Amorphous kinase inhibitor formulations and methods of use thereof

Abstract

Provided herein is an amorphous compound represented by formula (I) and a composition thereof, # imgabs0 # for use in the treatment of conditions associated with c-KIT and PDGFRalpha kinase activity and their oncogenic forms.

Description

[0001] This case is a divisional application of a case with an application date of December 30, 2020, an invention name of Amorphous Kinase Inhibitor Preparations and Methods of Use Thereof, and an application number of CN202080097454.9.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to USSN 62 / 955,073 filed on December 30, 2019, USSN 62 / 955,062 filed on December 30, 2019, USSN 62 / 968,695 filed on January 31, 2020, and USSN 62 / 968,724 filed on January 31, 2020, the contents of each of which are incorporated herein by reference in their entirety. Background Art

[0004] c-KIT (also known as KIT, CD117 and stem cell factor receptor) is a 145 kDa transmembrane tyrosine kinase protein that is a type III receptor. The c-KIT proto-oncogene located on chromosome 4ql 1-21 encodes the c-KIT receptor, whose ligands are stem cell factor (SCF), Steel factor, KIT ligand and mast cell growth factor. The receptor has tyrosine protein kinase activity, and binding to the ligand SCF leads to autophosphorylation of c-KIT and its binding to substrates such as phosphatidic acid inositol 3-kinase (PI3K). Phosphorylation of tyrosine by protein tyrosine kinases is particularly important in cell signal transduction and can mediate information for major cellular processes such as proliferation, survival, differentiation, apoptosis, connection, invasion and migration. c-KIT deficiency is the cause of variegated albinism, an autosomal dominant dysplasia of pigmentation characterized by congenital patches of white skin and hair lacking melanocytes. In most gastrointestinal stromal tumors (GIST) and mastocytosis, gain-of-function mutations in the c-KIT gene and expression of constitutively phosphorylated c-KIT are found. In addition, almost all gonadal seminomas / malignant germ cell tumors exhibit c-KIT membrane staining, and several reports have explained that some cell tumors (10-25%) have c-KIT gene mutations. c-KIT deficiency is also associated with testicular tumors, including germ cell tumors (GCT) and testicular germ cell tumors (TGCT). c-KIT mutations are also associated with some subgroups of skin or acral melanomas.

[0005] Oncogenic genomic alterations of the PDGFRα kinase, or overexpression of the DGFRα kinase, have been shown to be a cause of human cancer. Missense mutations of the PDGFRα kinase have been shown to be the cause of some GISTs. PDGFRα mutations are oncogenic drivers in approximately 8-10% of GISTs. The primary PDGFRα mutation is exon 18 D842V, although other exon 18 mutations (including D846Y, N848K, and Y849K), and exon 18 insertion-deletion mutations (INDELs) (including RD841-842KI, DI842-843-IM, and HDSN845-848P) have also been reported. In addition, rare mutations in PDGFRα exons 12 and 14 have also been reported. PDGFRα exon 18 deletion mutations ΔD842-H845 and ΔI843-D846 have been reported in GIST. Amplification or mutation of PDGFRα has been described in human malignant peripheral nerve sheath tumor (MPNST) tissue. Amplification of PDGFRα has been described in multiple skin lesions of undifferentiated pleomorphic sarcoma and in endometrial sarcomas. Amplification of DGFRα has been associated with some subsets of lung cancer patients. 4q12, which contains the DGFRα gene locus, is amplified in 3-7% of lung adenocarcinomas and 8-10% of squamous cell lung cancers. DGFRα amplification is common in pediatric and adult high-grade astrocytomas and identifies a poor prognosis group in IDH1-mutant glioblastomas. DGFRα amplification occurs frequently in pediatric (29.3%) and adult (20.9%) tumors. DGFRα amplification has been reported to increase with grade and is particularly associated with a less favorable prognosis in IDH1-mutant primary GBMs. It has been demonstrated that the DGFRα locus in DGFRα amplified gliomas exhibits a DGFRα exon 8,9 intragenic deletion recombination. This intragenic deletion is common, present in 40% of glioblastoma multiforme (GBM) presenting DGFRα amplification. Tumors with this recombination show histological features of oligodendritic gliomas, and the DGFRα exon 8,9 intragenic deletion shows constitutively elevated tyrosine kinase activity. The FIP1L1-PDGFRα fusion protein is oncogenic in some patients with hypereosinophilic syndrome. The FIP1L1-DGFRα fusion protein has also been identified in acute myeloid leukemia and lymphoblastic T-cell lymphoma associated with hypereosinophilic syndrome.

[0006] Such a broad range of c-KIT inhibitors and formulations thereof would be of high therapeutic value in treating patients with refractory GIST and other conditions. There is a need for oral formulations that provide patients with a remarkably stable product. Mutations, deletions, rearrangements, and amplifications of the DGFRα gene are associated with many solid and hematological cancers. Given the complex functions of the PDGRFα gene and the potential utility of PDGFRα inhibitors in treating a variety of solid and hematological cancers, there is a need for oral inhibitor formulations with good therapeutic properties. SUMMARY OF THE INVENTION

[0008] Provided herein, in part, are amorphous forms of compounds of Formula (I), solid dispersions comprising amorphous forms of compounds of Formula (I), and pharmaceutical compositions suitable for oral administration comprising amorphous forms of compounds of Formula (I):

[0009]

[0010] For example, a pharmaceutical composition is provided herein, comprising a spray-dried solid dispersion of a compound represented by formula (I) containing an amorphous form and a pharmaceutically acceptable polymer, and one or more pharmaceutically acceptable carriers. (For example) The contemplated compositions provided herein, including amorphous form of formula I in the solid dispersion described herein, can provide enhanced pharmacokinetic properties when administered to a patient in certain embodiments, for example, compared to administering a crystalline form of formula I. The compositions (e.g., tablets) disclosed herein can provide rapid release (e.g., within 30 min or less) and / or rapid dissolution of the compound of formula I in at least some embodiments.

[0011] In one embodiment, the present invention also provides a pharmaceutical composition comprising: (a) an intragranular blend and (b) an extragranular blend; wherein the intragranular blend comprises: (i) a solid dispersion comprising an amorphous compound represented by formula (I) and a pharmaceutically acceptable polymer; (ii) one or more fillers; (iii) a disintegrant; (iv) a glidant; and (v) a lubricant; and wherein the extragranular blend comprises: (i) a glidant and (ii) a lubricant.

[0012] In some embodiments, provided herein is an amorphous form of a compound of Formula (I) that is free of detectable amounts of any crystalline form.

[0013] In some embodiments, provided herein is an amorphous form of a compound of Formula (I) that does not contain a detectable amount of any crystalline form of the compound of Formula (I).

[0014] In some embodiments, provided herein is an amorphous form of a compound of Formula (I) having no more than about 5% (w / w) of any crystalline form of the compound of Formula (I).

[0015] In one embodiment, the present invention also provides an amorphous form of a compound of formula (I) which contains no more than about 5% (w / w) of any crystalline form or no detectable amount of any crystalline form of the compound of formula (I) when exposed to 25-40°C and 0-100% relative humidity for at least 3 months.

[0016] In one embodiment, provided herein is a compound of formula (I) and wherein the compound is greater than about 95% amorphous. In some embodiments, the compound of formula (I) is greater than about 95% amorphous when analyzed by PXRD.

[0017] In one embodiment, provided herein is a compound of formula (I) that is amorphous and substantially free of any other crystalline form of the compound of formula (I).

[0018] In one embodiment, provided herein is a compound of formula (I) in an amorphous form substantially free of crystalline material and having a purity of at least about 95% excluding residual solvent.

[0019] In one embodiment, the present invention also provides a pharmaceutical composition comprising an amorphous compound of formula (I) with a purity of greater than 95% as determined by HPLC, and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0020] In one embodiment, provided herein is a pharmaceutical composition comprising: an amorphous form of the compound of formula (I) without detectable amounts of any crystalline form, and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0021] In some embodiments, provided herein is a pharmaceutical composition comprising: an amorphous form of a compound of formula (I) that does not contain a detectable amount of any crystalline form of the compound of formula (I), and one or more pharmaceutically acceptable carriers, excipients, or diluents.

[0022] In some embodiments, provided herein is a pharmaceutical composition comprising: an amorphous form of a compound of formula (I) containing no more than about 5% (w / w) of any crystalline form of the compound of formula (I), and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0023] In one embodiment, the present invention also provides a pharmaceutical composition comprising: an amorphous form of the compound of formula (I) containing no more than about 5% (w / w) of any crystalline form of the compound of formula (I) or any detectable amount of any crystalline form when exposed to 25-40°C and 0-100% relative humidity for about at least 3 months, and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0024] In one embodiment, a pharmaceutical composition is also provided herein, comprising: an amorphous compound of formula (I) wherein the compound is greater than about 95% amorphous, and one or more pharmaceutically acceptable carriers, excipients, or diluents. In some embodiments, the pharmaceutical composition comprises a compound of formula (I) wherein the compound is greater than about 95% amorphous when analyzed by PXRD.

[0025] In one embodiment, provided herein is a pharmaceutical composition comprising: an amorphous form of a compound of formula (I) substantially free of any other crystalline form, and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0026] In one embodiment, provided herein is a pharmaceutical composition comprising: an amorphous form of a compound of formula (I) that is substantially free of crystalline form and has a purity of at least about 95% as determined by HPLC excluding residual solvents, and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0027] In one embodiment, the present invention also provides a solid dispersion comprising: an amorphous compound of formula (I) with a purity of greater than 95% as determined by HPLC, a polymer and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0028] In one embodiment, the present invention also provides an amorphous solid dispersion comprising a compound of formula (I) and a pharmaceutically acceptable polymer (e.g., hydroxypropylmethylcellulose acetate succinate), wherein the amorphous form is characterized by powder X-ray diffraction having a broad peak in 2θ (e.g., 2θ of about 9.5, and about 17 to about 29). In some embodiments, the amorphous form of the compound of formula (I) is substantially composed of Figure 1 The X-ray diffraction pattern shown is used to characterize.

[0029] In one embodiment, provided herein is a solid dispersion comprising: an amorphous form of the compound of formula (I) without detectable amounts of any crystalline form, and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0030] In some embodiments, provided herein is a solid dispersion comprising: an amorphous compound of Formula (I) without a detectable amount of any crystalline form of the compound of Formula (I), and a polymer and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0031] In one embodiment, the present invention also provides a solid dispersion comprising: an amorphous form of a compound of formula (I) containing no more than about 5% (w / w) of any crystalline form of the compound of formula (I), and a polymer and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0032] In one embodiment, the present invention also provides a solid dispersion comprising: an amorphous form of a compound of formula (I) containing no more than about 5% (w / w) of any crystalline form of a compound of formula (I) or any detectable amount of any crystalline form when exposed to 25-40°C and 0-100% relative humidity for about 3 months or longer, and a polymer and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0033] In one embodiment, provided herein is a solid dispersion comprising: an amorphous compound of formula (I) wherein greater than about 95% of the compound is amorphous, and a polymer and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0034] In one embodiment, provided herein is a solid dispersion comprising: an amorphous form of a compound of formula (I) substantially free of any other crystalline form, and a polymer and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0035] In one embodiment, provided herein is a solid dispersion comprising: an amorphous form of a compound of formula (I) that is substantially free of crystalline form and has a purity of at least about 95% as determined by HPLC excluding residual solvent, and a polymer and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0036] In one embodiment, provided herein is a pharmaceutically acceptable composition for oral administration, the composition comprising: (i) a solid dispersion, wherein the solid dispersion comprises: an amorphous compound represented by formula (I):

[0037]

[0038] and a pharmaceutically acceptable polymer; and (ii) one or more pharmaceutically acceptable excipients.

[0039] In another embodiment, described herein is a pharmaceutically acceptable composition comprising a compound represented by formula (I) and a pharmaceutically acceptable excipient,

[0040]

[0041] Wherein greater than about 96% (w / w) of the compound in the pharmaceutically acceptable composition is in amorphous form.

[0042] In another embodiment, described herein is a pharmaceutically acceptable composition for oral delivery of 50 mg of a compound represented by formula (I) to a patient,

[0043]

[0044] The composition comprises: an intragranular blend and an extragranular blend; wherein the intragranular blend comprises: a solid dispersion having 50 mg of the compound and wherein the compound is present in an amorphous form, and acid hydroxypropyl methylcellulose succinate; a bulking agent and / or a filler; and a lubricant and / or a glidant; and wherein the extragranular blend comprises: a glidant and / or a lubricant.

[0045] In another embodiment, described herein is a pharmaceutically acceptable composition for oral delivery of 50 mg of a compound represented by formula (I) to a patient,

[0046]

[0047] The composition comprises: a solid dispersion having 50 mg of the compound and wherein the compound is present in an amorphous form, and hydroxypropylmethylcellulose acetate succinate; a swelling agent; a filler; and a lubricant and / or a glidant.

[0048] In another embodiment, described herein is a pharmaceutically acceptable tablet having 50 mg of a compound represented by formula (I),

[0049]

[0050] The tablet comprises: an intragranular blend and an extragranular blend; wherein the intragranular blend comprises: a solid dispersion having 50 mg of the compound and wherein the compound is present in an amorphous form, and hydroxypropylmethylcellulose acetate succinate; about 25-35% (w / w) of a swelling agent, based on the total amount of the pharmaceutical composition; about 25-35% (w / w) of a filler, based on the total amount of the pharmaceutical composition; and wherein the extragranular blend comprises a glidant and / or a lubricant.

[0051] In another embodiment, described herein is a pharmaceutically acceptable tablet having 50 mg of a compound represented by formula (I),

[0052]

[0053] The tablet comprises: a solid dispersion having 50 mg of the compound and wherein the compound is present in an amorphous form, and hydroxypropylmethylcellulose acetate succinate; about 25-35% (w / w) of microcrystalline cellulose, based on the total weight of the tablet; and about 25-35% (w / w) of lactose or a hydrate thereof, based on the total amount of the pharmaceutical composition.

[0054] In another embodiment, described herein is a pharmaceutically acceptable composition for oral delivery of 50 mg of a compound represented by formula (I),

[0055]

[0056] The composition comprises: an intragranular blend and an extragranular blend; wherein the intragranular blend comprises: a solid dispersion having 50 mg of the compound and wherein the compound is present in an amorphous form, and hydroxypropylmethylcellulose acetate succinate; about 25-35% (w / w) microcrystalline cellulose, based on the total amount of the pharmaceutical composition; about 25-35% (w / w) lactose or a hydrate thereof, based on the total amount of the pharmaceutical composition; about 5% (w / w) cross-linked polyvinylpyrrolidone, based on the total amount of the pharmaceutical composition; about 0.5% (w / w) silicon dioxide, based on the total amount of the pharmaceutical composition; and about 0.5% (w / w) magnesium stearate, based on the total amount of the pharmaceutical composition; and wherein the extragranular blend comprises: about 0.5% (w / w) silicon dioxide, based on the total amount of the pharmaceutical composition; and (ii) about 0.5% (w / w) magnesium stearate, based on the total amount of the pharmaceutical composition.

[0057] In another embodiment, described herein is a method for preparing a solid dispersion comprising an amorphous form of a compound of formula (I),

[0058]

[0059] For example, the amorphous form described herein, the method comprises: (a) mixing a compound of formula (I), a solvent, the polymer and water to obtain a suspension; (b) optionally stirring and / or mixing the suspension while maintaining the temperature at about 10°C to about 25°C; (c) heating the suspension to dissolve the suspended particles, and then introducing it into a spray dryer; and (d) spray drying the suspension to obtain a spray-dried dispersion; (e) drying the spray-dried dispersion to obtain a solid dispersion. In some embodiments, a solid dispersion comprising an amorphous form of a compound of formula (I),

[0060]

[0061] Prepared by the method described.

[0062] In another embodiment, the present invention also provides a method for treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma, acute myeloid leukemia, germ cell tumor of seminoma or malignant germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic syndrome-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma, and non-small cell lung cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a composition described herein or one or more tablets.

[0063] In another embodiment, the present invention also provides a method for treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, lung cancer, glioblastoma, glioma, malignant peripheral nerve sheath sarcoma and hypereosinophilic syndrome in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a composition described herein or one or more tablets.

[0064] In another embodiment, provided herein is a method for treating a disease selected from the group consisting of KIT-driven germ cell tumors (e.g., testicular germ cell), KIT-driven skin cancer, or KIT-driven renal cell carcinoma in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a composition or one or more tablets described herein.

[0065] In another embodiment, the present invention also provides a method of treating a disease selected from the group consisting of penile cancer, PDGFRA-driven penile cancer, prostate cancer, PDGFRA-driven prostate cancer, PDGFRA-driven non-melanoma skin cancer, PDGFRA-driven glioma, PDGFRA-driven sarcoma, PDGFRA-driven glioblastoma, or PDGFRA-driven pancreatic cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a composition described herein or one or more tablets.

[0066] In another embodiment, the present invention also provides a method for treating a disease comprising a PDGFRB mutation in a patient in need thereof selected from the group consisting of vaginal cancer, prostate cancer, penile cancer, non-melanoma skin cancer, melanoma, or breast sarcoma, the method comprising administering to the patient a therapeutically effective amount of a composition or one or more tablets described herein.

[0067] In some embodiments, provided herein is a method for treating a disease driven by a KIT mutation or a PDGFRA mutation in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a composition described herein or one or more tablets. In some embodiments, provided herein is a method for treating a disease driven by a KIT mutation and a PDGFRA mutation in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a composition described herein or one or more tablets. In some embodiments, provided herein is a method for treating a disease driven by a KIT mutation or a PDGFRA mutation (including a passenger PDGFRB mutation) in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a composition described herein or one or more tablets. In some embodiments, provided herein is 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 (e.g., KIT-driven melanoma or PGDFRA-driven melanoma or PGDFR-driven melanoma), acute myeloid leukemia, seminoma, or germ cell tumor of a malignant germ cell tumor in a patient in need thereof. , mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, eosinophilic syndrome, idiopathic eosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic syndrome-related acute myeloid leukemia, lymphoblastic T-cell lymphoma and non-small cell lung cancer, the method comprising administering to the patient a therapeutically effective amount of the composition described herein or one or more tablets. In some embodiments, the melanoma is a skin melanoma or a non-skin melanoma. In some embodiments, the melanoma is a skin melanoma. In some embodiments, the melanoma is a superficial spreading melanoma, a nodular melanoma, an acral lentiginous melanoma, or amelanin-free and desmoplastic melanoma. In some embodiments, the melanoma is a non-skin (non-skin) melanoma. In some embodiments, the non-cutaneous melanoma is an ocular melanoma or a mucosal melanoma. In some embodiments, the disease is caused by the kinase activity of c-KIT and / or PDGFRA and / or its oncogenic form. In some embodiments, the disease is selected from the group consisting of KIT-driven germ cell tumors (e.g., testicular germ cells), KIT-driven skin cancers (e.g., KIT-driven cutaneous squamous cell carcinoma, KIT-driven Merkel cell carcinoma, uveal melanoma, non-melanoma skin cancer), or KIT-driven renal cell carcinomas (e.g., renal cell carcinoma, refractory renal cell carcinoma).In some embodiments, the disease is selected from the group consisting of penile cancer, PDGFRA-driven penile cancer, prostate cancer, PDGFRA-driven prostate cancer, PDGFRA-driven non-melanoma skin cancer, PDGFRA-driven glioma, PDGFRA-driven sarcoma, PDGFRA-driven glioblastoma, or PDGFRA-driven pancreatic cancer. In some embodiments, the disease comprising a PDGFRB mutation is selected from the group consisting of vaginal cancer, prostate cancer, penile cancer, non-melanoma skin cancer, melanoma, or breast sarcoma.

[0068] In another embodiment, also provided herein is the use of a composition or tablet described herein in the preparation of a medicament for treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma, acute myeloid leukemia, germ cell tumor of a seminoma or malignant germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic syndrome-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma, and non-small cell lung cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1 Depicted is a powder X-ray diffraction (PXRD) pattern of a solid dispersion comprising an amorphous form of the compound of formula (I).

[0070] Figure 2 The dissolution profile of an exemplary tablet containing Compound 1 using the dissolution method of Example 8 is depicted. DETAILED DESCRIPTION OF THE INVENTION

[0072] The features and other details of the present invention will now be described more clearly. Some of the terms used in this specification, examples and appended claims are summarized here. These definitions should be read in light of the remainder of the present invention and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0073] definition

[0074] As used herein, the term "excipient" refers to a substance that may be beneficially included in a composition having an active agent. The term "excipient" includes inert substances as well as functional excipients that may result in beneficial properties of the composition. Exemplary excipients include, but are not limited to, polymers, glidants, sugars, lubricants, salts, buffers, fats, fillers, disintegrants, binders, surfactants, high surface area substrates, flavors, carriers, matrix materials, and the like.

[0075] As used herein, the terms "individual / subject", "patient" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, and most preferably humans. The compounds described herein can be administered not only to mammals such as humans, but also to other mammals, such as animals in need of veterinary treatment, such as domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0076] As used herein, the term "pharmaceutically acceptable" or "pharmacologically acceptable" includes molecular entities and compositions that can be administered to animals or humans without adverse, allergic or other untoward reactions, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by the FDA Office of Biologics standards.

[0077] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" herein refers to any and all solvents, dispersion media, coatings, isotonic agents, absorption delaying agents, etc. that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide supplementary, additional or enhanced therapeutic functions.

[0078] As used herein, the term "pharmaceutical composition" herein refers to a composition comprising at least one compound as described herein formulated together with one or more pharmaceutically acceptable carriers.

[0079] As used herein, the terms "Impurity A" and "Compound 2" each refer to the compound 3-(5-amino-2-bromo-4-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one, which is a compound of formula (II) described herein. In some embodiments, the aniline species may be impurity A.

[0080] As used herein, the term "therapeutically effective amount" refers to the amount of the compound of the invention that will elicit the biological or medical response of a tissue, system or animal (e.g., mammal or human) that a researcher, veterinarian, medical doctor or other clinician is seeking. The compounds described herein are administered in a therapeutically effective amount to treat a condition.

[0081] As used herein, the term "treat," ...

[0082] As used herein, the term "active agent" refers to a drug, a medicament, a pharmaceutical agent, a therapeutic agent, for example, a compound of formula (I) described herein.

[0083] As used herein, the term "oral formulation" herein refers to a composition or vehicle for orally administering a compound described herein (e.g., a compound of formula (I)) to an individual in need thereof. Typically, oral formulations are administered orally, however, "oral formulations" as used herein are intended to encompass any substance that is administered to an individual and absorbed through a membrane (e.g., the mucous membrane of the gastrointestinal tract including, for example, the mouth, esophagus, stomach, small intestine, and large intestine). In some embodiments, the oral formulation is a pharmaceutical composition. In some embodiments, the oral formulation is a pharmaceutical composition administered orally to an individual in need thereof.

[0084] As used herein, the term "plasticizer" includes all compounds that are capable of plasticizing the polymer to which it is applied. Generally, plasticizers are additives that are capable of softening plastic polymers when added in a solid or liquid state, thereby increasing the flexibility of the polymer matrix during the melt extrusion process. Plasticizers generally lower the glass transition temperature and melting point of the polymer. Plasticizers also generally reduce the viscosity of the polymer melt, thereby allowing lower processing temperatures during hot melt extrusion. Examples of compounds that can be used as plasticizers include (but are not limited to): glycerol; polyethylene glycol (PEG), such as PEG300, PEG400, PEG1500; phthalates, such as diethyl phthalate; polysorbates; sorbitol; citrate esters; triacetin; block polyethers (pluronics), such as Pluronic P407; Labrasol glyceride mixture; and vitamin E TPGS.

[0085] As used herein, the term "stable" refers herein to an amorphous form of the compound of formula (I) that does not convert into any other solid form and contains less than 5% (wt / wt) of all other forms (or, for example, less than 4% w / w, less than 3% w / w, less than 2% w / w) when stored at a temperature up to about 40°C and a relative humidity of about 25% to about 75% for at least about three months.

[0086] As used herein, the term "solid dispersion" refers to any solid composition having at least two components. In certain embodiments, the solid dispersions disclosed herein include an active ingredient of a compound of formula (I) dispersed in at least one other component (eg, a polymer).

[0087] "Combination therapy" is a treatment that includes administering to a patient two or more therapeutic agents, such as a compound of Formula I and a MAPKAP pathway inhibitor. The two or more therapeutic agents may be delivered at the same time, such as in separate pharmaceutical compositions or in the same pharmaceutical composition, or they may be delivered at different times. For example, they may be delivered simultaneously or during overlapping time periods, and / or one therapeutic agent may be delivered before or after the other therapeutic agent. Treatment using combination therapy optionally includes treatment with any single agent before or after the period of simultaneous treatment with the two agents. However, it is contemplated that during some periods, an effective amount of the two or more therapeutic agents is present in the patient.

[0088] Generally, solid state forms (such as crystalline or amorphous) may be referred to herein by “ Figure 1 "as shown in" or "substantially as Figure 1 Such data include, for example, powder X-ray diffraction patterns and solid-state NMR spectra. As is well known in the art, such graphical data may provide additional technical information to further define the corresponding solid-state forms (i.e., so-called "fingerprints"), which are not necessarily described by reference to numerical values ​​or peak positions alone. In any case, it will be understood by those skilled in the art that there may be small variations in the graphical representation of such data, such as peak relative intensities and peak positions, due to certain factors, such as (but not limited to) variations in instrument response and variations in sample concentration and purity, which are well known to those skilled in the art. Crystals are composed of atoms arranged periodically in 3D space, while atoms in amorphous materials are randomly distributed in 3D space. Therefore, the X-ray diffraction pattern of a crystalline material will show narrow peaks of high intensity because the X-rays are scattered only in certain directions (due to the periodic arrangement of atoms). In contrast, the X-ray diffraction pattern of an amorphous material typically shows broad peaks of low intensity (halo patterns) because the X-rays are scattered in many different directions, resulting in large protrusions distributed over a wide range (2θ).

[0089] All ranges recited herein are inclusive, including those that recite a range "between" two values. The terms "substantially" and "about" should be understood to modify a term or value so that it is not absolute. This includes at least the expected degree of experimental error, technical error, and instrumental error for a given technique used to measure a value.

[0090] The present invention relates to an amorphous solid dispersion containing an amorphous form of a compound of formula (I) optionally in a polymer matrix and an amorphous form of the compound of formula (I). The amorphous nature and amount of the crystalline drug of the solid dispersion can be determined by powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) analysis, differential scanning calorimetry (DSC) or any other standard quantitative measurement method. For example, the material is X-ray amorphous and no sharp peaks are observed in its PXRD pattern, rather than a pattern like the halo. The sharp peaks in the pattern indicate the presence of crystalline material. The amorphous form of the compound of formula (I) can be substantially determined by Figure 1 The X-ray diffraction pattern shown is used to characterize.

[0091] The amorphous drug can be present in the solid amorphous dispersion as a pure phase, in the form of a solid drug solution homogeneously distributed in the polymer, or in the form of any combination of these states, or intermediate states therebetween. The dispersion is preferably substantially uniform, so that the amorphous drug is dispersed as evenly as possible in the polymer. As used herein, "substantially uniform" means that the portion of the drug present in the solid dispersion as a relatively pure amorphous region is relatively small.

[0092] method

[0093] Also provided herein is a method for preparing a solid dispersion comprising an amorphous form of a compound of formula (I) as described herein, the method comprising:

[0094] (a) weighing and dispensing a compound of formula (I), a solvent, a polymer and water;

[0095] (b) adding a compound of formula (I) and suspending it;

[0096] (c) optionally stirring and mixing the final suspension while maintaining the temperature at about 10-25° C.;

[0097] (d) passing the obtained suspension through an in-line heat exchanger to dissolve the suspended particles, and then introducing the suspension into a spray dryer; and

[0098] (e) optionally drying the spray-dried compound of formula (I).

[0099] For example, in one embodiment, provided herein is a method for preparing a solid dispersion comprising an amorphous form of a compound of formula (I),

[0100]

[0101] The method comprises: mixing a compound of formula (I), a solvent, a polymer (such as hydroxypropylmethylcellulose acetate succinate) and water to obtain a suspension; optionally stirring and / or mixing the suspension while maintaining a temperature of 10°C to about 25°C; heating the suspension to dissolve the suspended particles and then introducing it into a spray dryer; spray drying the suspension to obtain a spray-dried dispersion; drying the spray-dried dispersion to obtain a solid dispersion. In certain embodiments, the heating comprises passing the suspension through an in-line heat exchanger.

[0102] In another embodiment, described herein is a method for preparing a solid dispersion comprising an amorphous form of a compound of formula (I),

[0103]

[0104] The method comprises: (a) mixing a compound of formula (I), a solvent, the polymer and water to obtain a suspension; (b) optionally stirring and / or mixing the suspension while maintaining the temperature at about 10°C to about 25°C; (c) heating the suspension to dissolve the suspended particles and then introducing it into a spray dryer; and (d) spray drying the suspension to obtain a spray-dried dispersion; (e) drying the spray-dried dispersion to obtain a solid dispersion. In some embodiments, the heating comprises passing the suspension through an in-line heat exchanger. In some embodiments, the solid dispersion comprising an amorphous compound of formula (I),

[0105]

[0106] Prepared by the method described.

[0107] In some embodiments, the compound of formula (I), solvent, polymer and water are combined, the mixture is stirred and mixed into a suspension. In some embodiments, the solvent, water and polymer are combined and stirred, and then the compound of formula (I) is added. In some embodiments, the solvent and water are combined and stirred, and then the polymer and the compound of formula (I) are added. In some embodiments, the solvent and water are combined and stirred, and then the polymer is added, and then the compound of formula (I) is added.

[0108] In some embodiments, the ratio of solvent: water may be about 95:5, followed by addition and dissolution of the polymer. In some embodiments, the ratio of solvent: water may be about 90:10, followed by addition and dissolution of the polymer. In some embodiments, the ratio of solvent: water may be about 85:15, followed by addition and dissolution of the polymer. In some embodiments, the ratio of solvent: water may be about 80:20, followed by addition and dissolution of the polymer. In some embodiments, the ratio of solvent: water may be about 75:25, followed by addition and dissolution of the polymer. In some embodiments, the ratio of solvent: water may be about 70:30, followed by addition and dissolution of the polymer. In some embodiments, the ratio of solvent: water may be about 65:35, followed by addition and dissolution of the polymer. In some embodiments, the ratio of solvent: water may be about 60:40, followed by addition and dissolution of the polymer. In some embodiments, the ratio of solvent: water may be about 55:45, followed by addition and dissolution of the polymer. In some embodiments, the ratio of solvent: water may be about 50:50, followed by addition and dissolution of the polymer.

[0109] In some embodiments, the solvent is an organic compound, and wherein the active agent and polymer are mutually soluble. In some embodiments, the solvent is an alcohol, ketone, ether, ester, halogenated alkane, amide, sulfone, acid or nitro compound. In some embodiments, the solvent is methanol, ethanol, n-propanol, isopropanol or butanol. In some embodiments, the solvent is acetone, methyl ethyl ketone (MEK) or methyl isobutyl ketone (MIBK). In some embodiments, the solvent is methyl acetate, ethyl acetate or propyl acetate. In some embodiments, the solvent is diethyl ether, tetrahydrofuran (THF), 2-methyl THF, 2,5-dimethyl THF or 2,2,5,5-tetramethyl THF. In some embodiments, the solvent is acetonitrile, dichloromethane, toluene, 1,1,1-trichloroethane, dimethylacetamide (DMA), nitromethane, acetic acid or dimethyl sulfoxide (DMSO). As long as polymer and formula (I) compound can be fully dissolved so that spray drying method can be implemented, the mixture of solvent and water is suitable. In some embodiments, the water: solvent mixture is water: acetone. In some embodiments, the water: solvent mixture is water: THF. In some embodiments, the water: solvent mixture is water: methanol. In some embodiments, the water: solvent mixture is water: ethanol. In some embodiments, the water: solvent mixture is water: methyl ethyl ketone. In some embodiments, the water: solvent mixture is water: ethyl acetate. In some embodiments, the water: solvent mixture is water: dichloromethane. In some embodiments, as long as the polymer and the compound of formula (I) are sufficiently soluble so that the spray drying method can be implemented, the solvent mixture is suitable. In some embodiments, the solvent: solvent mixture is methanol: ethyl acetate. In some embodiments, the solvent: solvent mixture is ethanol: ethyl acetate. In some embodiments, the solvent: solvent mixture is methanol: dichloromethane. In some embodiments, the solvent: solvent mixture is ethanol: dichloromethane.

[0110] In some embodiments, the solvent is an organic compound, and the active agent is suspended. In some embodiments, the compound of formula (I) is suspended in a mixture of pure water and THF, and then the polymer is added. In some embodiments, compound 1 is suspended in a mixture of pure water and THF, and then HPMCAS-HG is added.

[0111] In some embodiments, the temperature range for stirring and mixing the final suspension is about 0-25°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 5-25°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 10-25°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 15-25°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 15-24°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 15-23°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 15-22°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 15-21°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 15-20°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 17-25°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 17-24°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 17-23°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 17-22°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 17-21°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 17-20°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 18-25°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 18-24°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 18-23°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 18-22°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 18-21°C. In some embodiments, the temperature range for stirring and mixing the final suspension is about 18-20°C.

[0112] In some embodiments, the suspension flow rate through the in-line heat exchanger operating range may be about 5-100kg / hr. In some embodiments, the suspension flow rate through the in-line heat exchanger operating range may be about 5-30kg / hr. In some embodiments, the suspension flow rate through the in-line heat exchanger operating range may be about 5-25kg / hr. In some embodiments, the suspension flow rate through the in-line heat exchanger operating range may be about 5-20kg / hr. In some embodiments, the suspension flow rate through the in-line heat exchanger operating range may be about 5-15kg / hr. In some embodiments, the suspension flow rate through the in-line heat exchanger operating range may be about 5-10kg / hr. In some embodiments, the suspension flow rate through the in-line heat exchanger operating range may be about 30-50kg / hr. In some embodiments, the suspension flow rate is about 35-45kg / hr. In some embodiments, the suspension flow rate is about 35-40kg / hr. In some embodiments, the suspension flow rate is about 40-45kg / hr. In some embodiments, the suspension flow rate is about 42-48kg / hr. In some embodiments, the suspension flow rate is about 45-50kg / hr. In some embodiments, the suspension flow rate through the in-line heat exchanger operating range may be about 50-100kg / hr. In some embodiments, the suspension flow rate is about 50-90kg / hr. In some embodiments, the suspension flow rate is about 50-80kg / hr. In some embodiments, the suspension flow rate is about 50-70kg / hr. In some embodiments, the suspension flow rate is about 50-60kg / hr.

[0113] In some embodiments, the temperature of the solution near or at the spray dryer nozzle may be about 110-130°C, preferably about 115-125°C, most preferably about 116°C, about 117°C, about 118°C, about 119°C, about 120°C, about 121°C, about 122°C, about 123°C, about 124°C, about 125°C. In some embodiments, the temperature of the solution near or at the spray dryer nozzle may be about 15-25°C. In some embodiments, the temperature of the solution near or at the spray dryer nozzle may be about 20-25°C. In some embodiments, the temperature of the solution near or at the spray dryer nozzle may be about 10-100°C. In some embodiments, the temperature of the solution near or at the spray dryer nozzle may be about 20-90°C. In some embodiments, the temperature of the solution near or at the spray dryer nozzle may be about 20-80°C. In some embodiments, the temperature of the solution near or at the spray dryer nozzle may be about 20-70°C. In some embodiments, the temperature of the solution near or at the spray dryer nozzle may be about 20-60° C. In some embodiments, the temperature of the solution near or at the spray dryer nozzle may be about 20-50° C. In some embodiments, the temperature of the solution near or at the spray dryer nozzle may be about 20-40° C. In some embodiments, the temperature of the solution near or at the spray dryer nozzle may be about 20-30° C.

[0114] In some embodiments, the air pressure of the spray drying nozzle hood may be about 50-100 psig. In some embodiments, the flow rate of the spray dryer overall drying gas may be about 400-500 kg / hr. In some embodiments, the spray dryer chamber outlet temperature may be about 45-75° C. In some embodiments, the condenser temperature of the spray dryer may be about -5 to about -20° C.

[0115] After spray drying is completed, the spray-dried intermediate is subjected to optional secondary spray drying in a stirred vacuum dryer. In some embodiments, the drying temperature is about 30-60° C., preferably about 35-55° C., and most preferably about 40-50° C. In some embodiments, the drying duration may be not less than about 3 hours, preferably not less than 6 hours, not less than 7 hours, not less than 8 hours, not less than 9 hours. In some embodiments, the chamber pressure may be about 30-60 mbar, preferably about 35-55 mbar, and most preferably about 40-50 mbar.

[0116] In some embodiments, the polymer may be ionic. In some embodiments, the polymer may be nonionic. In some embodiments, the pharmaceutically acceptable polymer is selected from the group consisting of polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, poly (vinyl pyrrolidone-co-vinyl acetate), polyoxyethylene-polyoxypropylene block copolymer, graft copolymer composed of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, polymethacrylate, polyoxyethylene alkyl ether, polyoxyethylene castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly (lactic acid-glycolic acid), lipid, cellulose, pullulan (pullulan ), dextran, maltodextrin, hyaluronic acid, polysialic acid, chondroitin sulfate, heparin, fucoidan, pentosan polysulfate, spirulan, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose propionate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate isophthalate, carboxymethyl ethyl cellulose, hydroxypropyl Methylcellulose, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl methylcellulose propionate phthalate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl methylcellulose propionate trimellitate, cellulose acetate succinate, methylcellulose acetate succinate, dextran, dextran acetate, dextran propionate, dextran succinate, dextran acetate propionate, dextran acetate succinate, dextran propionate succinate, dextran acetate propionate succinate, poly(methacrylic acid-co-methyl methacrylate) 1:1, poly(methacrylic acid) The invention relates to poly(butyl methacrylate-co-methyl methacrylate) 1:2, poly(methacrylic acid-co-ethyl acrylate) 1:1, hydroxyethyl cellulose, methyl cellulose and hydroxypropyl cellulose, polymethacrylic acid-ethyl acrylate, polymethacrylic acid-methyl methacrylate, polymethyl methacrylate-ethyl acrylate, polytrimethylammonioethyl methacrylate-methyl methacrylate-ethyl acrylate and poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), and mixtures thereof.In some embodiments, the pharmaceutically acceptable polymer is selected from the group consisting of polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, poly(vinyl pyrrolidone-co-vinyl acetate), polyoxyethylene-polyoxypropylene block copolymers, graft copolymers composed of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, polymethacrylates, polyoxyethylene alkyl ethers, polyoxyethylene castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic acid-glycolic acid), lipids, cellulose, pullulan, dextran, maltodextrin, hyaluronic acid, polysialic acid, chondroitin sulfate, heparin, fucoidan, pentosan polysulfate, spirulan, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose propionate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate , cellulose acetate trimellitate, methylcellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate isophthalate, carboxymethylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose propionate phthalate, hydroxypropylmethylcellulose acetate trimellitate, hydroxypropylmethylcellulose propionate trimellitate, cellulose acetate succinate, methylcellulose acetate succinate, dextran, dextran acetate, dextran propionate, dextran succinate, dextran acetate propionate, dextran acetate succinate, dextran propionate, dextran acetate succinate, dextran propionate, dextran propionate succinate, dextran acetate propionate, poly(methacrylic acid-co-methyl methacrylate) 1:1, poly(methacrylic acid-co-methyl methacrylate) 1:2, poly(methacrylic acid-co-ethyl acrylate) 1:1, and mixtures thereof. In some embodiments, the polymer is hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl alcohol having at least a portion of the repeating units in hydrolyzed form, polyvinyl pyrrolidone, poloxamer, or a blend thereof. In some embodiments, the pharmaceutically acceptable polymer is hydroxypropyl methylcellulose acetate succinate.

[0117] Characterization of crystalline and amorphous forms

[0118] In one general aspect, the free base of the compound of formula (I) may be used as the starting material, or may be prepared by the methods further described in US 8,940,756 and US 8,461,179, which are incorporated herein by reference.

[0119] In one general aspect, there is provided an amorphous form of a compound of formula (I).

[0120]

[0121] In another general aspect, there is provided an amorphous form of a compound of formula (I) having a purity greater than about 95% and less than about 0.5% residual solvent as determined by HPLC.

[0122] Typically, the amorphous form of the compound of formula (I) is substantially free of residual solvent. The term "substantially free" means that the residual solvent is within the permissible limits of ICH suitable for pharmaceutical preparations. In some embodiments, the amorphous form of the compound of formula (I) contains less than 1% of residual solvent. In some embodiments, the amorphous form of the compound of formula (I) contains less than 0.9% of residual solvent. In some embodiments, the amorphous form of the compound of formula (I) contains less than 0.8% of residual solvent. In some embodiments, the amorphous form of the compound of formula (I) contains less than 0.7% of residual solvent. In some embodiments, the amorphous form of the compound of formula (I) contains less than 0.6% of residual solvent. In some embodiments, the amorphous form of the compound of formula (I) contains less than 0.5% of residual solvent. In some embodiments, the amorphous form of the compound of formula (I) contains less than 0.4% of residual solvent. In some embodiments, the amorphous form of the compound of formula (I) contains less than 0.3% of residual solvent. In some embodiments, the amorphous form of the compound of formula (I) contains less than 0.2% of residual solvent. In some embodiments, the amorphous form of the compound of Formula (I) contains less than 0.1% of residual solvent.

[0123] In another general aspect, provided herein is an amorphous form of a compound of formula (I) having a purity greater than about 95% as determined by HPLC. In some embodiments, the purity as determined by HPLC is greater than about 96%. In some embodiments, the purity as determined by HPLC is greater than about 97%. In some embodiments, the purity as determined by HPLC is greater than about 98%. In some embodiments, the purity as determined by HPLC is greater than about 99%. In some embodiments, the purity as determined by HPLC is greater than about 99.5%. In some embodiments, the purity as determined by HPLC is greater than about 99.8%. In some embodiments, the purity as determined by HPLC is greater than about 99.9%. In some embodiments, the purity as determined by HPLC is greater than about 90%. In some embodiments, the purity as determined by HPLC is greater than about 92%. In some embodiments, the purity as determined by HPLC is greater than about 94%.

[0124] In another aspect, an amorphous form of a compound of formula (I) that is substantially free of any other crystalline form is provided herein. In some embodiments, the amorphous form of a compound of formula (I) contains less than about 5% of other crystalline forms. In some embodiments, the amorphous form of a compound of formula (I) contains no more than about 5% (w / w) of any crystalline form, or does not contain any detectable amount of any crystalline form. The amorphous form provided herein will not substantially transform into any crystalline form of the compound of formula (I) under various circumstances, i.e., contains no more than ("NMT") about 10% (w / w), about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), about 1% (w / w), about 0.5% (w / w) of any crystalline form of the compound of formula (I).

[0125] As used herein, "substantially free of any other form" means that the solid amorphous form of the compound of Formula (I) contains about 20% or less, about 10% or less, about 5% or less, about 2% or less, or about 1% or less of any other form of the subject compound as measured by, for example, PXRD; or, contains less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of any other form of the subject compound as measured by, for example, PXRD. Thus, a solid amorphous form of the compound of Formula (I) described herein as being substantially free of any other solid form is to be understood as greater than 80% (w / w), greater than 90% (w / w), greater than 95% (w / w), greater than 98% (w / w), or greater than 99% (w / w) of the solid amorphous form of the subject compound of Formula (I). Thus, in some embodiments, the solid state form of the amorphous compound of Formula (I) may contain 1-20% (w / w), 5-20% (w / w), or 5-10% (w / w) of one or more other solid state forms of the compound of Formula (I).

[0126] As used herein, "free of detectable amounts of any crystalline form" means that the solid amorphous form of the compound of formula (I) contains a crystalline form content equal to or less than a detectable amount of the detection and / or measurement instrument (e.g., by PXRD). This content, when measured by (e.g.) PXRD, preferably may include less than about 4% w / w, less than about 3% w / w, less than about 2% w / w, or less than about 1% w / w of any other form of the subject compound. This content may preferably be less than 4% w / w, less than 3% w / w, less than 2% w / w, or less than 1% w / w.

[0127] The content of the solid state form is generally measured by any suitable method known to those skilled in the art, such as PXRD, solid state NMR, IR, Raman or DSC.

[0128] Exemplary analysis methods are as follows: Powder X-ray diffraction can be performed using a Rigaku D / MAX 2200VPC diffractometer, or a PANALYTICAL ExpertPro DY2408, or other suitable instruments for implementation, using a Cu Kα filled tube (40 kV, 40 mA) as an X-ray source at room temperature, and using a wide angle goniometer with a 1° scattering slit, a 1° divergence slit, a graphite secondary single light instrument, and a scintillation counter to measure powder X-ray diffraction. In the 2° to 40° scanning range, data collection is performed in a 2θ continuous scanning mode at a scanning speed of 3° / min with a 0.02° scanning step.

[0129] In one aspect, provided herein is an amorphous form of a compound of formula (I) that contains no more than 5% (w / w) of any crystalline form, or no detectable amount of any crystalline form, when stored at a temperature of up to about 40° C. and a relative humidity of about 25% to about 75% for about at least three months. The present invention comprises an amorphous form of a compound of formula (I) in a stable form. In some embodiments, the amorphous form is substantially not converted into any crystalline form of the compound of formula (I) under various circumstances, i.e., contains no more than (“NMT”) 10% (w / w), 5% (w / w), 4% (w / w), 3% (w / w), 2% (w / w), 1% (w / w), 0.5% (w / w) of any crystalline form. In some embodiments, the amorphous form of the compound of formula (I) contains no more than 10% (w / w) of any crystalline form when stored at 25°C and the following conditions: 0% relative humidity for 3 days, preferably 7 days; or 20% relative humidity for 3 days, preferably 7 days; or 40% relative humidity for 3 days, preferably 7 days; or 60% relative humidity for 3 days, preferably 7 days; or 80% relative humidity for 3 days, preferably 7 days; or 100% relative humidity for 3 days, preferably 7 days. In some embodiments, the amorphous form of the compound of formula (I) described herein does not convert to a crystalline compound of formula (I) under 0-100% relative humidity, 25°C-40°C for at least 0-360 days. In some embodiments, the amorphous form of the compound of formula (I) contains no more than 10% (w / w) and preferably no detectable amount of any crystalline form when stored at 25°C, 60% relative humidity (RH) for 3 days (preferably 7 days). In some embodiments, the amorphous form of the compound of formula (I) contains no more than 10% (w / w) and preferably no detectable amount of any crystalline form when stored at 25°C, 80% relative humidity (RH) for 3 days (preferably 7 days). In some embodiments, the amorphous form of the compound of formula (I) contains no more than 5% and preferably no detectable amount of any crystalline form when exposed to 0-100% relative humidity at 25°C for 7 days. In some embodiments, the amorphous form of the compound of formula (I) contains no more than 5% and preferably no detectable amount of any crystalline form when exposed to 0-100% relative humidity at 25°C for 30 days. In some embodiments, the amorphous form of the compound of formula (I) contains no more than 5% and preferably no detectable amount of any crystalline form when exposed to 0-100% relative humidity at 25°C for 60 days. In some embodiments, the amorphous form of the compound of Formula (I) contains no more than about 5% (w / w) of any crystalline form or no detectable amount of any crystalline form of the compound of Formula (I) when exposed to 0-75% relative humidity at 25-40°C for 3 months.In some embodiments, the amorphous form of the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 4 months. In some embodiments, the amorphous form of the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 5 months. In some embodiments, the amorphous form of the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 6 months. In some embodiments, the amorphous form of the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 7 months. In some embodiments, the amorphous form of the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 8 months. In some embodiments, the amorphous form of the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 9 months. In some embodiments, the amorphous form of the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 10 months. In some embodiments, the amorphous form of the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 11 months. In some embodiments, the amorphous form of the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 12 months. In some embodiments, the amorphous form of the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 13 months. In some embodiments, the amorphous form of the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-100% relative humidity, 25-40°C for 14 months.In some embodiments, the amorphous form of the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-100% relative humidity, 25-40°C for 15 months. In some embodiments, the amorphous form of the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-100% relative humidity, 25-40°C for 16 months. In some embodiments, the amorphous form of the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-100% relative humidity, 25-40°C for 17 months. In some embodiments, the amorphous form of the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-100% relative humidity, 25-40°C for 18 months. In some embodiments, the amorphous form of the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-100% relative humidity, 25-40°C for 2 years. In some embodiments, the relative humidity is about 10%. In some embodiments, the relative humidity is about 20%. In some embodiments, the relative humidity is about 30%. In some embodiments, the relative humidity is about 40%. In some embodiments, the relative humidity is about 50%. In some embodiments, the relative humidity is about 60%. In some embodiments, the relative humidity is about 70%. In some embodiments, the relative humidity is about 80%. In some embodiments, the relative humidity is about 90%. In some embodiments, the temperature is 25°C. In some embodiments, the relative humidity is about 90%. In some embodiments, the temperature is 30°C. In some embodiments, the relative humidity is about 90%. In some embodiments, the temperature is 35°C. In some embodiments, the relative humidity is about 90%. In some embodiments, the temperature is 40°C.

[0130] In some embodiments, the amorphous form of the compound of formula (I) is a high purity and stable form. The high purity and amorphous form generally has an HPLC purity of at least 95% (w / w), preferably at least 96% (w / w), preferably at least 97% (w / w), preferably at least 98% (w / w), preferably at least 99% (w / w), and it will not transform into a crystalline form, as described above. Therefore, as disclosed herein, the amorphous form of the compound of formula (I) can have high chemical purity as well as high polymorphic purity. The high purity and amorphous form of the compound of formula (I) when stored under the conditions exemplified in Table 2 (a)-(c) (which includes the amorphous form of the compound of formula (I) prepared according to Example 1 below) contains no more than 10% (w / w), no more than 5% (w / w), no more than 4% (w / w), no more than 3% (w / w), no more than 2% (w / w), no more than 1% (w / w) of any crystalline form. In particular, the amorphous form of the compound of formula (I) is surprisingly highly stable and does not show polymorphic conversion to a crystalline form under stringent conditions of high relative humidity and elevated temperature.

[0131] In one aspect, provided herein is a solid dispersion comprising an amorphous form of a compound of formula (I), which contains no more than 5% (w / w) of any crystalline form, or no detectable amount of any crystalline form, when stored at a temperature of up to about 40° C. and a relative humidity of about 25% to about 75% for about at least three months. The present invention comprises a solid dispersion comprising an amorphous form of a compound of formula (I) in solid form. In some embodiments, the solid dispersion comprising an amorphous form of a compound of formula (I) is not substantially converted to any crystalline form of the compound of formula (I) under various circumstances, i.e., contains no more than (“NMT”) 10% (w / w), 5% (w / w), 4% (w / w), 3% (w / w), 2% (w / w), 1% (w / w), 0.5% (w / w) of any crystalline form. In some embodiments, a solid dispersion comprising an amorphous form of a compound of formula (I) contains no more than 10% (w / w) of any crystalline form, and preferably no detectable amount of any crystalline form, when stored at 25°C and under the following conditions: 0% relative humidity for 3 days, preferably 7 days; or 20% relative humidity for 3 days, preferably 7 days; or 40% relative humidity for 3 days, preferably 7 days; or 60% relative humidity for 3 days, preferably 7 days; or 80% relative humidity for 3 days, preferably 7 days; or 100% relative humidity for 3 days, preferably 7 days. In some embodiments, a solid dispersion comprising an amorphous form of a compound of formula (I) as described herein does not convert to a crystalline compound of formula (I) at 0-100% relative humidity, 25°C-40°C for at least 0-360 days. In some embodiments, the solid dispersion containing the amorphous form of the compound of formula (I) contains no more than 10% (w / w) and preferably no detectable amount of any crystalline form when stored at 25°C, 60% relative humidity (RH) for 3 days (preferably 7 days). In some embodiments, the solid dispersion containing the amorphous form of the compound of formula (I) contains no more than 10% (w / w) and preferably no detectable amount of any crystalline form when stored at 25°C, 80% relative humidity (RH) for 3 days (preferably 7 days). In some embodiments, the solid dispersion containing the amorphous form of the compound of formula (I) contains no more than 5% and preferably no detectable amount of any crystalline form when exposed to 0-100% relative humidity, 25°C for 7 days. In some embodiments, the solid dispersion containing the amorphous form of the compound of formula (I) contains no more than 5% and preferably no detectable amount of any crystalline form when exposed to 0-100% relative humidity, 25°C for 30 days. In some embodiments, a solid dispersion comprising an amorphous form of a compound of Formula (I) contains no more than 5%, and preferably no detectable amount, of any crystalline form when exposed to 0-100% relative humidity at 25°C for 60 days.In some embodiments, a solid dispersion comprising an amorphous form of a compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 3 months. In some embodiments, a solid dispersion comprising an amorphous form of a compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 4 months. In some embodiments, a solid dispersion comprising an amorphous form of a compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 5 months. In some embodiments, a solid dispersion comprising an amorphous compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 6 months. In some embodiments, a solid dispersion comprising a compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 7 months. In some embodiments, a solid dispersion comprising a compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 8 months. In some embodiments, the solid dispersion comprising the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 9 months. In some embodiments, the solid dispersion comprising the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 10 months. In some embodiments, the solid dispersion comprising the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 11 months. In some embodiments, a solid dispersion comprising a compound of Formula (I) contains no more than about 5% (w / w) of any crystalline form or no detectable amount of any crystalline form of the compound of Formula (I) when exposed to 0-75% relative humidity at 25-40°C for 12 months.In some embodiments, the solid dispersion comprising the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-75% relative humidity, 25-40°C for 13 months. In some embodiments, the solid dispersion comprising the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-100% relative humidity, 25-40°C for 14 months. In some embodiments, the solid dispersion comprising the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-100% relative humidity, 25-40°C for 15 months. In some embodiments, the solid dispersion comprising the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-100% relative humidity, 25-40°C for 16 months. In some embodiments, the solid dispersion comprising the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-100% relative humidity, 25-40°C for 17 months. In some embodiments, the solid dispersion comprising the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-100% relative humidity, 25-40°C for 18 months. In some embodiments, the solid dispersion comprising the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form or does not contain any detectable amount of any crystalline form of the compound of formula (I) when exposed to 0-100% relative humidity, 25-40°C for 2 years. In some embodiments, the relative humidity is about 10%. In some embodiments, the relative humidity is about 20%. In some embodiments, the relative humidity is about 30%. In some embodiments, the relative humidity is about 40%. In some embodiments, the relative humidity is about 50%. In some embodiments, the relative humidity is about 60%. In some embodiments, the relative humidity is about 70%. In some embodiments, the relative humidity is about 80%. In some embodiments, the relative humidity is about 90%. In some embodiments, the temperature is 25°C. In some embodiments, the relative humidity is about 90%. In some embodiments, the temperature is 30°C. In some embodiments, the relative humidity is about 90%. In some embodiments, the temperature is 35°C. In some embodiments, the relative humidity is about 90%. In some embodiments, the temperature is 40°C.

[0132] In some embodiments, the solid dispersion described herein comprises less than about 0.05% (w / w) (e.g., about 0.01% to about 1% w / w, or about 0.01% to about 0.08% w / w) of 3-(5-amino-2-bromo-4-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one, aniline, or a combination thereof as detected by HPLC.

[0133] In some embodiments, the amorphous form of the compound of formula (I) is a high purity and stable form. The high purity and amorphous form generally has an HPLC purity of at least 95% (w / w), preferably at least 96% (w / w), preferably at least 97% (w / w), preferably at least 98% (w / w), preferably at least 99% (w / w), and it will not be converted into a crystalline form, as described above. Therefore, as disclosed herein, a solid dispersion comprising a compound of formula (I) can have high chemical purity as well as high polymorphic purity. The high purity and amorphous form of the compound of formula (I) when stored under the conditions exemplified in Table 2 (a)-(c) (which includes a solid dispersion comprising a compound of formula (I) prepared according to Example 1 below) contains no more than 10% (w / w), no more than 5% (w / w), no more than 4% (w / w), no more than 3% (w / w), no more than 2% (w / w), no more than 1% (w / w) of any crystalline form. In particular, solid dispersions comprising the amorphous form of the compound of formula (I) have a surprisingly high stability and do not show polymorphic conversion to a crystalline form under stringent conditions of high relative humidity and elevated temperature.

[0134] In one aspect, the amorphous form of the compound of formula (I) is substantially Figure 1 Described herein is an amorphous form of a compound of formula (I) that can be identified by an amorphous "halo" PXRD pattern, substantially as Figure 1 The amorphous compound of formula (I) can be prepared by dissolving the compound of formula (I), spray drying the compound solution, and drying the spray dried compound.

[0135] In one aspect, the solid dispersion comprising amorphous form of formula (I) compound has unexpected enhanced solubility (Table 3). In some embodiments, the enhanced solubility of the solid dispersion comprising amorphous form of formula (I) compound is about 10 times greater than the solubility of the crystalline compound. In some embodiments, the enhanced solubility of the solid dispersion comprising amorphous form of formula (I) compound is about 20 times greater than the solubility of the crystalline compound. In some embodiments, the enhanced solubility of the solid dispersion comprising amorphous form of formula (I) compound is about 30 times greater than the solubility of the crystalline compound. In some embodiments, the enhanced solubility of the solid dispersion comprising amorphous form of formula (I) compound is about 40 times greater than the solubility of the crystalline compound. In some embodiments, the enhanced solubility of the solid dispersion comprising amorphous form of formula (I) compound is about 50 times greater than the solubility of the crystalline compound. In some embodiments, the enhanced solubility of the solid dispersion comprising amorphous form of formula (I) compound is about 60 times greater than the solubility of the crystalline compound. In some embodiments, the enhanced solubility of the solid dispersion comprising the amorphous form of the compound of formula (I) is about 70 times greater than the solubility of the crystalline compound. In some embodiments, the enhanced solubility of the solid dispersion comprising the amorphous form of the compound of formula (I) is about 80 times greater than the solubility of the crystalline compound. In some embodiments, the enhanced solubility of the solid dispersion comprising the amorphous form of the compound of formula (I) is about 90 times greater than the solubility of the crystalline compound. In some embodiments, the enhanced solubility of the solid dispersion comprising the amorphous form of the compound of formula (I) is about 100 times greater than the solubility of the crystalline compound. In some embodiments, the enhanced solubility of the solid dispersion comprising the amorphous form of the compound of formula (I) is about 110 times greater than the solubility of the crystalline compound. In some embodiments, the enhanced solubility of the solid dispersion comprising the amorphous form of the compound of formula (I) is about 120 times greater than the solubility of the crystalline compound. In some embodiments, the solid dispersion comprising the amorphous form of the compound of formula (I) has an enhanced solubility that is about 1 order of magnitude higher than the crystalline compound. In some embodiments, the solid dispersion comprising an amorphous form of the compound of Formula (I) has enhanced solubility of about 2 orders of magnitude greater than that of the crystalline compound.

[0136] In one aspect, the solid dispersion comprising the amorphous form of the compound of formula (I) has unexpectedly enhanced pharmacokinetic properties (Table 4). In some embodiments, the maximum concentration (C max ) is about 5 times greater than that of the crystalline compound. In some embodiments, the maximum concentration (C max ) is about 7 times greater than that of the crystalline compound. In some embodiments, the maximum concentration (C max) is about 10 times greater than that of the crystalline compound. In some embodiments, the maximum concentration (C max ) is about 12 times greater than that of the crystalline compound. In some embodiments, the maximum concentration (C max ) is about 15 times greater than that of the crystalline compound. In some embodiments, the maximum concentration (C max ) is about 20 times greater than that of the crystalline compound. In some embodiments, the total drug exposure (AUC) of the solid dispersion comprising the amorphous form of the compound of Formula (I) is about 20 times greater than that of the crystalline compound. (0-∞) ) is about 5 times greater than that of the crystalline compound. In some embodiments, the total drug exposure (AUC) of the solid dispersion comprising the amorphous form of the compound of Formula (I) is about 5 times greater than that of the crystalline compound. (0-∞) ) is about 7 times greater than that of the crystalline compound. In some embodiments, the total drug exposure (AUC) of the solid dispersion comprising the amorphous form of the compound of Formula (I) is about 7 times greater than that of the crystalline compound. (0-∞) ) is about 10 times greater than that of the crystalline compound. In some embodiments, the total drug exposure (AUC) of the solid dispersion comprising the amorphous form of the compound of Formula (I) is about 10 times greater than that of the crystalline compound. (0-∞) ) is about 12 times greater than that of the crystalline compound. In some embodiments, the total drug exposure (AUC) of the solid dispersion comprising the amorphous form of the compound of Formula (I) is about 12 times greater than that of the crystalline compound. (0-∞) ) is about 15 times greater than that of the crystalline compound. In some embodiments, the total drug exposure (AUC) of the solid dispersion comprising the amorphous form of the compound of Formula (I) is about 15 times greater than that of the crystalline compound. (0-∞) ) is about 20 times larger than the crystalline compound.

[0137] Spray dried dispersion

[0138] The dispersion containing the active agent and the pharmaceutically acceptable polymer described herein is made by a spray drying method. As used herein, the term "spray-dried dispersion" or "spray-dried powder dispersion" means the product of a spray drying method, wherein the product comprises a dispersion containing at least one active agent and at least one excipient (such as a polymer). In some embodiments, the polymer is a pharmaceutically acceptable polymer selected from the group consisting of polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, poly (vinyl pyrrolidone-co-vinyl acetate), polyoxyethylene-polyoxypropylene block copolymer, a graft copolymer composed of polyethylene glycol, polyethylene caprolactam and polyvinyl acetate, polymethacrylate, polyoxyethylene alkyl ether, polyoxyethylene castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly (lactic acid-glycolic acid), lipids, cellulose, pullulan (pull ulan), dextran, maltodextrin, hyaluronic acid, polysialic acid, chondroitin sulfate, heparin, fucoidan, pentosan polysulfate, spirulan, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose propionate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate, carboxymethyl ethyl cellulose, Hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl methylcellulose propionate phthalate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl methylcellulose propionate trimellitate, cellulose acetate succinate, methylcellulose acetate succinate, dextran, dextran acetate, dextran propionate, dextran succinate, dextran acetate propionate, dextran acetate succinate, dextran propionate succinate, dextran acetate propionate succinate, poly(methacrylic acid-co-methyl methacrylate) 1:1, poly(methyl acrylic acid-co-methyl methacrylate) 1:2, poly(methacrylic acid-co-ethyl acrylate) 1:1, hydroxyethyl cellulose, methyl cellulose and hydroxypropyl cellulose, polymethacrylic acid-ethyl acrylate, polymethacrylic acid-methyl methacrylate, polymethyl methacrylate-ethyl acrylate, polytrimethylammonioethyl methacrylate-methyl methacrylate-ethyl acrylate and poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), and mixtures thereof.

[0139] In the spray drying method, the active agent and one or more polymers are dissolved in a common solvent. "Common" here means that the solvent can be a mixture of compounds and will dissolve both the active agent and the polymer. After the active agent and the polymer have been dissolved, the solvent is quickly removed by evaporation in the spray drying equipment, resulting in the formation of a substantially uniform solid dispersion. In this type of dispersion, the active agent is dispersed as evenly as possible throughout the polymer and can be considered as a solid solution of the active agent dispersed in the polymer.

[0140] The solvent is removed by a spray drying process. The term "spray drying" is used conventionally and generally refers to a method of breaking a liquid mixture into small droplets (atomization) and rapidly removing the solvent from the mixture in a spray drying device, in which there is a strong driving force to evaporate the solvent from the droplets. Spray drying methods and spray drying apparatus are generally described in Perry's Chemical Engineers' Handbook, pages 20-54 to 20-57 (Sixth Edition, 1984). For more details on spray drying methods and apparatus, see the review Marshall, "Atomization and Spray-Drying," 50 Chem. Eng. Prog. Monogr. Series 2 (1954), and Masters, Spray Drying Handbook (Fourth Edition, 1985). In addition, other methods and spray drying techniques and apparatus are generally described in U.S. Pat. Nos. 8,343,550 and 7,780,988, and their contents are incorporated herein by reference in their entirety for all purposes. A strong driving force for solvent evaporation is generally provided by maintaining the solvent partial pressure in the spray drying apparatus well below the solvent vapor pressure at the temperature of the drying droplets. This is accomplished by: (1) maintaining the pressure in the spray drying apparatus under a partial vacuum (e.g., 0.01-0.50 atm); or (2) mixing the droplets with a warm drying gas; or (3) both (1) and (2). In addition, a portion of the heat required for evaporating the solvent may be provided by heating the spray solution.

[0141] The drying gas can be virtually any gas, but in order to minimize the risk of fire or explosion due to ignition of flammable vapors, and to minimize unwanted oxidation of the drug, increased concentration of the polymer, or other materials in the dispersion, an inert gas such as nitrogen, nitrogen-enriched air, or argon is utilized. The temperature of the drying gas at the inlet of the apparatus is typically in the range of about 60° C. to about 300° C. The temperature of the product particles, drying gas, and evaporated solvent at the outlet or end of the collecting cone is typically in the range of about 0° C. to about 100° C.

[0142] The solvent suitable for spray drying method can be any organic compound, and wherein the active agent and polymer are mutually soluble. The solvent should have relatively low toxicity, and can be removed from the dispersion to an acceptable degree according to the International Committee for Harmonization (ICH) guidelines. Removing the solvent to this extent may require subsequent processing steps, such as tray drying or secondary drying. In some embodiments, the solvent is an alcohol, ketone, ether, ester, halogenated alkane, amide, sulfone, acid, or nitro compound. In some embodiments, the solvent is methanol, ethanol, n-propanol, isopropanol, or butanol. In some embodiments, the solvent is acetone, methyl ethyl ketone (MEK) or methyl isobutyl ketone (MIBK). In some embodiments, the solvent is methyl acetate, ethyl acetate, or propyl acetate. In some embodiments, the solvent is diethyl ether, tetrahydrofuran (THF), 2-methyl THF, 2,5-dimethyl THF, or 2,2,5,5-tetramethyl THF. In some embodiments, the solvent is acetonitrile, dichloromethane, toluene, 1,1,1-trichloroethane, dimethylacetamide (DMA), nitromethane, acetic acid, or dimethyl sulfoxide (DMSO). A mixture of solvent and water is suitable as long as the polymer and the compound of formula (I) are sufficiently soluble to allow the spray drying method to be implemented. In some embodiments, the water: solvent mixture is water: acetone. In some embodiments, the water: solvent mixture is water: THF. In some embodiments, the water: solvent mixture is water: methanol. In some embodiments, the water: solvent mixture is water: ethanol. In some embodiments, the water: solvent mixture is water: methyl ethyl ketone. In some embodiments, the water: solvent mixture is water: ethyl acetate. In some embodiments, the water: solvent mixture is water: dichloromethane. In some embodiments, the solvent mixture is suitable as long as the polymer and the compound of formula (I) are sufficiently soluble to allow the spray drying method to be implemented. In some embodiments, the solvent: solvent mixture is methanol: ethyl acetate. In some embodiments, the solvent: solvent mixture is ethanol: ethyl acetate. In some embodiments, the solvent:solvent mixture is methanol:dichloromethane. In some embodiments, the solvent:solvent mixture is ethanol:dichloromethane.

[0143] The composition of the feed with solvent will depend on the desired ratio of the drug to the polymer in the dispersion, and the solubility of the drug and the polymer in the solvent. Generally, as long as the drug and the polymer are dissolved in the solvent in the temperature range of the method, it is desirable to use as high a combined drug and polymer concentration as possible in the feed with solvent to reduce the total amount of solvent that must be removed to form a solid amorphous dispersion. In some embodiments, the feed with solvent has a combined drug and polymer concentration of at least about 0.01wt% to at least about 20wt%. In some embodiments, the feed with solvent has a combined drug and polymer concentration of at least about 0.01wt%. In some embodiments, the feed with solvent has a combined drug and polymer concentration of at least about 0.1wt%. In some embodiments, the feed with solvent has a combined drug and polymer concentration of at least about 0.5wt%. In some embodiments, the feed with solvent has a combined drug and polymer concentration of at least about 1.0wt%. In some embodiments, the feed with solvent has a combined drug and polymer concentration of at least about 2.0 wt%. In some embodiments, the feed with solvent has a combined drug and polymer concentration of at least about 3.0 wt%. In some embodiments, the feed with solvent has a combined drug and polymer concentration of at least about 4.0 wt%. In some embodiments, the feed with solvent has a combined drug and polymer concentration of at least about 5.0 wt%. In some embodiments, the feed with solvent has a combined drug and polymer concentration of at least about 6.0 wt%. In some embodiments, the feed with solvent has a combined drug and polymer concentration of at least about 7.0 wt%. In some embodiments, the feed with solvent has a combined drug and polymer concentration of at least about 8.0 wt%. In some embodiments, the feed with solvent has a combined drug and polymer concentration of at least about 9.0 wt%. In some embodiments, the feed with solvent has a combined drug and polymer concentration of at least about 10.0 wt%.

[0144] The average residence time of particles in the drying chamber should be at least 10 seconds, preferably at least 20 seconds. Usually, after solidification, the formed powder will stay in the spray drying chamber for about 5-60 seconds, causing further solvent evaporation. The final solvent content of the solid dispersion when it leaves the dryer should be low, because this will reduce the mobility of the drug molecules in the dispersion, thereby improving its stability. Usually, the solvent content of the solid dispersion when it leaves the spray drying chamber should be less than about 10wt%. In some embodiments, the solvent content of the dispersion when it leaves the spray drying chamber is less than about 9wt%. In some embodiments, the solvent content of the dispersion when it leaves the spray drying chamber is less than about 8wt%. In some embodiments, the solvent content of the dispersion when it leaves the spray drying chamber is less than about 7wt%. In some embodiments, the solvent content of the dispersion when it leaves the spray drying chamber is less than about 6wt%. In some embodiments, the solvent content of the dispersion when it leaves the spray drying chamber is less than about 5wt%. In some embodiments, the solvent content of the dispersion when it leaves the spray drying chamber is less than about 4wt%. In some embodiments, the solvent content of the dispersion when it leaves the spray drying chamber is less than about 3wt%. In some embodiments, the dispersion has a solvent content of less than about 2 wt % when it leaves the spray drying chamber. In some embodiments, the dispersion has a solvent content of less than about 1 wt % when it leaves the spray drying chamber. In some embodiments, the dispersion has an acetone content of less than about 0.5 wt % when it leaves the spray drying chamber. In some embodiments, the dispersion has an acetone content of less than about 0.3 wt % when it leaves the spray drying chamber. In some embodiments, the dispersion has an acetone content of less than about 0.1 wt % when it leaves the spray drying chamber. Subsequent processing steps such as tray drying can be used to remove the solvent to this extent.

[0145] Hot melt dispersion

[0146] Dispersions containing active agents described herein and pharmaceutically acceptable polymers can be manufactured by hot melt extrusion. In one embodiment, a method for preparing a solid dispersion containing an amorphous or substantially amorphous compound of formula (I) is provided herein, the method comprising: (a) weighing and dispensing the compound of formula (I), one or more polymers, and optionally one or more additional additives (such as a plasticizer); (b) mixing the compound of formula (I), the polymer, and the additional additives in a blender; (c) feeding the mixed material into a hot melt extruder at a controlled rate and a controlled temperature; (d) cooling the extruded material; (e) recovering the cooled hot melt extruded material; (f) grinding or crushing the extruded material into a form suitable for blending with additional pharmaceutical excipients. In some embodiments, the hot melt extrudate of the compound of formula (I) is prepared in a heated screw hot melt extruder at a controlled rate and a controlled temperature. In some embodiments, the hot melt extrudate of the compound of formula (I) is prepared at a controlled temperature of 130° to 180°C. In some embodiments, the one or more polymers of the hot melt extrudate of the compound of formula (I) are hydroxypropyl methylcellulose acetate succinate. In some embodiments, the one or more polymers of the hot melt extrudate of the compound of formula (I) are vinyl pyrrolidone-vinyl acetate copolymer (e.g. VA64 or its analogue). In some embodiments, the solid dispersion of the hot-melt extrudate of the compound of formula (I) comprises from about 10% (w / w) to about 50% (w / w) of the compound of formula (I), based on the total weight of the hot-melt extrudate. In some embodiments, the solid dispersion of the hot-melt extrudate of the compound of formula (I) comprises from about 10% (w / w) to about 40% (w / w) of the compound of formula (I), based on the total weight of the hot-melt extrudate. In some embodiments, the solid dispersion of the hot-melt extrudate of the compound of formula (I) comprises from about 10% (w / w) to about 30% (w / w) of the compound of formula (I), based on the total weight of the hot-melt extrudate. In some embodiments, the solid dispersion of the hot-melt extrudate of the compound of formula (I) comprises from about 20% (w / w) to about 30% (w / w) of the compound of formula (I), based on the total weight of the hot-melt extrudate.

[0147] In some embodiments, the one or more additional additives are plasticizers. In some embodiments, the additive in the hot melt extrudate of the compound of formula (I) comprises PEG400. In some embodiments, the additive in the hot melt extrudate of the compound of formula (I) comprises PEG1500. In some embodiments, the additive in the hot melt extrudate of the compound of formula (I) comprises vitamin E TPGS. In some embodiments, the additive in the hot melt extrudate of the compound of formula (I) comprises Labrasol. In some embodiments, the additive in the hot melt extrudate of the compound of formula (I) comprises Pluronic P407. In some embodiments, the hot melt extrudate of the compound of formula (I) comprises about 5% (w / w) to about 30% (w / w) of the compound of formula (I), based on the total weight of the hot melt extrudate comprising the polymer and the plasticizer. In some embodiments, the hot melt extrudate of the compound of formula (I) comprises about 10% (w / w) to about 30% (w / w) of the compound of formula (I), based on the total weight of the hot melt extrudate comprising the polymer and the plasticizer. In some embodiments, the hot melt extrudate of the compound of formula (I) comprises from about 20% (w / w) to about 30% (w / w) of the compound of formula (I), based on the total weight of the hot melt extrudate comprising the polymer and the plasticizer.

[0148] In some embodiments, a hot melt extrudate of a compound of formula (I) comprising about 25% of the compound of formula (I), about 20% of PEG1500, and about 55% of VA64 may be extruded at about 160°C.

[0149] In some embodiments, the preparation of the dispersion is by mixing all individual components in a suitable agitator (such as a stirrer, an oscillator, a V-type blender or a grinder), the mixed material is fed into a hot melt extruder at a controlled rate and a controlled temperature, the extruded material is cooled in air or by an air stream or in a tank or on a surface or on a conveyor belt, and the cooled hot melt extruded material is recovered. In some embodiments, the hot melt extruded material is used as is. In some embodiments, the hot melt extruded material is suitable for the preparation of a controlled delivery compound of formula (I).

[0150] In some embodiments, the preparation of the dispersion is by mixing one or more of the individual components in a suitable agitator (such as a stirrer, an oscillator, a V-type blender or a grinder), one or more of these individual components are added to a hot melt extruder at a controlled rate and a controlled temperature during the extrusion process, the extruded material is cooled in air, or by an air stream, or in a liquid tank, or on a surface or on a conveyor belt, and the cooled hot melt extruded material is recovered. In some embodiments, the hot melt extruded material can be used as is. In some embodiments, the hot melt extruded material can be suitable for the preparation of a controlled delivery compound of formula (I).

[0151] Pharmaceutical compositions and preparations

[0152] In one aspect, a pharmaceutical composition is provided herein, comprising: an amorphous compound of formula (I) with a purity greater than 95% as determined by HPLC, and one or more pharmaceutically acceptable carriers, excipients or diluents. In one aspect, a solid dispersion is provided herein, comprising: an amorphous compound of formula (I) with a purity greater than 95% as determined by HPLC, and one or more pharmaceutically acceptable carriers, excipients or diluents and a polymer. In one aspect, a pharmaceutical composition is provided herein, comprising: an amorphous compound of formula (I) containing no more than 5% (w / w) of any crystalline form or containing no detectable amount of any crystalline form, and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0153] Such compositions or pharmaceutical compositions, for example, can be in the form of tablets, capsules, pills, powders, liquids, suspensions, emulsions, granules, sustained-release formulations, solutions and suspensions. The pharmaceutical composition can be in the form of an oral formulation suitable for single administration of precise doses.

[0154] The amorphous form of the compound of formula (I) may be formed into a finished dosage form. The finished dosage form comprises one or more liquid, solid or semisolid dosage forms, depending on the route of administration.

[0155] Excipients used in pharmaceutical compositions can impart good powder flow and compression properties to the compressed material. Desirable excipient properties may include: high compressibility to enable the manufacture of strong tablets under low compression forces; good powder flow properties to improve the powder flow of other excipients in the composition; and cohesion to prevent, for example, tablet breakage during handling, transportation and handling. Such properties are imparted to these excipients by pre-treatment steps, such as dry granulation (e.g., rolling, agglomeration), wet granulation, spray drying spheronization (e.g., spray dried dispersions, solid nanodispersions), or crystallization (e.g., salt forms) of the pharmaceutical composition. These can be classified according to the role they play in the final tablet. Other excipients that impart physical properties to the finished tablet are colorants and flavorings (e.g., in the case of chewable tablets). Examples of excipients are described in, for example, Handbook of Pharmaceutical Excipients (5th edition), edited by Raymond C. Rowe, Paul J. Sheskey and Sian C. Owen (Publisher: Pharmaceutical Press).

[0156] As described herein, the pharmaceutical composition may also include a pharmaceutically acceptable polymer. The pharmaceutically acceptable polymer may be ionic or non-ionic. Exemplary pharmaceutically acceptable polymers include: polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, poly (vinyl pyrrolidone-co-vinyl acetate), polyoxyethylene-polyoxypropylene block copolymers, graft copolymers composed of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, polymethacrylate, polyoxyethylene alkyl ether, polyoxyethylene castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly (lactic acid-glycolic acid), lipids, cellulose, pullulan, dextran, Maltodextrin, hyaluronic acid, polysialic acid, chondroitin sulfate, heparin, fucoidan, pentosan polysulfate, spirulan, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose propionate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose cellulose, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl methylcellulose propionate phthalate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl methylcellulose propionate trimellitate, cellulose acetate succinate, methylcellulose acetate succinate, dextran, dextran acetate, dextran propionate, dextran succinate, dextran acetate propionate, dextran acetate succinate, dextran propionate succinate, dextran acetate propionate succinate, poly(methacrylic acid-co-methyl methacrylate) 1:1, poly(methacrylic acid- The invention can be used in combination with poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate) 1:2, poly(methacrylic acid-co-ethyl acrylate) 1:1, hydroxyethyl cellulose, methyl cellulose and hydroxypropyl cellulose, polymethacrylic acid-ethyl acrylate, polymethacrylic acid-methyl methacrylate, polymethyl methacrylate-ethyl acrylate, polytrimethylammonioethyl methacrylate-methyl methacrylate-ethyl acrylate and poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate), or mixtures thereof.In some embodiments, the pharmaceutically acceptable polymer is selected from the group consisting of polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, poly(vinyl pyrrolidone-co-vinyl acetate), polyoxyethylene-polyoxypropylene block copolymers, graft copolymers composed of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, polymethacrylates, polyoxyethylene alkyl ethers, polyoxyethylene castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic acid-glycolic acid), lipids, cellulose, pullulan, dextran, maltodextrin, hyaluronic acid, polysialic acid, chondroitin sulfate, heparin, fucoidan, pentosan polysulfate, spirulan, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose propionate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate , cellulose acetate trimellitate, methylcellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate isophthalate, carboxymethylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose propionate phthalate, hydroxypropylmethylcellulose acetate trimellitate, hydroxypropylmethylcellulose propionate trimellitate, cellulose acetate succinate, methylcellulose acetate succinate, dextran, dextran acetate, dextran propionate, dextran succinate, dextran acetate propionate, dextran acetate succinate, dextran propionate, dextran acetate succinate, dextran propionate, dextran acetate propionate, poly(methacrylic acid-co-methyl methacrylate) 1:1, poly(methacrylic acid-co-methyl methacrylate) 1:2, poly(methacrylic acid-co-ethyl acrylate) 1:1, and mixtures thereof. In some embodiments, the pharmaceutically acceptable polymer is hydroxypropylmethylcellulose acetate succinate.

[0157] The pharmaceutical compositions provided herein may contain one or more fillers, which are added to, for example, increase the overall weight of the blend to produce the actual size of the tablet. Useful fillers include one or more calcium salts (such as calcium hydrogen phosphate) and sugars (such as lactose, sucrose, glucose, microcrystalline cellulose, mannitol and maltodextrin). Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to: powdered sugar, compressible sugar, glucose binder, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc. In some embodiments, the filler is microcrystalline cellulose, which can be manufactured by controlled hydrolysis of α-cellulose. Suitable microcrystalline cellulose will have an average particle size of about 20nm to about 200nm. Suitable microcrystalline cellulose includes: Avicel PH 101, Avicel PH102, Avicel PH 103, Avicel PH 105 and Avicel PH 200, for example manufactured by FMC Corporation. In some embodiments, the filler is lactose.

[0158] The pharmaceutical composition may also include a lubricant. As used herein, the term "lubricant" is typically added to prevent the tabletting material from sticking to the punch, to minimize friction during tabletting, and to allow the compressed tablet to be removed from the mold. Examples of lubricants include, but are not limited to: colloidal silicon dioxide, magnesium trisilicate, talc, magnesium carbonate, magnesium oxide, glyceryl behenate, polyethylene glycol, ethylene oxide polymers (e.g., Carowax), sodium lauryl sulfate, magnesium stearate, aluminum stearate, calcium stearate, sodium stearyl fumarate, stearic acid, lauryl magnesium stearate, and a mixture of magnesium stearate and sodium lauryl sulfate. Exemplary lubricants include calcium stearate, magnesium stearate, and sodium stearyl fumarate. In some embodiments, the lubricant is magnesium stearate.

[0159] The pharmaceutical compositions provided herein may also contain a glidant. As used herein, the term "glidant" is a substance added to a powder that improves the flowability of the powder, such as by reducing intra-particle friction. Exemplary glidants include, but are not limited to: colloidal silica, colloidal silicon dioxide, pyrogenic silica, M-5P, talc, Starch and magnesium aluminum silicate. In some embodiments, the glidant is silicon dioxide. It should be noted that excipients can provide multiple functions. In some embodiments, the lubricant (e.g., magnesium stearate) can also be used as a glidant.

[0160] Disintegrants may be present in an amount required to accelerate dissolution (e.g., increase the tablet disintegration rate). The term "disintegrant" as used herein refers to an excipient that counteracts the physical forces that bind the particles in a tablet or capsule when the oral formulation is placed in an aqueous environment. Disintegrants include starch derivatives and salts of carboxymethyl cellulose. Examples of pharmaceutically acceptable disintegrants include (but are not limited to): starches, e.g., sodium starch glycolate, pregelatinized starch; clays; celluloses; alginates; colloids; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone (e.g., cross-linked polyvinyl pyrrolidone (polyplasdone TM ), polyvinyl pyrrolidone, cross-linked polyvinylpyrrolidone), cross-linked carboxymethylcellulose calcium and cross-linked carboxymethylcellulose sodium (sodiumcroscarmellose); and soybean polysaccharide. In some embodiments, the disintegrant is cross-linked polyvinylpyrrolidone (eg, PVP-XL).

[0161] Also provided herein is a solid dispersion comprising a pharmaceutical composition, the pharmaceutical composition comprising: an amorphous form of a compound of formula (I) with a purity greater than 95% as determined by HPLC, and a polymer and one or more pharmaceutically acceptable carriers, excipients or diluents. In some embodiments, an amorphous solid dispersion is provided, comprising: an amorphous form of a compound of formula (I) with a purity greater than 95% as determined by HPLC, and a polymer and one or more pharmaceutically acceptable carriers, excipients or diluents. In some embodiments, a solid dispersion is provided, comprising: an amorphous form of a compound of formula (I) and a polymer, wherein the solid dispersion is substantially free of a crystalline form of a compound of formula (I). In some embodiments, a solid dispersion is provided, comprising: an amorphous form of a compound of formula (I) (containing no more than 5% (w / w) of any crystalline form or containing no detectable amount of any crystalline form), and a polymer and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0162] In some embodiments, provided herein is a pharmaceutical composition comprising a solid dispersion, the solid dispersion comprising an amorphous compound represented by formula (I) with a purity of greater than 95% as determined by HPLC. In some embodiments, provided is a pharmaceutical composition comprising an amorphous compound of formula (I) and a polymer, wherein the solid dispersion is substantially free of a crystalline form of the compound of formula (I). In some embodiments, provided is a pharmaceutical composition comprising: an amorphous compound of formula (I) (containing no more than 5% (w / w) of any crystalline form or containing no detectable amount of any crystalline form), and a pharmaceutically acceptable polymer.

[0163] In some embodiments, the solid dispersion comprises about 10% (w / w) to about 50% (w / w), or about 10% (w / w) to about 30% (w / w), or about 20% (w / w) to about 30% (w / w) of the compound represented by formula (I), based on the total weight of the solid dispersion. In some embodiments, the pharmaceutical composition may comprise about 25% (w / w) of the compound represented by formula (I), based on the total weight of the solid dispersion.

[0164] The solid dispersion provided herein comprises a pharmaceutically acceptable polymer selected from the group consisting of polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, poly(vinyl pyrrolidone-co-vinyl acetate), polyoxyethylene-polyoxypropylene block copolymers, graft copolymers composed of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, polymethacrylates, polyoxyethylene alkyl ethers, polyoxyethylene castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic acid-glycolic acid), lipids, cellulose, pullulan, dextran, maltodextrin, hyaluronic acid, polysialic acid, chondroitin sulfate, heparin, fucoidan, pentosan polysulfate, spirulan, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose propionate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate. Acid, cellulose acetate trimellitate, methylcellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate isophthalate, carboxymethylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose propionate phthalate, hydroxypropylmethylcellulose acetate trimellitate, hydroxypropylmethylcellulose propionate trimellitate, cellulose acetate succinate, methylcellulose acetate succinate, dextran, acetate dextran, propionate dextran, succinate dextran, acetate propionate dextran, acetate succinate dextran, propionate succinate dextran, acetate propionate succinate dextran, poly (methacrylic acid-co-methyl methacrylate) 1:1, poly (methacrylic acid-co-methyl methacrylate) 1:2, poly (methacrylic acid-co-ethyl acrylate) 1:1, or a mixture thereof. For example, the pharmaceutically acceptable polymer in the formulation provided herein is hydroxypropylmethylcellulose acetate succinate.

[0165] In some embodiments, provided herein is a pharmaceutically acceptable composition for oral administration, the composition comprising: (i) a solid dispersion, wherein the solid dispersion comprises: an amorphous compound represented by formula (I):

[0166] and a pharmaceutically acceptable polymer; and (ii) one or more pharmaceutically acceptable excipients.

[0167] In some embodiments, the solid dispersion has no more than about 5% (w / w) of any crystalline form of the compound. In some embodiments, the solid dispersion is substantially free of detectable amounts of any crystalline form of the compound. In some embodiments, the amorphous form has substantially Figure 1The X-ray powder diffraction pattern shown. In some embodiments, the composition contains no more than about 5% (w / w) of any crystalline form of the compound aggregated when exposed to 25°C, 60% relative humidity for 1 month, 3 months, or 6 months. In some embodiments, the composition contains no more than about 5% (w / w) of any crystalline form of the compound aggregated when exposed to 40°C, 75% relative humidity for 1 month, 3 months, or 6 months. In some embodiments, the pharmaceutically acceptable composition comprises about 10% (w / w) to about 30% (w / w) of the compound based on the total weight of the solid dispersion. In some embodiments, the pharmaceutically acceptable composition comprises about 20% (w / w) to about 30% (w / w) of the compound based on the total weight of the solid dispersion. In some embodiments, the pharmaceutically acceptable composition comprises about 25% (w / w) of the compound based on the total weight of the solid dispersion. In some embodiments, the pharmaceutically acceptable polymer is selected from the group consisting of polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, poly(vinyl pyrrolidone-co-vinyl acetate), polyoxyethylene-polyoxypropylene block copolymers, graft co-carriers composed of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, polymethacrylates, polyoxyethylene alkyl ethers, polyoxyethylene castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic acid-glycolic acid), lipids, cellulose, pullulan, dextran, maltodextrin, hyaluronic acid, polysialic acid, chondroitin sulfate, heparin, fucoidan, pentosan polysulfate, spirulan, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose propionate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate , cellulose acetate trimellitate, methylcellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate isophthalate, carboxymethylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose propionate phthalate, hydroxypropylmethylcellulose acetate trimellitate, hydroxypropylmethylcellulose propionate trimellitate, cellulose acetate succinate, methylcellulose acetate succinate, dextran, dextran acetate, dextran propionate, dextran succinate, dextran acetate propionate, dextran acetate succinate, dextran propionate, dextran acetate succinate, dextran propionate, dextran acetate propionate, poly(methacrylic acid-co-methyl methacrylate) 1:1, poly(methacrylic acid-co-methyl methacrylate) 1:2, poly(methacrylic acid-co-ethyl acrylate) 1:1, and mixtures thereof. In some embodiments, the pharmaceutically acceptable polymer is hydroxypropylmethylcellulose acetate succinate. In some embodiments, the compound and the pharmaceutically acceptable polymer are present in a compound:polymer ratio of about 40:60 to about 10:90.In some embodiments, the compound and the pharmaceutically acceptable polymer are present in a compound: polymer ratio of about 30:70 to about 20:80. In some embodiments, the compound and the pharmaceutically acceptable polymer are present in a compound: polymer ratio of about 25:75. In some embodiments, the solid dispersion is a spray-dried solid dispersion. In some embodiments, the solubility of the solid dispersion in water at pH 6.5 is about 100 μg / mL at 25°C to about 200 μg / mL at 25°C. In some embodiments, the solubility of the solid dispersion in water at pH 6.5 is about 120 μg / mL at 25°C. In some embodiments, the solubility of the solid dispersion in water at pH 2 is about 150 μg / mL at 25°C to about 300 μg / mL at 25°C. In some embodiments, the solubility of the solid dispersion in water at pH 2 is about 178 μg / mL at 25°C.

[0168] In some embodiments, the pharmaceutically acceptable composition comprises less than about 10% (w / w) of the compound represented by formula (II):

[0169]

[0170] It is based on the weight of the compound of formula (I).

[0171] In some embodiments, the pharmaceutically acceptable composition comprises less than about 3% (w / w) of the compound represented by formula (II):

[0172]

[0173] It is based on the weight of the compound of formula (I).

[0174] In some embodiments, the pharmaceutically acceptable composition comprises less than about 1% (w / w) of the compound represented by formula (II):

[0175]

[0176] It is based on the weight of the compound of formula (I).

[0177] In some embodiments, the pharmaceutically acceptable composition comprises less than about 0.1% (w / w) to about 0.5% (w / w) of a compound represented by formula (II):

[0178]

[0179] It is based on the weight of the compound of formula (I).

[0180] In some embodiments, the pharmaceutically acceptable composition comprises less than about 0.01% (w / w) to about 0.1% (w / w) of a compound represented by formula (II):

[0181]

[0182] It is based on the weight of the compound of formula (I).

[0183] In some embodiments, the pharmaceutically acceptable composition comprises less than about 10% (w / w) of the compound represented by formula (III):

[0184]

[0185] It is based on the weight of the compound of formula (I).

[0186] In some embodiments, the pharmaceutically acceptable composition comprises less than about 3% (w / w) of the compound represented by formula (III):

[0187]

[0188] It is based on the weight of the compound of formula (I).

[0189] In some embodiments, the pharmaceutically acceptable composition comprises less than about 3% (w / w) of the compound represented by formula (III):

[0190]

[0191] It is based on the weight of the compound of formula (I).

[0192] In some embodiments, the pharmaceutically acceptable composition comprises less than about 1% (w / w) of a compound represented by formula (III):

[0193]

[0194] It is based on the weight of the compound of formula (I).

[0195] In some embodiments, the pharmaceutically acceptable composition comprises less than about 0.1% (w / w) to about 0.5% (w / w) of a compound represented by formula (III):

[0196]

[0197] It is based on the weight of the compound of formula (I).

[0198] In some embodiments, the pharmaceutically acceptable composition comprises less than about 0.01% (w / w) to about 0.1% (w / w) of a compound represented by formula (III):

[0199]

[0200] It is based on the weight of the compound of formula (I).

[0201] In another embodiment, provided herein is a pharmaceutically acceptable composition comprising a compound represented by formula (I) and a pharmaceutically acceptable excipient.

[0202]

[0203] Wherein greater than about 96% (w / w) of the compound in the pharmaceutically acceptable composition is in amorphous form.

[0204] In some embodiments, the amorphous form has a characteristic amorphous powder X-ray diffraction halo pattern. In some embodiments, the amorphous form has substantially Figure 1 The X-ray powder diffraction pattern is shown.

[0205] In some embodiments, the powder X-ray diffraction spectrum is obtained using Cu Ka radiation. In some embodiments, the glass transition temperature of the amorphous compound is about 125° C. In some embodiments, the composition does not contain a detectable amount of any crystalline form of the compound of formula (I).

[0206] In one embodiment, described herein is a pharmaceutically acceptable composition for oral delivery to a patient of 50 mg of a compound represented by formula (I):

[0207]

[0208] The composition comprises: an intragranular blend and an extragranular blend, wherein the intragranular blend comprises: a solid dispersion having 50 mg of the compound and wherein the compound is present in an amorphous form, and hydroxypropylmethylcellulose acetate succinate; a bulking agent and / or a filler; and a lubricant and / or a glidant; and wherein the extragranular blend comprises: a glidant and / or a lubricant.

[0209] In one embodiment, described herein is a pharmaceutically acceptable composition for oral delivery to a patient of 50 mg of a compound represented by formula (I):

[0210]

[0211] The composition comprises: a solid dispersion having 50 mg of the compound and wherein the compound is present in an amorphous form, and hydroxypropylmethylcellulose acetate succinate; a swelling agent; a filler; and a lubricant and / or a glidant.

[0212] In some embodiments, the solid dispersion comprises a compound represented by amorphous form of formula (I) and a pharmaceutically acceptable polymer in a ratio of about 40:60 to about 10:90, or about 30:70 to about 20:80. In some embodiments, the ratio of the compound represented by amorphous form of formula (I) to the pharmaceutically acceptable polymer may be about 25:75.

[0213] Also provided herein is a pharmaceutical composition comprising: (a) an intragranular blend comprising: (i) a spray-dried solid dispersion comprising a compound represented by formula (I), and a pharmaceutically acceptable polymer; (ii) one or more fillers; (iii) a disintegrant; (iv) a glidant; and (v) a lubricant; and (b) an extragranular blend comprising: (i) a glidant; and (ii) a lubricant.

[0214] In some embodiments, the ratio of the intragranular blend to the extragranular blend in the blend is about 90:10 to about 99.5:0.5. For example, the ratio of the intragranular blend to the extragranular blend in the blend may be about 99:1.

[0215] In some embodiments, the solid dispersion of the intragranular blend comprises about 10% (w / w) to about 50% (w / w), or about 10% (w / w) to about 30% (w / w), or about 20% (w / w) to about 30% (w / w) of amorphous compound of formula (I), based on the total weight of the spray-dried solid dispersion. In some embodiments, the spray-dried solid dispersion may comprise about 25% (w / w) of amorphous compound of formula (I), based on the total weight of the spray-dried solid dispersion.

[0216] In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable polymer selected from the group consisting of polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, poly(vinyl pyrrolidone-co-vinyl acetate), polyoxyethylene-polyoxypropylene block copolymers, graft copolymers composed of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, polymethacrylates, polyoxyethylene alkyl ethers, polyoxyethylene castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic acid-glycolic acid), lipids, cellulose, pullulan, dextran, maltodextrin, hyaluronic acid, polysialic acid, chondroitin sulfate, heparin, fucoidan, pentosan polysulfate, spirulan, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose propionate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate The pharmaceutically acceptable polymer may be cellulose acetate phthalate, cellulose acetate trimellitate, methylcellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate isophthalate, carboxymethylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose propionate phthalate, hydroxypropylmethylcellulose acetate trimellitate, hydroxypropylmethylcellulose propionate trimellitate, cellulose acetate succinate, methylcellulose acetate succinate, dextran, dextran acetate, dextran propionate, dextran succinate, dextran acetate propionate, dextran acetate succinate, dextran propionate, dextran acetate succinate, dextran propionate, dextran acetate propionate, poly(methacrylic acid-co-methyl methacrylate) 1:1, poly(methacrylic acid-co-methyl methacrylate) 1:2, poly(methacrylic acid-co-ethyl acrylate) 1:1, or a mixture thereof. For example, the pharmaceutically acceptable polymer is hydroxypropylmethylcellulose acetate succinate.

[0217] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) in an amorphous form and a pharmaceutically acceptable polymer in a ratio of about 40:60 to about 10:90, or about 30:70 to about 20:80. In some embodiments, the ratio of the amorphous compound of formula (I) to the pharmaceutically acceptable polymer may be about 25:75.

[0218] In some embodiments, the intragranular blend of the pharmaceutical composition comprises one or more fillers, wherein the total amount of the one or more fillers is about 40% (w / w) to about 80% (w / w), based on the total weight of the pharmaceutical composition. The one or more fillers are lactose, maltodextrin, mannitol, microcrystalline cellulose, pregelatinized starch, sucrose esters, or hydrates thereof. In some embodiments, the intragranular blend comprises two fillers. When the intragranular blend comprises two fillers, each filler may be independently present in an amount of about 20% (w / w) to about 40% (w / w), for example, about 33% (w / w), based on the total weight of the pharmaceutical composition. In some embodiments, one filler may be microcrystalline cellulose, and the other filler may be lactose monohydrate.

[0219] In some embodiments, the intragranular blend of the pharmaceutical composition comprises about 1% (w / w) to about 10% (w / w), such as about 5% (w / w), of a disintegrant, based on the total weight of the pharmaceutical composition. The disintegrant is crospovidone, croscarmellose sodium, sodium starch glycolate, microcrystalline cellulose, or pregelatinized starch. In some embodiments, the disintegrant in the intragranular blend may be crospovidone.

[0220] In some embodiments, the glidant of the intragranular blend is present in an amount of about 0.1% (w / w) to about 1% (w / w), such as about 0.5% (w / w), based on the total weight of the pharmaceutical composition. For example, the glidant of the intragranular blend may be silicon dioxide.

[0221] In some embodiments, the glidant of the extragranular blend is present in an amount of about 0.1% (w / w) to about 1% (w / w), such as about 0.5% (w / w), based on the total weight of the pharmaceutical composition. In some embodiments, the glidant of the extragranular blend may be silicon dioxide.

[0222] In some embodiments, the lubricant of the intragranular blend is present in an amount of about 0.1% (w / w) to about 1% (w / w), such as about 0.5% (w / w), based on the total weight of the pharmaceutical composition. In some embodiments, the lubricant of the intragranular blend is magnesium stearate, calcium stearate, stearin monoesters, hydrogenated castor oil, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, zinc stearate, talc, microcrystalline cellulose, or sucrose esters. For example, the lubricant of the intragranular blend may be magnesium stearate.

[0223] In some embodiments, the lubricant of the extragranular blend is present in an amount of about 0.1% (w / w) to about 1% (w / w), such as about 0.5% (w / w), based on the total weight of the pharmaceutical composition. In some embodiments, the lubricant of the extragranular blend is magnesium stearate, calcium stearate, stearyl glycerol monoester, hydrogenated castor oil, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, zinc stearate, talc, microcrystalline cellulose, or sucrose ester. For example, the lubricant of the extragranular blend may be magnesium stearate.

[0224] In some embodiments, provided herein is a pharmaceutical composition comprising: (a) an intragranular blend comprising: (i) about 33% (w / w) of a spray-dried solid dispersion, based on the total weight of the pharmaceutical composition, and the spray-dried solid dispersion comprises an amorphous compound represented by formula (I) (with a purity of greater than 95% as determined by HPLC) and hydroxypropylmethylcellulose acetate succinate, wherein the spray-dried solid dispersion comprises about 25% (w / w) of the compound represented by formula (I), based on the total weight of the spray-dried solid dispersion; (ii) about 30% (w / w) of microcrystalline cellulose, based on the total weight of the pharmaceutical composition; (a) an extragranular blend comprising: (i) about 0.5% (w / w) silicon dioxide, based on the total amount of the pharmaceutical composition; and (ii) about 0.5% (w / w) magnesium stearate, based on the total amount of the pharmaceutical composition.

[0225] In some embodiments, provided herein is a pharmaceutical composition comprising: (a) an intragranular blend comprising: (i) about 200 mg of a spray-dried solid dispersion comprising an amorphous compound represented by formula (I) and hydroxypropylmethylcellulose acetate succinate, wherein the spray-dried solid dispersion comprises about 50 mg of the compound represented by formula (I); (ii) about 179 mg of microcrystalline cellulose; (iii) about 179 mg of lactose monohydrate; (iv) about 30 mg of crospovidone; (v) about 3 mg of silicon dioxide; and (vi) about 3 mg of magnesium stearate; and (b) an extragranular blend comprising: (i) about 3 mg of silicon dioxide; and (ii) about 3 mg of magnesium stearate.

[0226] tablet

[0227] The pharmaceutical composition can also be provided in tablet form. The tablets can be uncoated, film-coated, sugar-coated, bisected, embossed, uncoated, layered or sustained release. They can be made in a variety of sizes, shapes and colors. The tablets can be swallowed, chewed or dissolved in the mouth or under the tongue.

[0228] In some embodiments, described herein is a pharmaceutically acceptable tablet having 50 mg of a compound represented by formula (I),

[0229]

[0230] The tablet comprises: an intragranular blend and an extragranular blend, wherein the intragranular blend comprises: a solid dispersion having 50 mg of the compound and wherein the compound is present in an amorphous form, and hydroxypropylmethylcellulose acetate succinate; about 25-35% (w / w) of a bulking agent, based on the total amount of the pharmaceutical composition; about 25-35% (w / w) of a filler, based on the total amount of the pharmaceutical composition; and wherein the extragranular blend comprises: a glidant and / or a lubricant. In some embodiments, the bulking agent is microcrystalline cellulose. In some embodiments, the filler is lactose or a hydrate thereof.

[0231] In some embodiments, described herein is a pharmaceutically acceptable tablet having 10 mg of a compound represented by formula (I),

[0232]

[0233] The tablet comprises: an intragranular blend and an extragranular blend, wherein the intragranular blend comprises: a solid dispersion having 10 mg of the compound and wherein the compound is present in an amorphous form, and hydroxypropylmethylcellulose acetate succinate; about 25-35% (w / w) of a bulking agent, based on the total amount of the pharmaceutical composition; about 25-35% (w / w) of a filler, based on the total amount of the pharmaceutical composition; and wherein the extragranular blend comprises: a glidant and / or a lubricant. In some embodiments, the bulking agent is microcrystalline cellulose. In some embodiments, the filler is lactose or a hydrate thereof.

[0234] In another embodiment, provided herein is a pharmaceutically acceptable tablet having 50 mg of a compound represented by formula (I),

[0235]

[0236] wherein the tablet comprises: a solid dispersion having 50 mg of the compound and wherein the compound is present in an amorphous form, and hydroxypropylmethylcellulose acetate succinate; about 25-35% (w / w) of microcrystalline cellulose, based on the total weight of the tablet; and about 25-35% (w / w) of lactose or a hydrate thereof, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutically acceptable tablet further comprises at least one of: magnesium stearate, crospovidone, and silicon dioxide. In some embodiments, the USP <701> When tested against uncoated tablets, the tablets disintegrated in less than 1 minute.

[0237] In another embodiment, provided herein is a pharmaceutically acceptable tablet having 10 mg of a compound represented by formula (I),

[0238]

[0239] wherein the tablet comprises: a solid dispersion having 10 mg of the compound and wherein the compound is present in an amorphous form, and hydroxypropylmethylcellulose acetate succinate; about 25-35% (w / w) of microcrystalline cellulose, based on the total weight of the tablet; and about 25-35% (w / w) of lactose or a hydrate thereof, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutically acceptable tablet further comprises at least one of: magnesium stearate, crospovidone, and silicon dioxide. In some embodiments, the USP <701> When tested against uncoated tablets, the tablets disintegrated in less than 1 minute.

[0240] In another embodiment, described herein is a pharmaceutically acceptable composition for oral delivery of 50 mg of a compound represented by formula (I),

[0241]

[0242] The composition comprises: an intragranular blend and an extragranular blend, wherein the intragranular blend comprises: a solid dispersion having 50 mg of the compound and wherein the compound is present in an amorphous form, and hydroxypropylmethylcellulose acetate succinate; about 25-35% (w / w) microcrystalline cellulose, based on the total amount of the pharmaceutical composition; about 25-35% (w / w) lactose or a hydrate thereof, based on the total amount of the pharmaceutical composition; about 5% (w / w) cross-linked polyvinylpyrrolidone, based on the total amount of the pharmaceutical composition; about 0.5% (w / w) silicon dioxide, based on the total amount of the pharmaceutical composition; and about 0.5% (w / w) magnesium stearate, based on the total amount of the pharmaceutical composition; and the extragranular blend comprises: about 0.5% (w / w) silicon dioxide, based on the total amount of the pharmaceutical composition, and (ii) about 0.5% (w / w) magnesium stearate, based on the total amount of the pharmaceutical composition. In some embodiments, when the composition is tested in 900 mL of pH 4.5 sodium acetate buffer at 37° C. using USP Apparatus II (paddle method) at a paddle speed of 75 rpm, the composition or tablet releases at least 80% of the compound after 10-40 min. In some embodiments, when the composition is tested in 900 mL of pH 4.5 sodium acetate buffer at 37° C. using USP Apparatus II (paddle method) at a paddle speed of 75 rpm, the composition or tablet releases at least 80% of the compound after 10 min. In some embodiments, the composition is tested in 900 mL of pH 4.5 sodium acetate buffer at 37° C. using USP Apparatus II (paddle method) at a paddle speed of 75 rpm, and the composition or tablet releases at least 80% of the compound after 20 min. In some embodiments, the composition is tested in 900 mL of pH 4.5 sodium acetate buffer at 37° C. using USP Apparatus II (paddle method) at a paddle speed of 75 rpm, and after 30 min, the composition or tablet releases at least 80% of the compound. In some embodiments, the composition is tested in 900 mL of pH 4.5 sodium acetate buffer at 37° C. using USP Apparatus II (paddle method) at a paddle speed of 75 rpm, and after 40 min, the composition or tablet releases at least 80% of the compound.

[0243] In some embodiments, provided herein is a tablet containing about 50 mg of a non-crystalline compound represented by formula (I), wherein the tablet comprises: (a) an intragranular blend comprising: (i) about 195 mg to about 205 mg of a spray-dried solid dispersion comprising about 50 mg of the compound and hydroxypropylmethylcellulose acetate succinate; (ii) about 177 mg to about 181 mg of microcrystalline cellulose; (iii) about 177 mg to about 181 mg of lactose monohydrate; and (iv) about 28 mg to about 32 mg of cross-linked polyvinylpyrrolidone; and (b) an extragranular blend comprising: (i) about 2 mg to about 4 mg of silicon dioxide; and (ii) about 2 mg to about 4 mg of magnesium stearate. In some embodiments, microcrystalline cellulose can be substituted with lactose. In some embodiments, microcrystalline cellulose can be substituted with mannitol. In some embodiments, microcrystalline cellulose can be substituted with modified starch.

[0244] In some embodiments, provided herein is a tablet weighing about 600 mg and containing about 25 mg of amorphous compound represented by formula (I), wherein the tablet comprises: (a) an intragranular blend comprising: (i) about 16.7% of the total tablet weight of a spray-dried solid dispersion comprising about 25 mg of the compound and hydroxypropylmethylcellulose acetate succinate; (ii) about 37.7% of the total tablet weight of microcrystalline cellulose; (iii) about 37.6% of the total tablet weight of lactose monohydrate; (iv) about 6.0% of the total tablet weight of croscarmellose sodium; (v) about 0.5% of the total tablet weight of silicon dioxide; and (vi) about 0.5% of the total tablet weight of magnesium stearate; and (b) an extragranular blend comprising: (i) about 0.5% of the total tablet weight of silicon dioxide; and (ii) about 0.5% of the total tablet weight of magnesium stearate.

[0245] In some embodiments, provided herein is a tablet weighing about 600 mg and containing about 25 mg of amorphous compound represented by formula (I), wherein the tablet comprises: (a) an intragranular blend comprising: (i) about 16.7% of the total tablet weight of a spray-dried solid dispersion comprising about 25 mg of the compound and hydroxypropylmethylcellulose acetate succinate; (ii) about 38.2% of the total tablet weight of microcrystalline cellulose; (iii) about 38.1% of the total tablet weight of lactose monohydrate; (iv) about 5.0% of the total tablet weight of cross-linked polyvinylpyrrolidone; (v) about 0.5% of the total tablet weight of silicon dioxide; and (vi) about 0.5% of the total tablet weight of magnesium stearate; and (b) an extragranular blend comprising: (i) about 0.5% of the total tablet weight of silicon dioxide; and (ii) about 0.5% of the total tablet weight of magnesium stearate.

[0246] In some embodiments, provided herein is a tablet weighing about 600 mg and providing about 25 mg of amorphous form of a compound represented by formula (I), wherein the tablet comprises: (a) an intragranular blend comprising: (i) about 16.7% of the total tablet weight of a spray-dried solid dispersion comprising about 25 mg of the compound and hydroxypropylmethylcellulose acetate succinate; (ii) about 32.7% of the total tablet weight of microcrystalline cellulose; (iii) about 32.6% of the total tablet weight of lactose monohydrate; (iv) about 6.0% of the total tablet weight of croscarmellose sodium; (v) about 10.0% of the total tablet weight of 70 / 30 TPGS / Cabosil; (vi) about 0.5% of the total tablet weight of silicon dioxide; and (vii) about 0.5% of the total tablet weight of magnesium stearate; and (b) an extragranular blend comprising: (i) about 0.5% of the total tablet weight of silicon dioxide; and (ii) about 0.5% of the total tablet weight of magnesium stearate.

[0247] Treatment

[0248] The compounds of formula (I) are widely used c-KIT inhibitors. The conditions that can be treated by the compounds of formula (I) include (but are not limited to): 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 malignant germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, eosinophilic syndrome, idiopathic eosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic acute myeloid leukemia associated with hypereosinophilia, lymphoblastic T-cell lymphoma, non-small cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, endometrial sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic acute myeloid leukemia associated with hypereosinophilic syndrome, lymphoblastic T-cell lymphoma, non-small cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, endometrial sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, hypereosinophilic The invention relates to a disease comprising: a non-melanoma skin cancer, a non-melanoma skin cancer, a non-melanoma skin cancer, a non-melanoma sarcoma ...

[0249] Thus, in another embodiment, provided herein is a method for treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma, acute myeloid leukemia, germ cell tumor of a seminoma or malignant germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic syndrome-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma, and non-small cell lung cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a composition or one or more tablets described herein.

[0250] In another embodiment, the present invention also provides a method for treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, lung cancer, glioblastoma, glioma, malignant peripheral nerve sheath sarcoma and eosinophilic syndrome in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a composition described herein or one or more tablets. In some embodiments, the disease is intestinal stromal tumor (GIST).

[0251] In another embodiment, provided herein is a method for treating a disease selected from the group consisting of KIT-driven germ cell tumors (e.g., testicular germ cell), KIT-driven skin cancer, or KIT-driven renal cell carcinoma in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a composition or one or more tablets described herein.

[0252] In another embodiment, the present invention also provides a method of treating a disease selected from the group consisting of penile cancer, PDGFRA-driven penile cancer, prostate cancer, PDGFRA-driven prostate cancer, PDGFRA-driven non-melanoma skin cancer, PDGFRA-driven glioma, PDGFRA-driven sarcoma, PDGFRA-driven glioblastoma, or PDGFRA-driven pancreatic cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a composition described herein or one or more tablets.

[0253] In another embodiment, the present invention also provides a method for treating a disease comprising a PDGFRB mutation selected from the group consisting of vaginal cancer, prostate cancer, penile cancer, non-melanoma skin cancer, melanoma, or breast sarcoma in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a composition or one or more tablets described herein.

[0254] In some embodiments, provided herein is a method for treating a disease driven by a KIT mutation or a PDGFRA mutation in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a composition described herein or one or more tablets. In some embodiments, provided herein is a method for treating a disease driven by a KIT mutation and a PDGFRA mutation in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a composition described herein or one or more tablets. In some embodiments, provided herein is a method for treating a disease driven by a KIT mutation or a PDGFRA mutation (including an accompanying PDGFRB mutation) in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a composition described herein or one or more tablets.

[0255] In some embodiments, provided herein is a method of treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma (e.g., KIT-driven melanoma or PGDFRA-driven melanoma or PGDFR-driven melanoma), acute myeloid leukemia, germ cell tumor of a seminoma or malignant germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic syndrome-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma, and non-small cell lung cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a composition described herein or one or more tablets. In some embodiments, the melanoma is a cutaneous melanoma or a non-cutaneous melanoma. In some embodiments, the melanoma is a cutaneous melanoma. In some embodiments, the melanoma is a superficial spreading melanoma, a nodular melanoma, an acral lentiginous melanoma, or amelanotic and desmoplastic melanoma. In some embodiments, the melanoma is a non-cutaneous (non-cutaneous) melanoma. In some embodiments, the non-cutaneous melanoma is an ocular melanoma or a mucosal melanoma. In some embodiments, the disease is caused by the kinase activity of c-KIT and / or PDGFRA and / or its oncogenic form. In some embodiments, the disease is selected from the group consisting of KIT-driven germ cell tumors (e.g., testicular germ cells), KIT-driven skin cancers (e.g., KIT-driven cutaneous squamous cell carcinoma, KIT-driven Merkel cell carcinoma, uveal melanoma, non-melanoma skin cancer), or KIT-driven renal cell carcinomas (e.g., renal cell carcinoma, refractory renal cell carcinoma). In some embodiments, the disease is selected from the group consisting of penile cancer, PDGFRA-driven penile cancer, prostate cancer, PDGFRA-driven prostate cancer, PDGFRA-driven non-melanoma skin cancer, PDGFRA-driven glioma, PDGFRA-driven sarcoma, PDGFRA-driven glioblastoma, or PDGFRA-driven pancreatic cancer. In some embodiments, the disease comprising a PDGFRB mutation is selected from the group consisting of vaginal cancer, prostate cancer, penile cancer, non-melanoma skin cancer, melanoma, or breast sarcoma.

[0256] In another embodiment, the present invention also provides a use of a composition or tablet described herein in the preparation of a medicament for treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma, acute myeloid leukemia, germ cell tumors of seminoma or malignant germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic syndrome-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma and non-small cell lung cancer. In some embodiments, for the preparation of a medicament for treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, lung cancer, glioblastoma, glioma, malignant peripheral nerve sheath sarcoma, and hypereosinophilic syndrome.

[0257] The amorphous compound of formula (I) described herein with a purity of greater than 95% as determined by HPLC is a widely used c-KIT inhibitor. In some embodiments, provided herein is a method for treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma (e.g., skin melanoma, non-cutaneous melanoma, KIT-driven melanoma or PGDFRA-driven melanoma or PGDFR-driven melanoma), acute myeloid leukemia, germ cell tumors of seminoma or malignant germ cell tumor, mastocytosis, mast cell leukemia, pulmonary adenocarcinoma, pulmonary fibrosis ... Cancer, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, acute myeloid leukemia associated with hypereosinophilia, lymphoblastic T-cell lymphoma and non-small cell lung cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) having a purity greater than 95% as determined by HPLC. In some embodiments, the disease is caused by the following kinase activity: c-KIT and / or PDGFRA, and / or its oncogenic form. In some embodiments, the disease is intestinal stromal tumor (GIST). In some embodiments, the disease is KIT-driven gastrointestinal stromal tumor. In some embodiments, the disease is PDGFRA-driven gastrointestinal stromal tumor. In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is hypereosinophilic syndrome. In some embodiments, provided herein is a method for treating or preventing PDGFR kinase-mediated tumor growth of a tumor process, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) having a purity greater than 95% as determined by HPLC.

[0258] In some embodiments, the tumor growth or tumor progression is caused by PDGFRα kinase overexpression, oncogenic PDGFRα missense mutations, oncogenic deletion PDGFRα mutations, oncogenic PDGFRα gene recombination resulting in PDGFRα fusion protein, in-frame deletions within the PDGFRα gene, and / or oncogenic PDGFRα gene amplification. In some embodiments, a compound of formula (I) having a purity of greater than 95% as determined by HPLC is administered to a cancer patient, wherein the cancer is PDGFRA-driven gastrointestinal stromal tumor, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, hypereosinophilic syndrome-associated acute myeloid leukemia, or lymphoblastic T-cell lymphoma. In some embodiments, the disease is PDGFRA-driven gastrointestinal stromal tumor (GIST). In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is eosinophilic syndrome. In some embodiments, the compound of formula (I) is administered as a single agent with a purity greater than 95% as determined by HPLC, or is administered in combination with other targeted cancer therapeutics, targeted cancer biological agents, immune checkpoint inhibitors, or chemotherapeutic agents.

[0259] In some embodiments, the treatment methods described herein include administering an amorphous form of a compound of Formula (I) or a pharmaceutical composition thereof to an individual in need thereof prior to surgery (as a neoadjuvant therapy). In some embodiments, the treatment methods described herein include administering a composition containing a compound of Formula (I) as described herein to an individual in need thereof after surgery (as an adjuvant therapy).

[0260] The amorphous form of the compound of formula (I) described herein, which does not contain detectable amounts of any crystalline form, is a widely used c-KIT inhibitor. In some embodiments, provided herein is a method of treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma (e.g., skin melanoma, non-cutaneous melanoma, KIT-driven melanoma or PGDFRA-driven melanoma or PGDFR-driven melanoma), acute myeloid leukemia, germ cell tumors of seminoma or malignant germ cell tumor, mastocytosis, mast cell leukemia, lung Adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, acute myeloid leukemia associated with hypereosinophilia, lymphoblastic T-cell lymphoma and non-small cell lung cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) that does not contain a detectable amount of any crystalline form. In some embodiments, the disease is caused by the kinase activity of c-KIT and / or PDGFRA and / or its oncogenic form. In some embodiments, the disease is intestinal stromal tumor (GIST). In some embodiments, the disease is KIT-driven gastrointestinal stromal tumor. In some embodiments, the disease is PDGFRA-driven gastrointestinal stromal tumor. In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is eosinophilic syndrome. In some embodiments, a method of treating or preventing PDGFR kinase-mediated tumor growth of a tumor process is provided herein, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) that does not contain a detectable amount of any crystalline form. In some embodiments, the tumor growth or tumor process is caused by overexpression of PDGFRα kinase, oncogenic PDGFRα missense mutation, oncogenic deletion PDGFRα mutation, oncogenic PDGFRα gene recombination leading to PDGFRα fusion protein, PDGFRα gene in-frame deletion, and / or oncogenic PDGFRα gene amplification.In some embodiments, a compound of formula (I) is administered to a cancer patient without detectable amounts of any crystalline form, wherein the cancer is PDGFRA-driven gastrointestinal stromal tumor, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic syndrome-associated acute myeloid leukemia, or lymphoblastic T-cell lymphoma. In some embodiments, the disease is PDGFRA-driven gastrointestinal stromal tumor (GIST). In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is hypereosinophilic syndrome. In some embodiments, the compound of Formula (I) wherein the compound of Formula (I) does not contain a detectable amount of any crystalline form is administered as a single agent or in combination with other cancer-targeted therapeutic agents, cancer-targeted biologics, immune checkpoint inhibitors, or chemotherapeutic agents.

[0261] The amorphous form of the compound of formula (I) described herein containing no more than 5% (w / w) of any crystalline form, or no detectable amount of any crystalline form, is a widely used c-KIT inhibitor. In some embodiments, provided herein is a method of treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma (e.g., cutaneous melanoma, non-cutaneous melanoma, KIT-driven melanoma or PGDFRA-driven melanoma or PGDFR-driven melanoma), acute myeloid leukemia, germ cell tumor of seminoma or malignant germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, neuroendocrine tumor, leukemia ... Through glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, hypereosinophilic acute myeloid leukemia associated with hypereosinophilia, lymphoblastic T-cell lymphoma or non-small cell lung cancer, the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) containing no more than 5% (w / w) of any crystalline form, or containing no detectable amount of any crystalline form. In some embodiments, the disease is caused by the following kinase activity: c-KIT and / or PDGFRA, and / or its oncogenic form. In some embodiments, the disease is intestinal stromal tumor (GIST). In some embodiments, the disease is KIT-driven gastrointestinal stromal tumor. In some embodiments, the disease is PDGFRA-driven gastrointestinal stromal tumor. In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is eosinophilic syndrome. In some embodiments, a method of treating or preventing PDGFR kinase-mediated tumor growth of a tumor process is provided herein, the method comprising administering to a patient in need thereof a compound of formula (I) containing no more than 5% (w / w) of any crystalline form, or no detectable amount of any crystalline form. In some embodiments, the tumor growth or tumor process is caused by overexpression of PDGFRα kinase, oncogenic PDGFRα missense mutation, oncogenic deletion PDGFRα mutation, oncogenic PDGFRα gene recombination leading to PDGFRα fusion protein, PDGFRα gene in-frame deletion, and / or oncogenic PDGFRα gene amplification.In some embodiments, a compound of formula (I) is administered to a cancer patient without detectable amounts of any crystalline form, wherein the cancer is PDGFRA-driven gastrointestinal stromal tumor, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic syndrome-associated acute myeloid leukemia, or lymphoblastic T-cell lymphoma. In some embodiments, the disease is PDGFRA-driven gastrointestinal stromal tumor (GIST). In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is hypereosinophilic syndrome. In some embodiments, the compound of formula (I) contains no more than 5% (w / w) of any crystalline form, or does not contain a detectable amount of any crystalline form, is administered as a single agent, or in combination with other cancer-targeted therapeutic agents, cancer-targeted biologics, immune checkpoint inhibitors, or chemotherapeutic agents.

[0262] The amorphous form of the compound of formula (I) as described herein containing no more than about 5% (w / w) of any crystalline form of the compound of formula (I) is a widely used c-KIT inhibitor. In some embodiments, provided herein is a method of treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma (e.g., cutaneous melanoma, non-cutaneous melanoma, KIT-driven melanoma or PGDFRA-driven melanoma or PGDFR-driven melanoma), acute myeloid leukemia, germ cell tumor of seminoma or malignant germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell Lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic syndrome-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma, or non-small cell lung cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) containing no more than about 5% (w / w) of any crystalline form of the compound of formula (I). In some embodiments, the disease is intestinal stromal tumor (GIST). In some embodiments, the disease is KIT-driven gastrointestinal stromal tumor. In some embodiments, the disease is PDGFRA-driven gastrointestinal stromal tumor. In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is eosinophilic syndrome. In some embodiments, provided herein is a method for treating or preventing PDGFR kinase-mediated tumor growth of a tumor process, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) containing no more than about 5% (w / w) of any crystalline form of a compound of formula (I). In some embodiments, the tumor growth or tumor process is caused by overexpression of PDGFRα kinase, oncogenic PDGFRα missense mutation, oncogenic deletion PDGFRα mutation, oncogenic PDGFRα gene recombination leading to PDGFRα fusion protein, in-frame deletion within the PDGFRα gene, and / or oncogenic PDGFRα gene amplification.In some embodiments, a compound of formula (I) is administered to a cancer patient without detectable amounts of any crystalline form, wherein the cancer is PDGFRA-driven gastrointestinal stromal tumor, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic syndrome-associated acute myeloid leukemia, or lymphoblastic T-cell lymphoma. In some embodiments, the disease is PDGFRA-driven gastrointestinal stromal tumor (GIST). In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is hypereosinophilic syndrome. In some embodiments, the compound of formula (I) contains no more than about 5% (w / w) of any crystalline form of the compound of formula (I) and is administered as a single agent or in combination with other cancer-targeted therapeutic agents, cancer-targeted biologics, immune checkpoint inhibitors, or chemotherapeutic agents.

[0263] In some embodiments, an amorphous form of a compound of formula (I) having a purity greater than 95% as determined by HPLC is used to prepare a medicament for treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma (e.g., cutaneous melanoma, non-cutaneous melanoma, KIT-driven melanoma or PGDFRA-driven melanoma or PGDFR-driven melanoma), acute myeloid leukemia, germ cell tumors of seminoma or malignant germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic syndrome-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma, and non-small cell lung cancer. In some embodiments, the disease is caused by the following kinase activity: c-KIT and / or PDGFRA, and / or their oncogenic forms. In some embodiments, the disease is intestinal stromal tumor (GIST). In some embodiments, the disease is KIT-driven gastrointestinal stromal tumor. In some embodiments, the disease is PDGFRA-driven gastrointestinal stromal tumor. In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is eosinophilic syndrome. In some embodiments, the amorphous compound of formula (I) with a purity of greater than 95% as determined by HPLC is used to prepare a drug for treating or preventing PDGFR kinase-mediated tumor growth. In some embodiments, the tumor growth or tumor progression is caused by PDGFRα kinase overexpression, oncogenic PDGFRα missense mutation, oncogenic deletion PDGFRα mutation, oncogenic PDGFRα gene recombination leading to PDGFRα fusion protein, in-frame deletion within the PDGFRα gene, and / or oncogenic PDGFRα gene amplification. In some embodiments, the amorphous compound of formula (I) with a purity greater than 95% as determined by HPLC is used to prepare a medicament for treating a disease, wherein the disease is PDGFRA-driven gastrointestinal stromal tumor, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic syndrome-associated acute myeloid leukemia, or lymphoblastic T-cell lymphoma. In some embodiments, the disease is PDGFRA-driven gastrointestinal stromal tumor (GIST).In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is hypereosinophilic syndrome.

[0264] In some embodiments, an amorphous form of a compound of formula (I) that does not contain detectable amounts of any crystalline form is used to prepare a medicament for treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma (e.g., cutaneous melanoma, non-cutaneous melanoma, KIT-driven melanoma or PGDFRA-driven melanoma or PGDFR-driven melanoma), acute myeloid leukemia, germ cell tumor of a seminoma or malignant germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic syndrome-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma, and non-small cell lung cancer. In some embodiments, the disease is caused by the following kinase activity: c-KIT and / or PDGFRA, and / or their oncogenic forms. In some embodiments, the disease is intestinal stromal tumor (GIST). In some embodiments, the disease is KIT-driven gastrointestinal stromal tumor. In some embodiments, the disease is PDGFRA-driven gastrointestinal stromal tumor. In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is eosinophilic syndrome. In some embodiments, the amorphous form of the compound of formula (I) that does not contain a detectable amount of any crystalline form is used to prepare a drug for treating or preventing PDGFR kinase-mediated tumor growth. In some embodiments, the tumor growth or tumor progression is caused by PDGFRα kinase overexpression, oncogenic PDGFRα missense mutation, oncogenic deletion PDGFRα mutation, oncogenic PDGFRα gene recombination leading to PDGFRα fusion protein, in-frame deletion within the PDGFRα gene, and / or oncogenic PDGFRα gene amplification. In some embodiments, the amorphous form of the compound of formula (I) that does not contain a detectable amount of any crystalline form is used to prepare a medicament for treating a disease, wherein the disease is PDGFRA-driven gastrointestinal stromal tumor, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic syndrome-associated acute myeloid leukemia, or lymphoblastic T-cell lymphoma. In some embodiments, the disease is PDGFRA-driven gastrointestinal stromal tumor (GIST).In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is hypereosinophilic syndrome.

[0265] In some embodiments, an amorphous form of a compound of formula (I) containing no more than about 5% (w / w) of any crystalline form of a compound of formula (I) is used to prepare a medicament for treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma (e.g., cutaneous melanoma, non-cutaneous melanoma, KIT-driven melanoma or PGDFRA-driven melanoma or PGDFR-driven melanoma), acute myeloid leukemia In some embodiments, the disease is caused by the following kinase activity: c-KIT and / or PDGFRA, and / or their oncogenic forms. In some embodiments, the disease is intestinal stromal tumor (GIST). In some embodiments, the disease is KIT-driven gastrointestinal stromal tumor. In some embodiments, the disease is PDGFRA-driven gastrointestinal stromal tumor. In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is hypereosinophilic syndrome. In some embodiments, an amorphous compound of formula (I) containing no more than about 5% (w / w) of any crystalline form of the compound of formula (I) is used to prepare a drug for treating or preventing PDGFR kinase-mediated tumor growth. In some embodiments, the tumor growth or tumor progression is caused by overexpression of PDGFRα kinase, oncogenic PDGFRα missense mutations, oncogenic deletion PDGFRα mutations, oncogenic PDGFRα gene recombination leading to PDGFRα fusion protein, in-frame deletion within the PDGFRα gene, and / or oncogenic PDGFRα gene amplification. In some embodiments, an amorphous form of a compound of formula (I) containing no more than about 5% (w / w) of any crystalline form of a compound of formula (I) is used to prepare a medicament for treating a disease, wherein the disease is PDGFRA-driven gastrointestinal stromal tumor, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic syndrome-associated acute myeloid leukemia, or lymphoblastic T-cell lymphoma.In some embodiments, the disease is PDGFRA driven gastrointestinal stromal tumor (GIST). In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is hypereosinophilic syndrome.

[0266] In some embodiments, an amorphous compound of formula (I) containing no more than 5% (w / w) of any crystalline form of the compound of formula (I), or containing no detectable amount of any crystalline form, is used to prepare a medicament for treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma (e.g., cutaneous melanoma, non-cutaneous melanoma, KIT-driven melanoma or PGDFRA-driven melanoma or PGDFR-driven melanoma), Acute myeloid leukemia, germ cell tumors of seminoma or malignant germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, hypereosinophilic syndrome-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma, and non-small cell lung cancer. In some embodiments, the disease is caused by the following kinase activity: c-KIT and / or PDGFRA, and / or their oncogenic forms. In some embodiments, the disease is intestinal stromal tumor (GIST). In some embodiments, the disease is KIT-driven gastrointestinal stromal tumor. In some embodiments, the disease is PDGFRA-driven gastrointestinal stromal tumor. In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is eosinophilic syndrome. In some embodiments, an amorphous compound of formula (I) containing no more than 5% (w / w) of any crystalline form of the compound of formula (I), or no detectable amount of any crystalline form, is used to prepare a drug for treating or preventing PDGFR kinase-mediated tumor growth. In some embodiments, the tumor growth or tumor progression is caused by overexpression of PDGFRα kinase, oncogenic PDGFRα missense mutations, oncogenic deletion PDGFRα mutations, oncogenic PDGFRα gene recombination leading to PDGFRα fusion protein, in-frame deletion within the PDGFRα gene, and / or oncogenic PDGFRα gene amplification.In some embodiments, an amorphous compound of formula (I) containing no more than 5% (w / w) of any crystalline form of the compound of formula (I), or containing no detectable amount of any crystalline form, is used to prepare a medicament for treating a disease, wherein the disease is PDGFRA-driven gastrointestinal stromal tumor, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic syndrome-associated acute myeloid leukemia, or lymphoblastic T-cell lymphoma. In some embodiments, the disease is PDGFRA-driven gastrointestinal stromal tumor (GIST). In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is hypereosinophilic syndrome.

[0267] These pharmaceutical compositions and pharmaceutical compositions comprising the amorphous form of the compound of Formula (I) described herein may therefore be useful for treating certain disorders in patients in need thereof. In some embodiments, such disorders are caused by c-KIT or PDGFRA kinase activity and / or oncogenic forms thereof. In one embodiment, the disease is gastrointestinal stromal tumor (GIST), KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma (e.g., cutaneous melanoma, non-cutaneous melanoma, KIT-driven melanoma or PGDFRA-driven melanoma or PGDFR-driven melanoma), acute myeloid leukemia, germ cell tumor of seminoma or malignant germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic syndrome-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma, or non-small cell lung cancer. In some embodiments, the disease is intestinal stromal tumor (GIST). In some embodiments, the disease is KIT driven gastrointestinal stromal tumor. In some embodiments, the disease is PDGFRA driven gastrointestinal stromal tumor. In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is hypereosinophilic syndrome.

[0268] In some embodiments, such diseases are PDGFR kinase-mediated tumor growth. In some embodiments, the tumor growth or tumor progression is caused by PDGFRα kinase overexpression, oncogenic PDGFRα missense mutations, oncogenic deletion PDGFRα mutations, oncogenic PDGFRα gene recombination leading to PDGFRα fusion protein, PDGFRα gene in-frame deletion, and / or oncogenic PDGFRα gene amplification. In some embodiments, such diseases are PDGFRA-driven gastrointestinal stromal tumors, lung adenocarcinomas, squamous cell lung cancers, glioblastomas, gliomas, pediatric gliomas, astrocytomas, sarcomas, gastrointestinal stromal tumors, malignant peripheral nerve sheath sarcomas, intimal sarcomas, hypereosinophilic syndromes, idiopathic hypereosinophilic syndromes, chronic eosinophilic leukemias, eosinophilic syndrome-associated acute myeloid leukemias, or lymphoblastic T-cell lymphomas. In some embodiments, the disease is PDGFRA-driven gastrointestinal stromal tumors (GIST). In some embodiments, the disease is lung cancer. In some embodiments, the disease is glioblastoma. In some embodiments, the disease is glioma. In some embodiments, the disease is malignant peripheral nerve sheath sarcoma. In some embodiments, the disease is hypereosinophilic syndrome.

[0269] The pharmaceutical compositions described herein can be administered to patients (animals and humans) in need of such treatment in dosages that provide the most preferred pharmaceutical efficacy. It should be understood that the dosage required to be used in any particular application will vary from patient to patient, not only with the specific compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent drug therapy or special diet followed by the patient, and other factors that will be recognized by those skilled in the art, with the appropriate dosage ultimately being determined by the attending physician.

[0270] Treatment can be continued for a long period of time or a short period of time as needed. The composition can be administered, for example, one to four times a day or more. A suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or indefinitely. The treatment period can be terminated when the desired result is achieved.

[0271] Combination therapy

[0272] The present invention describes a combination therapy, which involves administering an amorphous form of a compound of formula (I) or a composition comprising an amorphous form of a compound of formula (I), and one or more therapeutic agents. The combination therapy described herein can be used by itself, or further combined with one or more additional therapeutic agents (e.g., one or more additional therapeutic agents described below). For example, the compound of formula (I) or a composition comprising an amorphous form of a compound of formula (I) can be administered in combination with a therapeutic agent for targeted cancer, a biological agent for targeted cancer, an immune checkpoint inhibitor, or a chemotherapeutic agent. These therapeutic agents can be administered in combination with another therapeutic agent described herein or administered sequentially in combination therapy.

[0273] Combination therapy can be achieved by administering two or more therapeutic agents that are each formulated and administered separately. Alternatively, combination therapy can be achieved by administering two or more therapeutic agents in a single formulation.

[0274] Combination therapy also encompasses other combinations. Although two or more medicaments in combination therapy can be administered simultaneously, it is not necessarily so. For example, the administration of the first medicament (or medicament combination) can be several minutes, hours, days or weeks ahead of the administration of the second medicament (or medicament combination). Therefore, the administration of two or more medicaments can be within a few minutes each other, or within 1, 2, 3, 6, 9, 12, 15, 18 or 24 hours each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days, or within 2, 3, 4, 5, 6, 7, 8, 9 weeks or weeks each other. In some cases, even longer time intervals are also possible. Although it is suitable in most cases that two or more medicaments used in combination therapy are present in the patient's body simultaneously, it is not necessarily so.

[0275] Combination therapy can also include two or more administrations of one or more agents used in the combination using different orders of the component agents. For example, if agent X and agent Y are used in combination, they can be administered one or more times in sequence in any combination, such as in the order of XYX, XXY, YXY, YYX, XXYY, etc.

[0276] In some embodiments, the additional therapeutic agents that can be administered according to the present invention include, but are not limited to, cytotoxic agents, cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarib ), tipifarnib, 4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-1-yl)methyl)-1H-imidazol-1-yl)methyl)benzonitrile hydrochloride, (R)-1-((1H-imidazol-5-yl)methyl)-3-benzyl-4-(thiophen-2-ylsulfonyl)-2,3,4,5-tetrahydro-1H-benzodiazepine-7-carbonitrile, cetuximab, imatinib, interferon α-2b, pegylated interferon α-2b, aromatase combination, gemcitabine, uracil mustard mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozotocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphatephosphate), leucovirin, oxaliplatin, pentostatine, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate acetate), methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, 17α-hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide acetate, flutamide, toremifene citrate,citrate, goserelinacetate, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, vinorelbine, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, bevacizumab, trastuzumab, tositumomab, bortezomib, ibritumomab tiuxetan, arsenic trioxide, porfimer sodium sodium), cetuximab, thiotepa, altretamine, fulvestrant, exemestane, rituximab, alemtuzumab, dexamethasone, bicalutamide, chlorambucil, and valrubicin.

[0277] In some embodiments, the additional therapeutic agents that may be administered include, but are not limited to, AKT inhibitors, alkylating agents, all-trans retinoic acid, anti-androgens, azacitidine, BCL2 inhibitors, BCL-XL inhibitors, BCR-ABL inhibitors, BTK inhibitors, BTK / LCK / LYN inhibitors, CDK1 / 2 / 4 / 6 / 7 / 9 inhibitors, CDK4 / 6 inhibitors, CDK9 inhibitors, CBP / p300 inhibitors, EGFR inhibitors, endothelin receptor antagonists, RAF inhibitors, MEK (filament-activated protein kinase kinase) inhibitors, ERK inhibitors, farnesyl Transferase inhibitors, FLT3 inhibitors, glucocorticoid receptor agonists, HDM2 inhibitors, histone deacetylase inhibitors, IKKβ inhibitors, immunomodulatory drugs (IMiDs), ingenol, ITK inhibitors, JAK1 / JAK2 / JAK3 / TYK2 inhibitors, MTOR inhibitors, PI3 kinase inhibitors, dual PI3 kinase / MTOR inhibitors, proteasome inhibitors, protein kinase C agonists, SUV39H1 inhibitors, TRAIL, VEGFR2 inhibitors, Wnt / β-catenin signaling inhibitors, decitabine, and anti-CD20 monoclonal antibodies.

[0278] In some embodiments, the additional therapeutic agent is an immunomodulator selected from the group consisting of: CTLA4 inhibitors, such as, but not limited to, ipilimumab and tremelimumab; PD1 inhibitors, such as, but not limited to, pembrolizumab and nivolumab; PDL1 inhibitors, such as, but not limited to, atezolizumab (formerly MPDL3280A), durvalumab (formerly MEDI4736), avelumab, PDR001; 4 1BB or 4 1BB ligand inhibitors, such as, but not limited to, urelumab and PF-05082566; OX40 ligand agonists, such as, but not limited to, MEDI6469; GITR agents, such as, but not limited to, TRX518; CD27 inhibitors, such as, but not limited to, varlilumab; TNFRSF25 or TL1A inhibitors; CD40 agonists, such as, but not limited to, CP-870893; HVEM, or LIGHT, or LTA, or BTLA, or CD160 inhibitors; LAG3 inhibitors, such as, but not limited to, BMS-986016; TIM3 inhibitors; Siglecs inhibitors; ICOS or ICOS ligand agonists; B7H3 inhibitors, such as, but not limited to, MGA271; B7 H4 inhibitors; VISTA inhibitors; HHLA2 or TMIGD2 inhibitors; butyrophilin inhibitors, including BTNL2 inhibitors; CD244 or CD48 inhibitors; inhibitors of TIGIT and PVR family members; KIR inhibitors, such as (but not limited to) lirilumab; inhibitors of ILT and LIR; NKG2D and NKG2A inhibitors, such as (but not limited to) IPH2201; inhibitors of MICA and MICB; CD244 inhibitors; CSF1R inhibitors, such as (but not limited to) (limited to) emactuzumab, cabiralizumab, pexidartinib, ARRY382, BLZ945; IDO inhibitors such as (but not limited to) INCB024360; thalidomide, lenalidomide, TGFβ inhibitors such as (but not limited to) galunisertib; adenosine or CD39 or CD73 inhibitors;CXCR4 or CXCL12 inhibitors, such as, but not limited to, ulocuplumab and (3S,6S,9S,12R,17R,20S,23S,26S,29S,34aS)-N-((S)-1-amino-5-guanidino-1-oxopentan-2-yl)-26,29-bis(4-aminobutyl)-17-((S)-2-((S)-2-((S)-2-(4-fluorobenzamide)-5-guanidinopentanoylamino)-5-guanidinopentanoylamino)-3-(naphthalen-2-yl)propionamido)-6-(3-guanidinopropyl)-3,20-bis(4-hydroxybenzyl)-1,4,7,1 0,18,21,24,27,30-nonoxo-9,23-bis(3-ureidopropyl)triacontahedral-1H,16H-pyrrolo[2,1-p][1,2]dithia[5,8,11,14,17,20,23,26,29]nonazacyclotriacontahedral-12-carboxamide BKT140; phosphatidylserine inhibitors such as, but not limited to, bavituximab; SIRPA or CD47 inhibitors such as, but not limited to, CC-90002; VEGF inhibitors such as, but not limited to, bevacizumab; and neuropilin inhibitors such as, but not limited to, MNRP1685A. ;

[0279] In some embodiments, the additional therapeutic agent is a chemotherapeutic agent selected from the group including, but not limited to, anti-tubulin agents (paclitaxel, paclitaxel protein-bound particles for injectable suspensions, such as nab-paclitaxel, eribulin, docetaxel, ixabepilone, vincristine), vinorelbine, DNA alkylating agents (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide), DNA intercalating agents (including doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, and epirubicin), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytidine, gemcitabine, and methotrexate.

[0280] In some embodiments, the additional therapeutic agent is selected from the group consisting of paclitaxel, paclitaxel protein-bound particles for injectable suspension, eribulin, docetaxel, ixabepilone, vincristine, vinorelbine, cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide, doxorubicin, pegylated liposomal doxorubicin, daunomycin, idarubicin, epirubicin, 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytidine, gemcitabine, methotrexate, erlotinib, gefitinib, lapatanib, everolimus, temsirolimus, LY2835219, LEE011, PD 0332991, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, axitinib, dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, trametinib, idelalisib, quizartinib, tamoxifen, fulvestrant, anastrozole, letrozole and exemestane, abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate acetate, prednisone, dexamethazone, irinotecan, camptothecin, topotecan, etoposide, etoposide phosphate, mitoxantrone, vorinostat, romidepsin, panobinostat, valproic acid, belinostat, DZNep5-aza-2'-deoxycytidine, bortezomib, carfilzomib, thalidomide, lenalidomide and pomalidomide, trastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab, labrolizumab, nivolumab, MPDL3280A, bevacizumab, aflibercept, brentuximab vedotin, ado-trastuzumab emtansine, radiation therapy, and sipuleucel T.

[0281] In some embodiments, the additional therapeutic agent is a kinase inhibitor selected from the group consisting of erlotinib, gefitinib, lapatinib, everolimus, temsirolimus, LY2835219, LEE011, PD 0332991, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, axitinib, dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, trametinib, idelalinib, and quizartinib.

[0282] In some embodiments, the additional therapeutic agent is an anti-PD1 therapeutic agent. Examples of anti-PD1 therapeutic agents that can be administered in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, include, but are not limited to: nivolumab, pidilizumab, cemiplimab, tislelizumab, AMP-224, AMP-514, and pembrolizumab.

[0283] In some embodiments, the additional therapeutic agent is an immunomodulator selected from the group consisting of, but not limited to, anti-PD-L1 therapeutic agents, including atezolizumab, durvalumab, BMS-936559, and avelumab; anti-TIM3 therapeutic agents, including TSR-022 and MBG453; anti-LAG3 therapeutic agents, including relatlimab, LAG525, and TSR-033; CD40 agonist therapeutic agents, including SGN-40, CP-870,893, and RO7009789; anti-CD47 therapeutic agents, including Hu5F9-G4; anti-CD20 therapeutic agents, anti-CD38 therapeutic agents, and other immunomodulatory therapeutic agents, including thalidomide, lenalidomide, pomalidomide, prednisone, and dexamethasone. In some embodiments, the additional therapeutic agent is avelumab.

[0284] In some embodiments, the additional therapeutic agent is a chemotherapeutic agent selected from the group consisting of an anti-tubulin agent (e.g., paclitaxel, paclitaxel protein-bound particles for injectable suspension, eribulin, albumin-bound paclitaxel injectable suspension (abraxane), docetaxel, ixabepilone, taxiterem, vincristine, or vinorelbine); an LHRH antagonist, including but not limited to leuprolide, goserelin, triptorelin, or histrelin; an anti-androgen agent, including but not limited to abiraterone.

[00136] The invention relates to anti-estrogens including, but not limited to, tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane; DNA alkylating agents including, but not limited to, cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, and temozolomide; DNA intercalating agents including doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, and epirubicin, 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytidine, gemcitabine, methotrexate, bortezomib, and carfilzomib.

[0285] In some embodiments, the additional therapeutic agent is a targeted therapeutic agent selected from the group consisting of kinase inhibitors erlotinib, gefitinib, lapatinib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, axitinib, dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, adranib, quizartinib, avapritinib, BLU-667, BLU-263, Loxo 292, larotrectinib and quizartinib; antiestrogens including but not limited to tamoxifen, fulvestrant, anastrozole, letrozole and exemestane; antiandrogens including but not limited to abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate; steroids including but not limited to prednisone and dexamethasone; PARP inhibitors including but not limited to neraparib, olaparib and rucaparib; topoisomerase I inhibitors including but not limited to irinotecan, camptothecin and topotecan; topoisomerase II inhibitors including but not limited to etoposide, etoposide phosphate and mitoxantrone; histone deacetylase (HDAC) inhibitors including (but not limited to) vorinostat, romidepsin, panobinostat, valproic acid and belinostat; DNA methylation inhibitors, including (but not limited to) DZNep and 5-aza-2'-deoxycytidine; proteasome inhibitors, including (but not limited to) bortezomib and carfilzomib, thalidomide, lenalidomide, pomalidomide; biologics, including (but not limited to) trastuzumab, ado-trastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab, tremelimumab; vaccines, including (but not limited to) sipuleucel-T; and radiation therapy.

[0286] In some embodiments, the additional therapeutic agent is selected from the group consisting of a TIE2 immunokinase inhibitor, including rebastinib or ARRY-614.

[0287] In some embodiments, the additional therapeutic agent is selected from the group consisting of a TIE2 immunokinase inhibitor, including reglatinib or ARRY-614, and an anti-PD1 therapeutic agent.

[0288] In some embodiments, the additional therapeutic agent is selected from the group consisting of anti-angiogenic agents, including AMG386, bevacizumab, and aflibercept; and antibody-drug conjugates (ADCs), including brentuximab, trastuzumab emtacin; and ADCs containing a payload, such as a derivative of camptothecin, pyrrolebenzodiazepine dimer (PBD), indolebenzodiazepine dimer (IGN), DM1, DM4, MMAE, or MMAF.

[0289] In some embodiments, the additional therapeutic agent is a luteinizing hormone releasing hormone (LHRH) analog selected from the group consisting of goserelin and leuprolide.

[0290] In some embodiments, the additional therapeutic agent is selected from the group consisting of everolimus, trabectedin, albumin-bound paclitaxel injection suspension, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, pemetrexed, erlotinib, dasatanib, imatinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2 171, batabulin, ofatumtunab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib;PD0325901, AZD-6244, capecitabine, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethyl]benzoyl]-L-glutamic acid disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl]-quinolinone, vatalanib, AG-013736, AVE-0005, [D-Ser(Bu t)6, Azgly 10] acetate (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH 2 acetate [C; 59 H 84 N 18 Oi4-(C2H4O2) x, wherein x=1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutanide, nilutamide, megestrol acetate, acetate), CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guérin (BacillusCalmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, actinomycin, daunomycin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, sole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozotocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard), uracilmustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosinearabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat at), COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody) and erbitux, cremophor-free paclitaxel, epithelone B (epithelium B), BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK222584, VX-745, PD184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab ximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunomycindaunorubicin), Edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, ipilumumab, vemurafenib, and mixtures thereof.

[0291] In some embodiments, the additional therapeutic agent is an HSP90 inhibitor (e.g., AT13387). In some embodiments, the additional therapeutic agent is cyclophosphamide. In some embodiments, the additional therapeutic agent is an AKT inhibitor (e.g., perifosine). In some embodiments, the additional therapeutic agent is a BCR-ABL inhibitor (e.g., nilotinib). In some embodiments, the additional therapeutic agent is an mTOR inhibitor (e.g., RAD001). In some embodiments, the additional therapeutic agent is a FGFR inhibitor (e.g., erdafitinib, KO947, or BGJ398). In some embodiments, the additional therapeutic agent is an anti-PDL1 therapeutic agent. In some embodiments, the additional therapeutic agent is a Bcl2 inhibitor (e.g., venetoclax). In some embodiments, the additional therapeutic agent is an autophagy inhibitor (e.g., hydroxychloroquine). In some embodiments, the additional therapeutic agent is a MET inhibitor. Example

[0292] The scope of protection of the present invention is not limited to the specific embodiments disclosed in the examples intended to illustrate several aspects of the present invention, and any embodiments that are functionally equivalent fall within the scope of protection of the present invention. In fact, various modifications of the present invention other than those shown and described herein will be apparent to those skilled in the art and are intended to fall within the scope of protection of the appended claims.

[0293] In the examples provided below, the following abbreviations are used: "HPMCAS-HG" refers to hydroxymethylpropylcellulose acetate succinate (high pH solubility grade; granular); "SDD" refers to spray dried dispersion; and "PVP-XL" refers to cross-linked polyvinyl pyrrolidone. In the examples provided below, "Compound 1" refers to the compound of formula (I) described herein. "Impurity A" and "Compound 2" each refer to the compound of formula (II) described herein. "Compound 3" refers to the compound of formula (III) described herein.

[0294] As used in Example 1 below, "w / w suspension fraction" refers to the fraction of the component in the suspension in weight percent form used to prepare the spray-dried dispersion based on the amount of Compound 1 in the suspension.

[0295] Example 1. Preparation of a spray-dried dispersion comprising Compound 1 and HPMCAS-HG.

[0296] Prepare a suspension. Add HPMCAS-HG to a solution of purified water and acetone and stir to ensure the polymer is dissolved. Add crystalline Compound 1 to the solution and mix the suspension at 15-25°C. Continue mixing during the rest of the spray drying process.

[0297] Preparation and use of start-up / shutdown solvents. Mix pure water with acetone. Spray the start-up and shutdown solvents at the beginning and end of the spray drying cycle.

[0298] Spray drying. The suspension is passed through an inline heat exchanger (flow rate 38-51 kg / hr) to heat the suspension to a temperature range of 112-124°C to dissolve the suspended particles before spray drying. The solution is then spray dried in a pharmaceutical spray dryer (PSD-2 or equivalent) equipped with a capillary nozzle, a nitrogen hood pressure of 65-85 psig, and a total drying gas of 400-500 kg / hr, a chamber outlet temperature of 50-70°C, and a condenser temperature of -10°C.

[0299] Secondary Drying The partially moist spray-dried intermediate produced in the above preparation was dried using a stirred vacuum dryer at a temperature range of 40-50° C. and a chamber pressure of 40-50 mbar to provide a SDD comprising Compound 1 and HPMCAS-HG.

[0300] Example 2. Preparation of a spray-dried dispersion comprising Compound 1 and HPMCAS-HG.

[0301] Prepare a solution. Add crystalline Compound 1 to a solution of pure water and THF and stir to ensure the polymer is dissolved. Add HPMCAS-HG to the solution and mix at ambient temperature until the polymer is dissolved.

[0302] Preparation and use of start-up / shutdown solvents. Mix pure water with THF. Spray the start-up and shutdown solvents at the beginning and end of the spray drying cycle.

[0303] Spray Drying The solution was then spray dried in a pharmaceutical spray dryer at a spray rate of 175-205 g / min, using an overall drying gas flow rate of 1550-2150 g / min and a chamber outlet temperature of 40-50°C.

[0304] Secondary Drying The partially moist spray-dried intermediate produced in the above preparation was dried using a tray dryer at a temperature range of 15-45°C to provide a SDD comprising Compound 1 and HPMCAS-HG.

[0305] Example 3. Purity of a solid dispersion containing an amorphous form of the compound of formula (I) as determined by HPLC.

[0306] Table 1 shows the purity of each solid dispersion containing the amorphous form of the compound of formula (I) as measured by HPLC. Each batch (Batch 1, Batch 2, Batch 3, Batch 4) was prepared according to the method outlined in Example 1.

[0307] Table 1. Solid dispersions comprising the compound of formula (I) in amorphous form.

[0308]

[0309]

[0310] Note: LOD: Level of Detection

[0311] Example 4. Stability study of amorphous form of the compound of formula (I) in solid dispersion.

[0312] Herein, studies of amorphous forms of the compound of formula (I) in solid dispersions are described. Tables 2(a)-(c) describe the studies for these samples (Batch 5, Batch 6 and Batch 7) prepared as described in Example 1 at the indicated time points, including the conditions used (temperature and relative humidity), glass transition temperature (T g ), evaluating crystallinity by XPRD, and determining the amount of impurity A in the sample. These studies show that solid dispersions containing amorphous compounds of formula (I) have surprisingly high stability and do not show polymorphic conversion to crystalline form under stringent conditions of high relative humidity and high temperature.

[0313] Table 2(a): Investigation of the 5th batch of samples prepared according to the method of Example 1.

[0314]

[0315]

[0316] Table 2(b): Study of the 6th batch of samples prepared according to the method of Example 1.

[0317]

[0318]

[0319] Table 2(c): Study of the 7th batch of samples prepared according to the method of Example 1.

[0320]

[0321] In one aspect, the amorphous form of the compound of formula (I) is substantially as Figure 1 The amorphous form of the compound of formula (I) is described herein. The amorphous form can be identified by an amorphous "halo" PXRD pattern, substantially as Figure 1 The amorphous compound of formula (I) can be prepared by dissolving the compound of formula (I), spray drying the compound solution, and drying the spray dried compound.

[0322] Example 5. Solubility studies of solid dispersions comprising the amorphous form of the compound of formula (I).

[0323] Here, the solid dispersion of amorphous compound 1 (25%) / HPMCAS-HG prepared in Example 1 was evaluated for a study at a selected pH value. Specifically, Table 3 shows the kinetic solubility study of the solid dispersion of crystalline compound 1 and amorphous compound 1 (25%) / HPMCAS-HG at a selected pH value. Table 3 shows that the solid dispersion has significantly enhanced solubility compared to the crystalline compound 1.

[0324] Table 3. Kinetic solubility of crystalline Compound 1 and solid dispersions containing the amorphous form at selected pH.

[0325]

[0326] Kinetic aqueous solubility of compound 1 in crystalline or amorphous SDI solid form as a function of pH at 25°C

[0327] Example 6. Pharmacokinetic Study of Spray-Dried Dispersion of Compound 1.

[0328] A pharmacokinetic comparison study of a solid dispersion of crystalline compound 1 and amorphous compound 1 (25%) prepared as in Example 1 was conducted in rats. The dose in both studies was 10 mg / kg (based on compound 1). An oral suspension of crystalline compound 1 in a 20% Captisol / 0.4% HPMC vehicle at pH 2 was administered to rats. An oral suspension of amorphous compound 1 in a 0.5% Methocel vehicle was administered to rats. The results of the study are shown in Table 4, which show that the solid dispersion has unexpectedly enhanced pharmacokinetic properties.

[0329] Table 4. Pharmacokinetic data.

[0330]

[0331] Pharmacokinetic parameters of Compound 1 after oral administration of crystalline Compound 1 free base to rats; Pharmacokinetic parameters of Compound 1 after oral administration of amorphous 25% spray dried dispersion (SDD) to rats.

[0332] Example 7. Preparation of tablets.

[0333] The spray-dried dispersion of compound 1 and HPMCAS-HG as in Example 1 is first mixed with all the intragranular components (except lubricating magnesium stearate) in a suitable diffusion mixer (storage silo mixer or equivalent). The initial pre-blend is crushed and re-blended (pre-lubricating blending) through a sifter (such as a comil granulator or equivalent), and then magnesium stearate is added and blended (post-lubricating blending). The final blend is pressed into tablets using a suitable power-assisted rotary tablet press. Tables 5 and 6 below provide compositions of exemplary tablets containing 25 mg of compound 1 or 50 mg of compound 1, respectively. In Table 5, the spray-dried intermediates of tablets 1, 2, and 3 are prepared by the method of Example 2, respectively. In Table 6, the spray-dried intermediate of tablet 4 is prepared by the method of Example 2, and the spray-dried intermediate of tablet 5 is prepared by the method of Example 1.

[0334] Table 5. Exemplary tablets containing 25 mg of Compound 1.

[0335]

[0336]

[0337] Table 6. Exemplary tablets containing 50 mg of Compound 1.

[0338]

[0339]

[0340] NF = National Formulary; USP = United States Pharmacopeia; N / A = not applicable for the specified preparation.

[0341] Example 8. Dissolution test of tablets

[0342] Tablets manufactured using the method and formulation described in Example 7 were subjected to dissolution testing using the dissolution equipment instrument parameters described in Table 7 and the HPLC instrument parameters for analyzing the dissolution samples in Table 8.

[0343] Table 8. Solubility.

[0344]

[0345] Table 9. HPLC analysis of dissolved samples.

[0346]

[0347]

[0348] Exemplary 50 mg Compound 1 tablets (DOE 1, DOE 2, DOE 3, and DOE 4) were studied for test attributes including the percent dissolved released over time using the dissolution method described above. Figure 2 The dissolution profiles for each tablet studied are summarized in Table 10.

[0349] Table 10. Tablet attributes

[0350]

[0351] In addition, Table 11 shows the solubility and other attributes of three exemplary batches of 50 mg Compound 1 tablets made as described in Example 7 (Table 5). These spray-dried intermediates were made according to the method in Example 1. The dissolved % released was measured using the solubility test method described above.

[0352] Table 11. Exemplary batches

[0353]

[0354] Example 9. Preparation of reference standards of compounds of formula (III).

[0355] 3-(5-Amino-2-bromo-4-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (40 g), phenyl isocyanate (30 g, 2.7 eq.), pyridine (3 eq.) and methanesulfonic acid (1 eq.) were combined in a solvent containing 1-methyl-2-pyrrolidone (10 volumes) and tetrahydrofuran (5 volumes). The mixture was stirred at 50° C. for 7 days, and additional 0.1-0.2 eq. of phenyl isocyanate (0.1-0.2 eq.) was occasionally added to give a crude 1-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1-methyl-3-phenylurea wet cake. The crude wet cake was crystallized from 1-methyl-2-pyrrolidone (4 volumes) and methanol (8 volumes) to obtain 57 g of 1-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1-methyl-3-phenylurea. MS m / z: 629 (M+1). 1 H NMR (400MHz, DMSO-d6): δ11.44(s,1H),9.12(s,1H),8.84(s,1H),8.74(s,1H),8.29and 8.27(d,1H),8.02(s,1H),7.72and 7.70(d,1H),7.59and 7.57(d,2H),7.45and 7.43(d,2H),7.34-7.26(m,4H),7.24(s,1H),7.06-6.97(m,2H),4.35-4.28(m,2H),3.53(s,3H),1.27-1.23(t,3H).

[0356] Equivalent

[0357] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed within the scope of protection of the appended claims.

Claims

1. A pharmaceutically acceptable composition for oral administration, comprising: (i) a solid dispersion, wherein the solid dispersion comprises: Amorphous compound represented by formula (I): a pharmaceutically acceptable polymer; and (ii) one or more pharmaceutically acceptable excipients.

2. The pharmaceutically acceptable composition of claim 1, wherein the solid dispersion has no more than about 5% (w / w) of any crystalline form of the compound.

3. The pharmaceutically acceptable composition of claim 1 or 2, wherein the solid dispersion is substantially free of detectable amounts of any crystalline form of the compound.

4. The pharmaceutically acceptable composition of any one of claims 1 to 3, wherein the amorphous form has an X-ray powder diffraction pattern substantially as shown in Figure 1.

5. The pharmaceutically acceptable composition of any one of claims 1-4, wherein the composition contains no more than about 5% (w / w) of aggregated any crystalline form of the compound when exposed to 60% relative humidity at 25°C for 1 month, 3 months or 6 months.

6. The pharmaceutically acceptable composition of any one of claims 1-4, wherein the composition contains no more than about 5% (w / w) of aggregated any crystalline form of the compound when exposed to 75% relative humidity at 40°C for 1 month, 3 months or 6 months.

7. The pharmaceutically acceptable composition of any one of claims 1-6, comprising from about 10% (w / w) to about 30% (w / w) of the compound, based on the total weight of the solid dispersion.

8. The pharmaceutically acceptable composition of any one of claims 1-7, comprising from about 20% (w / w) to about 30% (w / w) of the compound, based on the total weight of the solid dispersion.

9. The pharmaceutically acceptable composition of any one of claims 1-8, comprising about 25% (w / w) of the compound based on the total weight of the solid dispersion.

10. The pharmaceutically acceptable composition of any one of claims 1 to 9, wherein the pharmaceutically acceptable polymer is selected from the group consisting of polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, poly(vinyl pyrrolidone-co-vinyl acetate), polyoxyethylene-polyoxypropylene block copolymers, graft copolymers consisting of polyethylene glycol, polyethylene caprolactam and polyvinyl acetate, polymethacrylates, polyoxyethylene alkyl ethers, polyoxyethylene castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic acid-glycolic acid), lipids. Cellulose, pullulan, dextran, maltodextrin, hyaluronic acid, polysialic acid, chondroitin sulfate, heparin, fucoidan, pentosan polysulfate, spirulina polysaccharide, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose propionate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate isophthalate, carboxymethyl ethyl cellulose, hydroxypropyl Methylcellulose, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl methylcellulose propionate phthalate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl methylcellulose propionate trimellitate, cellulose acetate succinate, methylcellulose acetate succinate, dextran, dextran acetate, dextran propionate, dextran succinate, dextran acetate propionate, dextran acetate succinate, dextran propionate succinate, dextran acetate propionate succinate, poly(methacrylic acid-co-methyl methacrylate) 1:1, poly(methacrylic acid) The invention relates to poly(butyl methacrylate-co-methyl methacrylate) 1:2, poly(methacrylic acid-co-ethyl acrylate) 1:1, hydroxyethyl cellulose, methyl cellulose and hydroxypropyl cellulose, polymethacrylic acid-ethyl acrylate, polymethacrylic acid-methyl methacrylate, polymethyl methacrylate-ethyl acrylate, polytrimethylammonioethyl methacrylate-methyl methacrylate-ethyl acrylate and poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), and mixtures thereof.

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