Pharmaceutical compositions of a kinase inhibitor

Abstract

This invention relates to pharmaceutical compositions of c-Met inhibitor compound 1. It also relates to methods of using these pharmaceutical compositions to treat diseases, conditions, or syndromes at least in part mediated by the regulation of the in vivo activity of protein kinases, and methods of preparing such pharmaceutical compositions.

Description

Technical Field

[0001] This invention relates to pharmaceutical compositions of the free base or pharmaceutically acceptable salt of compound 1. This invention also relates to pharmaceutical formulations in the form of a crystalline salt of compound 1. This invention further relates to a method of treating diseases, symptoms, or syndromes mediated at least in part by regulating the in vivo activity of protein kinases using compound 1 as a pharmaceutical composition. Prior Technology

[0002] Human Axl belongs to the receptor tyrosine kinase family, which includes the Tyro3, ​​Axl, and Mer (TAM) subfamily. TAM kinases are characterized by an extracellular ligand-binding domain consisting of two immunoglobulin-like domains and two type III fibronectin domains. Axl is overexpressed in various tumor cell types and was initially selected from patients with chronic myeloid leukemia. In overexpression, Axl exhibits transformative potential. It is believed that Axl signaling induces tumor growth by activating proliferative and anti-apoptotic signaling pathways. Axl is associated with cancers such as lung cancer, myeloid leukemia, uterine cancer, ovarian cancer, glioma, melanoma, thyroid cancer, renal cell carcinoma, osteosarcoma, gastric cancer, prostate cancer, and breast cancer. Overexpression of Axl leads to poor prognosis in patients with the indicated cancers.

[0003] Activation of Mer (such as Axl) generates downstream signaling pathways that drive tumor growth and activation. Mer binds to ligands such as the soluble protein Gas-6. Gas-6 binding to Mer induces autophosphorylation of Mer in its intracellular domain, leading to downstream signal activation. Overexpression of Mer in cancer cells, resulting in increased metastasis, is most likely due to the generation of soluble Mer extracellular domain proteins as decoy receptors. Tumor cells secrete soluble forms of extracellular Mer receptors, which reduce the ability of soluble Gas-6 ligands to activate Mer on endothelial cells, thereby contributing to cancer progression.

[0004] Therefore, compounds that inhibit TAM receptor tyrosine kinases (such as Axl and Mer) are needed for the treatment of selected cancers. Summary of the Invention

[0005] This invention provides a pharmaceutical composition of compound 1, N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylaminomethoxy)quinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dimethamide or a pharmaceutically acceptable salt thereof, the compound having the following structure: . Compound 1 Compound 1 is a crystalline solid. Surprisingly, the formulations disclosed herein were found to have improved manufacturability and properties compared to other forms.

[0006] Compound 1 is disclosed in WO 2019 / 148044, the contents of which are incorporated herein by reference in their entirety. Various crystalline solid forms and crystalline salts of compound 1 are disclosed in WO 2020 / 123800, the entire contents of which are incorporated herein by reference in their entirety.

[0007] In one embodiment, the pharmaceutical composition is a pharmaceutical composition suitable for oral administration. The pharmaceutical composition comprises: a. Compound 1 or a pharmaceutically acceptable salt thereof; b. One or more diluents; c. One or more adhesives; d. One or more disintegrants; e. One or more gliding agents; f. One or more lubricants; and as appropriate g. Membrane coating.

[0008] Compound 1 may be present in the pharmaceutical composition in the form of a free base crystalline solid or in the form of a pharmaceutically acceptable crystalline salt. For the avoidance of doubt, unless otherwise indicated, "Compound 1" includes both the crystalline free base form and the crystalline salt form.

[0009] In one embodiment of the isomorphic sample, compound 1 is a crystalline solid form characterized as form A, form B, form C, form D, form E, form F, form G, form H, form K, form O, or form Q.

[0010] In another embodiment of the isomorphic sample, compound 1 is a crystalline hydrochloride salt of compound 1.

[0011] In another embodiment of the isomorphic sample, compound 1 is a crystalline fumarate of compound 1 or its hydrate or solvate.

[0012] In another embodiment, compound 1 is a crystalline phosphate of compound 1 or its hydrate or solvate.

[0013] In another embodiment, the invention relates to a method of treating a disease, symptom, or syndrome mediated at least in part by regulating the in vivo activity of a protein kinase, comprising administering a pharmaceutical composition of compound 1 or a pharmaceutically acceptable salt thereof to an individual in need.

[0014] In another embodiment, the present invention relates to a method for treating cancer, comprising administering a pharmaceutical composition of compound 1 or a pharmaceutically acceptable salt thereof to an individual in need.

[0015] In another embodiment, the present invention relates to a method for inhibiting a protein kinase, the method comprising contacting the protein kinase with a pharmaceutical composition of compound 1, which is in crystalline or crystalline salt form as described herein.

[0016] In another embodiment, the present invention relates to a process for preparing a pharmaceutical composition of compound 1. Implementation

[0017] [] Cross-reference to related applications

[0018] This application claims priority to U.S. Provisional Application No. 63 / 110,124, the entire contents of which are incorporated herein by reference. [Definitions, Abbreviations, and Acronyms] [Analysis Techniques] [] [Abbreviations] [ / ] [Abbreviations] [Full Name] [ / ] [describe] DSC Differential scanning calorimetry DVS Dynamic (water) vapor adsorption HSM High-temperature stage microscopy NMR Nuclear magnetic resonance spectroscopy OM Optical microscopy PLM Polarizing microscopy TGA Thermogravimetric analysis or thermogravimetric analysis XRPD X-ray powder diffraction [Experimental Techniques] [] [Abbreviations] [ / ] [Abbreviations] [Full Name] [ / ] [describe] CC Rapid cooling CP Rapid sedimentation FC Rapid cooling FE rapid evaporation RC Reaction crystallization SC Slow cooling SE Slow evaporation VD vapor diffusion VS vapor pressure [other] [] [Abbreviations] [ / ] [Abbreviations] [Full Name] [ / ] [describe] ~ about or approximately API Active pharmaceutical ingredients B / E Birefringence and extinction Endo / endo Endotherm (or endothermic) eq equivalent Exo / exo Exothermic (exotherm or exothermic) FB Free base FF Free form frz freezer LIMS Laboratory Information Management System Max / max Maximum value (maximum or maxima) Obs Observation results PO better orientation ppt Precipitation (or precipitation) ref refrigerator RH relative humidity RT room temperature Soln / soln solution vac vacuum wt% weight percentage [solvent] [] [Abbreviations] [ / ] [Abbreviations] [Full Name] [ / ] [describe] ACN Acetonitrile AcOH Acetic acid DCM dichloromethane DMSO Dimethicone EtOAc Ethyl acetate EtOH ethanol HFIPA Hexafluoroisopropanol IPA Isopropanol, 2-propanol MEK Methyl ethyl ketone MeOH methanol MTBE Methyl-tertiary butyl ether TFE 2,2,2-Trifluoroethanol THF Tetrahydrofuran

[0019] As used herein, unless otherwise indicated, the following definitions shall apply.

[0020] For the purposes of this invention, chemical elements are identified according to the periodic table (CAS edition, Handbook of Chemistry and Physics, 95th edition). Furthermore, the general principles of organic chemistry are explained in "Organic Chemistry," 2nd edition, Thomas Sorrell, University Science Books, Sausalito: 2006, and "March's Advanced Organic Chemistry," 7th edition, edited by Smith, MB, and March, J., John Wiley & Sons, New York: 2013, the entire contents of which are incorporated herein by reference.

[0021] As used herein, when referring to a value or range, the term "about" allows for a certain degree of variation within that value or range, for example, within 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of the specified value or range limit. The specified value may be a dosage, amount, or weight percentage of the composition or dosage form.

[0022] As used herein, the terms "low / limited / significant hygroscopicity" refer to materials exhibiting < 0.5 / < 2.0 / ≥ 2.0 wt% water uptake within a specified RH range.

[0023] As used herein, the term "stoichiometric hydrate" refers to a crystalline material with a defined water content over an extended RH range. Typical stoichiometric hydrates include hemihydrates, monohydrates, sesquihydrates, and dihydrates.

[0024] As used herein, the term "variable hydrate" refers to a crystalline material with variable water content over an extended RH range without a phase transition.

[0025] As used in this article, the chemical term "form" refers to a compound or its salt that consists of a single phase.

[0026] As used herein, the terms "low / limited / moderate / good / high solubility" refer to materials with a solubility of < 1 / 1 - 20 / 20 - 100 / 100 - 200 / > 200 mg / mL.

[0027] As used herein, the term "disordered crystallization" refers to materials that produce XRPD patterns with broad peaks (relative to instrument peak width) and / or strong diffuse scattering (relative to peak). Disordered materials may include: 1) Microcrystals, 2) Crystallization with high defect density, 3) A mixture of crystalline and X-ray amorphous phases, or 4) The above combinations.

[0028] As used herein, the term "insufficient signal" refers to a lack of signal above the expected background noise in the spectrum or pattern (output) produced by the spectral analysis of a sample.

[0029] As used herein, the term "single-crystal phase" refers to an XRPD pattern that provides evidence of a single crystalline form (as Bragg peaks are indexed by a single unit cell). Indexing is the process of assigning Miller index labels to each peak in the diffraction pattern. Furthermore, the size and shape of the crystal unit cell are determined during the indexing process.

[0030] As used herein, the term "slurry" refers to a suspension prepared by adding sufficient solids to a given solvent under ambient conditions to result in the presence of undissolved solids. A typical slurry involves prolonged agitation (usually by stirring or shaking) in a sealed vial at a given temperature; this process is also known as "pulping." Typically, after a given period, the solids are recovered using the methods described herein.

[0031] As used herein, the terms "X-ray amorphous" or "amorphous" refer to materials that exhibit diffuse scattering but for which there is no evidence of Bragg peaks in the XRPD pattern.

[0032] As used herein, the term "crystallization" refers to a solid compound that has a periodic and repetitive three-dimensional internal arrangement of atoms, ions, or molecules characteristic of crystals, for example, an arrangement of a fixed geometric pattern or lattice with rigid long-range order. The term crystallization does not necessarily mean that the compound exists in crystalline form, but rather that it has this crystalline internal structural arrangement. Crystallized compounds produce XRPD patterns with sharp peaks (similar to instrument peak widths) and weak diffuse scattering (relative to peaks).

[0033] As used herein, the term "substantially crystalline" refers to a solid material that is primarily arranged in a fixed geometric pattern or lattice with rigid long-range order. For example, substantially crystalline materials have a crystallinity exceeding about 85% (e.g., exceeding about 90%, about 95%, or about 99%, or about 100%). It should also be noted that the term "substantially crystalline" includes the descriptive term "crystallization," which is defined in the preceding paragraph.

[0034] For the purposes of this invention, "patient" includes humans and any other animals, specifically mammals, and other organisms. Therefore, these methods are applicable to both human therapeutics and veterinary applications. In a preferred embodiment, the patient is a mammal, and in the most preferred embodiment, the patient is a human. Examples of preferred mammals include mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, and primates.

[0035] "Kinetase-dependent diseases or disorders" refer to pathological conditions that depend on the activity of one or more kinases. Kinases are directly or indirectly involved in signal transduction pathways of various cellular activities, including proliferation, adhesion, migration, differentiation, and invasion. Diseases associated with kinase activity include tumor growth, pathological angiogenesis and inflammation (psoriasis, rheumatoid arthritis, etc.) that support solid tumor growth and involve excessive local angiogenesis (such as eye diseases (diabetic retinopathy, age-related macular degeneration, etc.)).

[0036] "Therapeutic effective amount" refers to the amount of the crystalline or crystalline salt form of the present invention that improves disease symptoms when administered to a patient. The amount of the crystalline or crystalline salt form of the present invention constituting the "therapeutic effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. Therapeutic effective amount can be determined by those skilled in the art based on their own knowledge and conventional methods of this disclosure.

[0037] The phrase "medically acceptable" is used in this article to refer to compounds, materials, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, and whose benefits are commensurate with the risk.

[0038] As used herein, the phrase "medically acceptable excipient" means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and include excipients acceptable for both veterinary and human medical use. In one embodiment, each component is "medically acceptable" as defined herein. For example, see Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of 'Pharmaceutical Excipients', 6th edition, edited by Rowe et al., The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd edition, edited by Ash and Ash, Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd edition, edited by Gibson, CRC Press LLC: Boca Raton, Fla., 2009.

[0039] As used herein, the term "strength" refers to the weight of Compound 1 as a free base equivalent in a unit dosage form of a pharmaceutical composition. For example, a tablet containing 22.20 mg of Compound 1 hemifumarate is a 20 mg dose strength tablet because 22.20 mg of Compound 1 hemifumarate is equivalent to 20 mg of Compound 1 free base. Similarly, a tablet containing 44.40 mg of Compound 1 hemifumarate is a 40 mg dose strength tablet.

[0040] As used in this article, the term "parallel" means simultaneous. For example, if two treatment regimens for a single patient are administered in parallel, they are administered simultaneously. It should be understood that the simultaneous occurrence of two treatment regimens does not necessarily mean that the actual delivery of the two drugs occurs simultaneously, as each regimen may require different dosing schedules and / or different delivery methods.

[0041] "Cancer" refers to any physiological disorder in mammals characterized by dysregulation of cell growth; specifically, it includes (but is not limited to) proliferative disorders. [Heart]: Sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; [Head and Neck:] Squamous cell carcinoma of the head and neck, laryngeal and hypopharyngeal carcinoma, nasal cavity and paranasal sinus carcinoma, nasopharyngeal carcinoma, salivary gland carcinoma, oral cavity and oropharyngeal carcinoma; [Lung]: Bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, non-small cell lung cancer), alveolar (bronchiolar) carcinoma, alveolar sarcoma, alveolar soft tissue sarcoma, bronchial adenoma, sarcoma, lymphoma, chondromaeoma, mesothelioma; [Colon:] Colorectal cancer, adenocarcinoma, gastrointestinal stromal tumor, lymphoma, carcinoid tumor, Turcot syndrome; [Gastrointestinal tract]: Gastric cancer, adenocarcinoma of the gastroesophageal junction, esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); [Breast:] Metastatic breast cancer, ductal carcinoma in situ, invasive ductal carcinoma, tubular carcinoma, medullary carcinoma, mucinous carcinoma, lobular carcinoma in situ, triple-negative breast cancer; [Urogenital Tract]: Kidneys (adenocarcinoma, Wilms' tumor, nephroblastoma, lymphoma, leukemia, renal cell carcinoma, metastatic renal cell carcinoma), Bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, urothelial carcinoma), Prostate (adenocarcinoma, sarcoma, castration-resistant prostate cancer, bone metastases, bone metastases associated with castration-resistant prostate cancer), Testes (seminomatous cyst, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma), Clear cell carcinoma, papillary carcinoma, penile cancer, penile squamous cell carcinoma; [Liver]: Hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; [Bone]: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondrial exostosis), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor; [Thyroid:] Medullary thyroid carcinoma, differentiated thyroid carcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma, Hurtle cell carcinoma, and undifferentiated thyroid carcinoma; [Nervous System]: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma), NF1, neurofibromatosis, plexiform neurofibroma; [Gynecology]: Uterus (endometrial cancer), Cervix (cervical cancer, pretumoral cervical dysplasia), Ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-theca cell tumor, Sertoli-Leydig cell tumor, malignant germ cell tumor, malignant teratoma), Vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)), Fallopian tube (cancer); [Hematology]: Blood disorders (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodyplasia syndrome), myelofibrosis, polycythemia vera, essential thrombocythemia, Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; [Skin]: Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, developmental nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and [Adrenal gland]: Neuroblastoma. Therefore, as used herein, the term "cancer cell" includes cells affected by any of the diseases identified above. In some embodiments, compounds or combinations disclosed herein may be used to treat diseases including HIV, sickle cell disease, graft-versus-host disease, acute graft-versus-host disease, chronic graft-versus-host disease, and sickle cell anemia. In some embodiments, the cancer is clear cell renal cell carcinoma, non-clear cell carcinoma, non-clear cell renal cell carcinoma, salivary gland carcinoma, penile squamous cell carcinoma, neuroendocrine tumor, adrenocortical carcinoma, or Merkel cell carcinoma.

[0042] The term "treating" refers to any successful or improved indication of the progression, severity, and / or duration of a disease, condition, or ailment, including any objective or subjective parameters such as relief; remission; reduction of symptoms or increased tolerance to the injury, condition, or ailment; slowing of the rate of degeneration or decline; lessening of degenerative endpoints; or improvement of the patient's physical or mental health.

[0043] The term "enhancement" refers to an increase or improvement in the function or activity of a protein or cell after exposure to or contact with the combination described herein, compared to the state before exposure or contact.

[0044] The term "administration" refers to the act of delivering the combination or mixture described herein to an individual via means such as oral, mucosal, topical, suppository, intravenous, non-enteric, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration. Non-enteric administration includes intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Administration is usually performed after the onset of a disease, condition, or disorder or its symptoms, but in some cases, it may be performed before the onset of the disease, condition, or disorder or its symptoms (e.g., administration to a patient susceptible to the disease, condition, or disorder).

[0045] The term "co-administration" refers to the administration of two or more agents (e.g., the combination described herein and another active agent, such as the anticancer agent described herein). The timing of co-administration depends in part on the combination and composition, and may include administration simultaneously, before, or immediately after the administration of one or more additional therapies (e.g., cancer therapies, such as chemotherapy, hormone therapy, radiotherapy, or immunotherapy). The compounds of this invention may be administered to a patient individually or co-administered. Co-administration is intended to include the administration of compounds individually or in combination (one or more compounds or agents) simultaneously or sequentially. Therefore, the formulation may also be combined with other active substances (e.g., to reduce metabolic degradation) when desired. The compounds described herein may be used in combination with each other and with other active agents known for their use in the treatment of cancer.

[0046] The term "anticancer agent" is used in its common sense and refers to a composition having anti-tumor properties or the ability to inhibit cell growth or proliferation. In the examples, the anticancer agent is a chemotherapeutic agent. In the examples, the anticancer agent is an agent identified herein as being used in methods for treating cancer. In the examples, the anticancer agent is an agent approved by the FDA or a similar regulatory agency in a country other than the United States for the treatment of cancer.

[0047] The term "chemotherapeutic agent" is used in its common sense and refers to a chemical composition or compound that has anti-tumor properties or the ability to inhibit cell growth or proliferation. "Chemotherapy" refers to a treatment or regimen that includes the administration of the chemotherapeutic agents or anticancer agents described herein.

[0048] Generally, the nomenclature used in this application is based on the naming conventions adopted by the International Union of Pure and Applied Chemistry (IUPAC). The chemical structures shown herein were generated using CHEMDRAW®. Any open valency on the carbon, oxygen, or nitrogen atoms in the structures herein indicates the presence of a hydrogen atom. [Example] [] [Pharmaceutical Compositions] []

[0049] This disclosure relates to a pharmaceutical composition suitable for oral administration, comprising compound I or a pharmaceutically acceptable salt thereof.

[0050] In one state, the pharmaceutical composition comprises: a. Compound 1; b. One or more diluents; c. One or more adhesives; d. One or more disintegrants; e. One or more gliding agents; f. One or more lubricants; and as appropriate g. Membrane coating.

[0051] Compound 1 has the following structure , Compound 1 It is also known as 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylaminomethoxy)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dimethylamine or N'-(4-fluorophenyl)-N-[4-[7-methoxy-6-(methylaminomethoxy)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dimethylamine. As used herein, Compound 1 includes the crystalline free base solid form of Compound 1 as well as the crystalline salt form of Compound 1 or its salts, solvates or hydrates.

[0052] Examples of pharmaceutically acceptable diluents, binders, disintegrants, glidants, lubricants, and coatings are described in more detail in references readily available to those skilled in the art, such as Handbook of Pharmaceutical Excipients, 7th edition, edited by R. Rowe, P. Sheskey, and S. Owen, 2012, Pharmaceutical Press, London, England; and Remington, The Science and Practice of Pharmacy, 21st edition, edited by P. Gerbino, Lipincott Willoiams & Wilkins, Phildelphia, PA.

[0053] The diluent may be any diluent known to those skilled in the art. In one embodiment, the diluent is an inorganic diluent, a polysaccharide, a monosaccharide or disaccharide, or a sugar alcohol. In another embodiment, the diluent comprises lactose, microcrystalline cellulose, starch, corn starch, croscarmellose sodium, or a mixture thereof.

[0054] The adhesive may be any adhesive known to those skilled in the art. Suitable adhesives include sodium carboxymethyl cellulose, polyvinylpyrrolidone (PVP), copovidone, polyvinylpyrrolidone-vinyl acetate (PVP / VA) copolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, or mixtures thereof. In another embodiment, the adhesive is PVP. In another embodiment, the adhesive is hydroxypropyl cellulose.

[0055] The disintegrant may be any disintegrant known to those skilled in the art. Suitable disintegrants include croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, sodium glycolate starch, or mixtures thereof.

[0056] The flow aid can be any flow aid known to those skilled in the art. Suitable flow aids include starch, corn starch, silica, colloidal silica, or mixtures thereof. In another embodiment, the flow aid is silica. In yet another embodiment, the flow aid is colloidal silica.

[0057] The lubricant can be any lubricant known to those skilled in the art. In another embodiment, the lubricant is stearic acid or magnesium stearate.

[0058] In these and other embodiments, the film coating can be any film coating known to those skilled in the art. Such coatings are widely commercially available, such as those containing coatings as components.

[0059] As used herein, the terms "film coating" and "transmembrane-coated" refer to pharmaceutically acceptable mixtures of excipients, typically applied to compressed tablets, beads, granules, or particles containing the active ingredient. It should be understood that the chosen coating must be compatible with the active ingredient. Furthermore, it should be understood that those skilled in this art will know how to manipulate the coating to achieve gastric disintegration by selecting the excipients constituting the coating, their type, and / or their thickness.

[0060] The polymers suitable for film coating of the present invention are soluble at a pH of about 1.2 to about 5, such as hydroxypropyl methylcellulose (HPMC) alone and / or in combination with the following: hydroxypropyl cellulose (HPC), carboxymethyl cellulose, methyl cellulose, ethyl cellulose, acrylic resins, and polyvinylpyrrolidone and gelatin or other commercially available film coating formulations, such as Dri-Klear® (Crompton & Knowles Corp., Mahwah, NJ) or Opadry® (Colorcon, West Point Pa.).

[0061] In another embodiment, the membrane coating comprises a commercially available membrane coating product designed for coating aqueous membranes, containing a water-soluble film-forming resin, hydroxypropyl methylcellulose, and polyethylene glycol (or other suitable plasticizers, such as propylene glycol or glycerin), and, where appropriate, titanium dioxide (or other colorants or devitrifying agents). This product is commercially available under the brand name Opadry® II Blue (Colorcon, West Point, Pa.).

[0062] The blend suitable for coating may contain 0% w / w to about 20% w / w titanium dioxide or a colorant, about 5% w / w to about 95% w / w hydroxypropyl methylcellulose, and 0% w / w to about 25% w / w polyethylene glycol. In one embodiment, the coating contains 10.5% non-aqueous additives relative to the total weight of the coating, of which 7.5% is Opadry®.

[0063] The coating may further contain small amounts of flavoring agents, masking agents, and saliva-inducing agents as defined above, such as 0.1% to 1.0% (w / w), preferably 0.1% to 0.4%, based on the weight of the total blend used for coating. Preferred flavoring agents and / or masking agents may be selected from the group of agents as defined above.

[0064] The amount of coating deposited on the tablets is typically in the range of about 1.0% to about 6.0% weight gain, preferably 2.0% to 5.0% weight gain, which means the weight gain of the tablets after coating relative to the weight of the uncoated tablets.

[0065] In one embodiment, the pharmaceutical composition comprises: a. Compound 1 or a pharmaceutically acceptable salt thereof; b. One or more diluents selected from the group consisting of: inorganic diluents, polysaccharides, monosaccharides or disaccharides, sugar alcohols and mixtures thereof; c. One or more adhesives selected from the group consisting of: sodium carboxymethyl cellulose, polyvinylpyrrolidone (PVP), copolyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate (PVP / VA) copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, and mixtures thereof; d. One or more disintegrants selected from the group consisting of: croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, starch, sodium glycolate starch, and mixtures thereof; e. One or more gliding agents; f. One or more lubricants; and as appropriate g. Membrane coating.

[0066] In one embodiment, the pharmaceutical composition comprises: a. Compound 1 or a pharmaceutically acceptable salt thereof; b. One or more diluents selected from the group consisting of: inorganic diluents, polysaccharides, monosaccharides or disaccharides, and sugar alcohols; c. One or more adhesives selected from the group consisting of: sodium carboxymethyl cellulose, polyvinylpyrrolidone (PVP), copolyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate (PVP / VA) copolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and ethyl cellulose; d. One or more disintegrants selected from the group consisting of: croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and sodium glycolate starch; e. One or more gliding agents; f. One or more lubricants; and as appropriate g. Membrane coating.

[0067] In one embodiment, the pharmaceutical composition comprises: a. Compound 1 or a pharmaceutically acceptable salt thereof; b. One or more diluents selected from the group consisting of: inorganic diluents, polysaccharides, monosaccharides or disaccharides, and sugar alcohols; c. One or more adhesives selected from the group consisting of: sodium carboxymethyl cellulose, polyvinylpyrrolidone (PVP), copolyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate (PVP / VA) copolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and ethyl cellulose; d. One or more disintegrants selected from the group consisting of: croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and sodium glycolate starch; e. Silicon dioxide; f. One or more lubricants; and as appropriate g. Membrane coating.

[0068] In one embodiment, the pharmaceutical composition comprises: a. Compound 1 or a pharmaceutically acceptable salt thereof; b. One or more diluents selected from the group consisting of: inorganic diluents, polysaccharides, monosaccharides or disaccharides, and sugar alcohols; c. One or more adhesives selected from the group consisting of: sodium carboxymethyl cellulose, polyvinylpyrrolidone (PVP), copolyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate (PVP / VA) copolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and ethyl cellulose; d. One or more disintegrants selected from the group consisting of: croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and sodium glycolate starch; e. Silicon dioxide; f. Stearic acid or magnesium stearate; and as appropriate g. Membrane coating.

[0069] In some embodiments, the pharmaceutical composition of this disclosure may be compacted into a unit dose form, such as tablets or capsules, or added to a unit dose form, such as capsules. In another embodiment, the pharmaceutical composition of this disclosure may be formulated as a powder or suspension for administration. The pharmaceutical formulation of this disclosure containing powder may, for example, be sprinkled on or mixed with a semi-solid carrier (such as applesauce) or another food product for administration to an individual. The powder may also, for example, be added to a liquid carrier suitable for administration to an individual, such as a solution of about 2% w / v hydroxypropyl cellulose and about 0.1% w / v polysorbate 80 in water or about 0.2% hydroxypropyl cellulose and 0.1% Tween 80 in water to form a suspension.

[0070] In one embodiment, the dosage form of this disclosure comprises a tablet containing about 5 mg to about 200 mg (free base equivalent), about 10 mg to about 150 mg (free base equivalent), about 15 mg to about 120 mg (free base equivalent), or about 20 mg to about 100 mg (free base equivalent) of compound 1 or a pharmaceutically acceptable salt thereof.

[0071] In one embodiment, the dosage form of this disclosure comprises a capsule containing about 5 mg to about 200 mg (free base equivalent), about 10 mg to about 150 mg (free base equivalent), about 15 mg to about 120 mg (free base equivalent), or about 20 mg to about 100 mg (free base equivalent) of compound 1 or a pharmaceutically acceptable salt thereof.

[0072] In one embodiment, the dosage form of this disclosure comprises tablets containing, for example, about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg of compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, the dosage form of this disclosure comprises tablets containing about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, or 200 mg of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form of this disclosure includes capsules, for example, at strengths of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg. In one embodiment, the dosage form of this disclosure comprises capsules containing about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, or 200 mg of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form of this disclosure is a tablet containing, for example, about 20 mg, 40 mg, 60 mg, 80 mg, or 100 mg of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form of this disclosure is a tablet containing, for example, a compound 1 with a strength of about 20 mg, 40 mg, 60 mg, 80 mg, 100 mg or 120 mg, or a pharmaceutically acceptable salt thereof.In another embodiment, the dosage form of this disclosure is a capsule containing, for example, a compound 1 at a strength of about 20 mg, 40 mg, 60 mg, 80 mg, or 100 mg, or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form of this disclosure is a capsule containing, for example, a compound 1 at a strength of about 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, or 120 mg, or a pharmaceutically acceptable salt thereof.

[0073] Suitable techniques for formulating the pharmaceutical compositions of this disclosure into tablets are well known in the art and may include mixing the active ingredient and a stabilizing polymer with one or more pharmaceutically acceptable tablet-forming excipients and, for example, compressing the mixture into tablets using a tablet press. The amount and nature of the tablet-forming excipients used can be easily selected based on desired tablet characteristics (such as size, hardness, brittleness, and the like). Tablets containing the pharmaceutical compositions of this disclosure may also be coated, for example, with a film coating (such as Opadry® coating available from Colorcon (West Point Pa)) or with an enteric coating designed to prevent tablet dissolution until it passes through the stomach and / or upper intestine. Suitable tablet coatings and methods for applying such tablet coatings are well known in the art.

[0074] Suitable techniques for formulating the pharmaceutical composition of this disclosure into capsules are also well known in this art, and may include mixing the active ingredient and a stabilizing polymer with one or more pharmaceutically acceptable capsule excipients and filling the mixture into capsules. In one embodiment, the pharmaceutical formulation of this disclosure (with or without additional excipients) may be filled into capsules, such as hard gelatin capsules. Hard gelatin capsules may be of any suitable size, such as size '0', '01', '3', '4', and the like. For example, in one embodiment, a capsule of this disclosure with a dose strength of 20 mg of compound 1 may be filled into a size 4 hard gelatin capsule, wherein the target capsule fill weight may be 100 mg. In another embodiment, a capsule of this disclosure with a dose strength of 100 mg of the active ingredient may be filled into a size '01' hard gelatin capsule, wherein the target capsule fill weight may be 400 mg.

[0075] In one embodiment of the pharmaceutical composition, compound 1 may be present at least about 1% by weight to about 99% by weight (w / w). In another embodiment, compound 1 may be present at least about 10% by weight to about 90% by weight (w / w). In another embodiment, compound 1 may be present at least about 20% by weight to about 70% by weight (w / w). In another embodiment, compound 1 may be present at least about 10% by weight to about 50% by weight (w / w). In another embodiment, compound 1 may be present at least about 20% by weight to about 40% by weight (w / w). In another embodiment, compound 1 may be present at least about 25% by weight to about 35% by weight (w / w). In another embodiment, compound 1 may be present in the pharmaceutical composition at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% by weight (w / w).

[0076] In some embodiments, the pharmaceutical composition of this disclosure is stable when subjected to predetermined conditions for a predetermined time. For example, the pharmaceutical formulation of this disclosure can be stored for a defined or predetermined period at various predetermined temperatures and relative humidityes, such as in open or closed containers. In some embodiments, the pharmaceutical composition of this disclosure is stored at approximately 5, 25, 30, 37, 40, or 45 degrees Celsius and approximately 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative humidity for at least approximately 0.5, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, respectively. The duration of stable conditions is 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 20, 25, 30, 35, 40, 45, 48, 50, 51, 52, 53, 55 or 60 hours; 1 week, 2 weeks, 3 weeks or 4 weeks; 1 month, 2 months, 3 months, 4 months, 5 months, 6 months or 12 months.

[0077] In some embodiments, the pharmaceutical compositions of this disclosure are stable when stored in open or closed containers under the following conditions: for at least about 20 hours at about 30 degrees Celsius and about 90% relative humidity; for at least about one, two, or three weeks at about 40 degrees Celsius and about 60% relative humidity; for at least one, two, or three weeks at about 40 degrees Celsius and about 75% relative humidity; for at least one month at about 25 degrees Celsius and about 60% relative humidity; for at least one month at about 40 degrees Celsius and about 75% relative humidity; for at least three months at about 25 degrees Celsius and about 75% relative humidity; or for at least three months at 5 degrees Celsius and any relative humidity. In some embodiments, “stored in an open container” means that the container is opened twice a day for a given period (e.g., up to four weeks), but remains closed at other times.

[0078] In another embodiment, the pharmaceutical composition comprising compound 1 is stable when stored in an open or closed container under the following conditions: for at least about 20 hours at about 30 degrees Celsius and about 90% relative humidity; for at least about one, two, or three weeks at about 40 degrees Celsius and about 60% relative humidity; for at least one, two, or three weeks at about 4 degrees Celsius and about 75% relative humidity; for at least one month at about 25 degrees Celsius and about 60% relative humidity; for at least one month at about 40 degrees Celsius and about 75% relative humidity; for at least about three months at about 25 degrees Celsius and about 75% relative humidity; or for at least three months at 5 degrees Celsius and any relative humidity.

[0079] In another embodiment, the pharmaceutical composition comprising Compound 1 is stable after being stored in an open or closed container at about 25 degrees Celsius and about 60% relative humidity for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. In another embodiment, the pharmaceutical composition comprising Compound 1 is stable after being stored in an open or closed container at about 25 degrees Celsius and about 60% relative humidity for at least 1 month, 2 months, or 3 months, wherein the total impurities are less than 0.1%. In another embodiment, the pharmaceutical composition comprising Compound 1 is stable after being stored in an open or closed container at about 25 degrees Celsius and about 60% relative humidity for at least 6 months, wherein the total impurities are less than 0.5%. In another embodiment, the pharmaceutical composition comprising Compound 1 is stable after being stored in an open or closed container at about 25 degrees Celsius and about 60% relative humidity for at least 12 months, wherein the total impurities are less than 0.5%.

[0080] In another embodiment, the pharmaceutical composition comprising Compound 1 is stable after being stored in an open or closed container at about 40 degrees Celsius and about 75% relative humidity for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. In another embodiment, the pharmaceutical composition comprising Compound 1 is stable after being stored in an open or closed container at about 40 degrees Celsius and about 75% relative humidity for at least 1 month, 2 months, or 3 months, wherein the total impurities are less than 0.1%. In another embodiment, the pharmaceutical composition comprising Compound 1 is stable after being stored in an open or closed container at about 40 degrees Celsius and about 75% relative humidity for at least 6 months, wherein the total impurities are less than 0.5%.

[0081] The stability of the pharmaceutical composition disclosed herein can also be measured by testing other physical characteristics, such as by testing the dissolution of the pharmaceutical composition at the end of a predetermined period after it has been subjected to predetermined conditions (e.g., temperature and relative humidity). Methods suitable for measuring the dissolution profile of the pharmaceutical composition of this invention are known in the art. Exemplary methods for measuring the dissolution profile of the pharmaceutical composition of this invention include basket dissolution testing or paddle dissolution testing, for example, in simulated gastric fluid.

[0082] In one embodiment, after being stored in an open or closed container at about 25 degrees Celsius and about 60% relative humidity for at least about 0 months, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, the pharmaceutical composition comprising Compound 1 exhibits a dissolution of greater than 25%, 30%, 40%, or 50% at 5 minutes. In another embodiment, after being stored in an open or closed container at about 25 degrees Celsius and about 60% relative humidity for at least about 1 month, 2 months, 3 months, 6 months, 7 months, or 12 months, the pharmaceutical composition comprising Compound 1 exhibits a dissolution of greater than 50% at 5 minutes. In another embodiment, the pharmaceutical composition comprising Compound 1 exhibits greater than 70% dissolution at 10 minutes after being stored in an open or closed container at about 25 degrees Celsius and about 60% relative humidity for at least about 0 months, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. In another embodiment, the pharmaceutical composition comprising Compound 1 exhibits greater than 90% dissolution at 45 minutes after being stored in an open or closed container at about 25 degrees Celsius and about 60% relative humidity for at least about 0 months, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. In another embodiment, the pharmaceutical composition comprising compound 1 exhibits greater than 95% dissolution at 75 minutes after being stored in an open or closed container at about 25 degrees Celsius and about 60% relative humidity for a period of about 0 months, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months.

[0083] In another embodiment, after being stored in an open or closed container at about 40 degrees Celsius and about 75% relative humidity for at least about 0 months, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months, the pharmaceutical composition comprising Compound 1 exhibits a dissolution of greater than 25%, 30%, 40%, or 50% at 5 minutes. In another embodiment, after being stored in an open or closed container at about 40 degrees Celsius and about 75% relative humidity for at least 0 months, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months, the pharmaceutical composition comprising Compound 1 exhibits a dissolution of greater than 40%, 50%, 60%, or 70% at 10 minutes. In another embodiment, after being stored in an open or closed container at about 40 degrees Celsius and about 75% relative humidity for at least 0 months, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months, the pharmaceutical composition comprising Compound 1 exhibits a dissolution of greater than 70%, 80%, or 90% at 45 minutes. In another embodiment, the pharmaceutical composition comprising compound 1 exhibits greater than 90% or 95% dissolution at 75 minutes after being stored in an open or closed container at about 40 degrees Celsius and about 75% relative humidity for a period of about 0 months, 1 month, 2 months, 3 months, 4 months, 5 months or 6 months.

[0084] In some embodiments, the pharmaceutical compositions of this disclosure comprise tablets, capsules, pouches, powders, suspensions, suppositories, and the like. In these dosage forms of this disclosure, the amount of the active ingredient constituting the dosage form can be any suitable amount, for example, about 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, or 100 mg per unit dosage form. In some embodiments, the dosage forms of this disclosure contain about 25 mg, 50 mg, 75 mg, 80 mg, or 100 mg of the active ingredient, such as compound 1, per dosage form.

[0085] Although illustrative amounts or ranges of Compound 1 and other pharmaceutical composition components have been given, the pharmaceutical compositions of this disclosure may contain any amount of such components suitable for achieving the desired pharmacological and stability properties as set forth herein. In addition to these components, other pharmaceutically acceptable ingredients may be added to the pharmaceutical compositions, such as adjuvants, antioxidants, buffers, colorants, compression aids, emulsifiers, softeners, encapsulation materials, fillers, flavoring agents, granulators, metal chelators, osmotic pressure regulators, pH adjusters, preservatives, solubilizers, adsorbents, stabilizers, sweeteners, surfactants, suspending agents, thickeners, or viscosity modifiers.

[0086] In one embodiment, the pharmaceutical composition is a tablet pharmaceutical composition suitable for oral administration.

[0087] In another embodiment, the tablet pharmaceutical composition comprises: a. Compound 1; b. Microcrystalline cellulose; c. Lactose; d. Hydroxypropyl cellulose; e. Cross-linked sodium carboxymethyl cellulose; f. Silicon dioxide; and g. Stearic acid or magnesium stearate; and as appropriate h. Membrane coating.

[0088] In one embodiment, the tablet pharmaceutical composition comprises: a. Compound 1; b. Microcrystalline cellulose c. Anhydrous lactose d. Hydroxypropyl cellulose; e. Cross-linked sodium carboxymethyl cellulose f. Colloidal silicon dioxide; and g. Stearic acid or magnesium stearate; and as appropriate h. Membrane coating.

[0089] The tablet pharmaceutical composition of Compound 1 can be described based on the weight percentage ("by weight") of each component present in the dosage form, wherein the sum of the weight percentages does not exceed 100%.

[0090] Therefore, in one embodiment, the tablet pharmaceutical composition comprises: a. About 20% to about 40% by weight of compound 1; b. Approximately 35% to approximately 45% by weight of microcrystalline cellulose; c. Approximately 15% to approximately 25% by weight of lactose; d. Hydroxypropyl cellulose, approximately 2% to approximately 8% by weight; e. Approximately 4% to approximately 8% by weight of croscarmellose sodium; f. About 0.1% by weight to about 0.5% by weight of silicon dioxide; and g. Magnesium stearate, about 0.5% to about 3.5% by weight; and as appropriate h. Membrane coating.

[0091] In one embodiment, the tablet pharmaceutical composition comprises: a. About 20% to about 40% by weight of compound 1; b. Approximately 35% to approximately 45% by weight of microcrystalline cellulose; c. Approximately 15% to approximately 25% by weight of anhydrous lactose; d. Hydroxypropyl cellulose, approximately 2% to approximately 8% by weight; e. Approximately 4% to approximately 8% by weight of croscarmellose sodium; f. about 0.1% to about 0.5% by weight of colloidal silicon dioxide; and g. Magnesium stearate, about 0.5% to about 3.5% by weight; and as appropriate h. Membrane coating.

[0092] In one embodiment, the tablet pharmaceutical composition comprises: a. About 25% to about 35% by weight of compound 1; b. Microcrystalline cellulose, approximately 37% to approximately 43% by weight; c. Approximately 18% to approximately 22% by weight of anhydrous lactose; d. About 2% to about 6% by weight of hydroxypropyl cellulose; e. Approximately 5% to approximately 7% by weight of croscarmellose sodium; f. about 0.2% by weight to about 0.4% by weight of colloidal silicon dioxide; and g. Magnesium stearate, about 0.5% to about 3.5% by weight; and as appropriate h. Membrane coating.

[0093] In one embodiment, the tablet pharmaceutical composition comprises: a. About 25% to about 35% by weight of compound 1; b. Microcrystalline cellulose, approximately 37% to approximately 43% by weight; c. Approximately 18% to approximately 22% by weight of anhydrous lactose; d. About 2% to about 4% by weight of hydroxypropyl cellulose; e. Approximately 5% to approximately 7% by weight of croscarmellose sodium; f. about 0.2% by weight to about 0.4% by weight of colloidal silicon dioxide; and g. Magnesium stearate, about 0.5% to about 1.5% by weight; and as appropriate h. Membrane coating.

[0094] Therefore, in another embodiment, the tablet pharmaceutical composition comprises: a. About 20% to about 40% by weight of compound 1; b. Approximately 35% to approximately 45% by weight of microcrystalline cellulose; c. Approximately 15% to approximately 25% by weight of lactose; d. Hydroxypropyl cellulose, approximately 2% to approximately 8% by weight; e. Approximately 2% to approximately 8% by weight of croscarmellose sodium; f. About 0.1% by weight to about 0.5% by weight of silicon dioxide; and g. Stearic acid, about 1% to about 5% by weight; and as appropriate h. Membrane coating.

[0095] Therefore, in another embodiment, the tablet pharmaceutical composition comprises: a. About 20% to about 40% by weight of compound 1; b. Approximately 35% to approximately 45% by weight of microcrystalline cellulose; c. Approximately 15% to approximately 25% by weight of anhydrous lactose; d. Hydroxypropyl cellulose, approximately 2% to approximately 8% by weight; e. Approximately 2% to approximately 8% by weight of croscarmellose sodium; f. about 0.1% to about 0.5% by weight of colloidal silicon dioxide; and g. Stearic acid, about 1% to about 5% by weight; and as appropriate h. Membrane coating.

[0096] In one embodiment, the tablet pharmaceutical composition comprises: a. About 25% to about 35% by weight of compound 1; b. Approximately 35% to approximately 40% by weight of microcrystalline cellulose; c. Approximately 16% to approximately 22% by weight of anhydrous lactose; d. Hydroxypropyl cellulose, approximately 3% to approximately 7% by weight; e. Approximately 3% to approximately 7% by weight of croscarmellose sodium; f. about 0.1% to about 0.5% by weight of colloidal silicon dioxide; and g. Stearic acid, about 0.5% to about 3.5% by weight; and as appropriate h. Membrane coating.

[0097] In one embodiment, the tablet pharmaceutical composition comprises: a. About 25% to about 35% by weight of compound 1; b. Approximately 35% to approximately 40% by weight of microcrystalline cellulose; c. Approximately 16% to approximately 22% by weight of anhydrous lactose; d. Hydroxypropyl cellulose, approximately 3% to approximately 7% by weight; e. Approximately 3% to approximately 7% by weight of croscarmellose sodium; f. about 0.1% to about 0.5% by weight of colloidal silicon dioxide; and g. Stearic acid, approximately 1.5% to approximately 3.5% by weight; and as appropriate. h. Membrane coating.

[0098] In another embodiment, the tablet pharmaceutical composition comprises about 10 mg to about 150 mg of compound 1 (free base equivalent) and a pharmaceutically acceptable excipient selected from one or more diluents, one or more binders, one or more disintegrants, one or more flow aids, one or more lubricants, and, where appropriate, film coating.

[0099] In another embodiment, the tablet pharmaceutical composition comprises about 10 mg to about 100 mg of compound 1 and a pharmaceutically acceptable excipient selected from one or more diluents, one or more binders, one or more disintegrants, one or more flow aids, one or more lubricants, and, where appropriate, film coating.

[0100] In another embodiment, the tablet pharmaceutical composition comprises about 10 mg to about 90 mg of compound 1; microcrystalline cellulose; lactose; hydroxypropyl cellulose; croscarmellose sodium; silicon dioxide; and stearic acid or magnesium stearate; and film coating as appropriate.

[0101] In another embodiment, the tablet pharmaceutical composition comprises about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg of compound 1 (free base equivalent); microcrystalline cellulose; lactose; hydroxypropyl cellulose; croscarmellose sodium; silicon dioxide; and stearic acid or magnesium stearate; and, as appropriate, film coating.

[0102] In another embodiment, the tablet pharmaceutical composition comprises about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg of compound 1; microcrystalline cellulose; lactose; hydroxypropyl cellulose; croscarmellose sodium; silicon dioxide; and stearic acid or magnesium stearate; and film coating as appropriate.

[0103] In one embodiment, the tablet pharmaceutical composition comprises: a. 15-150 mg of compound 1 (free base equivalent); b. Microcrystalline cellulose; c. Lactose; d. Hydroxypropyl cellulose; e. Cross-linked sodium carboxymethyl cellulose; f. Silicon dioxide; and g. Magnesium stearate or stearic acid; and as appropriate h. Membrane coating.

[0104] In one embodiment, the tablet pharmaceutical composition comprises: a. 15-150 mg of compound 1 (free base equivalent); b. Microcrystalline cellulose; c. Anhydrous lactose; d. Hydroxypropyl cellulose; e. Cross-linked sodium carboxymethyl cellulose; f. Colloidal silicon dioxide; and g. Magnesium stearate or stearic acid; and as appropriate h. Membrane coating.

[0105] In one embodiment, the tablet pharmaceutical composition comprises: a. 15-100 mg of compound 1; b. Microcrystalline cellulose; c. Lactose; d. Hydroxypropyl cellulose; e. Cross-linked sodium carboxymethyl cellulose; f. Silicon dioxide; and g. Magnesium stearate or stearic acid; and as appropriate h. Membrane coating.

[0106] In one embodiment, the tablet pharmaceutical composition comprises: a. 15-100 mg of compound 1; b. Microcrystalline cellulose; c. Anhydrous lactose; d. Hydroxypropyl cellulose; e. Cross-linked sodium carboxymethyl cellulose; f. Colloidal silicon dioxide; and g. Magnesium stearate or stearic acid; and as appropriate h. Membrane coating.

[0107] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 20 mg of compound 1; b. Microcrystalline cellulose; c. Anhydrous lactose; d. Hydroxypropyl cellulose; e. Cross-linked sodium carboxymethyl cellulose; f. Colloidal silicon dioxide; and g. Magnesium stearate or stearic acid; and as appropriate h. Membrane coating.

[0108] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 40 mg of compound 1; b. Microcrystalline cellulose; c. Anhydrous lactose; d. Hydroxypropyl cellulose; e. Cross-linked sodium carboxymethyl cellulose; f. Colloidal silicon dioxide; and g. Magnesium stearate or stearic acid; and as appropriate h. Membrane coating.

[0109] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 60 mg of compound 1; b. Microcrystalline cellulose; c. Anhydrous lactose; d. Hydroxypropyl cellulose; e. Cross-linked sodium carboxymethyl cellulose; f. Colloidal silicon dioxide; and g. Magnesium stearate or stearic acid; and as appropriate h. Membrane coating.

[0110] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 80 mg of compound 1; b. Microcrystalline cellulose; c. Anhydrous lactose; d. Hydroxypropyl cellulose; e. Cross-linked sodium carboxymethyl cellulose; f. Colloidal silicon dioxide; and g. Magnesium stearate or stearic acid; and as appropriate h. Membrane coating.

[0111] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 100 mg of compound 1; b. Microcrystalline cellulose; c. Anhydrous lactose; d. Hydroxypropyl cellulose; e. Cross-linked sodium carboxymethyl cellulose; f. Colloidal silicon dioxide; and g. Magnesium stearate or stearic acid; and as appropriate h. Membrane coating.

[0112] In one embodiment, the tablet pharmaceutical composition comprises: i. Approximately 120 mg of compound 1; j. Microcrystalline cellulose; k. Anhydrous lactose; 1. Hydroxypropyl cellulose; m. Crosslinked carboxymethyl cellulose sodium; n. Colloidal silicon dioxide; and o. Magnesium stearate or stearic acid; and as appropriate p. Membrane coating.

[0113] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 18 mg to 23 mg of compound 1; b. Approximately 30 mg to 35 mg of microcrystalline cellulose; c. Approximately 15 mg to 18 mg of anhydrous lactose; d. Approximately 1.5 mg to 4.5 mg of hydroxypropyl cellulose; e. Approximately 4 to 6 mg of croscarmellose sodium; f. Approximately 0.1 mg to 0.3 mg of colloidal silicon dioxide; and g. Approximately 0.5 mg to 0.7 mg of magnesium stearate; and as needed. h. Approximately 2 mg to 6 mg film-coated.

[0114] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 20 mg of compound 1; b. Approximately 30 mg to 35 mg of microcrystalline cellulose; c. Approximately 15 mg to 18 mg of anhydrous lactose; d. Approximately 1.5 mg to 4.5 mg of hydroxypropyl cellulose; e. Approximately 4 to 6 mg of croscarmellose sodium; f. Approximately 0.1 mg to 0.3 mg of colloidal silicon dioxide; and g. Approximately 0.5 mg to 0.7 mg of magnesium stearate; and as needed. h. Approximately 2 mg to 6 mg film-coated.

[0115] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 35 mg to 45 mg of compound 1; b. Approximately 60 mg to 70 mg of microcrystalline cellulose; c. Approximately 30 mg to 40 mg of lactose; d. Approximately 2 mg to 10 mg of hydroxypropyl cellulose; e. Approximately 8 mg to 12 mg of croscarmellose sodium; f. Approximately 0.2 mg to 0.6 mg of silicon dioxide; and g. Approximately 1 mg to 1.5 mg of magnesium stearate; and as needed. h. Approximately 4 mg to 12 mg film-coated.

[0116] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 40 mg of compound 1; b. Approximately 60 mg to 70 mg of microcrystalline cellulose; c. Approximately 30 mg to 40 mg of lactose; d. Approximately 2 mg to 10 mg of hydroxypropyl cellulose; e. Approximately 8 mg to 12 mg of croscarmellose sodium; f. Approximately 0.2 mg to 0.6 mg of silicon dioxide; and g. Approximately 1 mg to 1.5 mg of magnesium stearate; and as needed. h. Approximately 4 mg to 12 mg film-coated.

[0117] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 55 mg to 65 mg of compound 1; b. Approximately 90 mg to 110 mg of microcrystalline cellulose; c. Approximately 40 mg to 60 mg of anhydrous lactose; d. Approximately 4 mg to 14 mg of hydroxypropyl cellulose; e. Approximately 12 mg to 20 mg of croscarmellose sodium; f. Approximately 0.3 mg to 1 mg of colloidal silicon dioxide; and g. Approximately 1.5 mg to 2.5 mg of magnesium stearate; and as needed. h. Approximately 6 mg to 18 mg film-coated.

[0118] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 60 mg of compound 1; b. Approximately 90 mg to 110 mg of microcrystalline cellulose; c. Approximately 40 mg to 60 mg of anhydrous lactose; d. Approximately 4 mg to 14 mg of hydroxypropyl cellulose; e. Approximately 12 mg to 20 mg of croscarmellose sodium; f. Approximately 0.3 mg to 1 mg of colloidal silicon dioxide; and g. Approximately 1.5 mg to 2.5 mg of magnesium stearate; and as needed. h. Approximately 6 mg to 18 mg film-coated.

[0119] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 70 mg to 90 mg of compound 1; b. Approximately 120 mg to 150 mg of microcrystalline cellulose; c. Approximately 60 mg to 80 mg of anhydrous lactose; d. Approximately 6 mg to 18 mg of hydroxypropyl cellulose; e. Approximately 15 mg to 25 mg of croscarmellose sodium; f. Approximately 0.4 mg to 1.5 mg of colloidal silicon dioxide; and g. Approximately 2 to 3 mg of magnesium stearate; and as needed h. Approximately 8 mg to 26 mg film-coated.

[0120] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 80 mg of compound 1; b. Approximately 120 mg to 150 mg of microcrystalline cellulose; c. Approximately 60 mg to 80 mg of anhydrous lactose; d. Approximately 6 mg to 18 mg of hydroxypropyl cellulose; e. Approximately 15 mg to 25 mg of croscarmellose sodium; f. Approximately 0.4 mg to 1.5 mg of colloidal silicon dioxide; and g. Approximately 2 to 3 mg of magnesium stearate; and as needed h. Approximately 8 mg to 26 mg film-coated.

[0121] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 18 mg to 23 mg of compound 1; b. Approximately 30 mg to 40 mg of microcrystalline cellulose; c. Approximately 15 mg to 20 mg of anhydrous lactose; d. Approximately 3 mg to 7 mg of hydroxypropyl cellulose; e. Approximately 3 mg to 7 mg of croscarmellose sodium; f. Approximately 0.1 mg to 0.3 mg of colloidal silicon dioxide; and g. Approximately 2 mg to 4 mg of stearic acid; and as needed h. Approximately 2 mg to 5 mg film-coated.

[0122] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 20 mg of compound 1; b. Approximately 30 mg to 40 mg of microcrystalline cellulose; c. Approximately 15 mg to 20 mg of anhydrous lactose; d. Approximately 3 mg to 7 mg of hydroxypropyl cellulose; e. Approximately 3 mg to 7 mg of croscarmellose sodium; f. Approximately 0.1 mg to 0.3 mg of colloidal silicon dioxide; and g. Approximately 2 mg to 4 mg of stearic acid; and as needed h. Approximately 2 mg to 5 mg film-coated.

[0123] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 35 mg to 45 mg of compound 1; b. Approximately 50 mg to 70 mg of microcrystalline cellulose; c. Approximately 25 mg to 35 mg of anhydrous lactose; d. Approximately 6 mg to 10 mg of hydroxypropyl cellulose; e. Approximately 6 mg to 10 mg of croscarmellose sodium; f. Approximately 0.2 mg to 0.6 mg of colloidal silicon dioxide; and g. Approximately 4 mg to 8 mg of stearic acid; and as needed. h. Approximately 4 mg to 10 mg film-coated.

[0124] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 40 mg of compound 1; b. Approximately 50 mg to 70 mg of microcrystalline cellulose; c. Approximately 25 mg to 35 mg of anhydrous lactose; d. Approximately 6 mg to 10 mg of hydroxypropyl cellulose; e. Approximately 6 mg to 10 mg of croscarmellose sodium; f. Approximately 0.2 mg to 0.6 mg of colloidal silicon dioxide; and g. Approximately 4 mg to 8 mg of stearic acid; and as needed. h. Approximately 4 mg to 10 mg film-coated.

[0125] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 55 mg to 65 mg of compound 1; b. Approximately 80 mg to 120 mg of microcrystalline cellulose; c. Approximately 40 mg to 70 mg of anhydrous lactose; d. Approximately 12 mg to 15 mg of hydroxypropyl cellulose; e. Approximately 12 mg to 15 mg of croscarmellose sodium; f. Approximately 0.5 mg to 0.8 mg of colloidal silicon dioxide; and g. Approximately 6 mg to 12 mg of stearic acid; and as needed. h. Approximately 6 mg to 12 mg film-coated.

[0126] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 60 mg of compound 1; b. Approximately 80 mg to 120 mg of microcrystalline cellulose; c. Approximately 40 mg to 70 mg of anhydrous lactose; d. Approximately 12 mg to 15 mg of hydroxypropyl cellulose; e. Approximately 12 mg to 15 mg of croscarmellose sodium; f. Approximately 0.5 mg to 0.8 mg of colloidal silicon dioxide; and g. Approximately 6 mg to 12 mg of stearic acid; and as needed. h. Approximately 6 mg to 12 mg film-coated.

[0127] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 70 mg to 90 mg of compound 1; b. Approximately 120 mg to 150 mg of microcrystalline cellulose; c. Approximately 60 mg to 80 mg of anhydrous lactose; d. Approximately 12 mg to 30 mg of hydroxypropyl cellulose; e. Approximately 12 mg to 30 mg of croscarmellose sodium; f. Approximately 0.5 mg to 1.5 mg of colloidal silicon dioxide; and g. Approximately 8 mg to 16 mg of stearic acid; and as needed. h. Approximately 8 mg to 14 mg film-coated.

[0128] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 80 mg of compound 1; b. Approximately 120 mg to 150 mg of microcrystalline cellulose; c. Approximately 60 mg to 80 mg of anhydrous lactose; d. Approximately 12 mg to 30 mg of hydroxypropyl cellulose; e. Approximately 12 mg to 30 mg of croscarmellose sodium; f. Approximately 0.5 mg to 1.5 mg of colloidal silicon dioxide; and g. Approximately 8 mg to 16 mg of stearic acid; and as needed. h. Approximately 8 mg to 14 mg film-coated.

[0129] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 100 mg of compound 1; b. Approximately 140 mg to 160 mg of microcrystalline cellulose; c. Approximately 70 mg to 90 mg of anhydrous lactose; d. Approximately 15 mg to 25 mg of hydroxypropyl cellulose; e. Approximately 20 mg to 30 mg of croscarmellose sodium; f. Approximately 0.8 mg to 2.0 mg of colloidal silicon dioxide; and g. Approximately 9 mg to 18 mg of stearic acid; and as appropriate. h. Approximately 10 mg to 30 mg film-coated.

[0130] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 120 mg of compound 1; b. Approximately 165 mg to 195 mg of microcrystalline cellulose; c. Approximately 80 mg to 100 mg of anhydrous lactose; d. Approximately 20 mg to 30 mg of hydroxypropyl cellulose; e. Approximately 25 mg to 35 mg of croscarmellose sodium; f. Approximately 1.0 mg to 2.5 mg of colloidal silicon dioxide; and g. Approximately 10 mg to 20 mg of stearic acid; and as needed h. Approximately 15 mg to 35 mg film-coated. [Compound in crystalline solid form] []

[0131] As provided herein, compound 1 may exist in the pharmaceutical composition disclosed herein in crystalline (free base) solid form or crystalline salt form.

[0132] Therefore, in one embodiment, the tablet pharmaceutical composition comprises: a. About 20% to about 40% by weight of a compound 1 in the form of a crystalline solid or a crystalline salt; b. Approximately 35% to approximately 45% by weight of microcrystalline cellulose; c. Approximately 15% to approximately 25% by weight of lactose; d. Hydroxypropyl cellulose, approximately 2% to approximately 8% by weight; e. Approximately 4% to approximately 8% by weight of croscarmellose sodium; f. About 0.1% by weight to about 0.5% by weight of silicon dioxide; and g. Magnesium stearate, about 0.5% to about 3.5% by weight; and as appropriate h. Membrane coating.

[0133] In another embodiment, the tablet pharmaceutical composition comprises: a. About 20% by weight to about 40% by weight of compound 1 in the form of a crystalline solid or a crystalline salt, selected from the group consisting of: compound 1 hydrochloride, compound 1 fumarate and compound 1 phosphate; b. Approximately 35% to approximately 45% by weight of microcrystalline cellulose; c. Approximately 15% to approximately 25% by weight of lactose; d. Hydroxypropyl cellulose, approximately 2% to approximately 8% by weight; e. Approximately 4% to approximately 8% by weight of croscarmellose sodium; f. About 0.1% by weight to about 0.5% by weight of silicon dioxide; and g. Magnesium stearate, about 0.5% to about 3.5% by weight; and as appropriate h. Membrane coating.

[0134] In one embodiment, the tablet pharmaceutical composition comprises: a. About 20% by weight to about 40% by weight of compound 1 in the form of a crystalline solid or a crystalline salt, selected from the group consisting of: compound 1 hydrochloride, compound 1 fumarate and compound 1 phosphate; b. Approximately 35% to approximately 45% by weight of microcrystalline cellulose; c. Approximately 15% to approximately 25% by weight of anhydrous lactose; d. Hydroxypropyl cellulose, approximately 2% to approximately 8% by weight; e. Approximately 4% to approximately 8% by weight of croscarmellose sodium; f. about 0.1% to about 0.5% by weight of colloidal silicon dioxide; and g. Magnesium stearate, about 0.5% to about 3.5% by weight; and as appropriate h. Membrane coating.

[0135] In one embodiment, the tablet pharmaceutical composition comprises: a. About 25% by weight to about 35% by weight of compound 1 in the form of a crystalline solid or a crystalline salt, selected from the group consisting of: compound 1 hydrochloride, compound 1 fumarate and compound 1 phosphate; b. Microcrystalline cellulose, approximately 37% to approximately 43% by weight; c. Approximately 18% to approximately 22% by weight of anhydrous lactose; d. About 2% to about 6% by weight of hydroxypropyl cellulose; e. Approximately 5% to approximately 7% by weight of croscarmellose sodium; f. about 0.2% by weight to about 0.4% by weight of colloidal silicon dioxide; and g. Magnesium stearate, about 0.5% to about 3.5% by weight; and as appropriate h. Membrane coating.

[0136] In one embodiment, the tablet pharmaceutical composition comprises: a. About 25% by weight to about 35% by weight of compound 1 in the form of a crystalline solid or a crystalline salt, selected from the group consisting of: compound 1 hydrochloride, compound 1 fumarate and compound 1 phosphate; b. Microcrystalline cellulose, approximately 37% to approximately 43% by weight; c. Approximately 18% to approximately 22% by weight of anhydrous lactose; d. About 2% to about 4% by weight of hydroxypropyl cellulose; e. Approximately 5% to approximately 7% by weight of croscarmellose sodium; f. about 0.2% by weight to about 0.4% by weight of colloidal silicon dioxide; and g. Magnesium stearate, about 0.5% to about 1.5% by weight; and as appropriate h. Membrane coating.

[0137] Therefore, in another embodiment, the tablet pharmaceutical composition comprises: a. About 20% by weight to about 40% by weight of compound 1 in the form of a crystalline solid or a crystalline salt, selected from the group consisting of: compound 1 hydrochloride, compound 1 fumarate and compound 1 phosphate; b. Approximately 35% to approximately 45% by weight of microcrystalline cellulose; c. Approximately 15% to approximately 25% by weight of lactose; d. Hydroxypropyl cellulose, approximately 2% to approximately 8% by weight; e. Approximately 2% to approximately 8% by weight of croscarmellose sodium; f. About 0.1% by weight to about 0.5% by weight of silicon dioxide; and g. Stearic acid, about 1% to about 5% by weight; and as appropriate h. Membrane coating.

[0138] Therefore, in another embodiment, the tablet pharmaceutical composition comprises: a. About 20% by weight to about 40% by weight of compound 1 in the form of a crystalline solid or a crystalline salt, selected from the group consisting of: compound 1 hydrochloride, compound 1 fumarate and compound 1 phosphate; b. Approximately 35% to approximately 45% by weight of microcrystalline cellulose; c. Approximately 15% to approximately 25% by weight of anhydrous lactose; d. Hydroxypropyl cellulose, approximately 2% to approximately 8% by weight; e. Approximately 2% to approximately 8% by weight of croscarmellose sodium; f. about 0.1% to about 0.5% by weight of colloidal silicon dioxide; and g. Stearic acid, about 1% to about 5% by weight; and as appropriate h. Membrane coating.

[0139] In one embodiment, the tablet pharmaceutical composition comprises: a. About 25% by weight to about 35% by weight of compound 1 in the form of a crystalline solid or a crystalline salt, selected from the group consisting of: compound 1 hydrochloride, compound 1 fumarate and compound 1 phosphate; b. Approximately 35% to approximately 40% by weight of microcrystalline cellulose; c. Approximately 16% to approximately 22% by weight of anhydrous lactose; d. Hydroxypropyl cellulose, approximately 3% to approximately 7% by weight; e. Sodium croscarmellose, about 3% to about 7% by weight f. about 0.1% to about 0.5% by weight of colloidal silicon dioxide; and g. Stearic acid, about 0.5% to about 3.5% by weight; and as appropriate h. Membrane coating.

[0140] In one embodiment, the tablet pharmaceutical composition comprises: a. About 25% by weight to about 35% by weight of compound 1 in the form of a crystalline solid or a crystalline salt, selected from the group consisting of: compound 1 hydrochloride, compound 1 fumarate and compound 1 phosphate; b. Approximately 35% to approximately 40% by weight of microcrystalline cellulose; c. Approximately 16% to approximately 22% by weight of anhydrous lactose; d. Hydroxypropyl cellulose, approximately 3% to approximately 7% by weight; e. Sodium croscarmellose, about 3% to about 7% by weight f. about 0.1% to about 0.5% by weight of colloidal silicon dioxide; and g. Stearic acid, approximately 1.5% to approximately 3.5% by weight; and as appropriate. h. Membrane coating.

[0141] In one embodiment, the pharmaceutical composition of this disclosure comprises compound 1 in the form of a crystalline (free base) solid.

[0142] In one embodiment, the crystalline solid form of compound 1 is characterized as form A, form B, form C, form D, form E, form F, form G, form H, form I, form J, form K, form L, form M, form N, form O, form P, or form Q. In another embodiment, the crystalline solid form of compound 1 is characterized as form A, form B, form C, form D, form E, form F, form G, form H, form K, form O, or form Q. In yet another embodiment, the crystalline solid form of compound 1 is characterized as form I, form J, form L, form M, form N, or form P. The crystalline solid forms of compound 1 characterized as form A, form B, form C, form D, form E, form F, form G, form H, form I, form J, form K, form L, form M, form N, form O, form P, or form Q are disclosed in WO 2020 / 123800, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0143] In one embodiment, the crystalline solid is characterized as compound 1, form A.

[0144] In one embodiment, the crystalline solid is characterized as compound 1 in form B.

[0145] In one embodiment, the crystalline solid is characterized as compound 1 in form C.

[0146] In one embodiment, the crystalline solid is characterized as compound 1 in form D.

[0147] In one embodiment, the crystalline solid is characterized as compound 1 in form E.

[0148] In one embodiment, the crystalline solid is characterized as compound 1 in form F.

[0149] In one embodiment, the crystalline solid is characterized as compound 1 in form G.

[0150] In one embodiment, the crystalline solid is characterized as compound 1 in form H.

[0151] In one embodiment, the crystalline solid is characterized as compound 1, form I.

[0152] In one embodiment, the crystalline solid is characterized as compound 1 in form J.

[0153] In one embodiment, the crystalline solid is characterized as compound 1 in form K.

[0154] In one embodiment, the crystalline solid is characterized as compound 1 in form L.

[0155] In one embodiment, the crystalline solid is characterized as compound 1 in form M.

[0156] In one embodiment, the crystalline solid is characterized as compound 1 in form N.

[0157] In one embodiment, the crystalline solid is characterized as compound 1 in form O.

[0158] In one embodiment, the crystalline solid is characterized as compound 1 in form P.

[0159] In one embodiment, the crystalline solid is characterized as compound 1 in form Q. [Compound] [1] [Crystalled salt form]

[0160] In another embodiment, the pharmaceutical composition of this disclosure comprises compound 1 as a crystalline salt or its hydrate or solvate.

[0161] In one embodiment, the crystalline salt is characterized as compound 1 hydrochloride form A, compound 1 hydrochloride form B, compound 1 hydrochloride form C, or compound 1 hydrochloride form D. The crystalline salt forms characterized as compound 1 hydrochloride form A, compound 1 hydrochloride form B, compound 1 hydrochloride form C, or compound 1 hydrochloride form D are disclosed in WO 2020 / 123800, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0162] In one embodiment, the crystalline salt is characterized as compound 1 hydrochloride form A.

[0163] In one embodiment, the crystalline salt is characterized as compound 1 hydrochloride form B.

[0164] In one embodiment, the crystalline salt is characterized as the hydrochloride form C of compound 1.

[0165] In one embodiment, the crystalline salt is characterized as compound 1 hydrochloride form D.

[0166] In one embodiment, the pharmaceutical composition disclosed herein comprises crystalline fumarate of compound 1 or its hydrate or solvate. In some embodiments, the crystalline fumarate of compound 1 is characterized as fumarate form A or hemifumarate form B of compound 1. The crystalline fumarate of compound 1 characterized as fumarate form A or hemifumarate form B of compound 1 is disclosed in WO 2020 / 123800, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0167] In one embodiment, the crystalline salt is characterized as compound 1 fumarate form A.

[0168] In one embodiment, the crystalline fumarate is characterized as compound 1 hemifumarate form B.

[0169] In one embodiment, the pharmaceutical composition comprises a crystalline phosphate of compound 1 or a hydrate or solvate thereof. In some embodiments, the crystalline phosphate of compound 1 is characterized as phosphate form A of compound 1. The crystalline phosphate of compound 1 characterized as phosphate form A of compound 1 is disclosed in WO 2020 / 123800, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0170] In one embodiment, the tablet pharmaceutical composition comprises: a. About 25% by weight to about 35% by weight of compound 1 hemifumarate; b. Microcrystalline cellulose, approximately 37% to approximately 43% by weight; c. Approximately 18% to approximately 22% by weight of anhydrous lactose; d. About 2% to about 6% by weight of hydroxypropyl cellulose; e. Approximately 5% to approximately 7% by weight of croscarmellose sodium; f. about 0.2% by weight to about 0.4% by weight of colloidal silicon dioxide; and g. Magnesium stearate, about 0.5% to about 3.5% by weight; and as appropriate h. Membrane coating.

[0171] In one embodiment, the tablet pharmaceutical composition comprises: a. About 25% by weight to about 35% by weight of compound 1 hemifumarate; b. Microcrystalline cellulose, approximately 37% to approximately 43% by weight; c. Approximately 18% to approximately 22% by weight of anhydrous lactose; d. About 2% to about 4% by weight of hydroxypropyl cellulose; e. Approximately 5% to approximately 7% by weight of croscarmellose sodium; f. about 0.2% by weight to about 0.4% by weight of colloidal silicon dioxide; and g. Magnesium stearate, about 0.5% to about 1.5% by weight; and as appropriate h. Membrane coating.

[0172] In one embodiment, the tablet pharmaceutical composition comprises: a. About 25% by weight to about 35% by weight of compound 1 in hemifumarate form B; b. Microcrystalline cellulose, approximately 37% to approximately 43% by weight; c. Approximately 18% to approximately 22% by weight of anhydrous lactose; d. About 2% to about 6% by weight of hydroxypropyl cellulose; e. Approximately 5% to approximately 7% by weight of croscarmellose sodium; f. about 0.2% by weight to about 0.4% by weight of colloidal silicon dioxide; and g. Magnesium stearate, about 0.5% to about 3.5% by weight; and as appropriate h. Membrane coating.

[0173] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 27.75% by weight of compound 1 hemifumarate; b. Approximately 41.47% by weight of microcrystalline cellulose; c. Approximately 20.73% by weight of anhydrous lactose; d. Approximately 3% by weight of hydroxypropyl cellulose; e. Approximately 6% by weight of croscarmellose sodium; f. Approximately 0.3% by weight of colloidal silicon dioxide; and g. Approximately 0.75% by weight of magnesium stearate; and as appropriate h. Membrane coating.

[0174] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 27.75% by weight of compound 1 in its hemifumarate form B; b. Approximately 41.47% by weight of microcrystalline cellulose; c. Approximately 20.73% by weight of anhydrous lactose; d. Approximately 3% by weight of hydroxypropyl cellulose; e. Approximately 6% by weight of croscarmellose sodium; f. Approximately 0.3% by weight of colloidal silicon dioxide; and g. Approximately 0.75% by weight of magnesium stearate; and as appropriate h. Membrane coating.

[0175] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 20 to 25 mg of compound 1 hemifumarate; b. Approximately 30 mg to 35 mg of microcrystalline cellulose; c. Approximately 15 mg to 18 mg of anhydrous lactose; d. Approximately 1.5 mg to 4.5 mg of hydroxypropyl cellulose; e. Approximately 4 to 6 mg of croscarmellose sodium; f. Approximately 0.1 mg to 0.3 mg of colloidal silicon dioxide; and g. Approximately 0.5 mg to 0.7 mg of magnesium stearate; and as needed. h. Approximately 2 mg to 6 mg film-coated.

[0176] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 20 to 25 mg of compound 1 in hemifumarate form B; b. Approximately 30 mg to 35 mg of microcrystalline cellulose; c. Approximately 15 mg to 18 mg of anhydrous lactose; d. Approximately 1.5 mg to 4.5 mg of hydroxypropyl cellulose; e. Approximately 4 to 6 mg of croscarmellose sodium; f. Approximately 0.1 mg to 0.3 mg of colloidal silicon dioxide; and g. Approximately 0.5 mg to 0.7 mg of magnesium stearate; and as needed. h. Approximately 2 mg to 6 mg film-coated.

[0177] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 22.20 mg of compound 1 in hemifumarate form B; b. Approximately 30 mg to 35 mg of microcrystalline cellulose; c. Approximately 15 mg to 18 mg of anhydrous lactose; d. Approximately 1.5 mg to 4.5 mg of hydroxypropyl cellulose; e. Approximately 4 to 6 mg of croscarmellose sodium; f. Approximately 0.1 mg to 0.3 mg of colloidal silicon dioxide; and g. Approximately 0.5 mg to 0.7 mg of magnesium stearate; and as needed. h. Approximately 2 mg to 6 mg film-coated.

[0178] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 22.20 mg of compound 1 in hemifumarate form B; b. Approximately 33.17 mg of microcrystalline cellulose; c. Approximately 16.59 mg of anhydrous lactose; d. Approximately 2.4 mg of hydroxypropyl cellulose; e. Approximately 4.8 mg of croscarmellose sodium; f. Approximately 0.24 mg of colloidal silicon dioxide; and g. Approximately 0.6 mg of magnesium stearate; and as needed h. Approximately 3.2 mg film-coated.

[0179] In one embodiment, the tablet pharmaceutical composition comprises: a. About 25% by weight to about 35% by weight of compound 1 hemifumarate; b. Approximately 35% to approximately 40% by weight of microcrystalline cellulose; c. Approximately 16% to approximately 22% by weight of anhydrous lactose; d. Hydroxypropyl cellulose, approximately 3% to approximately 7% by weight; e. Sodium croscarmellose, about 3% to about 7% by weight f. about 0.1% to about 0.5% by weight of colloidal silicon dioxide; and g. Stearic acid, about 0.5% to about 3.5% by weight; and as appropriate h. Membrane coating.

[0180] In one embodiment, the tablet pharmaceutical composition comprises: a. About 25% by weight to about 35% by weight of compound 1 hemifumarate; b. Approximately 35% to approximately 40% by weight of microcrystalline cellulose; c. Approximately 16% to approximately 22% by weight of anhydrous lactose; d. Hydroxypropyl cellulose, approximately 3% to approximately 7% by weight; e. Sodium croscarmellose, about 3% to about 7% by weight f. about 0.1% to about 0.5% by weight of colloidal silicon dioxide; and g. Stearic acid, approximately 1.5% to approximately 3.5% by weight; and as appropriate. h. Membrane coating.

[0181] In one embodiment, the tablet pharmaceutical composition comprises: a. About 25% by weight to about 35% by weight of compound 1 in hemifumarate form B; b. Approximately 35% to approximately 40% by weight of microcrystalline cellulose; c. Approximately 16% to approximately 22% by weight of anhydrous lactose; d. Hydroxypropyl cellulose, approximately 3% to approximately 7% by weight; e. Sodium croscarmellose, about 3% to about 7% by weight f. about 0.1% to about 0.5% by weight of colloidal silicon dioxide; and g. Stearic acid, about 0.5% to about 3.5% by weight; and as appropriate h. Membrane coating.

[0182] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 27.75% by weight of compound 1 hemifumarate; b. Approximately 38.63% by weight of microcrystalline cellulose; c. Approximately 19.32% by weight of anhydrous lactose; d. Approximately 5% by weight of hydroxypropyl cellulose; e. Approximately 6% by weight of croscarmellose sodium f. Approximately 0.3% by weight of colloidal silicon dioxide; and g. Approximately 3% by weight of stearic acid; and as appropriate h. Membrane coating.

[0183] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 27.75% by weight of compound 1 in its hemifumarate form B; b. Approximately 38.63% by weight of microcrystalline cellulose; c. Approximately 19.32% by weight of anhydrous lactose; d. Approximately 5% by weight of hydroxypropyl cellulose; e. Approximately 6% by weight of croscarmellose sodium f. Approximately 0.3% by weight of colloidal silicon dioxide; and g. Approximately 3% by weight of stearic acid; and as appropriate h. Membrane coating.

[0184] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 20 to 25 mg of compound 1 hemifumarate; b. Approximately 30 mg to 40 mg of microcrystalline cellulose; c. Approximately 15 mg to 20 mg of anhydrous lactose; d. Approximately 3 mg to 7 mg of hydroxypropyl cellulose; e. Approximately 3 mg to 7 mg of croscarmellose sodium; f. Approximately 0.1 mg to 0.3 mg of colloidal silicon dioxide; and g. Approximately 2 mg to 4 mg of stearic acid; and as needed h. Approximately 2 mg to 5 mg film-coated.

[0185] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 20 to 25 mg of compound 1 in hemifumarate form B; b. Approximately 30 mg to 40 mg of microcrystalline cellulose; c. Approximately 15 mg to 20 mg of anhydrous lactose; d. Approximately 3 mg to 7 mg of hydroxypropyl cellulose; e. Approximately 3 mg to 7 mg of croscarmellose sodium; f. Approximately 0.1 mg to 0.3 mg of colloidal silicon dioxide; and g. Approximately 2 mg to 4 mg of stearic acid; and as needed h. Approximately 2 mg to 5 mg film-coated.

[0186] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 22.20 mg of compound 1 in hemifumarate form B; b. Approximately 30 mg to 40 mg of microcrystalline cellulose; c. Approximately 15 mg to 20 mg of anhydrous lactose; d. Approximately 3 mg to 7 mg of hydroxypropyl cellulose; e. Approximately 3 mg to 7 mg of croscarmellose sodium; f. Approximately 0.1 mg to 0.3 mg of colloidal silicon dioxide; and g. Approximately 2 mg to 4 mg of stearic acid; and as needed h. Approximately 2 mg to 5 mg film-coated.

[0187] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 22.20 mg of compound 1 in hemifumarate form B; b. Approximately 30.9 mg of microcrystalline cellulose; c. Approximately 15.46 mg of anhydrous lactose; d. Approximately 4 mg of hydroxypropyl cellulose; e. Approximately 4.8 mg of croscarmellose sodium; f. Approximately 0.24 mg of colloidal silicon dioxide; and g. Approximately 2.4 mg of stearic acid; and as needed h. Approximately 3.2 mg film-coated.

[0188] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 83 mg to 93 mg of compound 1 hemifumarate; b. Approximately 120 mg to 150 mg of microcrystalline cellulose; c. Approximately 60 mg to 80 mg of anhydrous lactose; d. Approximately 12 mg to 30 mg of hydroxypropyl cellulose; e. Approximately 12 mg to 30 mg of croscarmellose sodium; f. Approximately 0.5 mg to 1.5 mg of colloidal silicon dioxide; and g. Approximately 8 mg to 16 mg of stearic acid; and as needed. h. Approximately 8 mg to 14 mg film-coated.

[0189] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 83 mg to 93 mg of compound 1 in hemifumarate form B; b. Approximately 120 mg to 150 mg of microcrystalline cellulose; c. Approximately 60 mg to 80 mg of anhydrous lactose; d. Approximately 12 mg to 30 mg of hydroxypropyl cellulose; e. Approximately 12 mg to 30 mg of croscarmellose sodium; f. Approximately 0.5 mg to 1.5 mg of colloidal silicon dioxide; and g. Approximately 8 mg to 16 mg of stearic acid; and as needed. h. Approximately 8 mg to 14 mg film-coated.

[0190] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 88.78 mg of compound 1 in hemifumarate form B; b. Approximately 120 mg to 150 mg of microcrystalline cellulose; c. Approximately 60 mg to 80 mg of anhydrous lactose; d. Approximately 12 mg to 30 mg of hydroxypropyl cellulose; e. Approximately 12 mg to 30 mg of croscarmellose sodium; f. Approximately 0.5 mg to 1.5 mg of colloidal silicon dioxide; and g. Approximately 8 mg to 16 mg of stearic acid; and as needed. h. Approximately 8 mg to 14 mg film-coated.

[0191] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 88.78 mg of compound 1 in hemifumarate form B; b. Approximately 123.62 mg of microcrystalline cellulose; c. Approximately 61.82 mg of anhydrous lactose; d. Approximately 16 mg of hydroxypropyl cellulose; e. Approximately 19.2 mg of croscarmellose sodium; f. Approximately 0.96 mg of colloidal silicon dioxide; and g. Approximately 9.6 mg of stearic acid; and as needed h. Approximately 12.8 mg film-coated.

[0192] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 100 mg to 120 mg of compound 1 in hemifumarate form B; b. Approximately 140 mg to 160 mg of microcrystalline cellulose; c. Approximately 70 mg to 90 mg of anhydrous lactose; d. Approximately 15 mg to 25 mg of hydroxypropyl cellulose; e. Approximately 20 mg to 30 mg of croscarmellose sodium; f. Approximately 0.8 mg to 2.0 mg of colloidal silicon dioxide; and g. Approximately 9 mg to 18 mg of stearic acid; and as appropriate. h. Approximately 10 mg to 30 mg film-coated.

[0193] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 111 mg of compound 1 in hemifumarate form B; b. Approximately 140 mg to 160 mg of microcrystalline cellulose; c. Approximately 70 mg to 90 mg of anhydrous lactose; d. Approximately 15 mg to 25 mg of hydroxypropyl cellulose; e. Approximately 20 mg to 30 mg of croscarmellose sodium; f. Approximately 0.8 mg to 2.0 mg of colloidal silicon dioxide; and g. Approximately 9 mg to 18 mg of stearic acid; and as appropriate. h. Approximately 10 mg to 30 mg film-coated.

[0194] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 111 mg of compound 1 in hemifumarate form B; b. Approximately 154.52 mg of microcrystalline cellulose; c. Approximately 77.28 mg of anhydrous lactose; d. Approximately 20 mg of hydroxypropyl cellulose; e. Approximately 24 mg of croscarmellose sodium; f. Approximately 1.2 mg of colloidal silicon dioxide; and g. Approximately 12 mg of stearic acid; and as needed h. Approximately 16 mg film-coated.

[0195] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 130 mg to 140 mg of compound 1 in hemifumarate form B; b. Approximately 165 mg to 195 mg of microcrystalline cellulose; c. Approximately 80 mg to 100 mg of anhydrous lactose; d. Approximately 20 mg to 30 mg of hydroxypropyl cellulose; e. Approximately 25 mg to 35 mg of croscarmellose sodium; f. Approximately 1.0 mg to 2.5 mg of colloidal silicon dioxide; and g. Approximately 10 mg to 20 mg of stearic acid; and as needed h. Approximately 15 mg to 35 mg film-coated.

[0196] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 132 mg of compound 1 in hemifumarate form B; b. Approximately 165 mg to 195 mg of microcrystalline cellulose; c. Approximately 80 mg to 100 mg of anhydrous lactose; d. Approximately 20 mg to 30 mg of hydroxypropyl cellulose; e. Approximately 25 mg to 35 mg of croscarmellose sodium; f. Approximately 1.0 mg to 2.5 mg of colloidal silicon dioxide; and g. Approximately 10 mg to 20 mg of stearic acid; and as needed h. Approximately 15 mg to 35 mg film-coated.

[0197] In one embodiment, the tablet pharmaceutical composition comprises: a. Approximately 132 mg of compound 1 in hemifumarate form B; b. Approximately 185.42 mg of microcrystalline cellulose; c. Approximately 92.74 mg of anhydrous lactose; d. Approximately 24 mg of hydroxypropyl cellulose; e. Approximately 28.8 mg of croscarmellose sodium; f. Approximately 1.44 mg of colloidal silicon dioxide; and g. Approximately 14.4 mg of stearic acid; and as needed h. Approximately 19.2 mg film-coated. [Treatment methods] []

[0198] In another embodiment, the present invention relates to a method of treating a disease, symptom, or syndrome mediated at least in part by regulating the in vivo activity of a protein kinase, comprising administering to an individual in need a pharmaceutical composition in crystalline or crystalline salt form of compound 1 as described herein.

[0199] In one embodiment of this state, the disease, condition, or syndrome mediated at least in part by the regulation of the in vivo activity of protein kinases is cancer.

[0200] In one embodiment, the cancer is selected from cardia cancer, head and neck cancer, lung cancer, colon cancer, gastrointestinal cancer, breast cancer, urogenital tract cancer, liver cancer, bone cancer, thyroid cancer, nervous system cancer, gynecological cancer, blood cancer, skin cancer, and adrenal cancer.

[0201] In another embodiment, the gastric cardia cancer is selected from angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma.

[0202] In another embodiment, the head and neck cancer is selected from squamous cell carcinoma of the head and neck, laryngeal and hypopharyngeal carcinoma, nasal cavity and paranasal sinus carcinoma, nasopharyngeal carcinoma, salivary gland carcinoma, oral cavity and oropharyngeal carcinoma.

[0203] In another embodiment, the lung cancer is selected from bronchial carcinoma (selected from squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma and non-small cell lung cancer), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, and mesothelioma.

[0204] In another embodiment, colon cancer is selected from colorectal cancer, adenocarcinoma, gastrointestinal stromal tumor, lymphoma, carcinoid tumor, and Turner syndrome.

[0205] In another embodiment, the gastrointestinal cancer is selected from gastric cancer, gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, esophageal leiomyosarcoma, esophageal lymphoma, gastric carcinoma, gastric lymphoma, gastric leiomyosarcoma, pancreatic duct adenocarcinoma, insulinoma, glucagonoma, pancreatogastrominoma, pancreatic carcinoid tumor, vasoactive intestinal peptide tumor, small intestinal adenocarcinoma, small intestinal lymphoma, small intestinal carcinoid tumor, small intestinal Kaposi's sarcoma, small intestinal leiomyoma, small intestinal hemangioma, small intestinal lipoma, small intestinal neurofibroma, small intestinal fibroma, large intestinal adenocarcinoma, large intestinal tubular adenoma, large intestinal villous adenoma, large intestinal hamartoma, and large intestinal leiomyoma.

[0206] In another embodiment, the breast cancer is selected from metastatic breast cancer, ductal carcinoma in situ, invasive ductal carcinoma, tubular carcinoma, medullary carcinoma, mucinous carcinoma, lobular carcinoma in situ, and triple-negative breast cancer;

[0207] In another embodiment, the urogenital tract cancer is selected from renal adenocarcinoma, nephroblastoma, renal lymphoma, renal cell carcinoma, squamous cell carcinoma of the bladder or urethra, transitional cell carcinoma of the bladder or urethra, adenocarcinoma of the bladder or urethra, urothelial carcinoma of the bladder or urethra, prostate cancer, prostate sarcoma, castration-resistant prostate cancer, seminoma, testicular teratoma, embryonal carcinoma, testicular teratoma, choriocarcinoma of the testis, testicular sarcoma, testicular stromal cell carcinoma, testicular fibroma, testicular fibroadenoma, testicular adenoma-like tumor, testicular lipoma, clear cell carcinoma, and papillary carcinoma.

[0208] In another embodiment, the liver cancer is selected from hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0209] In another embodiment, the bone cancer is selected from osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma, benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor.

[0210] In another embodiment, the thyroid cancer is selected from medullary thyroid carcinoma, differentiated thyroid carcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma, Schulte cell carcinoma, and undifferentiated thyroid carcinoma;

[0211] In another embodiment, the nervous system cancer is selected from skull osteoma, skull hemangioma, skull granuloma, skull xanthoma, skull deforming osteitis, cerebrospinal meningioma, cerebrospinal meningeal sarcoma, cerebrospinal meningoblastoma, astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], multimorphic glioblastoma, oligodendroglioma, schwannoma, retinoblastoma, congenital brain tumor, spinal neurofibroma, cerebrospinal meningioma, and brain sarcoma.

[0212] In another embodiment, the gynecological cancers are selected from endometrial cancer, cervical cancer, pretumoral cervical dysplasia, ovarian cancer (selected from serous cystadenocarcinoma, mucinous cystadenocarcinoma and unclassified ovarian cancer), granulosa-theca cell tumors, Cetley-Ledich cell tumors, malignant germ cell tumors and malignant teratomas; vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulvar adenocarcinoma, vulvar fibrosarcoma, vulvar melanoma, vaginal clear cell carcinoma, vaginal squamous cell carcinoma, embryonal rhabdomyosarcoma and fallopian tube cancer.

[0213] In another embodiment, the blood cancer is selected from myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodyplasia syndrome, Hodgkin's disease, and non-Hodgkin's lymphoma [malignant lymphoma].

[0214] In another embodiment, the skin cancer is selected from malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, developmental nevus, lipoma, hemangioma, dermatofibroma, keloid, and psoriasis.

[0215] In another embodiment, the adrenal carcinoma is a neuroblastoma.

[0216] In another embodiment, the cancer is advanced clear cell renal cell carcinoma, hormone receptor-positive breast cancer, or castration-resistant prostate cancer.

[0217] In another embodiment, the cancer is advanced clear cell renal cell carcinoma.

[0218] In another embodiment, the cancer is hormone receptor-positive breast cancer.

[0219] In another embodiment, the cancer is castration-resistant prostate cancer.

[0220] In another embodiment, the cancer is non-clear cell renal cell carcinoma.

[0221] In another embodiment, the cancer is clear cell renal cell carcinoma. [Labeled Compounds and Analytical Methods] []

[0222] Another aspect relates to the labeled crystalline or crystalline salt forms of the present invention (radioactively labeled, fluorescently labeled, etc.), which can be used not only in imaging techniques but also in in vitro and in vivo analyses for locating and quantifying TAM kinases in tissue samples (including humans) and for identifying TAM kinase ligands by inhibiting the binding of the labeled compounds. Therefore, the present invention includes TAM kinase analysis containing such labeled compounds.

[0223] This invention further includes the isotopically labeled crystalline form or crystalline salt form of the invention. The "isotopically labeled" or "radioactively labeled" compound is the crystalline form or crystalline salt form of the invention, wherein one or more atoms are replaced or substituted with atomic masses or mass numbers different from those commonly found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the crystalline form or crystalline salt form of the invention include (but are not limited to) 2H (deuterium, also written as D), 3H (tritium, also written as T), 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I, and 131I. The radionuclides incorporated into the radiolabeled compounds of this invention will depend on the specific application of the radiolabeled compound. For example, for in vitro metalloproteinase labeling and competitive analysis, compounds containing 3H, 14C, 82Br, 125I, 131I, or 35S are generally most useful. For radiographic imaging applications, 11C, 18F, 125I, 123I, 124I, 131I, 75Br, 76Br, or 77Br are generally most useful. In some embodiments, the crystalline or crystalline salt forms described herein, wherein one or more hydrogen atoms are deuterated, such as hydrogen atoms bonded to carbon atoms, exhibit increased resistance to metabolism and are thus used to extend the half-life of any compound when administered to mammals, specifically humans.

[0224] It should be understood that "radiolabeled" or "labeled compound" refers to a compound having at least one radioactive nucleus. In some embodiments, the radioactive nucleus is selected from the group consisting of: 3H, 14C, 125I, 35S, and 82Br.

[0225] The present invention may further include a synthetic method incorporating a radioactive isotope into the crystalline form or crystalline salt form of the present invention. Synthetic methods incorporating radioactive isotopes into organic compounds are well known in the art, and those skilled in the art will readily identify methods applicable to the compounds of the present invention.

[0226] The labeled compounds of this invention can be used in screening analyses to identify / evaluate compounds. For example, the ability of a newly synthesized or identified labeled compound (i.e., the test compound) to bind to TAM can be evaluated by monitoring the concentration change of the test compound upon contact with TAM kinase (via label tracking). For example, the ability of the labeled test compound to reduce the binding of another compound known to bind to TAM kinase (i.e., the standard compound) can be evaluated. Therefore, the ability of the test compound to compete with the standard compound for binding to TAM kinase is directly related to its binding affinity. Conversely, in some other screening analyses, the standard compound is labeled, and the test compound is unlabeled. Therefore, the concentration of the labeled standard compound is monitored to assess the competition between the standard compound and the test compound, thereby determining the relative binding affinity of the test compound. [Example] [] [General Experimental Techniques] []

[0227] Aqueous slurry experiment: A salt of compound 1 with a water solubility of less than 1 mg / mL was prepared in 20 mL of water for 1 day at ambient temperature. The solids were then collected by vacuum filtration and analyzed by XRPD.

[0228] Rapid cooling (CC): Concentrated solutions of compound 1 and its various relative ions are prepared in MeOH under elevated temperature and stirring. The capped vials containing the hot solutions are transferred to a freezer (approximately -20°C) and rapidly cooled. The resulting solids are collected. If no solids are found, additional crystallization techniques are employed.

[0229] Rapid precipitation (CP): Clear solutions of compound 1 and its coconstitutes are prepared at room temperature in various solvents. Equal aliquots of various antisolvents are slowly added to the solution, with gentle stirring, until solids precipitate from the solution. The mixture is stirred for a specified period. The resulting solids are collected by positive pressure filtration.

[0230] Rapid cooling (FC): Concentrated solutions of compound 1 and its various relative ions are prepared in acetone or MeOH under elevated temperature and stirring. The capped vials containing the hot solutions are transferred to a tabletop at ambient temperature. The resulting solid is collected. If no solid is found, additional crystallization techniques are employed.

[0231] Rapid evaporation (FE): Preparation of clear solutions of compound 1 and its co-constitutes in various solvents. The solvent is evaporated under ambient conditions without capping the vial.

[0232] Tautomorphic slurry: A slurry of form A of compound 1 is prepared by adding sufficient solids to a given solvent system under ambient conditions to ensure the presence of insoluble solids. The mixture is then agitated for an extended period to ensure saturation. The solids of the form of interest are then added to an aliquot of the saturated solution (filtered via a 0.2 μm Nylon filter) to ensure the presence of insoluble solids. The mixture is then agitated at ambient temperature for an extended period, and the solids are separated.

[0233] Separation techniques: Generally, separation is performed rapidly after non-environmental samples are removed from their respective temperature control devices to minimize the equilibration with ambient temperature before the solids are separated.

[0234] Decantation: Some solids separated according to solution-based crystallization techniques are collected by centrifuging the suspension (if necessary) and discarding the liquid phase, leaving a moist solid. Unless specified herein as "analytical moisture", the solids are briefly dried (e.g., air-dried or dried under nitrogen).

[0235] Positive pressure filtration: Solids are collected on a 0.2-μm Nylon or PTFE filter by pressing the slurry through a syringe and a Swinnex filter holder assembly. Generally, the solids are briefly dried by blowing 20-mL of air through the syringe onto the filter. If designated "analytical moisture" herein, the solids are kept moist using the mother liquor. Some samples are further briefly dried under a gentle nitrogen flow prior to analysis.

[0236] Vacuum filtration: Solids are collected on paper or nylon filters by vacuum filtration, and then briefly air-dried on the filters under reduced pressure before being transferred to vials.

[0237] Reactive crystallization (RC): A mixture of compound 1 and various coconstitutes is combined in an acetone slurry heated to a temperature that makes the molar concentration of the coconstitutes twice that of the API. The solution is stirred for a given period. When a clear solution is observed, additional crystallization techniques are employed.

[0238] Stability testing: Various compound 1 salts were placed in open vials within a stability testing chamber (e.g., 60% or 75% relative humidity (RH) and a saturated sodium chloride solution). The RH chamber was then placed in an oven (e.g., 25°C or 40°C) for a period of time. At the end of the duration, the samples were analyzed using PLM and XRPD.

[0239] Dissolution test: The dissolution and release of compound 1 in various pharmaceutical compositions of compound 1 were determined by high performance liquid chromatography (HPCL). Pharmaceutical compositions or tablets of compound 1 were placed in a dissolution medium of 0.375% Triton X-100 in 0.01 N HCl at a temperature of 37.0 ± 0.5 °C. Sample solutions were collected at time points of 5, 10, 20, 30, 45, 60, 90, 120, 10, 180, and 210 minutes for HPLC analysis.

[0240] Slow cooling (SC): Concentrated solutions of compound 1 and various co-constitutes are prepared in various solvents under elevated temperature and stirring. The vials in the heated sample block are capped and the hot plate is closed, allowing the vials to gradually cool to ambient temperature within the heated vial block. The clarified solution is then further cooled to ambient temperature in a refrigerator (5°C to 7°C) and / or a freezer (approximately -20°C). If no solid is present, an additional crystallization technique is employed.

[0241] Slow evaporation: Prepare solutions in various solvents and agitate, typically through a 0.2-μm Nylon or PTFE filter. Unless otherwise specified, allow each solution to evaporate under ambient conditions in a capped vial (such as a loose cap or one covered with porous aluminum foil). Allow the solution to evaporate to dryness, unless specified as partial evaporation (the presence of solids with a small amount of residual solvent), in which case the solids are separated as described herein.

[0242] Solubility estimation: At a specified temperature, equal aliquots of various solvents are added to the compound 1 to be measured and stirred (usually with sonication) until complete dissolution is achieved as determined by visual observation. If dissolution occurs after the addition of the first aliquot, the value is reported as ">". If no dissolution occurs, the value is reported as "<".

[0243] Water solubility estimation: Equal portions of water were added to various compounds and salts to be measured and subjected to acoustic treatment.

[0244] Slurry preparation experiments: Saturated solutions of Compound 1 and various co-constitutes were prepared in a variety of solvents and solvent mixtures. The mixtures were stirred at ambient temperature and at elevated temperatures for the specified durations. Solids were collected using prescribed techniques, and additional crystallization techniques were employed where appropriate.

[0245] Vacuum Oven Desolvation: An attempt was made to desolvate the salt of compound 1, which was identified as a solvate by various analytical methods. The sample was placed in a vacuum oven at a temperature range of ambient to 80°C for a given period of time. The sample was analyzed by XRPD and / or TGA to determine whether the desolvation was successful.

[0246] Vapor diffusion: Concentrated solutions are prepared in various solvents, typically filtered through a 0.2-μm Nylon or PTFE filter. The filtered solution is dispensed into vials, which are then placed inside a larger vial containing the antisolvent. The vials are left uncapped, while the larger vial is capped to allow vapor diffusion. This is used to separate any solids present, as described herein.

[0247] Vapor stress: The selected solid is transferred to a vial, which is then placed inside a larger vial containing the solvent. The vial is left uncapped while the larger vial is capped to allow vapor stress to occur at a specified temperature.

[0248] Co-constitutes refer to one or more medically acceptable bases and / or medically acceptable acids that associate with compound 1 as disclosed herein. Exemplary co-constitutes used herein include fumaric acid, HCl, and phosphoric acid. [] [Instrument Technology] []

[0249] Differential Scanning Calorimetry (DSC): DSC was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Temperature calibration was performed using adamantane, phenyl salicylate, indium, tin, and zinc. The sample was placed in an airtight or open aluminum DSC pan, and its weight was accurately recorded. A weighing aluminum pan configured as the sample pan was placed on the reference side of the small division. The sample was analyzed from -30°C to 250°C at a ramp rate of 10°C / min. Although the temperature graph is plotted against a reference temperature (x-axis), the results are reported based on the sample temperature. Dynamic vapor adsorption (DVS)

[0250] a. VTI: Automated vapor adsorption (VS) data were collected on a VTI SGA-100 vapor adsorption analyzer. NaCl and PVP were used as calibration standards. Samples were dried before analysis. Adsorption and desorption data were collected in 10% RH increments from 5% to 95% RH under nitrogen purging. The equilibrium criterion used for analysis was a weight change of less than 0.0100% within 5 minutes, with a maximum equilibrium time of 3 hours. Data were not corrected for the initial moisture content of the samples.

[0251] b. Intrinsic: Automated vapor adsorption (VS) data were collected on the Surface Measurement System DVS Intrinsic instrument. Samples were not dried prior to analysis. Adsorption and desorption data were collected under nitrogen purging in 10% RH increments within the range of 5% to 95% RH. The equilibrium criterion used for analysis was a weight change of less than 0.0100% within 5 minutes, with a maximum equilibrium time of 3 hours. Data were not corrected for the initial moisture content of the samples.

[0252] High-Temperature Stage Microscopy (HSM): High-temperature stage microscopy was performed using a Linkam high-temperature stage (FTIR 600) mounted on a Leica DM LP microscope equipped with a SPOT Insight™ color digital camera. Temperature calibration was performed using USP melting point standards. The sample was placed on a cover glass, with a second cover glass placed on top of the sample. While the stage was heated, each sample was visually observed using a 20× objective lens with a cross polarizer and a first-order red compensator. Images were captured using SPOT software (version 4.5.9).

[0253] Optical microscopy: Observe the sample under a Motic or Wolfe optical microscope with a cross polarizer or a Leica stereo microscope with a first-order red compensator and a cross polarizer.

[0254] pKa and logP measurements: pKa and logP measurements were performed by Pion Inc. / Sirius Analytical Instruments Ltd., located in East Sussex, UK.

[0255] Solution proton nuclear magnetic resonance spectroscopy (¹H NMR): Solution ¹H NMR spectra were acquired by Spectral Data Services, Champaign, IL. Samples were prepared by dissolving approximately 5–10 mg of sample in DMSO-d6. Data acquisition parameters are shown on the first page of each spectrum in the Data section of this report.

[0256] Thermogravimetric analysis (TGA): Thermogravimetric analysis was performed using a Mettler Toledo TGA / DSC3+ analyzer. Temperature calibration was performed using phenyl salicylate, indium, tin, and zinc. Samples were placed in aluminum pans. The open pans were inserted into the TG furnace. The furnace was heated under nitrogen. Each sample was heated from ambient temperature to 350°C at ramp rates of 2°C / min, 5°C / min, or 10°C / min. Although temperature graphs are plotted against a reference temperature (x-axis), results are reported based on sample temperature. X-ray powder diffraction (XRPD)

[0257] a. Reflection: At room temperature (298 g / L), XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer with an incident beam of Cu Kα radiation generated by a long, fine-focus source and a nickel filter. The diffractometer used a symmetrical Bragg-Brentano geometry. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to confirm that the observed Si 111 peak position was consistent with the position demonstrated by NIST. The sample was mounted in a bore. An anti-scattering slit (SS) was used to minimize background from air. A Soller slit targeting both the incident and diffracted beams was used to minimize broadening caused by axial divergence. Diffraction patterns were collected using a scan position-sensitive detector (X'Celerator) located 240 mm from the sample and Data Collector software version 2.2b. The data acquisition parameters for each pattern are shown above the image in the data section of this report, including the divergence slit (DS) and the incident beam SS.

[0258] b. Transmission: At room temperature (298 g eV), an incident beam of Cu radiation generated using an Optix long-focus source was used to collect XRPD patterns using a PANalytical X'Pert PRO MPD diffractometer. Cu Kα X-rays were focused through the sample and onto the detector using an elliptical graded multilayer mirror. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to confirm that the observed Si 111 peak position was consistent with the position demonstrated by NIST. The sample was sandwiched between 3 μm thick films and analyzed using transmission geometry. Background from air was minimized using a beam trap, short antiscattering extension, and antiscattering kerf. Broadening caused by axial divergence was minimized using a Soler slit targeting both the incident and diffracted beams. The diffraction pattern was collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the sample and Data Collector software version 2.2b. The data acquisition parameters for each pattern are displayed above the image in the data section of this report, including the diverging slit (DS) in front of the mirror. [XRPD] [index]

[0259] Indexing and structural refinement are performed for computational studies. Within a reference plot of a given indexed XRPD pattern, the consistency between the permissible peak positions (marked with bars) and the observed peaks indicates the unit cell determination. Unless otherwise stated, successful indexing of the pattern indicates that the sample is primarily composed of a single-crystal phase. The space groups consistent with the assigned extinction symbol, unit cell parameter, and derived quantity are tabulated. [Examples of Compound Preparation] [] [Preparative Example] [1] [:compound] [1] [Synthesis] [] Step 1: N-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-dimethylamine (4):

[0260] 3-(ethyliminomethyleneamino)-N,N-dimethyl-propyl-1-amine hydrochloride (EDCI) (10.31 g, 53.8 mmol, 1.2 eq.) was added to a solution of compound 2 (10 g, 44.80 mmol, 1 eq.) in dimethylacetamide (DMA) (60 mL). The mixture was stirred vigorously at 20 °C until the reaction was complete. The mixture was poured into a saturated aqueous solution of NaHCO3 (aq) (400 mL) and extracted with EtOAc (4 × 100 mL). The combined organic phases were washed with a saturated aqueous solution of NaCl (100 mL), dried over anhydrous Na2SO4, and concentrated. Compound 4 (21 g, crude) (50% purity) was obtained. ¹H NMR (400 MHz, DMSO-d⁶) δ 10.16 (br s, ¹H), 9.72 (br s, ¹H), 7.61 (dd, 2H), 7.34 (d, 2H), 7.13 (t, 2H), 6.68 (d, 2H), 1.42 (s, 4H); MS (EI) of C₁₇H₁₅FN₂O₃, experimental value 314.9 (MH⁺). Step 2: 4-[4-[[1-[(4-fluorophenyl)aminomethoxy]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid methyl ester (6):

[0261] A mixture of compound 4 (5.99 g, 9.5 mmol, 1.2 eq.), compound 5 (2 g, 8.0 mmol, 1.0 eq.), Pd(OAc)₂ (89 mg, 397.4 μmol, 0.05 eq.), racemic-2-(di-tert-butylphosphino)-1,1′-binaphthyl (TrixiePhos, 316.71 mg, 794.7 μmol, 0.1 eq.), and K₃PO₄ (2.53 g, 11.9 mmol, 1.5 eq.) in anisole (50 mL) was stirred at 110 °C under a nitrogen atmosphere for 2 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by rapid silica gel chromatography (1:1 petroleum ether: EtOAc to 20:1 EtOAc: MeOH). Compound 6 was obtained (2.6 g, 61.8% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.38 (s, 1H), 8.80 (s, 1H), 8.63 (d, 2H), 7.64 (d, 2H), 7.54–7.41 (m, 3H), 7.18 (d, 2H), 7.09–7.01 (m, 2H), 6.43 (d, 1H), 4.05 (s, 3H), 3.97 (s, 3H), 1.78–1.72 (m, 2H), 1.69–1.63 (m, 2H); MS (EI) of C₂₉H₂₄FN₃O₆, experimental value 530.0 (MH⁺). Step 3: 4-[4-[[1-[(4-fluorophenyl)aminomethoxy]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (7)

[0262] To compounds [6] (1.8 g, 3.4 mmol, 1 eq.) was added to a solution of tetrahydrofuran (THF) (15 mL) and MeOH (15 mL) with 2 M NaOH aqueous solution (7 mL, 4.1 eq.). The mixture was stirred at 6 °C–13 °C for 4 hours. The mixture was adjusted to pH approximately 8 with 1 M HCl aqueous solution and concentrated to remove the solvent. Water (50 mL) was added, and the mixture was adjusted to pH approximately 6 with 1 M HCl aqueous solution. The resulting precipitate was filtered, washed with water (2 × 10 mL), and dried under vacuum. The compound was obtained. [7](1.7 g, 97.0% yield). ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.22 (s, 1H), 10.08 (s, 1H), 8.65 (d, 1H), 8.48 (s, 1H), 7.77 (d, 2H), 7.64 (dd, 2H) 7.47 (s, 1H), 7.25 (d, 2H), 7.15 (t, 2H), 6.45 (d, 1H), 3.96 (s, 3H), 1.47 (s, 4H); MS (EI) of C 28H 22FN 3O 6, experimental value 516.1 (MH+). Step 4: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylaminomethoxy)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dimethylamine (1)

[0263] compound [7] A solution of HATU (332 mg, 873.2 μmol, 1 eq.), DIEA (301 mg, 2.3 mmol, 406 μL, 4 eq.) in DMF (10 mL) was stirred at 6-10 °C for 1 hour. Methylamine hydrochloride (79 mg, 1.2 mmol, 2.0 eq.) was added, and the mixture was stirred at 6-10 °C for 17 hours. The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Waters Xbridge 150 mm * 25 mm * 5 μm, gradient: 33%-63% acetonitrile in 10 mM NH4HCO3 aqueous solution, flow rate: 25 mL / min). The compound was obtained. [1](105.4 mg, 34.3% yield). ¹H NMR (400 MHz, DMSO-d⁶) δ 10.20 (s, ¹H), 10.06 (s, ¹H), 8.65 (d, ¹H), 8.61 (s, ¹H), 8.42–8.33 (m, ¹H), 7.77 (d, 2H), 7.68–7.61 (m, 2H), 7.51 (s, ¹H), 7.25 (d, 2H), 7.19–7.11 (m, 2H), 6.46 (d, ¹H), 4.02 (s, 3H), 2.84 (d, 3H), 1.47 (s, 4H); MS (EI) of C₂₉H₂₅FN₄O₅, experimental value 529.1 (MH⁺). [Example] [1] [:compound] [1] [Fumarate Form] [A] [Preparation] []

[0264] Fumaric acid (1 eq.) in acetone was added to the free base (1 eq.) of compound 1, and the resulting red slurry was stirred at approximately 50°C for 4 days. The slurry was then slowly cooled to room temperature and stirred for another day to provide a pink slurry. The solids were then removed by positive pressure filtration to provide a mixture of fumarate form A and free base form A. [Example] [2] [:compound] [1] [Semi-fumarate form] [B] [Preparation] []

[0265] Fumaric acid (2 eq.) in acetone was added to the free base (1 eq.) of compound 1, and the resulting red slurry was stirred at about 50°C for 6 days to provide a grayish-white slurry. The solids were then removed by positive pressure filtration of the hot solution to provide hemifumarate form B. [Example] [3] [:compound] [1] [Hydrochloride form] [A] [Preparation] []

[0266] One eq. of HCl was added to the free base of compound 1 in THF, and the resulting deep red slurry was stirred at room temperature for 3 days to provide a thick, grayish-white slurry. The solids were then removed by positive pressure filtration to provide hydrochloride form A. [Example] [4] [:compound] [1] [Hydrochloride form] [B] [Preparation] []

[0267] One eq. of HCl was added to the free base of compound 1 in chloroform, and the resulting red slurry was stirred at 50°C for about 3 days to provide a light pink slurry. The solids were then removed by positive pressure filtration to provide hydrochloride form B. [Example] [5] [:compound] [1] [Hydrochloride form] [C] [Preparation] []

[0268] At approximately 60°C, 1 eq. of HCl was added to the free base of compound 1 in methanol, yielding a yellow slurry. The solution was then rapidly cooled to approximately -20°C and maintained at this temperature for approximately 2 days to provide a clear orange solution. Partial rapid evaporation provided a clear red solution, and then four volumes of the antisolvent MTBE were added. The solution was stirred at room temperature for 1 day to provide a grayish-white solid, compound 1 hydrochloride form C, which was separated by positive pressure filtration. [Example] [6] [:compound] [1] [Hydrochloride form] [D] [Preparation] []

[0269] 2 eq. HCl was added to the free base of compound 1 at approximately 50°C, and the resulting pink slurry was stirred at 50°C for 5 days. The solid compound 1 hydrochloride form D was separated by positive pressure filtration. [Example] [7] [:compound] [1] [form] [A] [Preparation] []

[0270] Compound 1, form A, is likely the most thermodynamically stable crystalline form of the free base of compound 1. Therefore, various procedures lead to the formation of this form. A list of some possible procedures for obtaining compound 1, form A, is presented in Table 1. This list in Table 1 is not intended to be exclusive; in fact, there may be many more procedures that will produce this form. [surface] [1] [:used to generate compounds] [1] [form] [A] [Selected Program] [] [solvent] [condition] ACN / Water 80:20 1) Pulping at 2℃-8℃ for 14 days; or 2) Pulping at room temperature for 14 days Chloroform Pulping was carried out at 57℃ for 2 days. DCM Pulping at room temperature for 14 days Ethyl acetate Pulping at 76℃ for 3 days ethanol 1) Pulping at room temperature for 14 days; or 2) Pulping at 76℃ for 3 days ethanol / water 90:10 Pulping at room temperature for 14 days Isopropanol 1) Pulping at room temperature for 14 days; or 2) Pulping at 76℃ for 3 days methanol 1) Pulping at room temperature for 14 days; 2) Pulping at 57℃-58℃ for 4 days; or 3) Rapid evaporation Methanol / ethyl acetate 3:2 Pulping at room temperature for 14 days 2,2,2-Trifluoroethanol 1) Slow evaporation; 2) Rapid evaporation; or 3) Use diethyl ether as an antisolvent for rapid precipitation, followed by pulping for 1 day. Tetrahydrofuran 1) Pulping at room temperature for 14 days; or 2) Pulping at 57℃-58℃ for 4 days Tetrahydrofuran / water 50:50 Pulping at room temperature for 14 days [Example] [8] [:compound] [1] [form] [B] [Preparation] []

[0271] Compound 1 was dissolved in AcOH, and crystallization was carried out by vapor diffusion using diethyl ether as an antisolvent. [Example] [9] [:compound] [1] [form] [C] [Preparation] []

[0272] Compound 1 was dissolved in HFIPA and crystallized by rapid precipitation using MTBE as an antisolvent. [Example]

[10] [:compound] [1] [form] [D] [Preparation] []

[0273] Compound 1 was dissolved in methanol and crystallized by rapid cooling. The mixture was then pulped at 2°C–8°C to provide form D. [Example]

[11] [:compound] [1] [form] [E] [Preparation] []

[0274] Method A: Compound 1 was dissolved in THF and crystallized by rapid cooling.

[0275] Method B: Compound 1 was dissolved in 90:10 THF: water and precipitated by rapid precipitation. [Example]

[12] [:compound] [1] [form] [F] [Preparation] []

[0276] Method A: Compound 1 was dissolved in chloroform and crystallized by slow evaporation.

[0277] Method B: Prepare compound 1 in chloroform. [Example]

[13] [:compound] [1] [form] [G] [Preparation] []

[0278] Compound 1 was dissolved in chloroform and crystallized by placing the mixture in a freezer. [Example]

[14] [:compound] [1] [form] [H] [Preparation] []

[0279] Form H was obtained by adsorbing amorphous compound 1 with DCM vapor. [Example]

[15] [:compound] [1] [form] [K] [Preparation] []

[0280] Compound 1, form K, is prepared by desolvating either form F or form G, which are chloroform solvates. [Example]

[16] [:compound] [1] [form] [O] [Preparation] []

[0281] Compound 1, in form O, was discovered during attempts with salts of various relative ions in solvent systems containing TFE, and may be a TFE solvate. [Example]

[17] [:compound] [1] [Phosphate form] [A] [Preparation] []

[0282] One mole equivalent of phosphoric acid was added to a slurry of compound 1 in chloroform, and the resulting mixture was then slurried at approximately 50°C for 3 days. The product was separated by positive pressure filtration. [Example]

[18] [:compound] [1] [form] [I] [Preparation] []

[0283] Compound 1 in a 90:10 THF / water mixture was rapidly precipitated with heptane, and then stirred at a freezing temperature for 7 days. [Example]

[19] [:compound] [1] [form] [J] [Preparation] []

[0284] Compound 1 was prepared in acetone for 14 days. [Example]

[20] [:compound] [1] [form] [L] [Preparation] []

[0285] Compound 1 was prepared in chloroform for 14 days. [Example] [twenty one] [:compound] [1] [form] [M] [Preparation] []

[0286] Compound 1, form E, was dehydrated for 1 day in a vacuum oven at approximately 77°C. [Example] [twenty two] [:compound] [1] [form] [N] [Preparation] []

[0287] Compound 1 was pulped at room temperature in a 70:30 mixture of TFE / MTBE for 7 days. [Preparative Example] [2] [:compound] [1] Synthesis of hemifumarate [] [4-] [chlorine] [-7-] [Methoxy] [-N-] [Methylquinoline] [-6-] Synthesis of methamide []

[0288] 4-Chloro-7-methoxyquinoline-6-carboxylic acid methyl ester [5] Methylamine (33% w / w, 8 M, 20 mL, 160 mmol) and H₂O (10 mL) in EtOH were added to a suspension of 2 g (8 mmol) in THF (20 mL). The mixture was stirred at room temperature. The mixture became a clear solution within about 10 min and remained a clear solution during the reaction. Stirring was continued until the starting material was completely exhausted as demonstrated by LCMS and HPLC. This took about 3 hours. The mixture was then concentrated, and the residue was slurried in 20 mL of water and filtered. The material was transferred from the flask to a filter funnel using some EtOAc. The product was dried to give 4-chloro-7-methoxy-N-methylquinoline-6-methylamine as a white solid (yield 1.8 g, 90%, HPLC purity > 97%). [4-(4-)] [aminophenoxy] [)-7-] [Methoxy] [-N-] [Methylquinoline] [-6-] Synthesis of methamide []

[0289] 4-Chloro-7-methoxy-N-methylquinoline-6-methamide was packed into a 5 L 3-necked round-bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer. [3]; 300 g; 1 eq.), 4-aminophenol (195.9 g; 1.5 eq.) and DMA (1500 mL). The resulting solution was stirred at room temperature, and sodium tripentoxide solution (184.52 g; 1.4 eq.) dissolved in anhydrous THF (313 mL) was added over a 5-minute period with stirring. The reaction mixture was then heated to 75-80°C and stirred for 2-6 hours. The reaction mixture was then cooled to room temperature and filled with water (3 L) and stirred for at least 1 hour. The product was filtered and washed twice with 600 mL of 1:1 DMA / water, followed by one wash with 1200 mL of water. The product was transferred to a crystallizing dish and dried in a vacuum oven at 40-45°C for at least 18 hours to produce a glossy light brown solid (370-377 g; 96%-97%). [1-((4-] [Fluorophenyl] [)] [Aminomethoxy] [)] [Cyclopropane] [-1-] Synthesis of carbonyl chloride [] []

[0290] 1-((4-fluorophenyl)aminomethyl)cyclopropane-1-carboxylic acid was packed into a 250 mL three-necked round-bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer. [2], 19.11 g; 1.3 eq.), 75 mL of anhydrous THF and 0.25 mL of DMF (catalyst). The mixture was stirred until all solids were dissolved, cooled to 5°C-10°C, and then oxalic acid (7.13 mL; 1.28 eq.) was added. The resulting mixture was aged at 10°C-15°C for 2-3 hours, and the reaction was confirmed to be complete by IPC (process control). After the reaction was completed, the resulting product mixture was used in the next step without further purification. [1-((4-] [Fluorophenyl] [)] [Aminomethoxy] [)] [Cyclopropane] [-1-] [Alternative Synthesis of Carbonyl Chloride] []

[0291] 1-((4-fluorophenyl)aminomethyl)cyclopropane-1-carboxylic acid was packed into a 250 mL three-necked round-bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer. [2], 19.11 g; 1.3 eq.), 75 mL of anhydrous THF and 0.25 mL of DMF (catalyst). The mixture was stirred until all solids were dissolved, cooled to 5°C–15°C, and then loaded with oxalichlor (7.13 mL; 1.28 eq.). The resulting mixture was heated to room temperature and stirred for 2–4 hours. The resulting product mixture was used in the next step without further purification. [N-(4-)] [Fluorophenyl] [)-N-(4-((7-] [Methoxy] [-6-(] [Methylaminomethyl] [)] [Quinoline] [-4-] [base] [)] [Oxygen group] [)] [Phenyl] [)] [Cyclopropane] [-1,1-] [Dimethylamine] [(1)] [Synthesis] []

[0292] 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-methamide was packed into a 500 mL three-necked round-bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer. [9], 21.3 g; 1.0 eq.), 210 mL of anhydrous THF and a solution of potassium carbonate (27.32 g; 3 eq) and 100 mL of water. The added K₂CO₃ aqueous solution was then rinsed with 6.4 mL of water. The mixture from the previous example containing the compound was stirred vigorously for at least 30 minutes.

[10] The reaction mixture was transferred to this reaction mixture while maintaining the internal temperature between 20°C and 25°C. The transfer apparatus was rinsed with 32 mL of anhydrous THF. The reaction mixture was stirred at ambient temperature for 0.5–1 hour. The resulting mixture was heated to 35°C–40°C and the phases were separated. The lower aqueous layer was discarded and the top organic phase was heated to 55°C–60°C, followed by purification filtration and rinsing with 21 mL of THF. The filtered organic phase was transferred to a 1 L 3-necked round-bottom flask equipped with a thermometer, nitrogen inlet and mechanical stirrer, and filled with water at 55°C–60°C. The resulting solution was seeded with compound 1, and water as an antisolvent was added to the resulting seed bed after 4–4.5 hours while maintaining the temperature at 50°C–55°C. The resulting slurry was cooled to 20°C–25°C and aged for at least 2 hours. The product was then filtered, washed with water / THF and dried. [N-(4-)] [Fluorophenyl] [)-N-(4-((7-] [Methoxy] [-6-(] [Methylaminomethyl] [)] [Quinoline] [-4-] [base] [)] [Oxygen group] [)] [Phenyl] [)] [Cyclopropane] [-1,1-] [Dimethylamine] [(1)] [Alternative Synthesis] []

[0293] 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-methamide was packed into a 500 mL three-necked round-bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer. [9], 21.3 g; 1.0 eq.), 210 mL of anhydrous THF and a solution of potassium carbonate (27.32 g; 3 eq) and 100 mL of water. The added K₂CO₃ aqueous solution was then rinsed with 6.4 mL of water. Under vigorous stirring, the solution containing the compound from the previous example was removed over a period of 0.5–1 hour.

[10] The reaction mixture was transferred to this reaction mixture while maintaining the internal temperature below 27°C. The transfer apparatus was rinsed with 32 mL of anhydrous THF. The reaction mixture was stirred at ambient temperature for 0.5–1 hour. The resulting mixture was heated to 35°C–40°C and the phases were separated. The lower aqueous layer was discarded and the top organic phase was heated to 45°C–50°C and then filtered through filter paper and rinsed with 21 mL of THF. The filtered organic phase was transferred to a 1 L 3-necked round-bottom flask equipped with a thermometer, nitrogen inlet and mechanical stirrer, and filled with 694 mL of filtered water for at least 1 hour. The resulting mixture was stirred at 20°C–25°C for at least 12 hours, and then the product was filtered and rinsed twice with 42 mL of a 2:1 water:THF mixture. The product was then dried on filter paper at room temperature or in a vacuum oven at 40°C–45°C to produce a white to beige solid (31.36 g; 90%). [N-(4-)] [Fluorophenyl] [)-N-(4-((7-] [Methoxy] [-6-(] [Methylaminomethyl] [)] [Quinoline] [-4-] [base] [)] [Oxygen group] [)] [Phenyl] [)] [Cyclopropane] [-1,1-] [Dimethylamine] [·1 / 2] [Fumaric acid] [(1·)] [Semi-fumarate] [)] [Synthesis] [-] [method] [1] []

[0294] A solution of fumaric acid (80 g; 0.82 eq.) and 1.2 L of 20% water in ethanol was added to a 2000 mL three-necked round-bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer. The mixture was heated to 45°C–50°C and stirred until all solids were dissolved. N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylaminomethyl)quinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dimethylamine was added to a separate 3 L three-necked round-bottom flask equipped with a thermometer, nitrogen inlet, and mechanical stirrer. [1], 500 g; 1.0 eq.). The fumaric acid solution was clarified by filter paper at 40-45°C and transferred at 40-45°C to a flask containing compound 1. The 2000 mL round-bottom flask was then rinsed with 300 mL of 20% water in ethanol at 45-50°C. The resulting mixture was heated to reflux (75-80°C) and stirred for 4-6 hours. The reaction mixture was then cooled to room temperature, and the product was filtered and the filter cake was washed twice with 300 mL of 20% water in ethanol. The product was then dried on filter paper at room temperature or in a vacuum oven at 40-45°C to produce a white to beige solid (472-474 g; 97%). [N-(4-)] [Fluorophenyl] [)-N-(4-((7-] [Methoxy] [-6-(]methylaminomethyl [)] [Quinoline] [-4-] [base] [)] [Oxygen group] [)] [Phenyl] [)] [Cyclopropane] [-1,1-] [Dimethylamine] [·1 / 2] [Fumaric acid] [(1·)] [Semi-fumarate] [)] [Synthesis] [-] [method] [2] []

[0295] Fumaric acid (2.68 g, 1 eq.) and 1:1 EtOH / acetone (48 mL) were added to a two-piece EasyMax (EM) reaction vessel and heated to a reaction temperature of 50°C to dissolve all materials. In an adjacent EM vessel, a one-piece EM vessel containing compound 1 (12.0 g, 1 eq.) was set to a jacket temperature of 50°C. The fumaric acid solution was transferred to the vessel containing compound 1. Seed crystals (2% seed crystals, 0.244 g) were added, and the vessel was heated to reflux (to 65°C). After 1 hour, 0.5 mL of the slurry was filtered, washed with EtOH (6 × 1.5 mL), and analyzed by HPLC to determine the fumaric acid content (the result should be approximately 10%). The slurry was then cooled to 25°C for 1 hour and stirred for another 1 hour. The solid was then filtered, washed with 1:1 EtOH / acetone (2 × 3 V), and dried under vacuum at 25°C over the entire weekend. 1H NMR 700 MHz (DMSO-d 6) δ 1.473 (s, 4H), δ 4.009 (s, 3H), δ 2.839 (d, 3H, 3J 1H-1H= 4.7 Hz), δ 2.840 (d, 3H, 3J 1H-1H= 4.7 Hz), δ 6.450 (d, 1H, 3J 1H-1H= 5.2 Hz), δ 6.632 (s, 2H), δ 6.635 (s, 2H), δ 7.137 (m, 2H), δ 7.244 (d, 2H, 3J 1H-1H= 8.6 Hz), δ 7.494 (s, 1H), δ 7.642 (m, 2H), δ 7.776 (d, 2H, 3J 1H-1H= 8.6 Hz), δ 8.361 (q, 1H, 3J 1H-1H= 4.7 Hz), δ 8.618 (s, 1H), 8.615 (s, 1H), δ 8.638 (d, 1H, 3J 1H-1H= 5.2 Hz), δ 10.070 (s, 1H), δ 10.216 (s, 1H), δ 13.164 (s, 1H). 19F NMR 700 MHz (DMSO-d 6; reference to trifluorotoluene at -63.72 ppm) δ -121.460.13C NMR 700 MHz (DMSO-d 6) δ 15.46, δ 26.47, δ 31.60, δ 56.15, δ 102.91, δ 107.83, δ 114.55, δ 115.05 (d, 2J 19F-13C= 22.2 Hz), δ 121.15, δ 122.23, δ 122.43 (d, 3J 19F-13C= 7.6 Hz), δ 124.35, δ 125.24, δ 134.03, δ 135.22 (d, 4J 19F-13C= 2.4 Hz), δ 136.73, δ 149.08, δ 151.46, δ 153.18, δ 157.94, δ 158.30 (d, 1J 19F-13C= 240.2 Hz), δ 161.76, δ 164.89, δ 168.16 and δ 168.16. 15N NMR 700 MHz (DMSO-d 6) δ 106.25 (15N), δ 127.79 (15N), δ 128.86 (15N), δ 166.04, δ 289.56 (15N). . [Examples of pharmaceutical compounds] []

[0296] Compound 1 was designed as a solid oral tablet formulation with a strength of 20 mg. The initial tablet contained a formulation with a 25% drug loading (free base equivalent). Each tablet consisted of the active pharmaceutical ingredient and a granular admixture of microcrystalline cellulose, anhydrous lactose, hydroxypropyl cellulose, sodium cross-linked carboxymethyl cellulose, colloidal silica, and magnesium stearate. This tablet formulation was named Pharmaceutical Composition A of Compound 1. Pharmaceutical Composition A tablets of Compound 1 were coated using the Opadry® II Blue (85F105057) (Colorcon, West Point, PA) film coating system. The table below presents a list of excipients and their functions in Pharmaceutical Composition A. [surface] [2] [:compound] [1] [Pharmaceutical Combinations] [A] [Element] [Function] Compound 1 Active ingredients Microcrystalline cellulose, pH-102 diluent Anhydrous lactose, 60M diluent Hydroxypropyl cellulose, EXF Adhesive Cross-linked carboxymethyl cellulose sodium Disintegrant Colloidal silicon dioxide Flow aid Magnesium stearate (non-bovine) lubricant Opadry® II Blue (85F105057) Film coating

[0297] The preparation of pharmaceutical composition A tablet (20 mg) of compound 1 includes de-agglomeration of excipients, followed by high-shear granulation, de-agglomeration of wet particles, fluidized bed drying, dry grinding, external particle blending, lubricant blending, tablet preparation, film coating and packaging.

[0298] Microcrystalline cellulose PH102, anhydrous lactose 60M, hydroxypropyl cellulose EXF, and croscarmellose sodium were passed through a 20-mesh sieve. Compound 1 was added, and the mixture was placed in a high-shear granulation bowl and granulated with purified water under high shear. The wet granules were then passed through a Comil or manually sieved. The wet granules were then dried using a fluidized bed dryer and then passed through a Comil. The milled granules, along with de-agglomerated colloidal silica and croscarmellose sodium, were then loaded into a blender and the mixture was blended. Magnesium stearate (non-nucleotide) that had passed through a 30-mesh sieve was then added to the mixture while blending continued. The lubricated blend was then pressed using an instrumented rotary press. A coating suspension was then prepared by adding Opadry® II blue to purified water to provide a dispersion. The dispersion was slowly sprayed onto the core tablets loaded into a porous disc coating machine. The coating tablets, along with the desiccant and polyester coil, are packaged together in a child-protective HDPE bottle.

[0299] Pharmaceutical composition B of Compound 1 offers improved manufacturing processes and increased manufacturing efficiency at the same drug loading. Due to adhesion issues, the manufacturing process of pharmaceutical composition A of Compound 1 requires frequent downtime for machine cleaning, which can result in defective tablets. Pharmaceutical composition B of Compound 1 does not require frequent downtime and cleaning. By changing the lubricant from magnesium stearate to stearic acid and increasing the binder concentration in the formulation (e.g., from 3% hydroxypropyl cellulose to 5% hydroxypropyl cellulose), the adhesion problem is avoided. Therefore, pharmaceutical composition B of Compound 1 can be produced continuously, thereby improving efficiency and meeting scale-up requirements.

[0300] Each compound 1 pharmaceutical composition B tablet is composed of an active pharmaceutical ingredient and a granular blend of microcrystalline cellulose, anhydrous lactose, hydroxypropyl cellulose, croscarmellose sodium, colloidal silica, and stearic acid. The tablets are coated using the Opadry® II Blue (85F105057) film coating system.

[0301] Pharmaceutical composition B tablets with a dosage strength of 80 mg were prepared to enable the administration of higher doses with fewer tablets; 100 mg and 120 mg dosage strengths of pharmaceutical composition B tablets were also prepared. The dosage strengths of pharmaceutical composition B tablets were prepared from common blends and film-coated. The tablet dosage strengths were differentiated by shape, with 20 mg tablets being round and 80 mg tablets being oval. The table below presents a list of excipients and their functions in pharmaceutical composition B. [surface] [3] [:] [] [Compound] [1] [Pharmaceutical Compositions] [B] [Element] [Function] Compound 1 Active ingredients Microcrystalline cellulose, pH-102 diluent Anhydrous lactose, 60M diluent Hydroxypropyl cellulose, EXF Adhesive Cross-linked carboxymethyl cellulose sodium Disintegrant Colloidal silicon dioxide Flow aid Stearic acid 50 (vegetable grade) lubricant Opadry® II Blue (85F105057) Film coating

[0302] The preparation of pharmaceutical composition B tablets (20 mg and 80 mg) of compound 1 consists of de-agglomeration of excipients, followed by high-shear granulation, de-agglomeration of wet particles, fluidized bed drying, dry grinding, external particle blending, lubricant blending, tablet forming, film coating and packaging.

[0303] Therefore, anhydrous microcrystalline cellulose PH102, anhydrous lactose, hydroxypropyl cellulose EXF, and croscarmellose sodium were passed through a 20-mesh sieve. A binding solution was prepared separately by adding hydroxypropyl cellulose and purified water. The sieved mixture of Compound 1, anhydrous microcrystalline cellulose PH102, anhydrous lactose, hydroxypropyl cellulose EXF, and croscarmellose sodium, along with the binder solution, was subjected to high-shear granulation in a high-shear granulation bowl. The resulting wet granules were passed through a Comil sieve or manually, dried using a fluidized bed dryer, and then passed through a Comil sieve again. The milled granules were then combined with colloidal silica and croscarmellose sodium and blended in a blender. Stearic acid, which had passed through a 30-mesh sieve, was then loaded into the blender. The lubricated blend was then pressed using an instrumented rotary press. A coating suspension was then prepared by adding Opadry® II blue to purified water to provide a dispersion. The dispersion was slowly sprayed onto the core tablets loaded into a porous disc coating machine. The coating tablets, along with the desiccant and polyester coil, are packaged together in a child-protective HDPE bottle.

[0304] The quantitative unit composition of the compound 1 tablets studied is presented in the table below, wherein compound 1 exists in the form of a free base, including forms A, B, C, D, D, E, F, G, H, K, O, or Q as disclosed herein. The composition may also accommodate salt forms of compound 1, including hydrochloride, fumarate, and phosphate as disclosed herein, including hydrochloride forms A, B, C, and D; fumarate form A; hemifumarate form B; and phosphate form A. The amount of compound 1 salt used is adjusted to provide 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, or 120 mg of compound 1 (free base equivalent). [surface] [4] [:compound] [1] [Pharmaceutical Compositions] [A] [] composition [Element] w / w% mg / unit dose Compound 1 27.75 20 1 Microcrystalline cellulose, pH-102 41.47 33.17 Anhydrous lactose, 60M 20.73 16.59 Hydroxypropyl cellulose, EXF 3.00 2.40 Cross-linked carboxymethyl cellulose sodium 6.00 4.80 Colloidal silicon dioxide 0.30 0.24 Magnesium stearate (non-bovine) 0.75 0.60 Total core tablet weight 80.00 Opadry® II Blue (85F105057) 4.00 3.20 Total weight of coated tablets 83.20 120 mg of the free base of compound 1 is equivalent to 22.20 mg of the hemifumarate of compound 1. [surface] [5] [:] [20 mg] [、] [40 mg] [、] [60 mg] [、] [80 mg] [、] [100 mg] [and] [120 mg] [Compound] [1] [Composition of the tablets] [(] [Pharmaceutical Compositions] [A)] [] [composition] [] [] [mg / ] [Unit dose] [Element] [w / w %] [20 mg] [40 mg] [60 mg] [80 mg] [100 mg] [120 mg] Compound 1 27.75 20 1 40 2 60 3 80 4 100 5 120 6 Microcrystalline cellulose, pH-102 41.47 33.17 66.34 99.51 132.68 165.85 199.02 Anhydrous lactose, 60M 20.73 16.59 33.18 49.77 66.36 82.95 99.54 Hydroxypropyl cellulose, EXF 3.00 2.40 4.80 7.20 9.60 12.0 14.4 Cross-linked carboxymethyl cellulose sodium 6.00 4.80 9.60 14.40 19.20 24.00 28.80 Colloidal silicon dioxide 0.30 0.24 0.48 0.72 0.96 1.20 1.44 Magnesium stearate (non-bovine) 0.75 0.60 1.20 1.80 2.40 3.00 3.60 Total core tablet weight 80.0 160.0 240.0 320.0 400.0 480.0 Opadry® II Blue (85F105057) 4.00 3.20 6.40 9.60 12.80 16.00 19.20 Total weight of coated tablets 83.2 166.4 249.6 332.8 416.0 499.2 120 mg of the free base of compound 1 is equivalent to 22.20 mg of the hemifumarate of compound 1. 240 mg of the free base of compound 1 is equivalent to 44.40 mg of the hemifumarate of compound 1. 360 mg of the free base of compound 1 is equivalent to 66.60 mg of the hemifumarate of compound 1. 480 mg of the free base of compound 1 is equivalent to 88.80 mg of the hemifumarate of compound 1. 5100 mg of the free base of compound 1 is equivalent to 111.00 mg of the hemifumarate of compound 1. 6120 mg of the free base of compound 1 is equivalent to 132.20 mg of the hemifumarate of compound 1. [surface] [6] [:] [20 mg] [and] [80 mg] [Compound] [1] [Composition of the tablets] [(] [Pharmaceutical Compositions] [B)] [] composition [Element] w / w% mg / unit dose 20 mg 80 mg Compound 1 27.75 20 1 80 2 Microcrystalline cellulose, pH-102 38.63 30.90 123.62 Anhydrous lactose, 60M 19.32 15.46 61.82 Hydroxypropyl cellulose, EXF 5.00 4.00 16.00 Cross-linked carboxymethyl cellulose sodium 6.00 4.80 19.20 Colloidal silicon dioxide 0.30 0.24 0.96 Stearic acid 50 3.00 2.40 9.60 Total core tablet weight 80.0 320.0 Opadry® II Blue (85F105057) 4.00 3.20 12.80 Total weight of coated tablets 83.2 332.8 120 mg of the free base of compound 1 is equivalent to 22.20 mg of the hemifumarate of compound 1. 280 mg of the free base of compound 1 is equivalent to 88.78 mg of the hemifumarate of compound 1. [] [surface] [7] [:] [20 mg] [、] [40 mg] [、] [60 mg] [、] [80 mg] [、] [100 mg] [and] [120 mg] [Compound] [1] [Composition of the tablets] [(] [Pharmaceutical Compositions] [B)] [] [composition] [] [] [mg / ] [Unit dose] [Element] [w / w%] [20 mg] [40 mg] [60 mg] [80 mg] [100 mg] [120 mg] Compound 1 27.75 20 1 40 2 60 3 80 4 100 5 120 6 Microcrystalline cellulose, pH-102 38.63 30.90 61.81 92.71 123.62 154.52 185.42 Anhydrous lactose, 60M 19.32 15.46 30.91 46.37 61.82 77.28 92.74 Hydroxypropyl cellulose, EXF 5.00 4.00 8.00 12.00 16.00 20.00 24.00 Cross-linked carboxymethyl cellulose sodium 6.00 4.80 9.60 14.40 19.20 24.00 28.80 Colloidal silicon dioxide 0.30 0.24 0.48 0.72 0.96 1.20 1.44 Stearic acid 50 3.00 2.40 4.80 7.20 9.60 12.00 14.40 Total core tablet weight 80.0 160.0 240.0 320.0 400.0 480.0 Opadry® II Blue (85F105057) 4.00 3.20 6.40 9.60 12.80 16.00 19.20 Total weight of coated tablets 83.2 166.4 249.6 332.8 416.0 499.2 120 mg of the free base of compound 1 is equivalent to 22.20 mg of the hemifumarate of compound 1. 240 mg of the free base of compound 1 is equivalent to 44.40 mg of the hemifumarate of compound 1. 360 mg of the free base of compound 1 is equivalent to 66.60 mg of the hemifumarate of compound 1. 480 mg of the free base of compound 1 is equivalent to 88.80 mg of the hemifumarate of compound 1. 5100 mg of the free base of compound 1 is equivalent to 111.00 mg of the hemifumarate of compound 1. 6120 mg of the free base of compound 1 is equivalent to 132.20 mg of the hemifumarate of compound 1.

[0305] [Stability.] Pharmaceutical composition B tablets containing compound 1 hemifumarate B underwent stability testing. The coated tablets, along with a desiccant and polyester coil, were packaged in child-protected HDPE bottles. The coated tablets were subjected to long-term stability testing conditions at 25°C and 60% relative humidity (RH). When the final examination was conducted after 12 months, the tablets showed less than 0.5% decomposition of compound 1 as hemifumarate B. The tablets are non-hygroscopic. []

[0306] The coated tablets, along with the desiccant and polyester coil, were packaged in a child-protected HDPE bottle. The coated tablets were subjected to accelerated stability testing at 40°C and 75% relative humidity (RH). At the final examination after 6 months, the tablets showed less than 0.5% decomposition of compound 1 as hemifumarate form B. []

[0307] [Dissolution.] Pharmaceutical composition B tablets containing compound 1 in hemifumarate form B, as determined by stability testing, were subjected to a dissolution test. After 12 months of storage at 25°C and 60% relative humidity (RH), the tablets showed greater than 50% dissolution at 5 minutes, greater than 70% at 10 minutes, greater than 85% at 20 minutes, and greater than 90% dissolution at 45 minutes. After 6 months of storage at 45°C and 75% relative humidity (RH), the tablets showed greater than 60% dissolution at 10 minutes, greater than 90% at 30 minutes, and greater than 95% dissolution at 45, 60, and 75 minutes. []

[0308] Table 8 shows the specifications of the 20 mg strength tablets after storage at 25°C and 60% relative humidity. [surface] [8] Time (month) 0 1 2 3 6 9 12 Total impurities (%) 0.32 0.24 0.43 0.19 0.47 0.48 0.46 Dissolution 5 min: 47.5% 10 min:71.9% 20 min:87.2% 30 min:91.5% 45 min:92.9% 60 min:93.3% 75 min:93.4% 5 min: 51.0% 10 min: 72.4% 20 min: 86.1% 30 min: 89.8% 45 min: 91.1% 60 min: 91.4% 75 minutes:91.5% 5 minutes:50.4% 10 minutes 72.6% 20 minutes:86.1% 30 minutes:90.7% 45 minutes:92.0% 60 minutes:92.0% 75 minutes:92.2% 5 minutes:46.5% 10 minutes:70.8% 20 minutes:85.9% 30 minutes:90.4% 45 minutes:92.0% 60 minutes:92.3% 75 minutes:92.5% 5 minutes:52.4% 10 minutes:73.4% 20 minutes:86.8% 30 minutes:90.5% 45 minutes:91.3% 60 minutes:91.9% 75 minutes:92.1% 5 minutes:43.0% 10 minutes:68.9% 20 mins 84.9% 30 minutes:89.3% 45 minutes:90.8% 60 minutes:91.2% 75 minutes:91.2% 5 minutes 51.0% 10 minutes:71.7% 20 minutes:85.5% 30 minutes:89.1% 45 minutes:90.2% 60 minutes:90.7% 90 minutes:90.7% 120 minutes:90.7% water content(%) 2.0 1.2 1.4 1.6 1.3 1.2 1.6

[0309] Table 9 shows the specifications of the 20 mg strength tablets after storage at 40°C and 75% relative humidity. [surface] [9] Time (month) 0 1 3 6 Total impurities (%) 0.51 0.57 0.45 0.41 Dissolution 5 min:47.8% 10 min:70.0% 20 min:88.6% 30 min:92.6% 45 min:95.3% 60 mm:96.2% 75 mm:96.5% 5 min: 37.4% 10 min: 66.8% 20 min:88.0% 30 min:94.4% 45 min:97.3% 60 min:98.2% 75 min:98.7% 5 min: 33.3% 10 min:61.5% 20 min:85.4% 30 min:92.9% 45 min:96.3% 60 min:97.5% 75 min:98.0% 5 min: 26.8% 10 min: 60.2% 20 min: 84.0% 30 min: 91.7% 45 min: 95.2% 60 min: 96.4% 75 min: 96.7% Water content (%) 2.4 1.6 1.7 1.7 [Other Embodiments] []

[0310] For purposes of clarity and understanding, the foregoing disclosure has been described in considerable detail with the aid of illustrations and examples. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made while maintaining the spirit and scope of the invention. Those skilled in the art will appreciate that changes and modifications can be practiced within the scope of the appended claims. Therefore, it should be understood that the foregoing description is intended to be illustrative and not restrictive.

[0311] Therefore, the scope of this invention should not be determined by reference to the above description, but rather by reference to the appended claims and all equivalents granted by those claims.

Claims

1. A pharmaceutical composition comprising: a. about 25% to about 35% by weight of compound 1 or a pharmaceutically acceptable salt thereof, wherein compound 1 has the following structure: 1.b. about 35% to about 40% by weight of microcrystalline cellulose; c. about 16% to about 22% by weight of lactose; d. about 3% to about 7% by weight of hydroxypropyl cellulose; e. about 3% to about 7% by weight of croscarmellose sodium; f. about 0.1% to about 0.5% by weight of colloidal silicon dioxide; g. about 0.5% to 3.5% by weight of stearic acid; and h. film coating, as appropriate.

2. A pharmaceutical composition comprising: a. about 25% to about 35% by weight of a hemifumarate of compound 1, wherein compound 1 has the following structure: 2.b. about 35% to about 40% by weight of microcrystalline cellulose; c. about 16% to about 22% by weight of anhydrous lactose; d. about 3% to about 7% by weight of hydroxypropyl cellulose; e. about 3% to about 7% by weight of croscarmellose sodium; f. about 0.1% to about 0.5% by weight of colloidal silicon dioxide; g. about 0.5% to 3.5% by weight of stearic acid; and h. film coating, as appropriate.

3. A pharmaceutical composition comprising: a. about 27.75% by weight of a hemifumarate of compound 1, wherein compound 1 has the following structure: 3.b. Approximately 38.63% by weight of microcrystalline cellulose; c. Approximately 19.32% by weight of anhydrous lactose; d. Approximately 5% by weight of g-hydroxypropyl cellulose; e. Approximately 6% by weight of croscarmellose sodium; f. Approximately 0.3% by weight of colloidal silicon dioxide; g. Approximately 3% by weight of stearic acid; and h. Film coating, as appropriate.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the composition comprises about 10 mg to about 150 mg of compound 1 (free base equivalent).

5. The pharmaceutical composition of claim 4, comprising: a. about 20 mg of compound 1 (free base equivalent); b. about 30.90 mg of microcrystalline cellulose; c. about 15.46 mg of anhydrous lactose; d. about 4 mg of hydroxypropyl cellulose; e. about 4.8 mg of croscarmellose sodium; f. about 0.24 mg of colloidal silica; g. about 2.4 mg of stearic acid; and h. film coating, as appropriate.

6. The pharmaceutical composition of claim 4, comprising: a. about 40 mg of compound 1 (free base equivalent); b. about 61.81 mg of microcrystalline cellulose; c. about 30.91 mg of anhydrous lactose; d. about 8 mg of hydroxypropyl cellulose; e. about 9.6 mg of croscarmellose sodium; f. about 0.48 mg of colloidal silica; g. about 4.8 mg of stearic acid; and h. film coating, as appropriate.

7. The pharmaceutical composition of claim 4, comprising: a. about 60 mg of compound 1 (free base equivalent); b. about 92.71 mg of microcrystalline cellulose; c. about 46.37 mg of anhydrous lactose; d. about 12 mg of hydroxypropyl cellulose; e. about 14.4 mg of croscarmellose sodium; f. about 0.72 mg of colloidal silicon dioxide; g. about 7.2 mg of stearic acid; and h. film coating, as appropriate.

8. The pharmaceutical composition of claim 4, comprising: a. about 100 mg of compound 1 (free base equivalent); b. about 154.52 mg of microcrystalline cellulose; c. about 77.28 mg of anhydrous lactose; d. about 20 mg of hydroxypropyl cellulose; e. about 24 mg of croscarmellose sodium; f. about 1.2 mg of colloidal silica; g. about 12 mg of stearic acid; and h. film coating, as appropriate.