Pharmaceutical composition of tricyclic AKR1C3 dependent KARS inhibitor and preparation method thereof

Abstract

The present invention relates to a solid phase pharmaceutical composition of 6 '-fluoro-N-(4-fluorobenzyl)-4'-oxo-3 ', 4'-dihydro-1 'H-spiro [piperidine-4, 2'-quinoline]-1-carboxamide useful as an AKR1C3 dependent KARS inhibitor. The invention also relates to processes for preparing said pharmaceutical compositions of said compounds, methods of using said pharmaceutical compositions in the treatment of various diseases and disorders, and their use in diseases and disorders mediated by AKR1C3 dependent KARS inhibitors.

Description

Technical Field

[0001] The present invention relates to pharmaceutical compositions of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide useful as AKR1C3-dependent KARS inhibitors. The present invention also relates to processes for preparing said pharmaceutical compositions of said compounds, methods for using said pharmaceutical compositions to treat various diseases and disorders, and their use in diseases and disorders mediated by AKR1C3-dependent KARS inhibitors. Background Art

[0002] The NFE2L2 / NRF2-KEAP1 pathway has a strong genetic basis in cancer. TCGA sequencing efforts reported alterations in this pathway in 34% of squamous cell lung cancers (Hammerman PS et al. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519–525 (2012)). In addition, TCGA and other groups have reported significant mutations in this pathway in other solid tumor indications, including head and neck squamous cell carcinoma and hepatocellular carcinoma. Aberrant activation of the NRF2 pathway may occur through gain-of-function genetic alterations in NRF2 or loss-of-function genetic alterations in KEAP1 or CUL3, which result in stabilization of NRF2 and elevated expression of its target genes. Uncontrolled transcription of these target genes confers advantages to cancer cells, such as malignancy and protection against oxidative stress, chemotherapy, and radiotherapy (Jaramillo MC, Zhang DD. The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev. 27, 2179-2191 (2013)). Increased NRF2 activity in tumors is associated with poor prognosis (Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, Hirohashi S. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci USA 105, 13568–13573 (2008)). To our knowledge, there are currently no approved therapies that selectively target cancers with genetic alterations in the NRF2 / KEAP1 pathway, which therefore represents an unmet medical need.

[0003] Aldo-keto reductase 1C3 (AKR1C3) is one of the many target genes of the transcription factor NRF2, and its expression is upregulated in NRF2 / KEAP1 mutant cancers (MacLeod AK, Acosta-Jimenez L, Coates PJ, McMahon M, Carey FA, ​​Honda T, Henderson CJ, and Wolf CR. Aldo-keto reductases are biomarkers of NRF2 activity and are coordinately overexpressed in non-small cell lung cancer. Br J Cancer 115, 1530–1539 (2016)). AKR1C3 (also known as 3α(17β)-hydroxysteroid dehydrogenase type 2) is a NADP(H)-dependent ketosteroid reductase and a member of the aldo-keto reductase (AKR) superfamily that plays a role in steroid hormone metabolism and signaling and xenobiotic detoxification. Some known substrates of AKR1C3 are the endogenous substrates 5α-dihydrotestosterone, Δ4-androstene-3,17-dione and progesterone (Penning TM, Burczynski ME, Jez JM, Hung CF, Lin HK, Ma H, Moore M, Palackal N, Ratnam K. Human 3α-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones. Biochem. J. 351, 67-77 (2000)) and the synthetic prodrug coumberone (Halim M,Yee DJ,Sames D.Imaging Induction of Cytoprotective Enzymes in Intact Human Cells: Coumberone, a Metabolic Reporter for Human AKR1C Enzymes Reveals Activation by Panaxytriol, an Active Component of Red Ginseng [Imaging Induction of Cytoprotective Enzymes in Intact Human Cells: Coumberone, a Metabolic Reporter for Human AKR1C Enzymes Reveals Activation by Panaxytriol, an Active Component of Red Ginseng] J. Am. Chem. Soc. 130, 14123-14128 (2008)), PR104 (Jamieson SM, Gu Y, Manesh DM, El-Hoss J, Jing D, Mackenzie KL, Guise CP, Foehrenbacher A, Pullen SM, Benito J, Smaill JB, Patterson AV, Mulaw MA, Konopleva M, Bohlander SK, Lock RB, Wilson WR. A novel A fluorometric assay for aldo-keto reductase1C3 predicts metabolic activation of the nitrogen mustardprodrug PR-104A in human leukaemia cells. [A novel fluorometric assay for aldo-keto reductase1C3 predicts metabolic activation of the nitrogen mustardprodrug PR-104A in human leukaemia cells] Biochem Pharmacol. 88, 36-45 (2014)) and TH3424 / OBI3424 (Threshold pharmaceuticals WO2016 / 145092 A1). We report the identification of tricyclic ketone compounds that are converted by AKR1C3 into inhibitors of lysine t-RNA synthetase (KARS) in the presence of NADPH. Lysine t-RNA synthetase is a ubiquitous enzyme essential for protein synthesis that is part of the multi-tRNA synthetase complex. .

[0004] AKR1C3-dependent KARS inhibitors offer an attractive strategy for selectively treating tumors that overexpress AKR1C3 compared with normal tissues, such as NRF2 / KEAP1 mutant cancers and other types of cancer reported to overexpress AKR1C3 (Guise CP, Abbattista MR, Singleton RS, Holford SD, Connolly J, Dachs GU, Fox SB, Pollock R, Harvey J, Guilford P, F, Wilson WR, Patterson AV. The bioreductive prodrug PR-104A is activated under aerobic conditions by humanaldo-keto reductase 1C3. Cancer Res. 70, 1573-1584 (2010), such as breast cancer (Lewis MJ, Wiebe JP, Heathcote JG. Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma. BMC Cancer [BMC Cancer] 4, 27 (2004)) and prostate cancer (Fung KM, Samara ENS, Wong C, Metwalli A, Krlin R, Bane B, Liu CZ et al. Increased expression of type 2 3α-hydroxysteroid dehydrogenase / type 517β-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma. [Increased expression of type 2 3α-hydroxysteroid dehydrogenase / type 517β-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma] Endocr Relat Cancer [Endocrine-related cancer] 13, 169-180 (2006)).

[0005] 6'-Fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, first disclosed in WO / 2021 / 005586, is a selective AKR1C3 reductase-dependent KARS inhibitor. There is still a need in the art for novel compositions for delivering AKR1C3 reductase KARS inhibitors and methods of using them for treating selective AKR1C3 reductase-dependent KARS inhibitor-related diseases, which novel compositions are stable and provide optimal bioavailability. Summary of the invention

[0006] It has now been discovered that the pharmaceutical compositions disclosed herein and compositions thereof can be used to administer selective AKR1C3 inhibitors to patients in need thereof and exhibit the same desired characteristics. In general, the pharmaceutically acceptable compositions disclosed herein can be used to treat or lessen the severity of various diseases or disorders, as described in detail herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figure 1 is a graphical representation of the desaturation curve of compound (I) in FaSSIF-V1 when added as a DMSO solution at drug loadings ranging from 100 to 2000 ppmw

[0008] Figure 2 :NSG tablet compression characteristics

[0009] Figure 3 : 2-step dissolution of ASG based on HPMC-AS, FaSSGF->FaSSIF-V1 conversion after 60 min, final drug loading 100 ppmw DETAILED DESCRIPTION

[0010] The present disclosure is based, at least in part, on the identification of compounds that inhibit AKR1C3 and methods of using the compounds to treat AKR1C3-related diseases. Compound (I) and pharmaceutical compositions thereof are disclosed herein.

[0011]

[0012] The compound of formula (I), 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, is active as a selective AKR1C3 inhibitor in various assays and therapeutic models.

[0013] It is desirable to provide pharmaceutically acceptable compositions comprising Compound (I) that impart improved stability, improved oral bioavailability and low risk of toxicity, among other properties. Accordingly, the present disclosure provides pharmaceutical compositions of Compound (I).

[0014] In one aspect, the present invention provides a pharmaceutical composition of a compound represented by formula (I)

[0015]

[0016] The pharmaceutical composition comprises a compound having formula (I) stabilized in an amorphous form together with a polymer.

[0017] Amorphous Spray Granule (ASG) Composition

[0018] In one aspect, the present invention provides a pharmaceutical composition for oral administration of compound (I) to a subject, wherein compound (I) is formulated as amorphous spray particles. In some embodiments, the pharmaceutical composition of the present invention comprises:

[0019] Pharmaceutical compositions of compounds represented by formula (I)

[0020]

[0021] The pharmaceutical composition comprises:

[0022] (i) an intragranular blend, wherein the intragranular blend comprises:

[0023] (a) Amorphous spray particles, the amorphous spray particles comprising:

[0024] (i) the compound of formula (I), wherein the compound exists in an amorphous form;

[0025] (ii) polymers;

[0026] (b) Suspending concentrates;

[0027] (c) a carrier;

[0028] (ii) an extragranular blend, wherein the extragranular blend comprises:

[0029] (d) one or more fillers;

[0030] (e) disintegrants;

[0031] (f) glidants; and

[0032] (g) Lubricants.

[0033] Nanospray particle (NSG) composition

[0034] In one aspect, the present invention provides a pharmaceutical composition for oral administration of compound (I) to a subject, wherein compound (I) is formulated as nanospray particles. In some embodiments, the pharmaceutical composition of the compound represented by formula (I) of the present invention is

[0035]

[0036] Include:

[0037] (i) Nanocrystalline spray particles, comprising:

[0038] (a) a compound of formula (I) in crystalline form A, wherein the crystals are nanoscale,

[0039] (b) polymers,

[0040] (c) surfactant;

[0041] (d) a carrier;

[0042] (ii) an extragranular blend, wherein the extragranular blend comprises:

[0043] (e) one or more fillers;

[0044] (f) disintegrants;

[0045] (g) glidants; and

[0046] (h) Lubricants.

[0047] A. Compound (I)

[0048] As defined above, the pharmaceutical composition of the present invention is an amorphous spray particle or nanospray particle comprising compound (I). Compound (I) can be prepared according to Example 40 of WO / 2021 / 005586, which is incorporated herein by reference.

[0049] In some embodiments, the crystalline solid of Compound (I) is anhydrous Form A of Compound (I). In some embodiments, Form A of Compound (I) is a form having at least 1, 2, 3, 4, or 5 X-ray powder diffraction peaks listed in Table 1 below:

[0050] Table 1: XRPD peak positions of Form A of Compound (I)

[0051]

[0052] In another aspect of the above embodiment, the crystalline Form A of the compound of Formula (I) is characterized by an x-ray powder diffraction pattern comprising two or more 2θ values ​​selected from the group consisting of: 9.6±0.2°2θ, 10.5±0.2°2θ, 13.4±0.2°2θ, 15.7±0.2°2θ, 17.1±0.2°2θ, 19.2±0.2°2θ, 21.0±0.2°2θ, 22.4±0.2°2θ, 27.3±0.2°2θ, 30.4±0.2°2θ, and 31.7±0.2°2θ measured at a temperature of about 25°C. In another aspect of the above embodiment, the crystalline Form A of the compound of Formula (I) is characterized by comprising three or more 2θ values ​​selected from the group consisting of: The x-ray powder diffraction pattern of is: 9.6±0.2°2θ, 10.5±0.2°2θ, 13.4±0.2°2θ, 15.7±0.2°2θ, 17.1±0.2°2θ, 19.2±0.2°2θ, 21.0±0.2°2θ, 22.4±0.2°2θ, 27.3±0.2°2θ, 30.4±0.2°2θ and 31.7±0.2°2θ. In another aspect of the above embodiment, crystalline Form A of the compound having Formula (I) is characterized by an x-ray powder diffraction pattern comprising four or more 2θ values ​​selected from the group consisting of 9.6±0.2°2θ, 10.5±0.2°2θ, 13.4±0.2°2θ, 15.7±0.2°2θ, 17.1±0.2°2θ, 19.2±0.2°2θ, 21.0±0.2°2θ, 22.4±0.2°2θ, 27.3±0.2°2θ, 30.4±0.2°2θ and 31.7±0.2°2θ measured at a temperature of about 25°C. In another aspect of the above embodiment, crystalline Form A of the compound having Formula (I) is characterized by an x-ray powder diffraction pattern comprising five or more 2θ values ​​selected from the group consisting of 9.6±0.2°2θ, 10.5±0.2°2θ, 13.4±0.2°2θ, 15.7±0.2°2θ, 17.1±0.2°2θ, 19.2±0.2°2θ, 21.0±0.2°2θ, 22.4±0.2°2θ, 27.3±0.2°2θ, 30.4±0.2°2θ and 31.7±0.2°2θ measured at a temperature of about 25°C.

[0053] In some embodiments, compound (I) is present in a pharmaceutical composition in an amount of about 1wt% to about 40wt%. In some embodiments, compound (I) is present in a pharmaceutical composition in an amount of about 5wt% to about 20wt%. In some embodiments, compound (I) is present in a pharmaceutical composition in an amount of about 8wt% to about 14wt%. In some embodiments, compound (I) is present in a pharmaceutical composition in an amount of about 1wt%, about 2wt%, about 3wt%, about 4wt%, about 5wt%, about 6wt%, about 7wt%, about 8wt%, about 9wt%, about 10wt%, about 11wt%, about 12wt%, about 13wt%, about 14wt%, about 15wt%, about 16wt%, about 17wt%, about 18wt%, about 19wt%, or about 20wt%. In some embodiments, compound (I) is present in a pharmaceutical composition in an amount of about 11.9wt%. In another embodiment, compound (I) is present in an amount of about 12.5%. In further embodiments, Compound (I) is present in an amount of about 20 wt% to 40 wt%. In some embodiments, Compound (I) is present in an amount of about 40 wt%.

[0054] Particle size distribution of nanosuspension particles

[0055] The particle size of the nanosuspension particles is measured, for example, by laser diffraction methods such as particle size distribution (PSD) using methods and instruments known to those skilled in the art.

[0056] According to the present invention, compound (I) can be used directly or can be subjected to mechanical means to reduce the average particle size to less than 1000nm. The particle size is measured, for example, by laser diffraction methods (e.g., particle size distribution (PSD)) using methods and instruments known to those skilled in the art. Preferably, the particle size measured by PCS is less than 500nm, more preferably less than 350nm, and most preferably less than 250nm. In one embodiment, the particle size of the suspension as measured by PCS is from about 50 nm to about 1000 nm, or from about 50 nm to 500 nm, or from about 50 nm to about 350 nm, or from about 100 nm to 170 nm, for example, a particle size of about 50 nm, or about 70 nm, or about 90 nm, or about 100 nm, or about 110 nm, or about 120 nm, or about 130 nm, or about 140 nm, or about 150 nm, or about 160 nm, or about 170 nm, or about 180 nm, or about 190 nm, or about 200 nm, or about 230 nm, or about 250 nm, or about 280 nm, or about 300 nm, or about 320 nm, or about 350 nm, or about 370 nm, or about 400 nm, or about 450 nm, or about 500 nm. More preferably, the particle size is from about 100 nm to about 350 nm, or from about 110 nm to about 180 nm, or from about 250 nm to about 350 nm. The particles formed are stabilized by the presence of a polymer in the intragranular blend, as defined herein, which polymer is capable of maintaining the particles in a stable state at the desired particle size.

[0057] The API particles can be prepared by suitable milling techniques such as those well known in the art, such as, for example, jet milling, pin milling, and wet ball milling.

[0058] B. Polymer

[0059] As defined above, the pharmaceutical composition of the present invention is an amorphous spray particle or nanospray particle comprising a polymer. In some embodiments, the polymer comprises an organic polymer. Suitable polymers include, but are not limited to, cellulose or starch, microcrystalline cellulose ("MCC"), Avicel PH 101 (FMC biopolymer), gum arabic, sodium alginate, gelatin, starch, pregelatinized starch, methylcellulose, hydroxypropyl methylcellulose ("HPMC"), hydroxypropyl methylcellulose acetate succinate ("HPMC-AS"), hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene glycol, polyvinyl pyrrolidone ("PVP"), polyvinyl acetate phthalate ("PVAP"), copolyvidone (e.g. VA 64), crospovidone (e.g. CL), carrageenan (such as Gelcarin GP 812 ethylcellulose and cellulose acetate) or polyacrylates (such as amino methacrylate copolymer) (Eudragit RS / RL), methacrylic acid-ethyl acrylate copolymer (Eudragit L100-55) polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or a combination thereof.

[0060] In some embodiments, the polymer comprises hydroxypropyl methylcellulose ("HPMC"). In some further embodiments, the polymer comprises hydroxypropyl methylcellulose acetate succinate ("HPMC-AS").

[0061] In some embodiments, the polymer comprises polyvinylpyrrolidone ("PVP"). In some further embodiments, the polymer comprises polyvinylpyrrolidone 30 ("PVP-30").

[0062] In some embodiments, the polymer is any amorphous carrier commonly used in the formulation of pharmaceutical compositions for oral administration.

[0063] In some embodiments, the polymer is present in the pharmaceutical composition in an amount of about 1wt% to about 40wt%. In some embodiments, the polymer is present in the pharmaceutical composition in an amount of about 15wt% to about 30wt%. In some embodiments, the polymer is present in the pharmaceutical composition in an amount of about 22wt% to about 28wt%. In some embodiments, the polymer is present in the pharmaceutical composition in an amount of about 1wt%, about 2wt%, about 3wt%, about 4wt%, about 5wt%, about 6wt%, about 7wt%, about 8wt%, about 9wt%, about 10wt%, about 11wt%, about 12wt%, about 13wt%, about 14wt%, about 15wt%, about 16wt%, about 17wt%, about 18wt%, about 19wt%, or about 20wt%. In some embodiments, the polymer is present in the pharmaceutical composition in an amount of about 8.34wt%. In some embodiments, the polymer is present in the pharmaceutical composition in an amount of about 16.67wt%. In some embodiments, the polymer is present in the pharmaceutical composition in an amount of about 26.6wt%.

[0064] C. Suspension

[0065] As defined above, the pharmaceutical composition of the present invention is an amorphous spray particle or nanospray particle containing a suspending agent.

[0066] In some embodiments, the suspending agent is any suspending agent commonly used in the formulation of pharmaceutical compositions for oral administration. In some embodiments, the pharmaceutical composition of the present invention comprises a suspending agent selected from the following: dimethicone, silicon dioxide, silica, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc and other forms of silicon dioxide (such as polymerized silicates and hydrated silicon dioxide). In other embodiments, the suspending agent is silicon dioxide.

[0067] D. Carrier

[0068] As defined above, the pharmaceutical composition of the present invention is an amorphous spray particle or nanospray particle comprising a carrier.

[0069] In certain embodiments, carrier is any carrier in the formulation of the pharmaceutical composition commonly used for oral administration.In certain embodiments, the pharmaceutical composition of the present invention comprises a carrier selected from the following: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose (including silicified microcrystalline cellulose), saccharin sodium, glucose and / or glycine.In addition, except those listed above, tablets and / or capsule diluents suitable for the present disclosure include but are not limited to calcium carbonate, calcium hydrogen phosphate, calcium phosphate, calcium sulfate, cellulose powder, dextran adhesive, fructose, kaolin, starch, pregelatinized starch, compressible sugar and icing sugar (confectionery sugar) and combinations thereof.In other embodiments, carrier is selected from lactose or mannitol and combinations thereof.

[0070] E. Fillers

[0071] As defined above, the pharmaceutical composition of the present invention is an amorphous spray particle or nanospray particle comprising at least one filler.

[0072] In some embodiments, the filler is any filler commonly used in the formulation of a pharmaceutical composition for oral administration. In some embodiments, the pharmaceutical composition of the present invention comprises a filler selected from the group consisting of cellulose derivatives (such as microcrystalline cellulose or lignocellulose) (including microcrystalline cellulose and silicified microcrystalline cellulose), lactose, anhydrous lactose or lactose monohydrate, sucrose, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC), dextrose, mannitol (including mannitol Pearlitol SD 200), fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts (such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate), dextrin / glucose binder, maltodextrin, compressible sugar and other known bulking agents or fillers / or a mixture of two or more thereof.

[0073] F. Disintegrant

[0074] As defined above, the pharmaceutical composition of the present invention is an amorphous spray granule or nano spray granule comprising a disintegrant.

[0075] In some embodiments, the disintegrant is any disintegrant commonly used in the formulation of a pharmaceutical composition for oral administration. In some embodiments, the pharmaceutical composition of the present invention comprises a disintegrant selected from the following: cross-linked sodium carboxymethylcellulose, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium carboxymethyl starch, sodium glycolate starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose (L-HPC), sodium carboxymethyl cellulose, and other known disintegrants. Several specific types of disintegrants are suitable for use in the formulations described herein. In addition, in addition to the above disintegrants, disintegrants suitable for use in tablets of the present disclosure include, but are not limited to, alginic acid, polakolin potassium, sodium glycolate starch, and pregelatinized starch, and combinations thereof. In further embodiments, the disintegrant is sodium carboxymethyl cellulose. In other embodiments, the disintegrant is low-substituted hydroxypropyl cellulose (L-HPC).

[0076] G. Glidants

[0077] As defined above, the pharmaceutical composition of the present invention is an amorphous spray particle or nanospray particle comprising a glidant.

[0078] In some embodiments, the glidant is any glidant commonly used in the formulation of pharmaceutical compositions for oral administration. In some embodiments, the pharmaceutical compositions of the present invention comprise a glidant selected from the group consisting of silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc and other forms of silicon dioxide (such as polymerized silicates and hydrated silicon dioxide).

[0079] H. Lubricant

[0080] As defined above, the pharmaceutical composition of the present invention is an amorphous spray particle or nano spray particle comprising a lubricant.

[0081] In certain embodiments, lubricant is any lubricant commonly used in the formulation of the pharmaceutical composition for oral administration. In certain embodiments, the pharmaceutical composition of the present invention comprises a lubricant selected from the following: magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, sodium lauryl sulfate, palmitic acid stearyl glyceride, palmitic acid, myristic acid and hydrogenated vegetable oil and fat and other known lubricants and / or a mixture of two or more thereof. In addition, in addition to the above-mentioned lubricant, the lubricant suitable for use in the tablet and / or capsule of this disclosure includes but is not limited to behenic acid glyceride, light mineral oil, polyethylene glycol, hard purified stearic acid, and a combination thereof.

[0082] I. Surfactants

[0083] As defined above, the pharmaceutical composition of the present invention is an amorphous spray particle or nanospray particle comprising a surfactant.

[0084] In some embodiments, the surfactant is any surfactant commonly used in the formulation of pharmaceutical compositions for oral administration. In some embodiments, the pharmaceutical compositions of the present invention comprise a surfactant selected from the group consisting of gum arabic, cholesterol, diethanolamine, glyceryl monostearate, lanolin alcohol, lecithin, mono- and diglycerides, monoethanolamine, oleic acid, oleyl alcohol, poloxamer, polyoxyl 50 stearate, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyethylene glycol 10 oleyl ether, polyoxyl 20 cetostearyl alcohol ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, propylene glycol diacetate, propylene glycol monostearate, sodium lauryl sulfate, sodium stearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, stearic acid, triethanolamine, emulsifying wax, and combinations thereof.

[0085] Pharmaceutical composition

[0086] As described above, in some embodiments, the pharmaceutical composition is an amorphous spray particle comprising:

[0087] Example:

[0088] 1. A pharmaceutical composition of a compound represented by formula (I)

[0089]

[0090] The pharmaceutical composition comprises a compound having formula (I) stabilized in an amorphous form together with a polymer.

[0091] 2. The pharmaceutical composition of claim 1, wherein the compound of formula (I) is present at about 5 wt% to 80 wt%, about 10 wt% to 50 wt%, about 25 wt% to 40 wt%, or about 30 wt%.

[0092] 3. The pharmaceutical composition as described in Example 1, wherein the polymer is selected from: hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose, povidone (PVP), copovidone (PVP VA 64), cellulose acetate, cellulose acetate phthalate, or polyacrylates such as amino methacrylate copolymers (e.g. Eudragit RS / RL), methacrylic acid-ethyl acrylate copolymers (e.g. Eudragit L100 or L100-55), polyvinyl acetate, polyvinyl acetate phthalate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers

[0093] 4. The pharmaceutical composition of embodiment 3, wherein the polymer is HPMC-AS-L, HPMC-AS-M, HPMC-AS-H, or Eudragit L.

[0094] 5. A pharmaceutical composition of a compound represented by formula (I)

[0095]

[0096] The pharmaceutical composition comprises:

[0097] (i) an intragranular blend, wherein the intragranular blend comprises:

[0098] (a) Amorphous spray particles comprising:

[0099] (i) the compound of formula (I), wherein the compound exists in an amorphous form;

[0100] (ii) polymers;

[0101] (b) Suspending concentrates;

[0102] (c) a carrier;

[0103] (ii) an extragranular blend, wherein the extragranular blend comprises:

[0104] (d) fillers;

[0105] (e) disintegrants;

[0106] (f) glidants; and

[0107] (g) Lubricants.

[0108] 6. The pharmaceutical composition as described in Example 5, comprising:

[0109] (i) an intragranular blend, wherein the intragranular blend comprises:

[0110] (a) Amorphous spray particles comprising:

[0111] (i) the compound of formula (I), wherein the compound is present in an amorphous form in an amount of about 5 wt % to 20 wt %;

[0112] (ii) a polymer in an amount of about 10 wt % to 60 wt %;

[0113] (b) a suspending agent in an amount of about 0.5 wt % to 2.0 wt %;

[0114] (c) a carrier in an amount of about 20 wt % to 80 wt %;

[0115] (ii) an extragranular blend, wherein the extragranular blend comprises:

[0116] (d) a filler in an amount of about 10 wt % to 40 wt %;

[0117] (e) a disintegrant in an amount of about 0 wt % to 5 wt %;

[0118] (f) a glidant in an amount of about 0.5 wt % to 2.0 wt %; and

[0119] (g) a lubricant in an amount of about 0.5 wt % to 3.0 wt %.

[0120] 7. The pharmaceutical composition as described in Example 6, comprising:

[0121] (i) an intragranular blend, wherein the intragranular blend comprises:

[0122] (a) Amorphous spray particles comprising:

[0123] (i) the compound of formula (I), wherein the compound is present in an amorphous form in an amount of 11.9 wt %;

[0124] (ii) a polymer in an amount of about 26.6 wt %;

[0125] (b) a suspending agent in an amount of about 1.3 wt %;

[0126] (c) a carrier in an amount of about 30.3 wt %;

[0127] (ii) an extragranular blend, wherein the extragranular blend comprises:

[0128] (d) a filler in an amount of about 24.6 wt %;

[0129] (e) a disintegrant in an amount of about 2.8 wt %;

[0130] (f) a glidant in an amount of about 1.0 wt %; and

[0131] (g) a lubricant in an amount of about 1.5 wt %.

[0132] 8. The pharmaceutical composition of any one of embodiments 5-7, wherein the polymer is hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

[0133] 9. The pharmaceutical composition of embodiment 8, wherein the hydroxypropyl methylcellulose acetate succinate is selected from hydroxypropyl methylcellulose acetate succinate L grade (HPMC-AS-L), hydroxypropyl methylcellulose acetate succinate M grade (HPMC-AS-M), and hydroxypropyl methylcellulose acetate succinate H grade (HPMC-AS-H).

[0134] 10. The pharmaceutical composition of embodiment 7, wherein the suspending agent is silicon dioxide.

[0135] 11. The pharmaceutical composition of embodiment 7, wherein the carrier is lactose.

[0136] 12. The pharmaceutical composition of embodiment 7, wherein the filler is lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose (L-HPC), or a combination thereof.

[0137] 13. The pharmaceutical composition of embodiment 7, wherein the disintegrant is croscarmellose sodium.

[0138] 14. The pharmaceutical composition of embodiment 7, wherein the glidant is silicon dioxide.

[0139] 15. The pharmaceutical composition of embodiment 7, wherein the lubricant is sodium stearyl fumarate.

[0140] 16. The pharmaceutical composition of embodiment 7, comprising:

[0141] (i) an intragranular blend, wherein the intragranular blend comprises:

[0142] (a) Amorphous spray particles comprising:

[0143] (i) the compound of formula (I), wherein the compound is present in an amorphous form in an amount of 11.9 wt %;

[0144] (ii) hydroxypropyl methylcellulose acetate succinate in an amount of about 26.6 wt %;

[0145] (b) silicon dioxide in an amount of about 1.3 wt %;

[0146] (c) lactose in an amount of about 30.3 wt %;

[0147] (ii) an extragranular blend, wherein the extragranular blend comprises:

[0148] (d) lactose and microcrystalline cellulose in an amount of about 24.6 wt %;

[0149] (e) croscarmellose sodium in an amount of about 2.8 wt %;

[0150] (f) silicon dioxide in an amount of about 1.0 wt %; and

[0151] (g) sodium stearyl fumarate in an amount of about 1.5 wt %.

[0152] 17. The pharmaceutically acceptable composition of any one of embodiments 1-16, wherein the composition is in the form of a capsule or a tablet.

[0153] 18. A process for producing the pharmaceutical composition of embodiment 5, comprising:

[0154] (i) preparing amorphous spray particles, comprising:

[0155] (a) suspending a compound having formula (I), a polymer and a suspending agent in an acetone organic solution containing water;

[0156] (b) mixing the suspension of (a) to form a dispersion of the dissolved compound of formula (I);

[0157] (c) spraying the dispersion of (b) onto a carrier in a fluidized bed dryer to form amorphous spray particles;

[0158] (ii) preparing an extra-granular phase, wherein the extra-granular phase comprises:

[0159] (d) fillers;

[0160] (e) disintegrants;

[0161] (f) glidants; and

[0162] (g) Lubricant

[0163] (iii) blending the amorphous spray particles (i) with the extragranular phase (ii) to form a final blend.

[0164] 19. The process for manufacturing a pharmaceutical composition according to embodiment 18, wherein the composition is filled into capsules.

[0165] 20. The process for manufacturing a pharmaceutical composition according to embodiment 18, wherein the composition is compressed into a tablet.

[0166] 21. A method of treating a disease selected from the group consisting of: gastrointestinal stromal tumor (GIST), NF-1-deficient gastrointestinal stromal tumor, succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor, KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma, acute myeloid leukemia, germ cell tumor of seminoma or dysgerminoma, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath tumor, endometrial sarcoma, hypereosinophilic syndrome , idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophil-associated acute myeloid leukemia, lymphocytic T-cell lymphoma, liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, castration-resistant prostate cancer (CRPC), T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and non-small cell lung cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a composition as described in any one of Examples 1-20.

[0167] 22. The method of embodiment 21, wherein the disease is non-small cell lung cancer (NSCLC).

[0168] 23. Use of the composition of any one of embodiments 1-20 for the preparation of a medicament for treating a disease selected from the group consisting of: gastrointestinal stromal tumor (GIST), NF-1-deficient gastrointestinal stromal tumor, succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor, KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma, acute myeloid leukemia, germ cell tumor of seminoma or dysgerminoma, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma cell tumor, sarcoma, malignant peripheral nerve sheath tumor, endometrial sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophil-associated acute myeloid leukemia, lymphocytic T-cell lymphoma, liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, castration-resistant prostate cancer (CRPC), T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and non-small cell lung cancer.

[0169] 24. The use as described in embodiment 23, wherein the disease is non-small cell lung cancer (NSCLC).

[0170] 25. A pharmaceutical composition of a compound represented by formula (I)

[0171]

[0172] The pharmaceutical composition comprises:

[0173] (i) Nanocrystalline spray particles, comprising:

[0174] (a) a compound of formula (I) in crystalline form A, wherein the crystals are nanoscale,

[0175] (b) polymers,

[0176] (c) surfactant;

[0177] (d) a carrier;

[0178] (ii) an extragranular blend, wherein the extragranular blend comprises:

[0179] (e) one or more fillers;

[0180] (f) disintegrants;

[0181] (g) glidants; and

[0182] (h) Lubricants.

[0183] 26. The pharmaceutical composition of embodiment 25, comprising:

[0184] (i) Nanocrystalline spray particles, wherein the nanocrystalline spray particles comprise:

[0185] (a) the compound of formula (I), wherein the compound of formula (I) is nanocrystalline Form A in an amount of about 5 wt % to about 20 wt %,

[0186] (b) a polymer in an amount of about 5 wt % to 20 wt %,

[0187] (c) a surfactant in an amount of about 0.1 wt % to 1.0 wt %;

[0188] (d) a carrier in an amount of about 20 wt % to 80 wt %;

[0189] (ii) an extragranular blend, wherein the extragranular blend comprises:

[0190] (e) one or more fillers in an amount of about 25 wt % to 50 wt %;

[0191] (f) a disintegrant in an amount of about 2 wt % to 10 wt %;

[0192] (g) a glidant in an amount of about 0.5 wt % to 2.0 wt %; and

[0193] (h) a lubricant in an amount of about 0.5 wt % to 2.0 wt %.

[0194] 27. The pharmaceutical composition of embodiment 26, comprising:

[0195] (i) Nanocrystalline spray particles, wherein the nanocrystalline spray particles comprise:

[0196] (a) the compound of formula (I), wherein the compound of formula (I) is nanocrystalline Form A in an amount of 12.5 wt%,

[0197] (b) a polymer in an amount of about 8.34%,

[0198] (c) a surfactant in an amount of about 0.25 wt %;

[0199] (d) a carrier in an amount of about 28.9 wt %;

[0200] (ii) an extragranular blend, wherein the extragranular blend comprises:

[0201] (e) one or more fillers in an amount of about 40 wt %;

[0202] (f) a disintegrant in an amount of about 6 wt %;

[0203] (g) a glidant in an amount of about 1.5 wt %; and

[0204] (h) a lubricant in an amount of about 1.5 wt %.

[0205] 28. The pharmaceutical composition of any one of embodiments 25-27, wherein the polymer is povidone or copovidone.

[0206] 29. The pharmaceutical composition of embodiment 28, wherein the povidone is PVP K30.

[0207] 30. The pharmaceutical composition of embodiment 27, comprising:

[0208] (i) Nanocrystalline spray particles, wherein the nanocrystalline spray particles comprise:

[0209] (a) the compound of formula (I), wherein the compound of formula (I) is nanocrystalline Form A in an amount of 12.5 wt%,

[0210] (b) povidone in an amount of about 8.34%,

[0211] (c) sodium lauryl sulfate in an amount of about 0.25 wt %;

[0212] (d) a lactose carrier in an amount of about 28.9 wt %;

[0213] (ii) an extragranular blend, wherein the extragranular blend comprises:

[0214] (e) lactose and microcrystalline cellulose in an amount of about 40 wt %;

[0215] (f) croscarmellose sodium in an amount of about 6 wt %;

[0216] (g) silicon dioxide in an amount of about 1.5 wt %; and

[0217] (h) sodium stearyl fumarate in an amount of about 1.5 wt %.

[0218] 31. The pharmaceutical composition of any one of embodiments 25 to 30, wherein the crystals of the compound of formula (I) in crystalline Form A have a median particle size (D50) of about 150 to 250 nm.

[0219] 32. A process for preparing the pharmaceutical composition of any one of embodiments 25 to 31, comprising the steps of:

[0220] (i) mixing a mixture comprising the compound of formula (I) in crystalline form A, a polymer, and a surfactant in a liquid medium, wherein the crystals are nanoscale, and

[0221] (ii) adding the mixture to the carrier to form dry granules.

[0222] 33. The process of embodiment 32, wherein step (i) is performed in a wet grinding chamber.

[0223] 34. The process of embodiment 32 or 33, wherein the liquid medium is an aqueous solution.

[0224] 35. The process of embodiments 32 to 34, wherein the mixture of step (i) is dispersed on the carrier and dried to form granules.

[0225] 36. The process of any one of embodiments 32 to 35, wherein the process further comprises preparing a final dosage form by blending the granules from step (ii) with an extragranular phase, wherein the extragranular phase comprises one or more of: a filler; a disintegrant; a glidant; a lubricant.

[0226] 37. The process of embodiment 36, wherein the final dosage form is packaged or tableted.

[0227] 38. The process as described in embodiment 37, wherein the final dosage form is tableted and the resulting tablets are further film coated.

[0228] 39. A process for preparing a suspension, the process comprising mixing the compound of formula (I) or a pharmaceutically acceptable salt thereof or a free form thereof, at least one polymer, and optionally a surfactant with a liquid medium.

[0229] 40. The process of embodiment 39, wherein the suspension is subjected to wet grinding to reduce the crystal size of the compound of formula (I).

[0230] 41. The suspension of embodiment 40, wherein the median particle size (D50) of the crystals of the compound of formula (I) in the suspension is about 100 nm to 500 nm.

[0231] 42. The suspension of Embodiment 41, wherein the median particle size (D50) of the crystals of the compound of Formula (I) in the suspension is about 150 nm to 250 nm.

[0232] Method for preparing pharmaceutical composition

[0233] The compositions of the invention may suitably be prepared by combining the components into a dry powder (e.g. tablet, capsule), or a powder for reconstitution may be prepared by dry granulating the components of a tablet blend and optionally applying a film coating (e.g. a moisture barrier film) to the compressed tablet.

[0234] Uses of compounds and pharmaceutically acceptable compositions

[0235] As outlined above, the compounds (I) described herein, and pharmaceutically acceptable solid compositions thereof are AKR1C3 inhibitors. In some embodiments, the disclosed AKR1C3-inhibiting compounds are found to be useful for inhibiting the activity of AKR1C3.

[0236] In one aspect, the present disclosure provides a method for treating an AKR1C3-mediated disease or disorder in a subject in need thereof. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein, i.e., a pharmaceutical composition comprising compound (I). In some embodiments, the disease or disorder is lung cancer, bladder cancer, cervical cancer, esophageal cancer, head and neck cancer, renal cancer, and liver cancer. In some embodiments, lung cancer is non-small cell lung cancer (NSCLC), lung adenocarcinoma, or lung squamous cell carcinoma. In some embodiments, administration is oral administration.

[0237] On the other hand, the present disclosure provides a pharmaceutical composition as disclosed herein for use in treating an AKR1C3-mediated disease or disorder in a subject in need, i.e., a pharmaceutical composition comprising compound (I). On yet another aspect, the present disclosure provides a pharmaceutical composition as disclosed herein for use in the manufacture of a drug for treating an AKR1C3-mediated disease or disorder in a subject in need, i.e., a pharmaceutical composition comprising compound (I). In some embodiments, the disease or disorder is lung cancer, bladder cancer, cervical cancer, esophageal cancer, head and neck cancer, renal cancer, and liver cancer. In some embodiments, lung cancer is non-small cell lung cancer (NSCLC), lung adenocarcinoma, or lung squamous cell carcinoma.

[0238] The term "treatment" is used interchangeably with the term "therapeutic method" herein and refers to both 1) therapeutic treatments or measures that cure, slow, alleviate the symptoms of, and / or prevent the progression of a diagnosed pathological condition, disease, or disorder, and 2) preventive / preventive measures. Those in need of treatment may include those who already have a particular medical disease or disorder, as well as those who eventually acquire the disorder (i.e., those at risk or in need of preventive measures).

[0239] As used herein, the term "subject" refers to any individual or patient for whom a subject method is performed. Typically, the subject is a human, although as will be appreciated by those skilled in the art, the subject can be an animal.

[0240] The terms "therapeutically effective amount", "effective dose", "therapeutically effective dose", "effective amount" and the like refer to the amount of a subject compound that will induce a biological or medical response in a tissue, system, animal or human by administering the compound. Typically, the response is either an improvement in a patient's symptoms or a desired biological outcome. In some embodiments, such an amount should be sufficient to inhibit AKR1C3.

[0241] In some embodiments, the effective amount of the compound that inhibits AKR1C3 of the present invention is an amount ranging from about 10 mg to 1000 mg. In other embodiments, the amount ranges from about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to 200 mg, about 200 mg to 300 mg, about 300 mg to 400 mg, about 400 mg to 500 mg, about 500 mg to 1000 mg. The amount can be a single dose or can be a daily amount. In some embodiments, the effective amount of the compound that inhibits AKR1C3 is about 100 mg.

[0242] definition

[0243] As used herein, the term "about" when used in reference to an amount refers to a stated value ±10% of the stated value. In some embodiments, "about" refers to a stated value ±5% of the stated value, ±2% of the stated value, or ±1% of the stated value.

[0244] As used herein, the terms "administer," "administering," and "administration" refer to any method within sound medical practice for delivering a provided composition, or an active agent contained therein, to a subject in such a manner as to provide a therapeutic effect.

[0245] As used herein, the following phrases, "effective amount" or "therapeutically effective amount" of an active agent or ingredient, or a pharmaceutical active agent or ingredient, refer to an amount of a pharmaceutical active agent sufficient to have a therapeutic effect upon administration. The effective amount of a pharmaceutical active agent will vary depending on factors such as the type of pharmaceutical active agent selected, the particular condition or conditions being treated, the severity of the condition, the duration of treatment, the specific components of the composition used, etc. Generally, the response is either an improvement in the patient's symptoms or a desired biological outcome. In some embodiments, such an amount should be sufficient to inhibit c-kit kinase and treat a disease or disorder associated with c-kit kinase.

[0246] As used herein, the phrase "pharmaceutically acceptable salt" refers to salts of a certain composition or compositions that have the same activity as the unmodified compound or compounds and are neither biologically nor otherwise undesirable. Salts can be formed, for example, with organic or inorganic acids. Such suitable acids include acetic acid, acetylsalicylic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, sulfurous acid, boric acid, butyric acid, camphoric acid, camphorsulfonic acid, carbonic acid, citric acid, cyclopentanepropionic acid, digluconic acid, dodecylsulfuric acid, ethanesulfonic acid, formic acid, fumaric acid, glyceric acid, glycerophosphoric acid, glycine, glucoheptanoic acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid, hemisulfuric acid, heptanoic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, naphthylic acid, nicotinic acid, nitrous acid, oxalic acid, nonanoic acid, phosphoric acid, propionic acid, saccharin, salicylic acid, sorbic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, thioglycolic acid, thiosulfuric acid, p-toluenesulfonic acid, undecylenic acid, and naturally and synthetically derived amino acids.

[0247] As used herein, the term "preservative" refers to any known pharmaceutically acceptable preservative, which functions to inhibit bacteria, fungi, yeasts, molds, other microorganisms, and / or inhibit oxidation. Suitable preservatives include, but are not limited to, antimicrobial agents and / or antioxidants. Suitable antimicrobial agents may include, but are not limited to, benzoates, benzyl alcohol, sodium benzoate, sorbates, propionates, and nitrites. Suitable antioxidants may include, but are not limited to, vitamin C, butylated hydroxytoluene (BHT), sulfites, and vitamin E. Other such preservatives for use in the present invention are described above and herein.

[0248] As used herein, the term "prevent, preventing, or prevention" refers to any reduction (no matter how slight) in the tendency or risk of a subject to develop a condition, disease, disorder, or its symptoms. For the purpose of prevention, a subject is any subject, and is preferably a subject at risk of developing a condition, disease, disorder, or a subject susceptible to a condition, disease, disorder. The term "prevention" includes completely preventing the onset of clinically significant conditions, diseases, disorders, or preventing the onset of preclinically significant conditions, diseases, disorders in individuals at risk. This includes prophylactic treatment of subjects at risk of developing conditions, diseases, disorders.

[0249] As used herein, the term "solvent" refers to any pharmaceutically acceptable medium that is liquid at ambient temperature in which one or more solutes can be dissolved, or one or more substances can be partially dissolved or suspended. Many solvents are well known in the chemical and pharmaceutical arts and are contemplated herein and hereinafter.

[0250] As used herein, the phrase "substantially pure" refers to an individual compound form that is substantially free of all other forms, as well as degradation products of a certain form and any residual solvent, and is at least 85% pure on a % weight basis, unless otherwise specified. The compound form may have a purity of at least 90% on a % weight basis, a purity of at least 93% on a % weight basis, a purity of at least 95% on a % weight basis, or a purity of at least 97%, 98%, 99%, or 99.5% on a % weight basis.

[0251] As used herein, "subject" or "individual" or "animal" or "patient" or "mammal" refers to any subject for whom diagnosis, prognosis or therapy is desired, particularly a mammalian subject, such as a human.

[0252] As used herein, "treatment" or "treating" of a disease, disorder, or condition encompasses alleviating at least one symptom thereof, reducing its severity, or delaying or inhibiting its progression. Treatment does not mean completely curing a disease, disorder, or condition. Compositions useful herein need only reduce the severity of a disease, disorder, or condition, reduce the severity of symptoms associated therewith, provide an improvement in the quality of life of a patient or subject, or delay or inhibit the onset of a disease, disorder, or condition.

[0253] Throughout this specification, where compositions are described as having, including, or comprising particular components, or where processes and methods are described as having, including, or comprising particular steps, it is contemplated that there are additional compositions of the invention that consist essentially of, or consist of, the recited components, as well as processes and methods of the invention that consist essentially of, or consist of, the recited processing steps.

[0254] As used herein, all percentages are by weight of the total composition (ie, wt %) unless otherwise indicated.

[0255] Unless otherwise indicated, any concentration range, percentage range, or ratio range recited herein should be understood to be expressly disclosed and include any concentration, percentage, or ratio of any integer and fraction thereof (e.g., tenths and hundredths of an integer) within that range, as well as any sub-range falling within a range.

[0256] Unless otherwise indicated, any numerical range recited herein relating to any physical characteristic (including, for example, polymer subunits, size, or thickness) should be understood to be expressly disclosed and include any integer or fraction of an integer within the disclosed range, or any sub-range within the disclosed range.

[0257] For the sake of clarity, any element or feature of any method or composition or process described herein can be combined with any other element or feature of any other method or composition or process described herein. As used herein, other terms are meant to be defined by their well-known meanings in the art.

[0258] All features of each aspect of the disclosure apply mutatis mutandis to all other aspects.Each reference mentioned herein (including but not limited to patents, patent applications, and journal articles) is incorporated herein by reference as if fully set forth in its entirety.

[0259] In order to make the disclosure described in this article more fully understood, the following examples are listed. It should be understood that these examples are only for illustrative purposes and should not be interpreted as limiting the present disclosure in any way.

[0260] Examples

[0261] Example 1

[0262] The supersaturation potential of compound (I) was investigated by mixing the drug dissolved in 1 mL DMSO into 99 mL FaSSIF-V1 stirred at 37 °C ( Figure 1 ). At higher drug loadings of 500, 1000 or 2000 ppmw (or μg / g or μg / mL), compound (I) precipitated almost instantaneously and reached a constant steady-state concentration of approximately 20 μg / mL or less within 5 minutes. In the final sampling at 90 minutes, the solid was confirmed to be crystalline compound (I) by XRPD. At lower drug loadings, supersaturation was maintained for longer periods of time, for example, approximately 110 μg / mL of drug dissolved at 5 minutes at a drug loading of 200 ppmw, and approximately 70 μg / mL of drug did not dissolve until 20 minutes at a drug loading of 100 ppmw. The situation after desupersaturation was similar to that described for higher drug loadings. Overall, compound (I) appears to be a rather poorly supersaturated compound because it recrystallizes very quickly into free form Mod.A. Only low supersaturation can be maintained for a relatively short period of time.

[0263] Example 2

[0264] The following example illustrates the initial feasibility assessment of an amorphous solid dispersion formulation. Amorphous solid dispersions (ASDs) were initially evaluated as potential formulations for Compound (I). Solid dispersion screening was performed by lyophilizing solid Compound (I) with a polymer. VA64, HPMC-AS-LF, L100-55 and HPMC603 were tested for miscibility with Compound (I) by DSC measurements of the lyophilized material to determine whether the material was amorphous or crystalline. As shown in Table 2, HPMC 603 with a drug loading of 40% recrystallized after 3 weeks under stress conditions. VA64 recrystallized after 5 weeks at 50% and 40% drug loading. HPMC-AS-LF and L100-55 remained amorphous under stress conditions. However, according to UPLC analysis, HPMC-AS-LF and L100-55 all had significant impurities after 5 weeks.

[0265] Table 2: Initial stability evaluation of compound (I) in solid dispersion polymer

[0266]

[0267]

[0268] The initial purity of compound (I) was 99.3%.

[0269] Based on the miscibility, stability (stability at 50°C / 75% RH for 5 weeks by mDSC), kinetic solubility data (Example 1), and poor supersaturation and very rapid recrystallization of the compound, the feasibility of ASD formulation for compound (I) was considered very challenging. Therefore, the first option was to formulate compound (I) into a crystalline form, but to improve bioavailability by nano-sizing the drug crystals. It has been determined that the second formulation option via an amorphous solid dispersion will be very challenging and will only be beneficial if the drug can be protected in an amorphous form until it reaches the absorption site (duodenum, intestine) and gradually released to maintain sufficiently low supersaturation to prevent rapid recrystallization.

[0270] Example 3: Beagle Study

[0271] The following examples illustrate three PK beagle dog studies that were conducted using a variety of formulations containing compound (I) at a dose of 100 mg / animal. Table 3 summarizes the AUC, Cmax, and Tmax data for the three studies. The first dog PK study (dog study #1) was conducted to compare the spray-dried particles of micronized crystalline drug (MSG) and the spray-dried particles of nanocrystalline drug (NSG) with a hot melt extruded amorphous solid dispersion (HME-ASD) based on HPMC-AS. All powders were administered in hard gelatin capsules (HGC). The HME-ASD formulation was superior to MSG and NSG.

[0272] The second dog PK study (Dog Study #2) compared film-coated tablets (FCT) made from nanocrystalline particles (NSG) with those made from neutral polymers (i.e., HPMC or ) were prepared by spray-dried amorphous solid dispersion (ASD) prepared with . The PK parameters were comparable between all formulations.

[0273] The third dog PK study (Dog Study #3) compared the exposure of HPMC (neutral polymer) based amorphous spray granules (ASG) with and without enteric polymer coating of HPMC-AS-L or HPMC-AS-H. The PK parameters were comparable between all formulations.

[0274] Based on the results of three dog PK studies summarized in Table 3, it was concluded that only amorphous solid dispersions (ASDs) with enteric polymers (e.g., HPMC-AS) provided the greatest exposure. Since the exposure of ASDs with neutral polymers was similar to that of nanocrystalline drug formulations, the approach of spray-dried particles of nanocrystalline drug (NSG) was considered another attractive formulation opportunity, especially considering the substantial exposure advantage of NSG compared to the inferior exposure of spray-dried particles of micronized crystalline drug (MSG).

[0275] Table 3: Beagle Dog PK Study

[0276]

[0277]

[0278] Example 4: Nanosuspension spray particles and hot melt extrusion

[0279] The following example illustrates nanosuspension spray particles (NSG). The median particle size distribution (D50) of unmilled compound (I) is between about 50 and 200 μm. Compound (I) is micronized by jet milling to obtain a very fine drug substance with a D50 between about 1 and 3 μm. A nanosuspension is prepared by mixing 10% jet-milled compound (I), 2% PVP K30 and 0.1% SLS with water. Then, a nanosuspension spray particle (NSG) is prepared by spray drying the nanosuspension and additional PVP K30 and SLS onto a sugar core carrier. Then, NSG is mixed with additional extragranular excipients (e.g., mannitol, lactose, Avicel PH012 (MCC), cross-linked sodium carboxymethylcellulose, cross-polyvidone, silicon dioxide, sodium stearyl fumarate). The blend is compressed into tablets using a tablet press and film-coated.

[0280] Several batches of NSG tablets were produced to evaluate the best composition. Lactose SD, mannitol SD were used as sugar cores in NSG. Lactose SD, mannitol SD and microcrystalline cellulose (MCC) were used as fillers, and cross-linked carboxymethylcellulose sodium and crospovidone were evaluated as disintegrants to produce the final tablets. Table 4 details the excipients used in several batches to evaluate the effect of these excipients on compression properties. Figure 2 The effect of excipients on compression properties was demonstrated. The formulation was optimized to reduce the disintegration time to less than 10 minutes at 2 MPa. The ratio of soluble filler to insoluble filler was optimized to 40% soluble filler and 60% insoluble filler.

[0281] Table 4: Evaluation of excipients on compression properties

[0282]

[0283] The final composition of NSG can be found in Table 5.

[0284] Table 5: Final composition of NSG

[0285]

[0286] Manufacturing process of nano suspension spray granule tablets:

[0287] a. Dissolve a binder such as polyvinylpyrrolidone (PVP) in water with stirring.

[0288] b. Add a surfactant such as sodium lauryl sulfate (SLS) to the solution of step a and dissolve under stirring.

[0289] c. Add compound (I) to the solution of step b and suspend under stirring.

[0290] d. Grinding the suspension of step c, such as wet ball grinding.

[0291] e. Dissolve the required amount of SLS and polyvinylpyrrolidone in additional purified water under stirring.

[0292] f. Weigh the required amount of the suspension from step d and add to the solution from step e to complete the suspension for spraying, such as spray granulation.

[0293] g. Loading with an inert matrix (carrier particles), such as lactose SD or mannitol SD.

[0294] h. Spraying, eg spray granulation, is performed by spraying the suspension from step e onto an inert matrix from step g, such as lactose SD or mannitol SD200.

[0295] i. Blending the granule particles from step h with an extragranular blend of lactose, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, and sodium stearyl fumarate.

[0296] j. The blended mixture from step i is introduced into capsules or compressed to form tablets.

[0297] Hot melt extrusion (HME) was also attempted. Although amorphous solid dispersions (ASDs) of compound (I) and different polymers could be prepared, this approach was quickly abandoned due to thermal degradation of compound (I) as the compound-polymer mixture needed to be extruded at temperatures exceeding 160°C.

[0298] Example 5: Development of amorphous solid dispersion spray particles

[0299] The following examples illustrate the chemical and physical stability of Compound (I) in different polymers when stored over time under conditions of elevated temperature and varying relative humidity.Amorphous solid dispersion (ASD) powders were prepared by spray drying a mixture of Compound (I) and different polymers in an organic solution.

[0300] All powders exhibited good chemical and physical stability when stored at ambient temperatures (e.g., for at least 3 months). However, storage at elevated temperatures showed significant differences, see Table 6. In general, impurities increased with increasing temperature, moisture, and time. The highest impurity levels were observed with enteric polymers. HPMC-AS had more impurities than Eudragit L100-55. This may point to specific drug degradation in the presence of acidic functional groups, consistent with the drug instability in acidic solutions described previously. Lower but still significant impurity levels were observed with neutral HPMC. Additionally, more drug and less polymer seemed to reduce the total impurities generated. Interestingly, the use of neutral polymers reduced the total impurities generated. There was almost no degradation. On the other hand, It is the only polymer of compound (I) that has recrystallized at 40°C (8 weeks, 75% RH) and the recrystallization is more obvious at 60°C. Another unfavorable property of the material is that it softens at 40°C, 75% RH or at 60°C, 50% RH, resulting in the powder being converted into a hard sintered plug. Powder sintering and plug formation were also observed for L100-55 after storage at 40°C, 75% RH or at 60°C, 11% RH, but no recrystallization was found. The HPMC-AS powder was slightly consolidated and the plug could be redispersed with no indication of recrystallization. All HPMC powders remained flowable with no signs of recrystallization. The TGA results indicated that, depending on the storage conditions, hygroscopicity was relatively limited, with the lowest levels associated with HPMC-AS as an ASD polymer.

[0301] HPMC-based ASG

[0302] The following development converts ASD manufacturing to spray granulation via spray drying, and takes the opportunity to cover the particles with enteric coating. In order to obtain previous chemical and physical stability experience, HPMC is used as the polymer of ASD or amorphous spray particles (ASG). Other ASG ingredients are mannitol SD as a carrier, and a small amount of silicon dioxide. The drug and polymer are dissolved in acetone / water for spray solution preparation. Through further spray granulation, an insulating layer of HPMC, silicon dioxide, and SLS is added to pure ASG, and an enteric layer of HPMC-AS-L or HPMC-AS-H is added on top. All three types of particles have been tested for bioperformance (as discussed above) in the third dog PK study #3. There is not much difference in exposure between HPMC-based ASG, whether it is only carrying a neutral sealing layer or covering an additional HPMC-AS-L or HPMC-AS-H enteric layer. Furthermore, only pure HPMC-based ASG showed little drug degradation, i.e., total impurities of about 0.1% after 8 weeks at 40°C, 75% RH, while enteric coating showed significant, i.e., total impurities of about 1.5% and 0.9%, respectively, after 8 weeks at 40°C, 75% RH. In conclusion, the addition of a neutral seal layer did not protect the drug from further degradation in combination with HPMC-AS, nor did the layering help improve the bioperformance beyond what the nanocrystal approach already provided.

[0303] ASG based on HPMC-AS

[0304] The final approach is to return to an enteric polymer, i.e., an ASD based on HPMC-AS, because the chemical and physical stability appears to be acceptable when stored in an environment. The manufacturing method is similar to the above method. However, the carrier is changed to lactose SD. The spray solution contains about 9% solids (compound (I), HPMC-AS-LF, silica) dissolved / suspended in acetone / water 9 / 1 (w / w). As expected, there is no need to worry about the physical and chemical stability of the ASG based on HPMC-AS under ambient storage conditions of 8 weeks or 4 months. Slightly increased stress storage at 30°C and 75% RH indicates the first drug degradation after 8 weeks. On the other hand, at 60°C and 11% RH, significant drug degradation was observed. In order to support the shelf life, it was decided to limit the degradation level to about 2%.

[0305] Another trend of ASG is the residual acetone content of 1.8%–2.3%, which also reflects to some extent the greater mass loss of ASG based on HPMC-AS by TGA. By applying vacuum drying (approximately 20 mbar) at 50°C or 60°C for about 1 day, the residual acetone can be reduced to levels below 0.5% without significant degradation.

[0306] The powder properties of the ASG batch were good, i.e. high bulk density, good flowability and reasonable PSD. Nevertheless, grinding had to be explored for different purposes. Manual hammer milling was first performed to adjust the particle size for better compactibility. Two major limitations were faced: First, a large amount of material accumulated on the sieve when hammer milling, such as observed with a 0.2 mm sieve. Second, size reduction (e.g. from 229 μm of median particle size (D50) to 155 μm of D50) resulted in more drug release with shorter supersaturation, such as Figure 3 This is considered less desirable since the goal is to maximize the concentration of drug in solution for as long as possible. Figure 3 It was also shown that an increase in the drug load in ASG to 20% (35% for the ASD layer) was also detrimental to this. On the other hand, independently of the observed in vitro dissolution, pin milling must be applied to reduce the particles to a finer powder in order to further improve the compactability or to match the oral gavage holes used for dosing rodents. For example, pin milling of ASG at different impact forces resulted in powders with a median particle size (D50) between about 20 and 100 μm.

[0307] Table 6: Chemical and physical stability of compound (I) in different polymers under various conditions

[0308]

[0309]

[0310] Example 6: PK performance of HPMC-AS ASG in cynomolgus monkeys

[0311] The following example illustrates the bioperformance of ASG based on HPMC-AS in cynomolgus monkeys. The (hammer-milled) particles were suspended in 50mM NaH2PO4 buffer (pH 4.6) and administered via oral gavage. It was found that at doses of 3 to 15 mg / kg, linear exposure (AUC) increased, while at 50 mg / kg it was less than proportional, see Table 7. The latter may be confounded to some extent because 2 of the 3 animals were incompletely dosed. However, the higher driving force of compound (I) desupersaturation at high doses may be the key factor.

[0312] Table 7

[0313]

[0314] Example 7: PK performance of HPMC-AS ASG formulation in Wistar rats

[0315] The following examples illustrate the biological performance of ASG based on HPMC-AS, and are used to examine the dose-dependent exposure of the final ASG based on HPMC-AS. The ASG based on HPMC-AS of the pin mill is suspended in 50mM NaH2PO4 buffer (pH 4.6), and administered via oral gavage. Under the 100mg / kg dosage, the biological performance of ASG based on HPMC-AS is similar to nanosuspension. However, when compared with the limited exposure increase under 300 or 1000mg / kg dosage of nanosuspension, the significant advantage of ASG based on HPMC-AS is produced under 600mg / kg, as shown in Table 8.

[0316] Table 8

[0317]

[0318] Example 8: Manufacturing process of amorphous solid dispersion spray granules and capsule formulations The following example describes a process for making an amorphous spray particle formulation of Compound (I).

[0319] Part A. Granules (ASG):

[0320] 1. Combine compound (I), silica and HPMC-AS into a solution of acetone and water.

[0321] 2. Mix in a suitable container until a visually uniform fine yellow dispersion is formed.

[0322] 3. Sieve lactose monohydrate SD.

[0323] 4. Load the fluid bed granulator with lactose monohydrate SD from step 3 and perform fluid bed granulation with the dispersion from step 2

[0324] 5. Grind the fluidized bed granules from step 4

[0325] Part B. Hard Gelatin Capsules (HGC):

[0326] 1. Add the following materials to a suitable container: Lactose Monohydrate SD, Compound (I) Granules (from Part A, Step 5), Silicon Dioxide, Croscarmellose Sodium, Sodium Stearyl Fumarate, Microcrystalline Cellulose and Blend.

[0327] 2. Sieve the blend from step 1

[0328] 3. Blend the mixture from step 2

[0329] 4. Encapsulate the final blend from step 3

[0330] Example 9: Manufacturing process of amorphous solid dispersion spray granules and tablet formulations The following example describes a process for making an amorphous spray particle formulation of Compound (I).

[0331] Part A. Granules (ASG):

[0332] 1. Combine compound (I), silica and HPMC-AS into a solution of acetone and water.

[0333] 2. Mix in a suitable container until a visually uniform fine yellow dispersion is formed.

[0334] 3. Sieve lactose monohydrate SD.

[0335] 4. Load the fluid bed granulator with lactose monohydrate SD from step 3 and perform fluid bed granulation with the dispersion from step 2

[0336] 5. Grind the fluidized bed granules from step 4

[0337] Part B. Film-coated tablets (FCT)

[0338] 1. Add the following materials to a suitable container: Compound (I) granules (from Part A, Step 5), silicon dioxide, croscarmellose sodium, sodium stearyl fumarate, microcrystalline cellulose and blend.

[0339] 2. Sieve the blend from step 1

[0340] 3. Blend the mixture from step 2

[0341] 4. Compress the final blend from step 3 into tablets

[0342] 5. Film coat the tablets from step 4

[0343] Part C. Film-coated tablets (FCT)

[0344] 1. Add the following materials to a suitable container: Compound (I) granules (from Part A, step 5), silicon dioxide, low-substituted hydroxypropyl cellulose (L-HPC), sodium stearyl fumarate and blend.

[0345] 2. Sieve the blend from step 1

[0346] 3. Blend the mixture from step 2

[0347] 4. Compress the final blend from step 3 into tablets

[0348] 5. The tablets from step 4 were film coated.

Claims

1. A pharmaceutical composition of a compound represented by formula (I) The pharmaceutical composition comprises the compound having formula (I) stabilized in an amorphous form together with a polymer.

2. The pharmaceutical composition of claim 1, wherein the compound of formula (I) is present at about 5 wt% to 80 wt%, about 10 wt% to 50 wt%, about 25 wt% to 40 wt%, or about 30 wt%.

3. The pharmaceutical composition of claim 1, wherein the polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose, povidone (PVP), copovidone (PVP VA 64), cellulose acetate, cellulose acetate phthalate, or polyacrylates such as aminomethacrylate copolymers (e.g. Eudragit RS / RL), methacrylic acid-ethylacrylate copolymers (e.g. Eudragit L100 or L100-55), polyvinyl acetate, polyvinyl acetate phthalate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers 4. The pharmaceutical composition of claim 3, wherein the polymer is HPMC-AS-L, HPMC-AS-M, HPMC-AS-H, or Eudragit L.

5. A pharmaceutical composition of a compound represented by formula (I) The pharmaceutical composition comprises: (i) an intragranular blend, wherein the intragranular blend comprises: (a) Amorphous spray particles comprising: (i) the compound of formula (I), wherein the compound exists in an amorphous form; (ii) polymers; (b) Suspension concentrates; (c) a carrier; (ii) an extragranular blend, wherein the extragranular blend comprises: (d) fillers; (e) disintegrants; (f) glidants; and (g) Lubricants.

6. The pharmaceutical composition according to claim 5, comprising: (i) an intragranular blend, wherein the intragranular blend comprises: (a) Amorphous spray particles comprising: (i) the compound of formula (I), wherein the compound is present in an amorphous form in an amount of about 5 wt % to 20 wt %; (ii) a polymer in an amount of about 10 wt % to 60 wt %; (b) a suspending agent in an amount of about 0.5 wt % to 2.0 wt %; (c) a carrier in an amount of about 20 wt % to 80 wt %; (ii) an extragranular blend, wherein the extragranular blend comprises: (d) a filler in an amount of about 10 wt % to 40 wt %; (e) a disintegrant in an amount of about 0 wt % to 5 wt %; (f) a glidant in an amount of about 0.5 wt % to 2.0 wt %; and (g) a lubricant in an amount of about 0.5 wt % to 3.0 wt %.

7. The pharmaceutical composition according to claim 6, comprising: (i) an intragranular blend, wherein the intragranular blend comprises: (a) Amorphous spray particles comprising: (i) the compound of formula (I), wherein the compound is present in an amorphous form in an amount of 11.9 wt %; (ii) a polymer in an amount of about 26.6 wt %; (b) a suspending agent in an amount of about 1.3 wt %; (c) a carrier in an amount of about 30.3 wt %; (ii) an extragranular blend, wherein the extragranular blend comprises: (d) a filler in an amount of about 24.6 wt %; (e) a disintegrant in an amount of about 2.8 wt %; (f) a glidant in an amount of about 1.0 wt %; and (g) a lubricant in an amount of about 1.5 wt %.

8. The pharmaceutical composition of any one of claims 5-7, wherein the polymer is hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

9. The pharmaceutical composition of claim 8, wherein the hydroxypropyl methylcellulose acetate succinate is selected from hydroxypropyl methylcellulose acetate succinate L grade (HPMC-AS-L), hydroxypropyl methylcellulose acetate succinate M grade (HPMC-AS-M), and hydroxypropyl methylcellulose acetate succinate H grade (HPMC-AS-H).

10. The pharmaceutical composition of claim 7, wherein the suspending agent is silicon dioxide.

11. The pharmaceutical composition of claim 7, wherein the carrier is lactose.

12. The pharmaceutical composition of claim 7, wherein the filler is lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose (L-HPC), or a combination thereof.

13. The pharmaceutical composition of claim 7, wherein the disintegrant is croscarmellose sodium.

14. The pharmaceutical composition of claim 7, wherein the glidant is silicon dioxide.

15. The pharmaceutical composition of claim 7, wherein the lubricant is sodium stearyl fumarate.

16. The pharmaceutical composition according to claim 7, comprising: (i) an intragranular blend, wherein the intragranular blend comprises: (a) Amorphous spray particles comprising: (i) the compound of formula (I), wherein the compound is present in an amorphous form in an amount of 11.9 wt %; (ii) hydroxypropylmethylcellulose acetate succinate in an amount of about 26.6 wt %; (b) silicon dioxide in an amount of about 1.3 wt %; (c) lactose in an amount of about 30.3 wt %; (ii) an extragranular blend, wherein the extragranular blend comprises: (d) lactose and microcrystalline cellulose in an amount of about 24.6 wt %; (e) croscarmellose sodium in an amount of about 2.8 wt %; (f) silicon dioxide in an amount of about 1.0 wt %; and (g) sodium stearyl fumarate in an amount of about 1.5 wt %.

17. The pharmaceutically acceptable composition of any one of claims 1-16, wherein the composition is in the form of a capsule or a tablet.

18. A process for producing the pharmaceutical composition of claim 5, comprising: (i) preparing amorphous spray particles, comprising: (a) suspending a compound having formula (I), a polymer and a suspending agent in an acetone organic solution containing water; (b) mixing the suspensions of (a) to form a dispersion of dissolved compound of formula (I); (c) spraying the dispersion of (b) onto a carrier in a fluidized bed dryer to form amorphous spray particles; (ii) preparing an extra-granular phase, wherein the extra-granular phase comprises: (d) fillers; (e) disintegrants; (f) glidants; and (g) Lubricant (iii) blending the amorphous spray particles (i) with the extragranular phase (ii) to form a final blend.

19. A process for the manufacture of a pharmaceutical composition as claimed in claim 18, wherein the composition is filled into capsules.

20. A process for manufacturing the pharmaceutical composition of claim 18, wherein the composition is compressed into a tablet.

21. A method of treating a disease selected from the group consisting of: gastrointestinal stromal tumor (GIST), NF-1-deficient gastrointestinal stromal tumor, succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor, KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma, acute myeloid leukemia, germ cell tumor of seminoma or dysgerminoma, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath tumor, endometrial sarcoma, hypereosinophilic syndrome, Idiopathic eosinophilic syndrome, chronic eosinophilic leukemia, eosinophil-associated acute myeloid leukemia, lymphocytic T-cell lymphoma, liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, castration-resistant prostate cancer (CRPC), T-cell acute lymphocytic leukemia (T-ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and non-small cell lung cancer, the method comprising administering a therapeutically effective amount of a composition as described in any one of claims 1-20 to a patient in need thereof.

22. The method of claim 21, wherein the disease is non-small cell lung cancer (NSCLC).

23. Use of the composition of any one of claims 1 to 20 for the preparation of a medicament for treating a disease selected from the group consisting of: gastrointestinal stromal tumor (GIST), NF-1-deficient gastrointestinal stromal tumor, succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor, KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma, acute myeloid leukemia, germ cell tumors of seminoma or dysgerminoma, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytes, Cytoma, sarcoma, malignant peripheral nerve sheath tumor, endometrial sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophil-associated acute myeloid leukemia, lymphocytic T-cell lymphoma, liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, castration-resistant prostate cancer (CRPC), T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and non-small cell lung cancer.

24. The use according to claim 23, wherein the disease is non-small cell lung cancer (NSCLC).

25. A pharmaceutical composition of a compound represented by formula (I) The pharmaceutical composition comprises: (i) Nanocrystalline spray particles, comprising: (a) said compound of formula (I) in crystalline form A, wherein said crystals are nanoscale, (b) polymers, (c) surfactant; (d) a carrier; (ii) an extragranular blend, wherein the extragranular blend comprises: (e) one or more fillers; (f) disintegrants; (g) glidants; and (h) Lubricants.

26. The pharmaceutical composition of claim 25, comprising: (i) Nanocrystalline spray particles, wherein the nanocrystalline spray particles comprise: (a) the compound of formula (I), wherein the compound of formula (I) is nanocrystalline Form A in an amount of about 5 wt % to about 20 wt %, (b) a polymer in an amount of about 5 wt % to 20 wt %, (c) a surfactant in an amount of about 0.1 wt % to 1.0 wt %; (d) a carrier in an amount of about 20 wt % to 80 wt %; (ii) an extragranular blend, wherein the extragranular blend comprises: (e) one or more fillers in an amount of about 25 wt % to 50 wt %; (f) a disintegrant in an amount of about 2 wt % to 10 wt %; (g) a glidant in an amount of about 0.5 wt % to 2.0 wt %; and (h) a lubricant in an amount of about 0.5 wt % to 2.0 wt %.

27. The pharmaceutical composition of claim 26, comprising: (i) Nanocrystalline spray particles, wherein the nanocrystalline spray particles comprise: (a) the compound of formula (I), wherein the compound of formula (I) is nanocrystalline form A in an amount of 12.5 wt%, (b) a polymer in an amount of about 8.34%, (c) a surfactant in an amount of about 0.25 wt %; (d) a carrier in an amount of about 28.9 wt %; (ii) an extragranular blend, wherein the extragranular blend comprises: (e) one or more fillers in an amount of about 40 wt %; (f) a disintegrant in an amount of about 6 wt %; (g) a glidant in an amount of about 1.5 wt %; and (h) a lubricant in an amount of about 1.5 wt %.

28. The pharmaceutical composition of any one of claims 25-27, wherein the polymer is povidone or copovidone.

29. The pharmaceutical composition of claim 28, wherein the povidone is PVP K30.

30. The pharmaceutical composition of claim 27, comprising: (i) Nanocrystalline spray particles, wherein the nanocrystalline spray particles comprise: (a) the compound of formula (I), wherein the compound of formula (I) is nanocrystalline form A in an amount of 12.5 wt%, (b) povidone in an amount of about 8.34%, (c) sodium lauryl sulfate in an amount of about 0.25 wt %; (d) a lactose carrier in an amount of about 28.9 wt %; (ii) an extragranular blend, wherein the extragranular blend comprises: (e) lactose and microcrystalline cellulose in an amount of about 40 wt %; (f) croscarmellose sodium in an amount of about 6 wt %; (g) silicon dioxide in an amount of about 1.5 wt %; and (h) sodium stearyl fumarate in an amount of about 1.5 wt %.

31. A pharmaceutical composition as described in any one of claims 25 to 30, wherein the crystals of the compound of formula (I) in crystalline form A have a median particle size (D50) of about 150 to 250 nm.

32. A process for preparing a pharmaceutical composition as claimed in any one of claims 25 to 31, comprising the following steps: (i) mixing a mixture comprising the compound of formula (I) in crystalline form A, a polymer, and a surfactant in a liquid medium, wherein the crystals are nanoscale, and (ii) adding the mixture to the carrier to form dry granules.

33. A process as claimed in claim 32, wherein step (i) is carried out in a wet grinding chamber.

34. A process as claimed in claim 32 or 33, wherein the liquid medium is an aqueous solution.

35. A process as claimed in claims 32 to 34, wherein the mixture of step (i) is dispersed onto the carrier and dried to form granules.

36. A process as claimed in any one of claims 32 to 35, wherein the process further comprises preparing the final dosage form by blending the granules from step (ii) with an extragranular phase, wherein the extragranular phase comprises one or more of: a filler; a disintegrant; a glidant; a lubricant.

37. The process of claim 36, wherein the final dosage form is packaged or tableted.

38. A process as claimed in claim 37, wherein the final dosage form is tableted and the resulting tablets are further film coated.

39. A process for preparing a suspension, the process comprising mixing the compound of formula (I) or a pharmaceutically acceptable salt thereof or a free form thereof, at least one polymer, and optionally a surfactant with a liquid medium.

40. The process of claim 39, wherein the suspension is subjected to wet grinding to reduce the crystal size of the compound of formula (I).

41. The suspension of claim 40, wherein the median particle size (D50) of the crystals of the compound of formula (I) in the suspension is about 100 nm to 500 nm.

42. The suspension of claim 41, wherein the median particle size (D50) of the crystals of the compound of formula (I) in the suspension is about 150 nm to 250 nm.

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