds of formula (III):

[0253]

[0254] In some embodiments, the compound of formula (III) is diastereomerically pure. The desired diastereomer has the S configuration at the carbon center.

[0255] In some embodiments, the compound of formula (III) is substantially free of the undesired diastereomers (C) and (D):

[0256]

[0257] In some embodiments, the amount of (C) and (D) does not exceed 0.4% w / w (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%.

[0258] In some embodiments, X2 is selected from a carbamate protecting group, 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 group is tert-butyl carbamate, 9-fluorenylmethylcarbamate, and benzyl carbamate. In some embodiments, X2 is tert-butyl carbamate. In some embodiments, X2 is 9-fluorenylmethylcarbamate. In some embodiments, X2 is benzyl carbamate.

[0259] The present disclosure provides a method for preparing a compound of formula (III) in diastereomeric pure form (e.g., such as compound 7). It has been found that the diastereomeric purity of the compound of formula (III) is important for ensuring the purity of the final compound (I). In some embodiments, the method for preparing a compound of formula (III) in diastereomeric pure form includes grinding. In some embodiments, the grinding solvent in the grinding step of the compound of formula (VI) comprises n-heptane and methanol. In some embodiments, the method for preparing a compound of formula III in diastereomeric pure form includes recrystallization. In some embodiments, the recrystallization solvent is isopropanol. In some embodiments, the recrystallization solvent is a mixture of ethyl acetate and heptane.

[0260] In some embodiments, the present disclosure provides a method for preparing (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethane-1-amine (Compound (I)):

[0261]

[0262] or a pharmaceutically acceptable salt thereof, comprising:

[0263] (a) Make (S)-1-(2-(4λ 2 -piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine (2) or a salt thereof;

[0264]

[0265] Reaction with a compound of formula (I):

[0266]

[0267] 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.

[0268] In some embodiments, (S)-1-(2-(4λ 2 -piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine (2) is the free base. In some embodiments, (S)-1-(2-(4λ 2The salt of (S)-1-(2-(4λ-piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethane-1-amine (2) is a hydrochloride or a trifluoroacetate salt. 2 -piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethane-1-amine (2) is a hydrochloride salt. In some embodiments, (S)-1-(2-(4λ 2 -piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethane-1-amine (II) hydrochloride is (S)-1-(2-(4λ 2 -piperazine-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethane-1-amine 3.5 HCl (2A). In some embodiments, (S)-1-(2-(4λ 2 The salt of 1-(4-fluorophenyl)-1-piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine (2) is the trifluoroacetate salt.

[0269] In some embodiments, 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine (3):

[0270] Prepared by

[0271] (b) 6-bromopyrrolo[2,1-f][1,2,4]triazine-4-ol (4):

[0272]

[0273] Reaction with a compound of formula (II):

[0274]

[0275] To form 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-ol (6):

[0276] as well as

[0277] (c) 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-ol (6):

[0278]

[0279] Conversion to 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine (3):

[0280]

[0281] In some embodiments, B(OR)2 is selected from:

[0282] Catechol borane:

[0283]

[0284] Pinacol borane:

[0285] and

[0286] Boric acid.

[0287] In some embodiments, B(OR)2 is catechol borane. In some embodiments, B(OR)2 is pinacol borane. In some embodiments, B(OR)2 is selected from boric acid. In some embodiments, the boric acid is, for example, isopropyl boronic acid, methyl boronic acid, or BF3 boronic acid. In some embodiments, B(OR)2 is B(OH)2.

[0288] 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).

[0289] In some embodiments, step (c) is performed 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.

[0290] In some embodiments, step (c) is carried out in the presence of sulfur chloride and a phosphorus reagent. In some embodiments, the sulfur chloride and phosphorus reagent are selected from phosphorus oxychloride, phosphorus pentachloride, sulfuryl chloride and trichloromethanesulfonyl chloride. In some embodiments, the sulfur chloride and phosphorus reagent are phosphorus oxychloride. In some embodiments, the sulfur chloride and phosphorus reagent are phosphorus pentachloride. In some embodiments, the sulfur chloride and phosphorus reagent are selected from sulfuryl chloride. In some embodiments, the sulfur chloride and phosphorus reagent are trichloromethanesulfonyl chloride.

[0291] In some embodiments, (S)-1-(2-(4λ 2 -piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethane-1-amine (2) or a pharmaceutically acceptable salt thereof:

[0292] or a pharmaceutically acceptable salt thereof is prepared by

[0293] (d) a compound of formula (III):

[0294]

[0295] Transformed into (S)-1-(2-(4λ 2 -piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethane-1-amine (2) or a pharmaceutically acceptable salt thereof:

[0296]

[0297] In some embodiments, X2 is selected from a carbamate protecting group, 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 group is tert-butyl carbamate, 9-fluorenylmethylcarbamate, and benzyl carbamate. In some embodiments, X2 is tert-butyl carbamate. In some embodiments, X2 is 9-fluorenylmethylcarbamate. In some embodiments, X2 is benzyl carbamate.

[0298] In some embodiments, the pharmaceutically acceptable salt is (S)-1-(2-(4λ 2 -piperazine-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethane-1-amine (2) hydrochloride. In some embodiments, the pharmaceutically acceptable salt is (S)-1-(2-(4λ 2 -piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine 3.5 HCl (2A):

[0299]

[0300] In some embodiments, the pharmaceutically acceptable salt (S)-1-(2-(4λ 2-piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine 3.5 HCl (2A) was not isolated.

[0301] In some embodiments, step (d) is carried out 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 carried out in the presence of iodine. In some embodiments, step (d) is carried out under pyrolysis conditions.

[0302] Some embodiments of the present disclosure include:

[0303] (e) treating a compound of formula (IV):

[0304]

[0305] Conversion to a compound of formula (V):

[0306]

[0307] 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-sulfenamide or (S)-p-toluenesulfenamide. In some embodiments, step (e) is carried out in the presence of (S)-2-methylpropane-2-sulfenamide. In some embodiments, step (e) is carried out in the presence of (S)-p-toluenesulfenamide.

[0308] Some embodiments of the present disclosure include:

[0309] (f) treating a compound of formula (V):

[0310]

[0311] Converted into a compound of formula (VI):

[0312]

[0313] 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.

[0314] Some embodiments of the present disclosure include:

[0315] (g) grinding the compound of formula (VI):

[0316]

[0317] To obtain a compound of formula (III):

[0318]

[0319] In some embodiments, the grinding solvent in step (g) comprises n-heptane and methanol.

[0320] Some embodiments of the present disclosure include:

[0321] (g) Recrystallizing the compound of formula (VI):

[0322]

[0323] To obtain a compound of formula (III):

[0324]

[0325] 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.

[0326] Some embodiments of the present disclosure include:

[0327] (h) making a compound of formula (VII):

[0328]

[0329] Reaction with 4-fluoro-N-methoxy-N-methylbenzamide (12):

[0330]

[0331] To form a compound of formula (IV):

[0332]

[0333] 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.

[0334] In some embodiments, the present disclosure provides a method for preparing a compound

[0335] A method comprising

[0336] Grind or recrystallize the compound of formula (VI):

[0337]

[0338] To obtain a compound of formula (III):

[0339]

[0340] In some embodiments, X2 is selected from a carbamate protecting group, 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 group is tert-butyl carbamate, 9-fluorenylmethylcarbamate, and benzyl carbamate. In some embodiments, X2 is tert-butyl carbamate. In some embodiments, X2 is 9-fluorenylmethylcarbamate. In some embodiments, X2 is benzyl carbamate.

[0341] In some embodiments, the grinding solvent in the grinding step of the compound of formula (VI) comprises n-heptane and methanol, or the recrystallization solvent in the recrystallization step of the compound of formula (VI) is isopropanol or heptane / ethyl acetate.

[0342] The present disclosure provides a method for purifying compound (I) to remove its undesirable enantiomer (compound (E)). Compound (I) can be crystalline, a mixture of crystalline forms or non-crystalline, such as an amorphous solid. Specifically, the present disclosure provides a method for preparing compound (I), which includes forming a salt of compound (I) and D-quinic acid in an organic solvent, and crystallizing the salt from a 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 method further includes recrystallizing compound (I) in acetone and water as described herein.

[0343] Indications

[0344] The crystalline form of compound (I) described herein, its pharmaceutically acceptable salt, and any solvate of the foregoing substances described herein can be used to treat human or non-human conditions associated with abnormal KIT activity. Activating mutations of KIT exist in a variety of indications, including systemic mastocytosis, gastrointestinal stromal tumors (GIST), acute myeloid leukemia (AML), melanoma, seminoma, intercranial germ cell tumors and mediastinal B-cell lymphoma.

[0345] Mastocytosis refers to a group of conditions characterized by excessive accumulation of mast cells in one or more tissues. Mastocytosis is subdivided into two groups of conditions: (1) cutaneous mastocytosis (CM) describes a form that is limited to the skin; and (2) systemic mastocytosis (SM) describes a form in which mast cells infiltrate extracutaneous organs, with or without cutaneous 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) with no documented systemic involvement) to be 0.89 / 100,000 per year. The prevalence of ISM in the Groningen region of the Netherlands (the main referral area for patients with SM) is estimated to be 13 / 100,000. Mutations in KIT D816 are confirmed in 90% to 95% of patients with SM.

[0346] SM is further subdivided into five forms: indolent (ISM), smoldering (SSM), aggressive (ASM), SM with associated hematologic non-mast cell lineage disorders (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-AdvSM) refers to ISM and SSM.

[0347] The diagnosis of systemic mastocytosis is based in part on histologic and cytologic studies of the bone marrow, which show infiltration of mast cells that often have atypical morphology and often aberrantly express non-mast cell markers (CD25 and / or CD2). SM is diagnosed 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 above 20 ng / mL; or (3) the presence of an activating KIT D816V mutation.

[0348] Activating mutations at position D816 are found in the majority of mastocytosis cases (90%-98%), with the most common mutations being D816V, D816H, and D816Y. The D816V mutation resides in the activation loop of the kinase domain and results in constitutive activation of the KIT kinase.

[0349] There are no approved treatments for ISM and SSM; symptoms are managed with symptom-directed therapies, such as antihistamines. Therefore, safe, effective treatments for ISM and SSM are needed. In addition, because patients with ISM and SSM have a lower disease burden than patients with AdvSM and are expected to remain on treatment long-term, lower doses (if effective) are desirable.

[0350] The crystalline form of compound (I), its pharmaceutically acceptable salt, and any solvate of the foregoing can also be used to treat GIST, such as PDGFRα-exon 18 mutation-driven GIST, PDGFRα-exon 18D842-driven GIST (e.g., PDGFRα-D842I-driven GIST, PDGFRα-D842V-driven GIST or PDGFRα-D842Y-driven GIST), PDGFRα-exon 18 mutation non-D842-driven GIST (e.g., PDGFRα-D842-H845-driven GIST, PDGFRα-DI842-843V-driven GIST), regardless of previous treatment. Approximately 90% of patients with GIST have tumors that are dependent on mutations in either V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) (75%-80%) or the highly 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 in the juxtamembrane domain (exon 11 [60%-70%]) and extracellular domain (exon 9 [5%-15%]) of KIT and in the activation loop (exon 18) of PDGFRα, with the most common activation loop mutation being D842V.

[0351] Complete surgical resection remains the main treatment option for patients with primary GIST. GIST is considered insensitive to neither systemic cytotoxic chemotherapy nor radiation therapy. Surgery is effective in approximately 50% of patients with GIST. For the remaining patients, tumor recurrence is frequent. Initial treatment with KIT inhibitors such as imatinib has also been shown to be sufficient for the initial treatment of GIST. However, GIST patients develop resistance to imatinib within a few months through somatic mutations of KIT, which significantly reduce the binding affinity of imatinib. 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 the treatment of GIST are selective targeted drugs. Instead, the agents 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 mutants. In addition, the therapeutic value of multikinase inhibitors may be limited due to a more complex safety profile and a smaller therapeutic window. Therefore, therapeutic agents are needed to treat patients with GIST that are resistant to imatinib.

[0352] There is a subgroup of patients with unresectable or metastatic GIST who have received at least three prior courses of therapy. The compounds described herein can be used to treat these patients.

[0353] In addition to using a crystalline form of compound (I), a pharmaceutically acceptable salt thereof, and any solvate of the foregoing substances described herein as a medicament in the setting of refractory GIST, the use of imatinib, sunitinib and / or regorafenib in combination with at least one crystalline form selected from a crystalline form of compound (I), a pharmaceutically acceptable salt thereof, and any solvate of the foregoing substances disclosed herein can prevent the emergence of resistance to exon 17 mutations.

[0354] There is a subgroup of GIST patients with changes in the PDGFRα activation loop. There is a subgroup of GIST patients with point mutations in the PDGFRα activation loop. There is a subgroup of GIST patients with D842V mutations in PDGFRα; this subgroup of GIST patients can be stratified by identifying this mutation. This subgroup of patients is refractory to all currently available tyrosine kinase inhibitors. Due to their selective activity against PDGFRαD842V, the compounds described herein can be used to treat these patients.

[0355] Mutating the aspartic acid (D) residue at position 842 of exon 18 of PDGFRα to isoleucine (I) or tyrosine (Y) results in ligand-independent, constitutive activation of PDGFRα tyrosine kinase activity. There is also a subgroup of GIST patients that have a D842I mutation in PDGFRα; this subgroup of GIST patients can be stratified by identifying this mutation. Due to their selective activity for PDGFRαD842I, the compounds described herein can be used to treat these patients. In addition, there is a subgroup of GIST patients that have a D842Y mutation in PDGFRα; this subgroup of GIST patients can be stratified by identifying this mutation. Due to their selective activity for PDGFRαD842Y, the compounds described herein can be used to treat these patients.

[0356] There is a subgroup of GIST patients that have indels in the PDGFRα activation loop. There is a subgroup of GIST patients that have changes D842-H845 in PDGFRα; this subgroup of GIST patients can be stratified by identifying this change. Due to their selective activity against PDGFRα D842-H845 in PDGFRα, the compounds described herein can be used to treat these patients.

[0357] There is a subgroup of GIST patients that have the alteration DI842-843V in PDGFRα; this subgroup of GIST patients can be stratified by identifying this alteration. Due to their selective activity against PDGFRα DI842-843V in PDGFRα, the compounds described herein can be used to treat these patients.

[0358] The crystalline form of Compound (I) described herein, its pharmaceutically acceptable salt, and any solvate of the foregoing substances can also be used to treat AML. AML patients also contain KIT mutations, wherein most KIT mutations occur at position D816.

[0359] Additionally, mutations in KIT have been associated with Ewing's sarcoma, DLBCL (diffuse large B-cell lymphoma), dysgerminoma, MDS (myelodysplastic syndrome), NKTCL (nasal NK / T-cell lymphoma), CMML (chronic myelomonocytic leukemia), and brain cancer.

[0360] The crystalline form of compound (I) disclosed herein, its pharmaceutically acceptable salt, and the solvate of any of the foregoing substances 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 form can also be used to treat conditions associated with wild-type KIT. The crystalline form of compound (I) herein, its pharmaceutically acceptable salt, and the solvate of any of the foregoing substances can be used as a medicament for treating 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 agents include compounds described in WO 2014 / 039714 and WO 2014 / 100620.

[0361] The crystalline forms of Compound (I) described herein, pharmaceutically acceptable salts thereof, and solvates of any of the foregoing may be 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 have much less activity against wild-type KIT. In some embodiments, the crystalline form of Compound (I) herein, a pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing substances may be active against at least one KIT mutant exon 11, 11 / 17, and 17 mutants (d557-558, V560G, V560G / D816V, V560G / N822K, D816E, D816F, D816H, D816I, D816V, D816Y, D820E, D820Y, and Y823D).

[0362] The crystalline form can be administered in combination with an agent that is (a) active against other activating mutations of KIT (such as exon 9 and 11 mutations) but (b) inactive against exon 17 mutations. Such agents include imatinib, sunitinib and regorafenib. Thus, a combination of at least one crystalline form selected from a crystalline form of compound (I), a pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing substances and an agent will inhibit exon 17 mutant KIT and inhibit exon 9 / 11 mutant KIT. The at least one crystalline form and the agent can be administered together or in an alternating regimen. That is, the exon 17 mutant KIT inhibitor can be administered alone for a period of time; then the exon 9 / 11 mutant KIT inhibitor can be administered alone for a subsequent period of time. The cycle can then be repeated. It is believed that this regimen can slow the development of resistance to exon 17 mutant KIT inhibitors and / or exon 9 / 11 mutant KIT inhibitors.

[0363] In addition, at least one crystalline form selected from the crystalline forms of compound (I) described herein, its pharmaceutically acceptable salt, and any solvate of the foregoing that is selective for exon 17 KIT mutations can be administered together with at least one agent that is active against exon 9 / 11 mutations, which is combined with a third agent that covers mutations missed by the two-way combination. The combination of these three agents can inhibit a range of KIT mutations and, in some cases, wild-type KIT. The agents can be administered simultaneously or in alternating regimens. They can be administered one at a time, or two agents can be administered together for a period of time; then the third agent can be administered alone over a subsequent period of time. It is believed that this regimen can slow the development of resistance to mutant KIT inhibitors.

[0364] In some embodiments, at least one crystalline form selected from the crystalline form of Compound (I), a pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing can be used alone or in combination with imatinib, sunitinib and / or regorafenib.

[0365] In some embodiments, at least one crystalline form selected from the crystalline form of Compound (I), a pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing substances can be used in combination with other treatment modalities (such as surgery or radiotherapy).

[0366] Drug administration

[0367] The effective dosage for any particular patient or subject will depend on a variety of factors, including: the condition being treated and the severity of the condition; the specific pharmaceutical composition employed; the age, weight, general health, sex, and diet of the patient or subject; the time of administration, route of administration, duration of treatment; and similar factors well known in the medical art.

[0368] In some embodiments, a therapeutically effective amount of at least one crystalline form selected from a crystalline form of Compound (I), a pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing substances (e.g., 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 a crystalline form of Compound (I), a pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing substances (e.g., Form A of Compound (I)) is administered to a patient in need thereof once daily.

[0369] In some embodiments, the therapeutically effective amount of at least one crystalline form administered to a patient once daily is in the range of 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, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 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., Form A of Compound (I), Form B of Compound (I) or Form O of Compound (I)) or a weight equivalent amount of a crystalline form of a pharmaceutically acceptable salt thereof (e.g., Form T of a tosylate salt of Compound (I), Form Tr of a tartrate salt of Compound (I) or Form H of a hydrochloride salt of Compound (I)) or a weight equivalent amount of a solvate of Compound (I) or a crystalline form of a pharmaceutically acceptable salt thereof (e.g., Form C of Compound (I)).

[0370] The present disclosure provides an improved method for treating Adv SM 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, or 300 mg) of a crystalline form of compound (I) (e.g., Form A of compound (I), Form B of compound (I), or Form O of compound (I)) or a weight equivalent of a crystalline form of a pharmaceutically acceptable salt thereof (e.g., Form T of a tosylate salt of compound (I), Form Tr of a tartrate salt of compound (I), or Form H of a hydrochloride salt of compound (I)) or a weight equivalent of a solvate of compound (I) or a crystalline form of a pharmaceutically acceptable salt thereof (e.g., 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 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 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 Form A of Compound (I) is 300 mg administered once daily.

[0371] The present disclosure provides an improved method for treating GIST in patients in need 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 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)) in the range of 300 mg to 400 mg (e.g., 325 mg, 350 mg, 375 mg, or 400 mg) or a weight equivalent of a crystalline form of a pharmaceutically acceptable salt thereof (e.g., crystalline form T of a toluenesulfonate of compound (I), crystalline form Tr of a tartrate of compound (I), or crystalline form H of a hydrochloride of compound (I)) or a weight equivalent of a solvate of compound (I) or a crystalline form of a pharmaceutically acceptable salt thereof (e.g., crystalline form C of compound (I)). In some embodiments, the patient suffers from gastrointestinal stromal tumors and the therapeutically effective amount of Form A of Compound (I) is 300 mg to 400 mg administered once daily. In some embodiments, the patient suffers from GIST and the therapeutically effective amount of Form A of Compound (I) is 300 mg administered once daily. In some embodiments, the patient suffers from GIST and the therapeutically effective amount of Form A of Compound (I) is 400 mg administered once daily. If 300 mg of 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 Form A of Compound (I) once daily is well tolerated by the patient 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.

[0372] 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 a safe and effective dosing regimen 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.

[0373] According to the latest clinical studies as shown in Example 12, it has now been found that compound (I) administered once a day at 25 mg in patients with ISM or SSM shows improvements in all three aspects of its clinical characteristics, including reduction of mast cell load, improvement of symptoms of the disease and improvement of quality of life. Specifically, compound (I) administered once a day at 25 mg has statistically significant reductions in each symptom in ISM-SAF TSS and total domain scores at 16 weeks. Surprisingly, the 25 mg dose provides TSS average improvements and better tolerability similar to higher doses of 50 mg and 100 mg. For example, similar to the 50 mg QD dose and the 100 mg QD dose, the 25 mg QD dose shows a significant reduction in the blood KIT D816V allele score. In addition, compound (I) administered once a day at 25 mg in patients has good safety in patients with ISM. For example, 95% of patients continue clinical studies without interruption due to adverse reactions (AEs). No AEs of grade ≥3 occurred in the 25 mg cohort once a day. At week 16, patients' quality of life (QoL) improved as measured by the MC-QoL overall score and all domain scores.

[0374] The present disclosure provides an improved method 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, the therapeutically effective amount of at least one crystalline form administered to a patient once daily is an amount ranging from 25 mg to 100 mg (e.g., 25, 50, or 100 mg) of a crystalline form of compound (I) (e.g., Form A of compound (I), Form B of compound (I), or Form O of compound (I)) or a weight equivalent of a crystalline form of a pharmaceutically acceptable salt thereof (e.g., Form T of a tosylate salt of compound (I), Form Tr of a tartrate salt of compound (I), or Form H of a hydrochloride salt of compound (I)) or a weight equivalent of a solvate of compound (I) or a crystalline form of a pharmaceutically acceptable salt thereof (e.g., Form C of compound (I)). In some embodiments, the patient suffers from indolent or smoldering systemic mastocytosis and the therapeutically effective amount of Form A of Compound (I) is 25 mg to 100 mg administered once daily. In some embodiments, the patient suffers from indolent or smoldering systemic mastocytosis and the therapeutically effective amount of Form A of Compound (I) is 25 mg administered once daily. In some embodiments, the patient suffers from indolent or smoldering systemic mastocytosis and the therapeutically effective amount of Form A of Compound (I) is 50 mg administered once daily. In some embodiments, the patient suffers from indolent or smoldering systemic mastocytosis and the therapeutically effective amount of Form A of Compound (I) is 100 mg administered once daily.

[0375] The present disclosure provides a method for treating indolent systemic mastocytosis (ISM) or smoldering systemic mastocytosis (SSM), comprising administering to a patient in need thereof an amount of 10 mg to 100 mg of a compound (I) or a pharmaceutically acceptable salt thereof, equivalent to 10 mg to 100 mg of the compound (I), once a day. In some embodiments, 10 mg to 100 mg of the compound (I) is administered to a patient in need thereof once a day. In some embodiments, 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)) is administered to a patient in need once a day. In some embodiments, the amount is 10 mg to 25 mg once a day. In some embodiments, the amount is 10 mg to 50 mg once a day. In some embodiments, the amount is 10 mg to 75 mg once a day. In some embodiments, the amount is 10 mg to 100 mg once a day. In some embodiments, the amount is 25 mg to 50 mg once a day. In some embodiments, the amount is 25 mg to 100 mg once a day. In some embodiments, the amount is 50 mg to 100 mg once a day. In some embodiments, the amount is 75 mg to 100 mg once a day. In some embodiments, the amount is 10 mg once a day. In some embodiments, the amount is 15 mg once a day. In some embodiments, the amount is 20 mg once a day. In some embodiments, the amount is 25 mg once a day. In some embodiments, the amount is 30 mg once a day. In some embodiments, the amount is 35 mg once a day. In some embodiments, the amount is 35 mg once a day. In some embodiments, the amount is 40 mg once a day. In some embodiments, the amount is 45 mg once a day. In some embodiments, the amount is 50 mg once a day. In some embodiments, the amount is 55 mg once a day. In some embodiments, the amount is 60 mg once a day. In some embodiments, the amount is 65 mg once a day. In some embodiments, the amount is 70 mg once a day. In some embodiments, the amount is 75 mg once a day. In some embodiments, the amount is 80 mg once a day. In some embodiments, the amount is 85 mg once a day.In some embodiments, the amount is 90 mg once a day. In some embodiments, the amount is 95 mg once a day. In some embodiments, the amount is 100 mg once a day.

[0376] In some embodiments, at least one crystalline form selected from the crystalline form of compound (I) disclosed herein, its pharmaceutically acceptable salt, and any solvate of the foregoing is administered orally. In some embodiments, at least one crystalline form selected from the crystalline form of compound (I) disclosed herein, its pharmaceutically acceptable salt, and any solvate of the foregoing is administered until disease progression, unacceptable toxicity, or individual choice.

[0377] In clinical trials using Form A of Compound (I), adverse reactions were graded 1-5 in terms of severity. Most adverse events reported were Grade 1 or 2, indicating that Form A of Compound (I) was well tolerated. Patients administered Form A of Compound (I) did not exhibit severe dose-limiting toxicities observed with other tyrosine kinase inhibitors (TKIs), such as skin, liver, and cardiovascular toxicities. The severe dose-limiting toxicities of other TKIs may be the result of inhibiting multiple kinases.

[0378] Pharmaceutical composition

[0379] The crystalline forms described herein can be used as active pharmaceutical ingredients (API) and materials for preparing pharmaceutical compositions that incorporate one or more pharmaceutically acceptable excipients and are suitable for administration to human subjects. In some embodiments, these pharmaceutical compositions will be pharmaceutical products, such as solid oral dosage forms, such as tablets and / or capsules. In the preparation of these pharmaceutical compositions, it may be impossible to detect any sufficient amount of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl))pyrrolo[2,1-f][1,2,4]triazine-4-yl)piperazine-yl)pyrimidin-5-yl)ethyl-1-amine crystalline forms. For example, in the case where the crystalline API is contacted with one or more pharmaceutically acceptable excipients in the presence of a solvent (such as water), the crystalline form may be undetectable, and the amount of the solvent is sufficient to promote the dissolution of the API, for example, so that its crystalline characteristics are lost and therefore not present in the final pharmaceutical product.

[0380] 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)piperazinyl)pyrimidin-5-yl)ethan-1-amine can be used in a method of preparing a pharmaceutical composition, for example, involving spray drying or wet granulation. In cases where the method involves spray drying or wet granulation, little or no crystalline form will likely be detected in the resulting pharmaceutical composition.

[0381] In some embodiments, the present disclosure provides a pharmaceutical composition consisting of at least one crystalline form selected from the crystalline form of Compound (I), a pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing.

[0382] In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one crystalline form selected from a crystalline form of compound (I), a pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing substances. 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 toluenesulfonate of compound (I), crystalline form Tr of tartrate of compound (I) and / or crystalline form H of hydrochloride of compound (I) can be formulated into a pharmaceutical composition and administered in any convenient manner for use in humans or veterinary medicine.

[0383] In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one crystalline form selected from a crystalline form of compound (I), a pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing substances, 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. In the sense of being compatible with the subject composition and its components and harmless to the patient, each excipient must be "pharmaceutically acceptable". Unless any conventional pharmaceutically acceptable excipient is incompatible with a crystalline form of compound (I) and / or compound (I), a pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing substances, such as by producing any undesirable biological effect or interacting with any other component of a pharmaceutically acceptable composition in a harmful manner, its use is considered to be within the scope of the present disclosure.

[0384] Some non-limiting examples of materials that can be used as pharmaceutically acceptable excipients include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn starch, and sesame oil. Rice oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffered saline; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0385] Remington: The Science and Practice of Pharmacy, 21st edition, 2005 edition, DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, ed. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York (the contents of each of which are incorporated herein by reference) also discloses additional non-limiting examples of pharmaceutically acceptable excipients, as well as known techniques for making and using the same.

[0386] Pharmaceutical compositions disclosed herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or by implanted reservoirs. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions disclosed herein are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the pharmaceutical compositions disclosed herein can be an aqueous or oily suspension. These suspensions can be formulated using appropriate dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspension media.

[0387] For this purpose, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids (such as oleic acid and its glyceride derivatives) can be used to prepare injectables, as can natural pharmaceutically acceptable oils (such as olive oil or castor oil), especially their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tween, Spans and other emulsifiers or bioavailability enhancers (which are commonly used to make pharmaceutically acceptable solids, liquids or other dosage forms) can also be used for formulation purposes.

[0388] Pharmaceutical compositions disclosed herein can also be orally administered in any oral acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. When oral use requires an aqueous suspension, the active ingredient is usually combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavoring agents or coloring agents may also be added.

[0389] Alternatively, the pharmaceutical compositions disclosed herein can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the medicament with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0390] Pharmaceutical compositions of the present disclosure may also be applied topically, particularly when the therapeutic target includes areas or organs that are easily accessible by topical application, including eye diseases, skin diseases, or lower intestinal diseases. It is easy to prepare suitable topical formulations for each of these areas or organs. Topical application of the lower intestinal tract may be achieved with a rectal suppository formulation (see above) or with a suitable enema formulation. Topical transdermal patches may also be used.

[0391] For topical application, the pharmaceutical composition can be formulated into a suitable ointment containing an active component suspended or dissolved in at least one excipient. Excipients for topical application of the disclosed compound 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 can be formulated into a suitable lotion or cream containing an active component 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.

[0392] 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 pharmaceutical formulation and may be prepared as saline solutions, using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0393] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: at least one pharmaceutically acceptable excipient; and at least one crystalline form selected from a crystalline form of Compound (I), a pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing.

[0394] 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, comprising the extragranular portion of the pharmaceutical composition.

[0395] The fillers suitable for the pharmaceutical compositions disclosed herein are compatible with the other ingredients of the pharmaceutical compositions, i.e., they do not substantially reduce the solubility, hardness, chemical stability, physical stability or biological activity of the pharmaceutical compositions. Non-limiting examples of suitable fillers include cellulose, modified cellulose (e.g., sodium carboxymethylcellulose, ethylcellulose hydroxymethylcellulose, hydroxypropyl cellulose), cellulose acetate, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, starch (e.g., corn starch, potato starch), sugars (e.g., mannitol, lactose, sucrose, etc.), or any combination thereof. In some embodiments, the filler is microcrystalline cellulose.

[0396] In some embodiments, the pharmaceutical composition comprises at least one extragranular filler in an amount of 15 wt% to 20 wt% (e.g., 15 wt%, 15.5 wt%, 16 wt%, 16.5 wt%, 17%, 17.5 wt%, 18 wt%, 18.5 wt%, 19 wt%, 19.5 wt%, or 20 wt%) based on the weight of the pharmaceutical composition. For example, in some embodiments, the pharmaceutical composition comprises 15 wt% to 20 wt% (e.g., 15 wt%, 15.5 wt%, 16 wt%, 16.5 wt%, 17%, 17.5 wt%, 18 wt%, 18.5 wt%, 19 wt%, 19.5 wt%, or 20 wt%) of extragranular microcrystalline cellulose, such as MCC Avicel PH-200, based on the weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises 17 wt% of extragranular microcrystalline cellulose, such as MCC Avicel PH-200, based on the weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises 17 wt% of extragranular Avicel PH-200, based on the weight of the pharmaceutical composition.

[0397] Disintegrants suitable for use in pharmaceutical compositions disclosed herein can enhance the dispersion of the pharmaceutical composition and are compatible with the other ingredients 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 cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, crospovidone, or any combination thereof. In some embodiments, the disintegrant is cross-linked sodium carboxymethyl cellulose. In some embodiments, the disintegrant is Ac-Di-Sol.

[0398] In some embodiments, the pharmaceutical compositions disclosed herein include an extragranular disintegrant in an amount of 2 wt% to 3 wt% (e.g., 2 wt%, 2.1 wt%, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3 wt%) based on the weight of the pharmaceutical composition. For example, in some embodiments, the pharmaceutical composition includes 2 wt% to 3 wt% (e.g., 2 wt%, 2.1 wt%, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3 wt%) of extragranular cross-linked sodium carboxymethylcellulose, such as Ac-Di-Sol, based on the weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition includes 2.5 wt% of extragranular cross-linked sodium carboxymethylcellulose, such as Ac-Di-Sol, based on the weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises 2.5 wt% of extragranular Ac-Di-Sol, based on the weight of the pharmaceutical composition.

[0399] In some embodiments, pharmaceutical compositions disclosed herein include lubricants. Lubricants can prevent mixture components from adhering to surfaces (e.g., surfaces of mixing bowls, granulation rollers, die pressing and / or punches). Lubricants can also reduce intragranular friction between particles, and improve compression and discharge of compressed pharmaceutical compositions from granulators and / or molding presses. Suitable lubricants for pharmaceutical compositions disclosed herein are compatible with other ingredients of pharmaceutical compositions, i.e., they do not substantially reduce the solubility, hardness or biological activity of pharmaceutical compositions. 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, lubricant is magnesium stearate.

[0400] In some embodiments, the pharmaceutical composition comprises an extragranular lubricant in an amount of 0.25 wt% to 1 wt% (e.g., 0.25 wt%, 0.3 wt%, 0.35 wt%, 0.4 wt%, 0.45 wt%, 0.5 wt%, 0.55 wt%, 0.6 wt%, 0.65 wt%, 0.7 wt%, 0.75 wt%, 0.8 wt%, 0.85 wt%, 0.9 wt%, 0.95 wt%, 1 wt%) based on the weight of the pharmaceutical composition. For example, in some embodiments, the pharmaceutical composition comprises 0.25 wt% to 1 wt% (e.g., 0.25 wt%, 0.3 wt%, 0.35 wt%, 0.4 wt%, 0.45 wt%, 0.5 wt%, 0.55 wt%, 0.6 wt%, 0.65 wt%, 0.7 wt%, 0.75 wt%, 0.8 wt%, 0.85 wt%, 0.9 wt%, 0.95 wt%, 1 wt%) of extragranular magnesium stearate, based on the weight of the pharmaceutical composition.

[0401] In some embodiments, pharmaceutical compositions disclosed herein are in tablet form. Tablets disclosed herein can be produced by compacting or compressing a mixture or composition (e.g., powder or granules) under pressure to form a stable three-dimensional shape. As used herein, "tablet" refers to a compressed drug dosage unit form of any shape or size, whether coated or uncoated. In some embodiments, tablets disclosed herein include an intragranular portion and an extragranular portion.

[0402] In some embodiments, the method for preparing a tablet disclosed herein comprises: (a) mixing at least one crystalline form selected from a crystalline form of compound (I), a pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing substances, at least one first filler, at least one binder, at least one first disintegrant, and at least one first lubricant (intragranular mixture); (b) granulating the intragranular mixture (granular 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; (e) compressing the tablet mixture comprising the granular mixture and the extragranular mixture into a tablet. Steps (a), (b), and (c) may occur in any order. Any suitable method known in the art for granulation and compression of pharmaceutical compositions may be used.

[0403] The adhesive that is suitable for pharmaceutical composition disclosed herein (for example, tablet) can enhance the cohesion and / or tensile strength of pharmaceutical composition (for example, tablet), and is compatible with other components of pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, physical stability, hardness or biological activity of pharmaceutical composition. The non-limiting examples of suitable adhesive include copolyvidone, calcium hydrogen phosphate, sucrose, corn (maize) starch, microcrystalline cellulose and modified cellulose (for example, hydroxymethyl cellulose). In some embodiments, adhesive is copolyvidone. In some embodiments, adhesive is Kollidon VA64Fine.

[0404] In some embodiments, the methods disclosed herein further include coating tablets. The tablets disclosed herein can be coated with a film coating, waxed, and optionally marked with a logo, other images, and / or text using a suitable ink. Suitable film coatings and inks are compatible with the other ingredients of the tablet, e.g., they do not substantially reduce the solubility, chemical stability, physical stability, hardness, or biological activity of the tablet.

[0405] 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.

[0406] In some embodiments, tablets disclosed herein can be coated with a film coating (eg, Opadry II) and optionally marked with a logo, other images, and / or text using a suitable ink.

[0407] In some embodiments, at least one crystalline form selected from the crystalline form of Compound (I), a pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing is in the form of particles.

[0408] In some embodiments, the tablet described herein comprises granules, the granules comprising 30-50 wt% of granules of at least one crystalline form of Compound (I) or an equivalent amount of granules of a pharmaceutically acceptable salt thereof or a solvate of any of the foregoing substances, 30-35 wt% of at least one first filler; 2.5-7.5 wt% of at least one binder; 2-3 wt% of at least one first disintegrant; and 0.25-1 wt% of at least one first lubricant. In some embodiments, the granules comprise the intragranular portion of the tablet disclosed herein.

[0409] In some embodiments, the tablet comprises particles of at least one crystalline form of compound (I) having an average diameter of 10 to 150 microns. 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 microns. 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 at least one crystalline form of a pharmaceutically acceptable salt thereof equivalent in weight (e.g., crystalline form T of toluenesulfonate of compound (I), crystalline form Tr of tartrate of compound (I) and / or crystalline form H of hydrochloride of compound (I)) or at least one crystalline form of a solvate of compound (I) equivalent in weight or a pharmaceutically acceptable salt thereof (e.g., crystalline form C of compound (I)).

[0410] All publications and patents mentioned herein are hereby 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.

[0411] In the claims, articles such as "a," "an," and "the" may mean at least one rather than one, unless indicated to the contrary or otherwise obvious from the context. Claims or descriptions that include an "or" between at least one member of the group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process, unless indicated to the contrary or otherwise obvious from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0412] In addition, the present disclosure encompasses all variations, combinations and arrangements in which at least one limitation, element, clause and descriptive term from at least one of the listed claims is introduced into another claim. For example, any claim subordinate to another claim can be modified to include at least one limitation found in any other claim subordinate to the same basic claim. In the case where the element is presented in a list form (e.g., in a Markush group format), each subgroup of the element is also disclosed, and any element can be removed from the group. It should be understood that, in general, in the case where the present disclosure or aspects of the present disclosure are referred to as including specific elements and / or features, the embodiments of the present disclosure or aspects of the present disclosure are composed of or substantially composed of such elements and / or features. For simplicity, these embodiments are not specifically described herein. In the case of giving a range, endpoints are included. In addition, unless otherwise indicated or otherwise apparent from the context and the understanding of a person of ordinary skill in the art, in different embodiments of the present disclosure, the value represented as a range can adopt any specific value or subrange within the range, up to one tenth of the lower limit of the range, unless otherwise clearly indicated by the context.

[0413] 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 disclosure described herein. Such equivalents are intended to be encompassed by the following claims. Example

[0414] The following examples are intended to be illustrative and are not meant to limit the scope of the present disclosure in any way.

[0415] The synthetic schemes listed below are intended to provide general guidance related to the preparation of the compounds of the present disclosure. One of ordinary skill in the art will appreciate that the preparations shown can be modified and / or optimized using general knowledge of organic chemistry.

[0416] abbreviation

[0417] %w / w weight percentage

[0418] Approx.

[0419] Celsius

[0420] degree°

[0421] Deionization DI

[0422] Differential Scanning Calorimetry DSC

[0423] Dynamic Vapor Sorption DVS

[0424] Equivalent eq.

[0425] g

[0426] High Pressure Liquid Chromatography HPLC

[0427] Karl Fisher titration

[0428] Kelvin K

[0429] L

[0430] mg

[0431] mL

[0432] Moore's M

[0433] molemol.

[0434] Normal N

[0435] Nuclear Magnetic Resonance (NMR)

[0436] Powder X-ray Diffraction XRPD

[0437] Relative humidity RH

[0438] Thermogravimetric analysis (TGA)

[0439] Volumevol.

[0440] Weight wt.

[0441] 1,1'-Bis(di-tert-butylphosphino)ferrocene DTBPF

[0442] 1,1'-Ferrocenyldiyl-bis(diphenylphosphine) DPPF

[0443] 2-Methyltetrahydrofuran 2-MeTHF

[0444] 2-Propanol IPA

[0445] Acetonitrile ACN

[0446] Ammonium chloride NH4Cl

[0447] Charcoal CPW per Weight

[0448] Dichloromethane (DCM)

[0449] Dimethyl sulfoxide (DMSO)

[0450] Potassium Hydrogen Phosphate K2HPO4

[0451] Ethanol EtOH

[0452] Ethyl acetate AcOEt

[0453] Hydrochloric acid

[0454] Isopropyl acetate IPAc

[0455] Lithium Hydroxide LiOH

[0456] Methanol MeOH

[0457] Methylmagnesium chloride MeMgCl

[0458] Methyl tert-butyl ether MTBE

[0459] N-Methyl-2-pyrrolidone NMP

[0460] N,N-Diisopropylethylamine DIPEA

[0461] Palladium(II) acetate Pd(OAc)2

[0462] Phosphorus oxychloride POCl3

[0463] Potassium Hydroxide KOH

[0464] Sodium bicarbonate NaHCO3

[0465] Sulfuric acid H2SO4

[0466] Tetrahydrofuran (THF)

[0467] Tetrabutylammonium bromide TBAB

[0468] Titanium isopropoxide Ti(OiPr)4

[0469] Trifluoroacetic acid (TFA)

[0470] Trifluoroethanol TFE

[0471] Tripotassium phosphate K3PO4

[0472] General approach

[0473] Optical Microscope : Light microscopy was performed using a Zeiss AxioScope A1 equipped with 2.5X, 10X, and 40X objectives and a polarizer. Images were captured by a built-in Axiocam 105 digital camera and processed using ZEN 2 (Blue Edition) software provided by Zeiss.

[0474] DVS Dynamic Vapor Sorption (DVS) was performed using a DVS Intrinsic 1. The sample was loaded into a sample pan and suspended on a microbalance. The typical sample mass for DVS measurements was 25 mg. Nitrogen was bubbled through distilled water to provide the desired relative humidity. A typical measurement involves the following steps:

[0475] 1. Equilibrated at 50% RH

[0476] 2.50% to 2%. (50%, 40%, 30%, 20%, 10% and 2%)

[0477] a. Maintain at each humidity for a minimum of 5 minutes and a maximum of 60 minutes. The change in passing standard is less than 0.002%; 3.2% to 95% (2%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%)

[0478] a. Maintain at each humidity for a minimum of 5 minutes and a maximum of 60 minutes. The change in passing standard is less than 0.002%; 4.95% to 2% (95%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 2%)

[0479] a. Maintain at each humidity for a minimum of 5 minutes and a maximum of 60 minutes. The change in passing standard is less than 0.002%; 5.2% to 50% (2%, 10%, 20%, 30%, 40%, 50%)

[0480] a. Maintain at each humidity for a minimum of 5 minutes and a maximum of 60 minutes. The change in passing standard is less than 0.002%.

[0481] Thermal Analysis Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed using a Mettler Toledo TGA / DSC3+. The samples were weighed in an aluminum sealed pan with a pinhole. The parameters used are shown below.

[0482]

[0483] Karl Fisher titration : Karl Fisher titration for water determination using a 785DMP Titrino equipped with a 6.0338.100 double platinum wire electrode and a 703Ti Stand. The sample is dissolved in HPLC grade or anhydrous methanol and titrated with Hydranal-Composite 5. Typical sample masses for measurement are 0.03 g to 0.10 g. A Hydranal 1 wt.% water standard is used for calibration.

[0484] Chloride content measured 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 to an Accumet combined chloride electrode. Microsoft Excel software was used to determine the inflection point of the titration curve.

[0485] NMR: Proton and carbon NMR analysis was performed on a Bruker Avance 500MHz spectrometer. Alternatively, proton NMR was performed on a Bruker Avance 300MHz spectrometer. The solid was dissolved in 0.75mL of deuterated solvent in a 4mL vial and transferred to an NMR tube (Wilmad 5mm thin wall 8" 200MHz, 506-PP-8). Typical parameters for NMR on a Bruker Avance 300MHz or 500MHz spectrometer are listed below.

[0486]

[0487]

[0488] XRPD : X-ray powder diffraction was performed using a Rigaku MiniFlex 600. Samples were prepared on Si zero return wafers. Typical scans were obtained from 4 to 30 degrees 2θ with a step size of 0.05 degrees over 5 minutes at 40 kV and 15 mA. High resolution scans were obtained from 4 to 40 degrees 2θ with a step size of 0.05 degrees over 30 minutes at 40 kV and 15 mA. Typical parameters for XRPD are listed below.

[0489]

[0490]

[0491] Example 1 : Preparation of Crystalline Form A of Compound (I)

[0492] Compound (I) (10.0 g) was dissolved in acetone (17.4 volumes) and deionized water (3.2 volumes, 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 for 15 minutes at 40°C to 50°C. A clear yellow solution was obtained. Subsequently, fine filtration was performed at 40°C to 50°C. The filter was washed with acetone / water 85 / 15 (1 volume). The solution was then distilled at 55°C to 65°C under normal pressure until a volume of about 146 mL (14.6 volumes, about 74 mL distillate) was reached. The solution was cooled to 45°C to 55°C within 15 minutes. Deionized water (10.5 volumes) was then added to the solution at 45°C to 55°C within 30 minutes to obtain a light yellow suspension. The suspension was cooled to 20°C to 25°C within 2.5 hours and then stirred for 3 hours at 20°C to 25°C. The product was collected by filtration; the filter cake was washed twice by displacement with acetone / water 1 / 1 (2 volumes each). The wet product was dried under vacuum at 68-72°C to give Form A of Compound (I) as a pale yellow solid (92% isolated yield).

[0493] By optical microscopy, XRPD, 13 C NMR, DVS, DSC and TGA analysis of the crystalline form A of compound (I). The XRPD data of the crystalline form A of compound (I) are shown in Table 1. The X-ray powder diffraction pattern of the crystalline form A of compound (I) is shown in Figure 2 The DSC thermogram and TGA thermal curve of the crystalline form A of compound (I) are shown in Figure 3 middle.

[0494] Example 2 : Preparation of Crystalline Form B of Compound (I)

[0495] Compound (I) was heated and maintained at 195°C for 10 minutes and then cooled to room temperature. The resulting solid was isolated by filtration.

[0496] By optical microscopy, XRPD, 13 C NMR, DSC and TGA analysis of the crystalline form B of compound (I). The XRPD data of the crystalline form B of compound (I) are shown in Table 2. The X-ray powder diffraction pattern of the crystalline form B of compound (I) is shown in Figure 4 The DSC thermogram of the crystalline form B of compound (I) is shown in Figure 5 middle.

[0497] Example 3 : Preparation of Crystalline Form C of Compound (I)

[0498] Form C was prepared by slurrying Compound (I) in methanol or 1:1 THF:water. The resulting solid was isolated by filtration.

[0499] By optical microscopy, XRPD, 13 C NMR, DVS, DSC and TGA analysis of the crystalline form C of compound (I). The XRPD data of the crystalline form C of compound (I) are shown in Table 3. The X-ray powder diffraction pattern of the crystalline form C of compound (I) is shown in Figure 6 middle.

[0500] Example 4 : Preparation of Crystalline Form O of Compound (I)

[0501] Form O was prepared by stagnation cooling of Compound (I) in THF from room temperature to -20°C. The resulting solid was isolated by filtration.

[0502] By optical microscopy, XRPD, 13 C NMR, DSC and TGA analysis of the crystalline form O of compound (I). The XRPD data of the crystalline form O of compound (I) are shown in Table 4. The X-ray powder diffraction pattern of the crystalline form O of compound (I) is shown in Figure 7 middle.

[0503] Example 5 : Preparation of Form T of Tosylate Salt of Compound (I)

[0504] Compound (I) (169.7 mg) was weighed into a 4 mL vial with a 10 mm stirring bar. Toluenesulfonic acid (75.8 mg, 1.1 equivalents) was weighed into the same vial. 20 volumes (3.39 mL) of IPA: H2O (95: 5 volumes) were added to the vial. The sample was frozen and vortexed, then stirred at room temperature for 5 minutes. The vial was transferred to a hot plate of 48°C-50°C and stirred at 600 rpm. The sample entered the solution and was then precipitated into a thick slurry almost immediately. After 10 minutes, the vial was transferred to a hot plate of 35°C to 40°C and stirred (340 rpm) for 1 hour, then stirred at room temperature (340 rpm) for 1 hour. The sample was filtered, washed twice with 2 volumes (2x339 μL) of IPA: H2O (95: 5 volumes), and dried under an active vacuum at 50°C. 170.6 mg of salt was collected.

[0505] By optical microscopy, XRPD, 13 C NMR, DSC, TGA and Karl Fisher (KF) titration were used to analyze the water content of the crystalline form T of the tosylate salt of compound (I). The water content of the crystalline form T of the tosylate salt of compound (I) was 1.7 wt.%. The XRPD data of the crystalline form T of the tosylate salt of compound (I) are shown in Table 5. The X-ray powder diffraction pattern of the crystalline form T of compound (I) is shown in Figure 8 middle.

[0506] Example 6 : Preparation of the crystalline form Tr of the tartrate salt of compound (I)

[0507] Compound (I) (145.2 mg) was weighed into a 4 mL vial with a 10 mm stirring bar. Tartaric acid (50.3 mg, 1.1 equivalents) was weighed into the same vial. TFE (450 μL) was added. Since the solid did not dissolve, EtOH (250 μL) was also added. Stirring at room temperature, the slurry thinned slightly. Water (200 μL) was added to completely dissolve the solid, and the vial was stirred at room temperature (350 rpm) overnight.

[0508] The solution remained clear the next day. Remove the lid and place the vial on a hot plate at 35°C to 40°C to evaporate slowly under gentle stirring (300rpm). After 3 hours, all solids had precipitated from the solution and the vial was placed under an active vacuum at 50°C for 2 hours. 15 volumes (2.18mL) of acetone were added to the vial, and the sample was heated to 45°C and stirred (400rpm) for 1 hour. The temperature was reduced by 5 degrees per hour, and stirred overnight at room temperature. The sample was filtered, washed twice with 2 volumes (2x 290μL) of acetone, and placed under an active vacuum at 50°C to dry. 152.1mg of salt was collected.

[0509] By optical microscopy, XRPD, 13 C NMR, DVS, DSC, TGA and Karl Fisher (KF) titration were used to analyze the water content of the crystalline form Tr of the tartrate of compound (I). The water content of the crystalline form Tr of the tartrate of compound (I) was 6.4 wt.%. The XRPD data of the crystalline form Tr of the tartrate of compound (I) are shown in Table 6. The X-ray powder diffraction pattern of the crystalline form Tr of the tartrate of compound (I) is shown in Fig. 9 middle.

[0510] Example 7 : Preparation of Crystalline Form H of the Hydrochloride Salt of Compound (I)

[0511] Compound (I) (154.0mg) is weighed into a 4mL vial with a 10mm stirring bar. A solution of concentrated HCl in ethanol (5:95 volume) of 564 μL (1.1 equivalents) is added. The sample is immediately glued, and the solid has a slight yellow color. TFE (450 μL) is added, and the vial is placed on a hot plate at 35°C to 40°C and stirred for half an hour (340rpm). At the 15 minute mark, the glue is broken up with a spatula. After half an hour, the sample is still sticky, so additional TFE (100 μL) is added, and the sample is vortexed to produce a flowable white slurry. The vial is transferred to a stirring plate at room temperature, and the sample is stirred for another 45 minutes. The lid is removed from the vial, and the solution is slowly evaporated overnight.

[0512] The next morning, the solution was retained and the vial was placed back on a hot plate at 35°C to 40°C for 2 hours, then placed under an active vacuum in a 50°C oven for 2 hours. Once taken out, the gummy solid in the vial was broken up with a spatula and 15 volumes (2.31 mL) of acetone were added. The vial was placed on a hot plate at 48°C and stirred (450 rpm) for 1 hour, then transferred to a hot plate (340 rpm) at room temperature and kept for another 2 hours. The sample was filtered, washed twice with 2 volumes (2x 308 μL) of acetone, and dried under an active vacuum at 50°C. 138.4 mg of salt was collected.

[0513] By optical microscopy, XRPD, 13 C NMR, DVS, DSC, TGA and Karl Fisher (KF) titration were used to analyze the water content of the crystalline form H of the hydrochloride of compound (I). The water content of the crystalline form Tr of the tartrate of compound (I) was 3.9 wt.%. The XRPD data of the crystalline form H of the hydrochloride of compound (I) are shown in Table 7. The X-ray powder diffraction pattern of the crystalline form Tr of the tartrate of compound (I) is shown in Fig.10 middle.

[0514] Example 8 : Solubility in water and simulated fluids

[0515] By dissolving NaOH granules (0.105g), NaH2PO4.H2O (0.9875g) and NaCl (1.5475g) in distilled water (225mL), and adjusting the pH to 6.57 by adding 1N NaOH solution and 1N HCl, fasting simulated intestinal fluid (FaSSIF) (pH=6.57) is prepared. Then water is added to a volume of 250mL to produce a phosphate buffer. The biologically relevant powder (0.56g) is dissolved in a phosphate buffer (125mL), and then supplemented to 250mL with a phosphate buffer. The prepared solution is left to stand for 2 hours and then used for solubility measurement.

[0516] Prepare fasting simulated gastric fluid (FaSSGF)) (pH = 1.67) by dissolving NaCl (0.5 g) in distilled water (225 mL). Use 1N HCl to adjust the pH to 1.67, and then use distilled water to make up the solution to 250 mL to produce a NaCl / HCl solution. Dissolve the biologically relevant powder (0.015 g) in NaCl / HCl solution (125 mL), and then use NaCl / HCl solution to make up to 250 mL. The prepared solution is ready for use.

[0517] Crystalline forms A and C of compound (I)

[0518] The solubility of Form A and a mixture of Form A and Form C was measured in 37°C fasting simulated intestinal fluid (FaSSIF), fasting simulated gastric fluid (FaSSGF) and water. The slurry was stirred overnight, and the supernatant was then collected for HPLC analysis. The solubility of Form A and a mixture of Form A and Form C in FaSSIF was 0.03 mg / mL. The solubility of Form A and a mixture of Form A and Form C in FaSSGF was higher, 2.11 mg / mL and 2.72 mg / mL, respectively. For both Form A and a mixture of Form A and Form C, the solubility in water at about pH 7 was below the detection limit (BDL). The solubility data are summarized in Table 8 below.

[0519] Crystalline form of salt of compound (I)

[0520] The solubility of the crystalline form H of the hydrochloride of compound (I), the crystalline form Tr of the tartrate of compound (I) and the crystalline form T of the toluenesulfonate of compound (I) was measured in fasting state simulated intestinal fluid (FaSSIF), fasting state simulated gastric fluid (FaSSGF) and water at 37°C. About 1.5 mL of the solution was stirred at 37°C. Salt was then added stepwise until a slurry was formed, followed by stirring overnight. The solid was allowed to settle, and the pH of the supernatant was determined. The supernatant was recovered for injection into HPLC, and the solid was recovered for XRPD.

[0521] Solubility was determined based on interpolation of a calibration curve prepared using the free base. The R of the linear fit 2 is 0.999.

[0522] Compared to the free base, Form H and Form Tr are more soluble in both FaSSIF and water. Solubility in FaSSGF is also higher, but further dilution of the sample is required. Form Tr is more soluble in FaSSIF than Form H (0.27 vs. 0.10 mg / mL). Form Tr gels in FaSSIF.

[0523] Solids were recovered from the slurry for analysis by XRPD. Form H was stable when slurried in all solutions. Form Tr was stable when slurried in water. Form Tr converted to Form H when slurried in FaSSGF. The solubility data are summarized in Table 8 below.

[0524] Table 8

[0525]

[0526]

[0527] Example 9 : Preparation of compound (I) 1

[0528] Step e: (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl) Preparation of tert-butyl piperazine-1-carboxylate

[0529] Tert-butyl 4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)piperazine-1-carboxylate (4.0 g, 1 eq.), (S)-(-)-2-methyl-2-propanethioamide (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 vols) were mixed and heated to 55°C. The reaction was maintained for 3.5 hours and then cooled to 23°C. A saline solution (8.0 mL, 2 vols) was added. The mixture was stirred for 2 to 3 hours and filtered through celite to clarify. Additional brine washes (8.0 mL, 2 vols) were added and the phases were separated. The organic phase was distilled in vacuo and chased 3 times with 2-MeTHF (40 mL, 10 vols). 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 h, the mixture was filtered to isolate the solid product, which was dried under vacuum for 16 h (75% yield of (S,Z)-tert-butyl 4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylate).

[0530] Step f: 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidine-2-yl Preparation of tert-butyl piperazine-1-carboxylate

[0531] 2-MeTHF (32 mL, 8 volumes) was added to (S,Z)-4-(5-(((tert-butylsulfinyl)imino)-(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (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 hours. Methanol (4.0 mL, 1 volume) was added at no more than 0°C. The temperature was raised to 0-5°C. NH4Cl solution (24 mL, 6 volumes) 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 volumes). MeOH (140 mL) was then added and the mixture was distilled under vacuum while 2-MeTHF (250 mL) was added. Three vacuum distillations and 2-MeTHF chases were continued to finally give 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 volumes) was added followed by seed crystals (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 and washed with heptane (2×8 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 to 99.8% de) was directly purified according to the following protocol.

[0532] Step g: 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)-ethyl)pyrimidine- Purification of tert-butyl 2-aminopiperazine-1-carboxylate

[0533] 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 h, the mixture was cooled to 22° C. and stirred for 1 h. Filtered with heptane washes (2×2 vol) and the material dried in vacuo overnight (35% yield of tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)-ethyl)pyrimidin-2-yl)piperazine-1-carboxylate in two steps, >99.8% de).

[0534] Step b: Preparation of 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-ol

[0535] To a solution of 6-bromopyrrolo[1,2-f][1,2,4]triazine-4(3H)-one (2.50 g, 1 eq.) in NMP (15 mL, 6 vols) 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)2 (0.026 g, 1 mol.%) and DTBPF (0.055 g, 1 mol.%). The mixture was degassed and then K3PO4 (23.7 g, 6.0 eq.) in water (7.5 mL, 3 vols) was added. Finally, the reaction mixture was heated to 100°C for 12 h. The reaction mixture was cooled to 20°C and water (25 mL, 10 vols) was added and the mixture was stirred at 20°C for 20 min. The filter was washed with water (2.5 mL, 1 volume) and the mixture was clarified by filtration. The filtrate was heated to 57 ° C and 6M HCl (12.5 mL, 5 volumes) was added. The resulting slurry was cooled to 3 ° C in 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 × 5 mL), followed by a 1: 1 mixture of THF and IPA (2 × 5 mL). The solid was dried to obtain 6- (1- methyl -1H- pyrazole -4-yl) pyrrolo [2,1-f] [1,2,4] triazine -4- alcohol in 80% yield.

[0536] Step c: Preparation of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine

[0537] 6-(1-methyl-1H-pyrazole-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-ol (4.0 g, 1 eq.) was suspended in toluene (40 mL, 10 volumes) containing 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 hours. After reaching the completion of the reaction, the reaction was cooled to 22 ° C and added to a solution of K2HPO4 (32.5 g, 10 eq.) in water (25.9 mL, 6.5 volumes). The solid was filtered and washed with water (1 volume) and toluene (1 volume). At 22 ° C, the filtered solid was re-slurried in DCM (28 mL, 7 volumes). The product solution was mixed with activated carbon (5%). After the activated carbon was filtered, the solution was concentrated to 2.4 volumes. 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 overnight at 0-5°C. Filtration followed by heptane wash gave a solid (78% yield of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine).

[0538] Step d: Preparation of (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethane-1-amine hydrochloride Preparation

[0539] 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 vols) and 4M HCl in dioxane (10.0 mL, 6.0 eq.). The reaction was heated to 40° C. for 1 hour. After reaching reaction completion, the mixture was cooled to 22° C. and MTBE (34 mL, 10 vols) was added over 30 minutes. The mixture was filtered and washed with MTBE (3×10 mL, 3×3 vols) and dried under vacuum for 15 hours (97.0% yield of (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethane-1-amine hydrochloride).

[0540] Step a: (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f] Preparation of [1,2,4]triazine-4-yl)piperazine-1-yl)pyrimidin-5-yl)ethane-1-amine (compound (I))

[0541] 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 volumes) followed by the addition of (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethane-1-amine hydrochloride (7.4 kg, 1.0 eq.) and DIPEA (10.0 kg, 4.5 eq.). The reaction was heated at reflux temperature for 12 hours. After the reaction conversion was reached, the mixture was washed with brine (2×13% NaCl, 2×10 volumes). Concentrated at atmospheric pressure until 3.7 volumes, then IPA (61.3 kg) was added and further concentrated under vacuum to 14.5 volumes. The mixture was stirred at less than 25°C and then IPA (20.4 kg) was added again. Further vacuum distillation to 14.5 volumes was followed by the addition of another portion of IPA (20.4 kg). 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).

[0542] At 50°C, the crude solid was dissolved in a mixture of acetone (10.8 volumes) and water (1.9 volumes). Additional water (8.5 volumes) was added over 30 minutes, and the resulting suspension was cooled to 20°C over 1 hour and stirred at this temperature for 2.5 hours. The resulting solid was isolated by filtration and washed with a water / acetone mixture (1:1, 2×2 volumes). The solid was dried to give solid Compound (I) (77% yield of Compound (I)).

[0543] Example 10 : Preparation of compound (I) 2

[0544] Step e: (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl) Preparation of tert-butyl piperazine-1-carboxylate

[0545] Tert-butyl 4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)piperazine-1-carboxylate (20.0 g, 1.0 eq.), (S)-(-)-2-methyl-2-propanethioamide (9.43 g, 1.5 eq.) and LiOH (0.64 g, 0.5 eq.) were added to a reaction vessel containing toluene (160 mL). To this mixture was added titanium (IV) isopropoxide (18.42 g, 1.25 eq.) and the reaction was stirred at 50-60° C. for 1 hour. The reaction was then distilled to remove 80 mL while additional toluene (80 mL) was added at 40-60° C. The reaction mixture was cooled to 20-30° C. and then added to a monosodium citrate solution (80 mL, 30%-w / w citric acid, pH 3-4). The mixture was stirred at 45-55° C. for 1.5 hours and then the phases were separated. The organic phase was washed with potassium bicarbonate (40 mL, 25%-w / w aqueous solution), and the organic phase was distilled to remove 40 mL. The product solution was diluted with tetrahydrofuran (30 mL) and then used directly in the next step as a solution (approximately 15% w / w of (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester).

[0546] Step f: Preparation of 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl) by separation tert-Butyl (ethyl)pyrimidin-2-yl)piperazine-1-carboxylate

[0547] Methylmagnesium chloride (27.8 g, 22%-w / w in THF, 2.0 eq.) was added to a reaction solution of (S,Z)-tert-butyl 4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylate in toluene / THF (120 g corresponding to 20 g input material) at 10° C. over 2 to 3 hours. The reaction mixture was stirred for 1.5 hours to reach reaction completion. The reaction mixture was quenched by adding 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. To a solution of 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 added n-heptane (80 mL) and then cooled to 42°C, at which time seed crystals (25-50 mg) were added. The solution was maintained for 30 minutes and then cooled to 0-10°C for 30 minutes. The solid was isolated by filtration and washed with a mixture of n-heptane and toluene (1:1, 30 mL) and subsequently with 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 to 97.2% de).

[0548] 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperidin Recrystallization of tert-butyl oxazine-1-carboxylate

[0549] 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 and washed / rinsed 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., then cooled to 40° C., at which time it was seeded with 25-50 mg. The mixture was further cooled to 20-25° C. and water (20 mL) was added. The solid was isolated by filtration, washed with an isopropanol / water mixture (1:1, 20 mL), and then the slurry was washed with isopropanol / water (1:2, 30 mL). Drying gave 8.5 g (85%) of tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (>99.8% de).

[0550] Step b: Preparation of 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-ol

[0551] 6-Bromopyrrolo[1,2-f][1,2,4]triazine-4(3H)-one (10.0 g) was added to the 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 h. The reaction mixture was cooled to 80° C. and added to a mixture of N-acetyl-L-cysteine ​​(1.5 g) and Na2EDTA·2H2O (1.5 g) in water (100 mL). The obtained mixture was stirred at 45 ° C for 1.5h and then cooled to 20 ° C. The organic layer was clarified and diluted with water (100mL). Hydrochloric acid (10%-w / w) was added to adjust to pH 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 kept for 1 hour. The product was collected by filtration and washed twice with water / isopropanol (20mL, 8: 1v / v) to obtain 8.2g of dry product 6- (1- methyl -1H- pyrazole -4- bases) pyrrolo [2,1-f] [1,2,4] triazine -4- alcohol.

[0552] Step c: Preparation of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine

[0553] 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-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 minutes. The mixture was then heated to 100°C. The mixture was cooled to 80-90°C and then quenched over 25 minutes onto a mixture of K2HPO4 (2.4 g, 0.20 eq.) and THF (50 mL) in 50 mL of deionized water. During the quenching at 40-60°C, the pH was maintained between pH 7 and pH 9 by adding KOH (about 62 g, 50% aqueous solution, about 8 eq.). The obtained solution is then heated to 50-60 ° C, and stirring is continued for 30 minutes before the phase separation. The organic phase is washed twice with 45mL deionized water at 50 ° C. After phase separation, the organic phase is vacuum distilled to 4 volumes at 60 ° C. The product is precipitated as a yellow solid. Heptane (150mL) is added, and the product is then filtered and washed with heptane (50mL). After drying under reduced pressure, the product 4-chloro-6-(1-methyl-1H-pyrazole-4-yl)pyrrolo[2,1-f][1,2,4]triazine (12.7g) is obtained as a yellow powder.

[0554] Step a: (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f] Preparation of [1,2,4]triazine-4-yl)piperazine-1-yl)pyrimidin-5-yl)ethane-1-amine (compound (I))

[0555] tert-Butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (7) (9.0 g) was heated to 45-55° C. in acetonitrile (40 mL) with hydrochloric acid (33%, 8.14 g, 4.1 eq.) for 1 hour to give tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)-ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (2).

[0556] The mixture was cooled to 20-35°C, and 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 at 45-55°C, followed by methyl tert-butyl ether (20 mL). The reaction mixture was stirred at 50-65°C for 30 minutes. Water (95 mL) was slowly added at 55-65°C and IPC over 1 hour to a pH of 7.3-7.7 (adjusted with DIPEA or HCl if necessary). The reaction mixture was cooled to 20-30°C over 1 hour and maintained at this temperature for 1 hour. 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)).

[0557] (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)ethane-1-amine (Compound (I)) (10.0 g) was dissolved in acetone (17.4 volumes) and deionized water (3.2 volumes, final ratio: acetone / water 85 / 15). The suspension was heated to 43-48° C. and stirred at this temperature for 15 minutes. A clear yellow solution was obtained. Subsequently, fine filtration was carried out at 43-48° C. and the filter was washed with acetone / water 85 / 15 (1 volume). The yellow solution was then distilled at atmospheric pressure at 57-62° C. until a volume of about 146 mL was reached (14.6 volumes, about 74 mL distillate, final ratio: acetone / water 76 / 24). The solution was cooled to 48-53° C. within 15 minutes. Afterwards, deionized water (10.5 volumes) was added at 48-53° C. within 30 minutes (final ratio: acetone / water 44 / 56). The pale yellow suspension was cooled to 20-25° C. within 2.5 hours and stirred at 20-25° C. for 3 hours. The product was collected by filtration and the filter cake was washed twice with acetone / water 1 / 1 (2 volumes each time). The wet product was dried at 67-72° C. and 35 mbar. Compound (I) was isolated as a pale yellow solid (92% of theory) as Form A.

[0558] Embodiment 11 : Preparation of compound (I) 3

[0559] Step e: (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl) Preparation of tert-butyl piperazine-1-carboxylate

[0560] 4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (500 g, 1 eq.), (S)-(-)-2-methyl-2-propanesulfamide (1.5 eq.), Ti(OiPr)4 (2.0 eq.), LiOH (0.5 eq.) and toluene (4 L, 8 volumes) were mixed and heated to 60°C under partial vacuum to remove IPA. The reaction was maintained for 5 hours and then cooled to 5-10°C. Citrate solution (30%, 4 volumes) was added. The mixture was decanted at 40°C and then extracted with toluene (1 volume). The combined organic phases were washed with aqueous NaHCO3. The solution of (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was used directly in the next step.

[0561] Step f: 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidine-2-yl Preparation of tert-butyl piperazine-1-carboxylate

[0562] To a reaction solution of (S,Z)-4-(5-(((tert-butylsulfinyl)imino)-(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in toluene (50 g solid, 1 eq.) 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 hour. Additional MeMgCl (22.5% in THF, 0.5 eq.) was added, and the mixture was stirred at -10°C to -15°C for 5 hours. Methanol (0.26 vol) was added at -10±5°C. The temperature was raised 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 volumes) was added and the solution was filtered under a silica gel pad (50 g). The silica gel pad was eluted with ethyl acetate (6×3.6 volumes) and the fractions were mixed and concentrated until 1.65 volumes. 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 obtain a solution. Heptane (2.6 volumes) was added and the precipitate was stirred at 30-40° C. for 30 minutes and then cooled to 5° C. The yellow precipitate was filtered and washed with heptane (2×1 volumes). The solid was dried under vacuum (45.4% yield of crude tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (94.4% de)).

[0563] 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)-ethyl)pyrimidin-2-yl)piperidin Recrystallization of tert-butyl oxazine-1-carboxylate

[0564] 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). Heptane (0.3 vol) was added at reflux temperature. More heptane (1.7 vol) was added over 32 min followed by cooling to 20-25 °C overnight. Filtering was performed with heptane washes (2 x 0.5 vol) and the material was dried in vacuo overnight (88.2% yield of tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)-ethyl)pyrimidin-2-yl)piperazine-1-carboxylate, 100% de).

[0565] Step b: Preparation of 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-ol

[0566] To a solution of 6-bromopyrrolo[1,2-f][1,2,4]triazine-4(3H)-one (50 g, 1 eq.) in NMP (6 volumes) 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)2 (0.01 eq.) and DPPF (0.01 eq.) were added. The mixture was degassed again. Water (3 vol.) was added immediately, followed by K3PO4 (6 eq.) in portions. Finally, the reaction mixture was degassed again and heated to 100±2°C. After reaching completion of the reaction, 10 volumes of water were added, and the suspension was stirred at 50°C for 1 hour. At 21°C, HCl (6N) was added to adjust the mixture to pH 6.51. The product was cooled to -10 °C for 1 hour, then filtered and the filter cake was washed with 3.6 volumes of water. The solid was ground with 5 volumes of IPAc and then filtered. Additional grinding was carried out in 5 volumes of IPAc and then filtered again. The third grinding was carried out in 5 volumes of IPAc, then filtered and finally ground in 5 volumes of water. The solid product was washed with 5 volumes of water and dried in vacuo at 50 °C (70% yield of 6-(1-methyl-1H-pyrazole-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-ol).

[0567] Step c: Preparation of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine

[0568] 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 vols) containing DIPEA (1.2 eq.). To this mixture was added POCl3 (2.0 eq) at 70-80°C over 12 min. The suspension was heated to 70-80°C. After reaching completion of the reaction, the reaction was added to a solution of K2HPO4 (13 eq.) in water (11 vols) at a temperature below 30°C. The solid was filtered and washed with toluene and water. The filtrate was decanted; the aqueous layer was extracted with DCM. The filtered solid was re-slurried in DCM (10 vols). The organic layer was mixed with activated carbon (5%) and stirred. After filtration of the activated carbon, the solution was concentrated to 2.4 vols. Heptane (7 vols) was added and the mixture was concentrated to 2.4 vols. Additional heptane was added and the mixture was concentrated to 7 volumes and stirred overnight at 0-5°C. Filtering and washing with heptane gave a crude solid. The wet solid was reslurried in water (7 volumes) 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).

[0569] Preparation of (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethane-1-amine hydrochloride

[0570] 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 volumes) and concentrated hydrochloric acid (11.2 M, 5.6 eq.). The reaction was heated to reflux temperature. After reaching completion of the reaction, the mixture was concentrated to 5 volumes at atmospheric pressure. Concentration was continued, and ethanol was added to maintain 5 volumes until the water content was less than or equal to 3%. Concentration was finally stopped at 2 volumes, followed by cooling to 0-5°C within 30 minutes. After filtration, it was dried under vacuum to obtain a solid product (92.0% yield of (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethane-1-amine hydrochloride).

[0571] Step a: (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f] Preparation of [1,2,4]triazine-4-yl)piperazine-1-yl)pyrimidin-5-yl)ethane-1-amine (compound (I))

[0572] 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 vols) followed by the addition of (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethane-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 less than or equal to 30°C. The reaction was heated at reflux temperature for 5.5 hours. After the reaction conversion was reached, the mixture was washed with brine (2×22% NaCl in 2×8.9 vols) and the organic phase was treated with charcoal (10% CPW) for 2 hours. Concentrated at atmospheric pressure until 3.7 vols followed by the addition of IPA (26.8 vols). The mixture was further concentrated to 18.3 volumes at atmospheric pressure and then cooled to 20-25°C. The mixture was stirred at 20-25°C for 1.5 hours and then filtered and washed with IPA (1.8 volumes). The wet solid was dissolved in a mixture of acetone (23.2 volumes) and water (4.1 volumes) at reflux temperature. Additional water (21.4 volumes) was added at 45-55°C and the resulting suspension was cooled to 15-25°C overnight. Cooling to 0-5°C continued for 1 hour, then filtered and washed with water (2×3.6 volumes) and acetone (3.6 volumes) to obtain a 79.5% yield of compound (I).

[0573] Example 12 : Phase 1 dose escalation and expansion study of compound (I) in advanced GIST

[0574] patient Eligibility criteria for the Phase 1 dose-escalation and expansion study included providing written informed consent, age ≥18 years, Eastern Cooperative Oncology Group performance status ≤2, and adequate end-organ function. The dose-escalation portion of the trial was open to patients with refractory solid tumors or unresectable GIST; however, only patients with GIST were recruited. Patients with unresectable GIST with one or more measurable target lesions according to modified response evaluation criteria in solid tumors version 1.1 (mRECIST 1.1) were eligible for dose expansion, which included three cohorts: patients with PDGFRA D842V-mutant GIST, regardless of prior treatment; patients who progressed after imatinib and one or more other kinase inhibitors; and patients who received imatinib alone.

[0575] Study Design:The primary endpoint of the Phase 1, open-label dose escalation / extension study is the safety and tolerability of compound (I) administered orally once daily, and the overall response rate (ORR) of each expansion cohort. Part 1 follows a 3+3 dose escalation design, starting from 30 mg until the maximum tolerated dose (MTD) or the recommended Phase 2 dose (RP2D) below the MTD is determined. Intra-patient dose escalation is allowed, and additional increases to previously determined tolerable dose levels are allowed. The Part 1 MTD is used to initiate the Part 2 expansion. Continue to treat with compound (I) until excluded due to toxicity, non-compliance, withdrawal of consent, physician decision, disease progression, death, or end of study.

[0576] Safety and response assessment :Each visit from the beginning of the study drug application to 30 days after the final dose of compound (I) was used to assess adverse events, and was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03. All patients were screened for tumor imaging to assess response by computed tomography (CT) or magnetic resonance imaging (MRI), every two cycles until and including the 13th cycle, and then every three months, until progression or interruption. By independent, blinded, central radiology review (BioTelemetry, Inc., Rockville, Maryland, USA), target and non-target lesions were identified and assessed according to mRECIST 1.1 of GIST.

[0577] Pharmacokinetics : In Part 1, serial blood samples were collected prior to dosing and at multiple time points up to Cycle 4. Parameters were calculated from the plasma concentration-time data using standard non-compartmental methods.

[0578] Statistical methods : The MTD (defined as the highest dose level with ≤1 cycle 1 dose-limiting toxicity among 6 patients) was determined by all Part 1 patients (dose-determining population) who completed cycle 1 and received at least 75% of the prescribed dose or experienced dose-limiting toxicity (DLT). The efficacy population included patients with PDGFRαD842V-mutant GIST who received at least one dose of compound (I), participated in Part 1 or Part 2, had one or more target lesions, and underwent at least one post-baseline disease assessment by central radiology. For the primary endpoint of partial or complete response, a sample size of 31 patients allowed testing the null hypothesis of an overall response rate of ≤10% versus the alternative hypothesis of an objective response rate of ≥35%, with 90% power, assuming a 2-sided type I error rate of 0.05. The Kaplan-Meier method was used to estimate duration of response, PFS, and OS, including medians with 95% confidence intervals. Estimated duration of response, PFS, and OS rates at 3, 6, and 12 months were also calculated.

[0579] result : Between October 2015 and January 2017, 46 patients with PDGFRA mutation (D842V, n=20, N659K, n=1; D842-H845, n=1, D1 842-843V, n=1) or KIT mutation GIST (n=23) were enrolled in Part 1, and the data cutoff date was November 16, 2018. Based on early efficacy observations, enrichment recruitment was limited to patients with PDGFRA D842 mutation GIST. An additional 36 patients with PDGFRA D842V mutation GIST participated in Part 2, resulting in a total of 56 patients in the efficacy population (PDGFRA D842V mutation GIST) and 82 patients in the safety population. In the D842V mutation GIST population, the median age was 64 years, 41% were male, and 69% were white. The majority had metastatic disease (96.4%), had at least 1 target lesion ≥5 cm (58.6%), and had received ≥1 prior kinase inhibitor. 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.

[0580] Security : Patients (n=46) enrolled in Part 1 received a dose of 30 to 600 mg of compound (I) once daily. No dose-limiting toxicity in Cycle 1 was observed at doses of 30 to 400 mg per day. Two patients experienced dose-limiting toxicity in Cycle 1 at 600 mg (Patient 1: Grade 2 hypertension, acneiform dermatitis, and memory impairment; Patient 2: Grade 2 hyperbilirubinemia). Both patients temporarily interrupted dosing and restarted dosing at 400 mg. 400 mg of compound (I) was considered the maximum tolerated dose and was selected as the starting dose for Part 2. Based on data showing a lower incidence of grade 3 cognitive AEs and similar frequencies of tumor responses, where compound (I) exposure achieved predicted therapeutic levels, the starting dose of Part 2 was subsequently reduced to 300 mg. Therefore, 300 mg of compound (I) was considered the recommended Phase 2 dose and was selected as the starting dose for the remainder of the study.

[0581] 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%), mainly grade 1 (19, 23%), and led to treatment discontinuation in only 2 patients (2%). Intracranial hemorrhage occurred in 2 patients. Both events were grade 3, non-fatal, and improved, while at the 400 mg dose, the most common were nausea (71%), vomiting (47%), fatigue (47%), and periorbital edema (47%). Regardless of dose, grade 3 / 4 events occurred in 47 (57%) patients, the most common being anemia (30%). Adverse events of particular concern 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%). Cognitive effects may resolve after treatment discontinuation.

[0582] A total of 69 patients (84%) required at least one dose reduction or treatment interruption, however, among the 84 patients who started at 300 mg, the median daily dose intensity remained as high as 267 mg.

[0583] Of the 82 patients enrolled, 44 (54%) discontinued treatment. The most common reasons for treatment 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 treatment discontinuation were disease progression (21%) and adverse events (60%), of which 14% were considered related to compound (I). As of data cutoff, 46% of all patients and 66% of the PDGFRA D842V population remained on treatment.

[0584] Efficacy : Across all dose levels, 56 patients with PDGFRA D842V-mutant GIST were evaluable for response. Confirmed responses per central radiology mRECIST 1.1 assessment were observed in 88% (95% CI: 75.9.94.8) of patients (complete responses: 5 / 56 [8.9%], partial responses: 44 / 56 [78.6%], and stable disease 7 / 56 (12.5%) ( Fig.11, Table 9). The clinical benefit rate (CBR) (defined as the proportion of patients with confirmed CR / PR or stable disease lasting at least 16 weeks from the start of treatment) was 95%. In patients who started treatment at the recommended 300 mg dose (n=28), the overall response rate was higher at 93% (95% C: 76.5, 99.1). The median duration of response was not reached; the duration of response at 12 months was 70%. The median PFS was not reached; the progression-free survival rates at 3, 6, and 12 months were 100%, 94%, and 90%, respectively. OS was estimated to be 100%, 91%, and 81% at 6, 12, and 24 months, respectively, with a median follow-up of 15.9 months (95% CI: 54.87%).

[0585] Table 9

[0586]

[0587] In part 1, 3 patients with other PDGFRA mutants were enrolled, 1 with exon 14 N659K mutation and 2 with other exon 18 activation loop mutations (D842-H845, n=1, D1 842-843V, n=1). Both patients with activation loop mutations responded, however, the patient with N659K mutation progressed.

[0588] Example 13: ISM and SSM studies of compound (I)

[0589] This is a Phase 2, randomized, double-blind, placebo-controlled study comparing the efficacy and safety of compound (I) + best supportive care (BSC) with placebo + BSC in patients with ISM and SSM whose symptoms were not adequately controlled by BSC. The study was conducted in three parts. In Part 1, the optimal dose of compound (I) for patients with ISM (recommended Phase 2 dose (RP2D)) was identified. In Part 2, patients with ISM and SSM were randomly assigned to RP2D + BSC of compound (I) identified in Part 1, or matching placebo + BSC. In Part 3, patients who completed treatment in Part 1 or Part 2 of the study participated in a long-term extension to receive compound (I) at RP2D + BSC.

[0590] In Part 1, management of SM symptoms was optimized immediately after informed consent was obtained, and BSC medication doses and SM symptom management schedules were stabilized as needed over a 4-week period. Within five days of informed consent, ISM-SAF (ISM Symptom Assessment Form) data collection began. The number of anaphylactic episodes treated with epinephrine and all concomitant medications received for any indication were collected from the time of informed consent.

[0591] Once the BSC is optimized (between days -98 and -71) and the dose is stable for ≥14 days, an additional 14 days of ISM-SAF data are collected to determine eligibility based on symptom severity, i.e., to identify ISM and SSM patients with moderate to severe symptoms. Patients who do not meet the symptom severity threshold are considered to have failed screening and are not eligible to participate in the study. Patients with moderate to severe symptoms and who meet the symptom severity threshold begin other screening procedures, including the following: bone marrow (BM) biopsy (archive samples or fresh samples obtained within the previous 24 weeks) and skin biopsies of lesions and non-lesions (in patients with cutaneous mastocytosis (CM)) for confirmation of SM diagnosis and quantification of mast cells (MC); skin photos were taken for patients with CM (maculopapular rash). Additional procedures include: brain magnetic resonance imaging / computed tomography; bone density determination; serum tryptase, KIT D816 mutation testing; routine laboratory tests; ECG; and physical examination. All procedures were completed within 6 weeks before the start of the last 14-day baseline ISM-SAF symptom collection.

[0592] Once the screening procedure was completed, patients collected ISM-SAF data over the next 2 weeks (14 days) to establish baseline scores, after which patients who met all eligibility requirements were randomized to treatment groups and began dosing.

[0593] Part 1

[0594] In Part 1 of the study, approximately 40 patients were randomized to 1 of 3 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) were tested in parallel: 25, 50, and 100 mg. Patients, investigators, and sponsors were blinded to treatment assignment.

[0595] Compound (I) was administered orally once a day in a continuous 28-day cycle. Patients were evaluated weekly for the first 4 weeks, and then every 4 weeks (until RP2D was determined) for safety, laboratory monitoring, and quality of life (QoL) assessments. All patients were subjected to enhanced pharmacokinetic (PK) sampling. ISM-SAF was completed once a day. After completing 12 weeks of treatment, BM and skin biopsies were repeated for MC quantification, and skin photos were taken for patients with baseline CM.

[0596] The RP2D is determined based on the efficacy, safety, and PK of each dose level. The primary assessment of efficacy is symptom improvement using ISM-SAF. The main criterion for selecting the RP2D is the dose of compound (I) that causes the greatest decrease in total symptom score (TSS), as assessed using ISM-SAF at Week 12 compared to baseline (Day -14 to Day -1). Other measures of efficacy (e.g., changes in serum tryptase) are also taken into account. Once the Week 12 assessment is completed, patients continue to receive the assigned treatment and dose until the RP2D is determined, at which time they will be transferred to Part 3 of the study, where they will receive the RP2D of compound (I).

[0597] For each dose level of compound (I) or placebo, the average change in TSS was calculated as the arithmetic mean of the TSS change in the intention-to-treat (ITT) population. The baseline TSS of each patient was defined as the 14-day TSS mean from C1D-14 to C1D-1. The 1st day TSS of the 4th cycle of each patient was defined as the 14-day TSS mean from C3D15 to C3D28. For each patient, the change in TSS was calculated as (C4D1 TSS-baseline TSS). If the patient's TSS between C1D-14 and C1D-1 was missing for more than 7 days, the patient's baseline TSS was considered to be missing. If the patient's TSS between C3D15 and C3D28 was missing for more than 7 days, the patient's C4D1 TSS was considered to be missing.

[0598] Part 2

[0599] The above screening procedures of Part 1 were used for Part 2. In Part 2 of the study, approximately 72 patients were enrolled. Patients were randomly assigned to receive Compound (I) of RP2D+BSC or matching placebo+BSC. Patients assigned to placebo in Part 2 received Compound (I) once they were transferred to Part 3. Patients, investigators, and sponsors were blinded to treatment allocation.

[0600] Compound (I) and placebo were administered orally once a day in a continuous 28-day cycle. Compound (I) was administered orally once a day at 25 mg. Patients were evaluated weekly for the first 4 weeks, and then safety, laboratory monitoring, and QoL assessments were performed every 4 weeks until the 12th week. Sparse PK sampling was performed in all patients. ISM-SAF was completed once a day. After completing 12 weeks of treatment and ISM-SAF until the 7th day of the 12th week, BM and skin biopsies were repeated by the central pathology laboratory for MC quantification, and skin photos were taken for patients with baseline CM. Once all 12th week assessments were completed, the patient was transferred to the 3rd part of the long-term extension. After all patients were transferred to Part 3, the primary endpoint and other efficacy endpoints of the average change of ISM-SAF TSS from baseline to Week 12 were analyzed.

[0601] The primary efficacy endpoint of Part 2 is the mean change in ISM-SAF TSS from baseline to Cycle 4 Day 1 (C4D1). Analysis of the mean change in TSS will primarily use the intention-to-treat population and will be performed as a sensitivity analysis in the per-protocol population. The mean change in TSS will be calculated as the arithmetic mean of the change in TSS in each treatment group. A 2-sample t-test will be used to compare Compound (I) and placebo.

[0602] Part 3

[0603] Patients who completed Part 1 were transferred to Part 3 of the study, where all patients received treatment with compound (I) + BSC at 25 mg QD. Similarly, patients who completed all Part 2 Week 12 study assessments were transferred to Part 3 of the study, where they received treatment with compound (I) + BSC at 25 mg QD. All patients were visited weekly for 4 weeks, then every 4 weeks for 5 months, and then every 3 months, starting from Day 1 of Cycle 1 (C1D1) for a total of 2 years. Patients who were still undergoing the study after 2 years were visited every 6 months (24 weeks), and the entire study duration was 5 years, including Part 1 and Part 2. ISM-SAF was completed once a day, and QoL assessment was performed until Week 52. For patients with maculopapular CM (cutaneous mastocytosis) at Part 1 or Part 2 baseline, skin photos were taken at Part 3 baseline (if not obtained within the first 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 Parts 1 and 2 may serve as baseline assessments for Part 3. Assessments performed at the final study visit of Parts 1 and 2 may serve as baseline assessments for Part 3 if obtained within the first 4 weeks. Any procedure required at Part 3 baseline and not performed within 4 weeks on Part 3 Day 1 in Parts 1 or 2 will be performed on Part 3 Day 1. Patients who choose not to continue with Compound (I) will have an end-of-treatment visit 14 days after the last dose of study treatment. Patients may continue with Compound (I) until unacceptable toxicity, death, or patient discontinuation for up to 5 years.

[0604] In Part 1, patients were treated for 12 weeks, then continued on their assigned treatment and were dosed until the RP2D of 25 mg QD was determined. In Part 2, patients were treated for up to 12 weeks. In Part 3, patients were treated for up to 5 years, including Parts 1 and 2.

[0605] 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.

[0606] In Part 1, the estimated recruitment period is approximately 6 months, and the estimated duration of this part of the study is approximately 15 months. In Part 2, the estimated recruitment period is approximately 9 months, and the estimated duration of this part of the study is approximately 18 months. The estimated duration of Part 3 is approximately 5 years (including Part 1 and Part 2).

[0607] Results of Part 1:

[0608] Results from the Phase 2 PIONEER trial of compound (I) in patients with indolent systemic mastocytosis (SM) showed significant clinical improvements compared to placebo, including meaningful benefits for all assessed symptoms. In Part 1 of the PIONEER trial, patients treated with 25 mg of compound (I) once daily (QD) showed improved clinical outcomes from baseline to 16 weeks, with an average reduction of 31% in total symptom scores (TSS) (as measured by the Indolent SM Symptom Assessment Form (ISM-SAF)) and increased activity over time. In addition, patients treated with 25 mg QD showed robust reductions in objective measures of mast cell load and improvements in patient-reported quality of life. Compound (I) showed good safety, supporting long-term dosing in ISM, and all adverse events (AEs) reported in the 25 mg QD dose cohort were grade 1 or 2. Based on the complete Part 1 data, 25 mg QD has been selected as the recommended Part 2 dose (RP2D).

[0609] 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) compared to placebo. Key eligibility criteria included adults with ISM confirmed by central pathology review of bone marrow biopsy (according to WHO criteria) and moderate to severe symptom burden despite the use of best supportive care medications. Overall, 39 patients were enrolled in four concurrent cohorts in Part 1, with 10 patients in each compound (I) dose cohort and 9 patients in the placebo cohort.

[0610] Patient-reported outcome data were collected using the ISM-SAF, which was designed with input from disease experts, patients, and regulators as a measure of clinical benefit to support registration. The ISM-SAF assesses symptoms in the skin domain (spots, itching, and flushing) and gastrointestinal domain (abdominal pain, diarrhea, and nausea), as well as other key symptoms affecting patients with ISM (brain fog, headache, dizziness, bone pain, and fatigue). All results are current as of the data cutoff date of December 27, 2019.

[0611] The complete Part 1 data demonstrated the robust clinical activity and well-tolerated safety of Compound (I) at 25 mg QD. Based on these results, 25 mg QD has been selected as the optimal dose for further evaluation in the long-term treatment of ISM.

[0612] Baseline Patient Characteristics

[0613] Patients had a high symptom burden at baseline, with a mean ISM-SAF TSS of 53. The mean ECOG performance status was 2 in 8 patients (21%), reflecting the inability to perform any work activities. Patients received a median of four best supportive care medications at baseline (range: 2-9). The median serum tryptase was 45 μg / L (upper limit of normal, 11.4 μg / L). A high-sensitivity polymerase chain reaction assay of peripheral blood detected the KIT D816V mutation in 37 patients (95%).

[0614] Clinical activity data

[0615] Compound (I) demonstrated clinically meaningful benefits in all measures of mast cell burden, patient-reported symptoms, and quality of life. The consistency of results across multiple disease measures supports the broad potential of Compound (I) in ISM.

[0616] Patients in the 25 mg QD dose cohort of Compound (I) demonstrated a robust reduction in mast cell burden based on assessments of serum tryptase, bone marrow mast cells, and KIT D816V allele burden. Figure 12-13 .

[0617] Compound (I) demonstrated clinically meaningful reductions in ISM-SAF TSS as well as the gastrointestinal domain, skin domain, and each individual symptom tested. Improvements continued to deepen over the course of 16 weeks, with further reductions possible with additional patient follow-up. At 16 weeks, patients in the Compound (I) 25 mg QD dose cohort demonstrated a similar reduction in mean symptom burden as the 50 mg QD dose cohort and the 100 mg QD dose cohort. 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).

[0618] Mean Percent Change in ISM-SAF at 16 Weeks

[0619]

[0620]

[0621] At Week 16, patients had a statistically significant reduction in ISM-SAF TSS (p=0.001), with a mean improvement of approximately 30% across all Compound (I) dose cohorts and approximately 3% in the placebo cohort (p=0.001).

[0622] Data from the Mastocytosis Quality of Life (MC-QoL) questionnaire, a commonly used patient-reported outcome tool for mast cell disorders, demonstrated improved quality of life in patients receiving Compound (I) and validated the clinical benefit observed using the ISM-SAF. At Week 16, seven patients in the 25 mg QD cohort of Compound (I) and six patients in the placebo cohort completed the MC-QoL questionnaire. Patients in the 25 mg QD dose cohort showed a mean reduction of 34% in the total MC-QoL score and improvements in all four assessment domains (symptoms, social life function, mood, and skin). A 7% increase from baseline was observed in the placebo cohort.

[0623] Security Data

[0624] As shown in the table below, compound (I) showed good safety, supporting long-term dosing in ISM. In the 25mg QD dose cohort, patients treated with compound (I) had no serious AEs, grade 3 or higher AEs, or dose adjustments. In the placebo cohort, two patients (22%) had at least one grade 3 AE, and two patients (22%) had dose adjustments due to AEs. All doses of compound (I) were well tolerated, and as of the data cutoff date, no patient discontinued treatment due to AEs.

[0625]

[0626] Example 14: Method for purifying compound (I)

[0627]

[0628] The purification of compound (I) and its undesirable enantiomer (compound (E)) is difficult. For example, recrystallization of compound (I) in acetone and water will not remove compound (E). In order to find a method for removing the undesirable enantiomer, several acids need to be studied. The research summarized in Table 10 was carried out on a scale of 500 mg each, and D-quinic acid was determined to be the best acid for purifying compound (I).

[0629] Table 10.

[0630]

[0631]

[0632] “-” indicates undetermined

[0633] *Poor filtration **Solution at 50°C and precipitation at 20°C

[0634] Specifically, D-quinic acid (1.5 eq.) was added to a suspension of compound (I) (25.0 g, 1 eq.) and 5% compound (E) in tetrahydrofuran (375 mL). The suspension was refluxed for 1 h, water (5.5 eq.) was added, and then cooled to 15–25 ° C. The solid was separated by filtration and washed with tetrahydrofuran (2×50 mL). If necessary, THF and water recrystallization can be repeated to improve the enantiomeric excess.

[0635] The isolated solid compound (I) quinate was suspended in dichloromethane (250 mL) and water (125 mL) and NaOH (6.0 equivalents) was added. The organic layer was separated and washed with water (2×150 mL). The target volume of 5 mL / g of input compound (I) was completed by distillation using acetone instead of dichloromethane. The crude compound (I) was separated by filtration, free of undesired enantiomers, 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 ≤0.55% w / w enantiomer (compound (E)).

Claims

1. Crystalline Form A of Compound (I): Features The X-ray powder diffraction pattern comprises 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.

2. Crystalline Form A of Compound (I): Features The X-ray powder diffraction pattern comprises at least seven peaks at 2θ angles 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.

3. The crystalline form A according to claim 2, characterized in that The X-ray powder diffraction pattern comprises at least eight peaks at 2θ angles 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.

4. The crystalline form A according to claim 2, characterized in that The X-ray powder diffraction pattern comprises 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.

5. The crystalline form A according to any one of claims 1 to 4, characterized in that A DSC thermogram having an endothermic event with a signal in a temperature range of 194°C to 195°C or an endothermic event with an onset temperature of 193°C.

6. The crystalline form A of compound (I) according to claim 1, which is prepared by a method comprising the following steps: dissolving compound (I) in a mixture of acetone and water to obtain a suspension; heating the suspension to a temperature ranging from 40°C to 50°C to obtain a solution; and The solution was cooled.

7. A method for preparing the crystalline form A of compound (I) according to claim 1, comprising dissolving compound (I) in a mixture of acetone and water to obtain a suspension; heating the suspension to a temperature ranging from 40°C to 50°C to obtain a solution; and The solution was cooled.

8. A pharmaceutical composition comprising: at least one pharmaceutically acceptable excipient; and The crystalline form A of compound (I) according to any one of claims 1 to 6.

9. Use of a therapeutically effective amount of the crystalline form A of compound (I) according to any one of claims 1 to 6 in the preparation of a medicament for treating mastocytosis.

10. The use according to claim 9, wherein the mastocytosis is selected from cutaneous mastocytosis and systemic mastocytosis.

11. The use according to claim 10, wherein the systemic mastocytosis is selected from indolent systemic mastocytosis, smoldering systemic mastocytosis and advanced systemic mastocytosis.

12. The use according to claim 11, wherein the systemic mastocytosis is late stage systemic mastocytosis.

13. The use according to claim 12, wherein the therapeutically effective amount is 200 mg of crystalline form A of compound (I) administered once daily.

14. The use according to claim 11, wherein the systemic mastocytosis is indolent systemic mastocytosis.

15. The use according to claim 14, wherein the therapeutically effective amount is 25 mg of crystalline form A of compound (I) administered once daily.

16. Use of a therapeutically effective amount of the crystalline form A of compound (I) according to any one of claims 1 to 6 in the preparation of a medicament for treating gastrointestinal stromal tumors.

17. Use according to claim 16, wherein the gastrointestinal stromal tumor is characterized by an exon 18 mutation in PDGFRα.

18. The use according to claim 16 or 17, wherein the therapeutically effective amount is 300 mg of crystalline form A of compound (I) administered once daily.

19. Use of a therapeutically effective amount of the crystalline form A of compound (I) according to any one of claims 1 to 6 in the preparation of a medicament for treating acute myeloid leukemia.

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