Pharmaceutical formulations of erbb2 inhibitors

Abstract

Disclosed herein are pharmaceutical compositions and dosage forms comprising (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine, which are useful for treating a subject having cancer. The present disclosure also provides methods for making the pharmaceutical compositions and dosage forms provided herein, as well as methods of treating a subject having cancer with the pharmaceutical compositions and dosage forms provided herein.

Description

Background Technology

[0001] This disclosure relates to pharmaceutical compositions and dosage forms comprising (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, particularly wherein these pharmaceutical compositions and dosage forms are indicated for the treatment of subjects with cancer. This disclosure also provides methods for preparing the pharmaceutical compositions and dosage forms provided herein, and methods for treating subjects with cancer using the pharmaceutical compositions and dosage forms provided herein. Specifically, this disclosure relates to a pharmaceutical composition in capsule form.

[0002] The type I tyrosine kinase receptor family consists of four structurally related receptors: EGFR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4) (reviewed by Riese and Stern). Bioessays ,1998, 20: 41-48; Olayioye et al., EMBO Journal , 2000, 19: 3159-3167; and Schlessinger, Cell (2002, 110: 669-672). These four family members have almost identical structures, consisting of an extracellular region or extracellular domain or ligand-binding region, a single transmembrane region, and an intracellular cytoplasmic tyrosine kinase domain.

[0003] ErbB2 has been shown to play a role in cancer development. Overexpression of ErbB2 is present in 20% to 25% of breast cancer (BC) patients (Leyland-Jones B1). J Clin Oncol. (Cardoso F et al., 2009, 5278-86). Approximately 1.7 million new cases of BC are diagnosed each year (Cardoso F et al., 2009, 5278-86). Breast (Dai X. et al., 2018, 131-138), and 80% of BC are invasive, requiring chemotherapy, radiation therapy, or targeted therapy in addition to surgery (Dai X. et al., 2018, 131-138). Am J Cancer Research (Leone JP, 2015, 2929-2943). Brain metastases frequently occur in patients with metastatic breast cancer. Overall survival for patients with breast cancer brain metastases (BCBM) ranges from 2 months to 25.3 months (Leone JP). Exp. Hematol.Oncol.(2015, 4, 33). Surgery, whole-brain radiotherapy (WBRT), and stereotactic radiosurgery (SRS) are the three main treatment options for brain metastases (BCBM). Surgery is used to treat single or up to three brain metastases. SRS can be used for patients with four or fewer intracranial lesions. WBRT is used to manage multiple brain metastases, but may result in significant neurocognitive decline (Venur VA et al., 2015, 4, 33). Int. J. Mol. Sci. , 2016, 1543).

[0004] Compared to other types of breast cancer, ErbB2-positive tumors have a higher incidence of brain metastases, with up to 50% of ErbB2-positive breast cancer patients developing intracranial metastases (Leyland-Jones B). J Clin Oncol. , 2009, 5278-86). The high prevalence of BCBM in ErbB2-positive patients is attributed to the inherent tropism of ErbB2-positive breast cancer cells to the brain, the prolonged survival of patients receiving anti-ErbB2 therapy, and the limited intracranial activity of existing anti-ErbB2 therapies (Venur VA et al., 2009, 5278-86). Int. J. Mol. Sci. , 2016, 17, 1543).

[0005] Several anti-ErbB2 agents have been developed for clinical use, including monoclonal antibodies (such as trastuzumab), antibody-drug conjugates (ADCs) (such as T-DM1), and tyrosine kinase inhibitors (TKIs) (such as lapatinib, neratinib, afatinib, and tucatinib) (Kabraji S. et al., Clinical Cancer Research , 2018, 3351; Askoxylakis V. et al., JNCI J Natl Cancer Institute , 2015, 763-763; Tanaka, Y. et al., Scientific Reports , 2018, 343; Zhang, Shirong et al., Acta Pharmacologica Sinica , 2017, 233-240; Dinkel V et al., Cancer Research (2012, 72). However, these antibodies, ADCs, and TKIs are believed to lack central nervous system (CNS) penetration. Limited clinical efficacy has been observed when these non-brain-penetrating antibodies, ADCs, and TKIs are used to treat patients with BCBM.

[0006] International Patent Publication No. WO 2020 / 057511 A1 (which is incorporated herein by reference in its entirety) discloses a quinazoline derivative that inhibits type I receptor tyrosine kinase, exhibits good brain penetration in animals, and has favorable toxicity characteristics (e.g., reduced activity against hERG), and is therefore particularly useful for the treatment of type I receptor tyrosine kinase-mediated diseases or conditions, especially ErbB2-related diseases or conditions (including cancers such as metastatic cancers, such as brain metastases). Summary of the Invention

[0007] Compound (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine and its preparation have been disclosed in International Patent Publication WO2020 / 057511 A1. (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is a potent inhibitor of type I receptor tyrosine kinases and the following related kinases: EGFR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). It is worth noting that (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has been recognized as a potent ErbB2 (HER2) inhibitor that can cross the blood-brain barrier (BBB). It exhibits high selectivity for wild-type EGFR to minimize EGFR-mediated diarrhea and rash, and therefore can be used to treat ErbB2-positive BC patients with or without brain metastases.

[0008] There is a need for capsules with high drug loading capacity of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to aid patient compliance by minimizing the unit size and quantity taken for a given dose. The inventors of this application have discovered that high drug loading capacity can be achieved using a wet granulation method (manufacturing method C). This method also unexpectedly has the advantage of improving the flowability and density of the granules used for capsule filling.

[0009] The pharmaceutical compositions of the present invention, and the capsules comprising the pharmaceutical compositions, also possess beneficial pharmacokinetic properties. For example, Figure 3 illustrates their favorable pharmacokinetic characteristics. These pharmacokinetic properties may be advantageous for the treatment of brain metastases.

[0010] The first embodiment provided herein is a pharmaceutical composition comprising: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (b) at least one filler, and (c) At least one flow aid.

[0011] The second embodiment provided herein is a capsule comprising the composition as described herein.

[0012] The third embodiment provided herein is a kit comprising: a pharmaceutical composition as described herein, in capsule form, particularly enteric-coated capsule form, the pharmaceutical composition containing a therapeutically effective amount of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine; prescription information, also known as “instructions for use”; blister packs or bottles (HDPE or glass), particularly moisture-proof primary packaging, more particularly Alu / Alu Blister or plastic bottle containing desiccant; and container, in particular where the prescription information specifically includes advice to the patient regarding the administration of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine.

[0013] The fourth embodiment provided herein is a method for manufacturing particles comprising (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine as described herein, fillers, binders, and flow aids, the method comprising the following steps: (a) The (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, fillers, binders, disintegrants, and flow aids are sieved, wherein the fillers, binders, disintegrants, and flow aids are as defined herein. (b) Dissolve the adhesive in water, wherein the adhesive is as defined herein, thereby obtaining solution b). (c) Mixing (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, filler, disintegrant, and flow aid, optionally in a wet granulator pot. (d) Add solution b) to mixture c) and perform high-shear granulation to produce wet granules. (e) Dry wet granules, (f) Grinding the dried particles from step (e), and (g) Optionally, the particles from step (f) are blended with the extraparticle portion (e.g., lubricant).

[0014] The fifth embodiment provided herein is a pharmaceutical composition for treating cancers, including but not limited to: for example, the heart (sarcomas [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma), the mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissues; the respiratory tract, such as the nasal cavity and middle ear, paranasal sinuses, larynx, trachea, bronchi, and lungs, such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), and bronchogenic carcinomas (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma). Alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal system, such as esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), stomach, pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyosarcoma); genitourinary tract, such as kidney (adenocarcinoma, Wilms' disease). Hepatoblastoma (nephroblastoma), lymphoma, leukemia), bladder and / or urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoblastoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver, such as hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pancreatic endocrine tumors (such as pheochromocytoma, pancreatic...). Insulinoma, vasoactive intestinal peptide tumor, islet cell tumor, and glucagonoma; skeletal tumors, such as osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor; nervous system tumors, such as the central nervous system (CNS). Tumors, primary CNS lymphomas, skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);Reproductive system diseases, such as gynecological diseases, uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell carcinoma, Sertoli-Leydig cell carcinoma). The female reproductive organs include: cytomas, dysgerminomas, malignant teratomas; vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)); fallopian tubes (cancer); and other sites related to the female reproductive organs; placenta, penis, prostate, testes; and other sites related to the male reproductive organs; hematopoietic system, such as blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; oral cavity, such as lips, tongue, gums, floor of mouth, palate, and other parts of the oral cavity. Parts of the parotid gland and other parts of the salivary glands, tonsils, oropharynx, nasopharynx, piriform sinus, hypopharynx, and lips, other parts of the oral cavity and pharynx; skin, such as malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid; adrenal glands: neuroblastoma; and other tissues, including connective tissue and soft tissue, retroperitoneum and peritoneum, eye, intraocular melanoma and adnexa, breast, head and / or neck, anal region, thyroid gland, parathyroid glands, adrenal glands and other endocrine glands and related structures, secondary and unspecified malignant tumors of lymph nodes, secondary malignant tumors of the respiratory and digestive systems, and secondary malignant tumors of other sites. Attached Figure Description

[0015] Figure 1 shows the appearance of the enteric-coated capsules after being exposed to 0.1N HCl solution for 120 min.

[0016] Figure 2 shows the dissolution profile of formulation P in a buffer solution at pH 6.8 (dissolution % versus time (in minutes)).

[0017] Figure 3 shows the canine pharmacokinetic (PK) results of formulation P (plasma concentration (ng / mL) versus time (hours)). Detailed Implementation

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although similar or equivalent methods and materials may be used in the practice or testing of this invention, suitable methods and materials are described below.

[0019] All publications, patent applications, patents and other references mentioned in this article are incorporated herein by reference in their full text.

[0020] Unless otherwise indicated, the nomenclature used in this disclosure is based on the IUPAC system nomenclature.

[0021] Unless otherwise indicated, any open valence on carbon, oxygen, sulfur, or nitrogen atoms in the structure described herein indicates the presence of hydrogen.

[0022] This document discloses various features and embodiments of the invention; however, other features, modifications, and equivalents of the invention will be apparent to those skilled in the art based on the teachings provided. The invention described is not limited to the examples and embodiments provided, and various alternative equivalents will be apparent to those skilled in the art.

[0023] As used herein, the singular forms “a,” “an,” and “the” include the plural unless the context clearly specifies otherwise. For example, “a” individual will also include “multiple individuals.”

[0024] Unless otherwise defined, all technical and scientific terms used in this specification and claims have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although similar or equivalent methods and materials may be used in the practice or testing of this invention, suitable methods and materials are described below.

[0025] As used herein, the parameters Dv(10), Dv(50), and Dv(90) represent the particle size distribution of the undersize material at 10%, 50%, and 90% of the cumulative quantity or volume. Therefore, “Dv(10)” of a material indicates that 10% of the material by quantity or volume consists of particles with a particle size equal to or less than the value of Dv(10). “Dv(50)” of a material indicates that 50% of the material by quantity or volume consists of particles with a particle size equal to or less than the value of Dv(50). “Dv(90)” of a material indicates that 90% of the material by quantity or volume consists of particles with a particle size equal to or less than the value of Dv(90).

[0026] Particle size can be measured using laser diffraction (LD). LD measurements can be performed using a Malvern Mastersizer 3000 particle size analyzer equipped with a HydroMV dispersion unit. Pre-dispersion can be performed for 30 seconds under external sonication. For this, 30 mg of sample can be added to 5 mL of dispersant liquid (8% SPAN 80 in n-heptane). Background and sample measurement duration can be 10 seconds (for both red and blue light). The stirring speed during measurement can be 2000 min. -1 .

[0027] Terms such as “x% ± y%” refer to the range from x% - y% to x% + y%. For example, 5% ± 1% means the range from 4% (inclusive) to 6% (inclusive).

[0028] In the context of any disintegrant, filler, gliding agent, lubricant, and / or compound of formula (I), terms such as “x ± y wt%” refer to “x ± y wt%” of the total weight of the core (which is the pharmaceutical composition excluding the weight of the capsule). For example, 66 mg of salt of compound of formula (I) (equal to 50 mg of free base). In a 90 mg capsule core, the salt of compound of formula (I) (equal to 56% free base) accounts for 73% by weight of the total weight of the composition.

[0029] As used herein, the term "administration / administering" refers to the delivery of a bioactive composition or formulation to a subject via a route of administration, including but not limited to oral, intravenous, intra-arterial, intramuscular, intraperitoneal, subcutaneous, intramuscular, local, or combinations thereof. In some embodiments, the route of administration to the subject is oral.

[0030] The term "environmental conditions" refers to the conditions experienced in a standard laboratory, such as atmospheric pressure, air, ambient temperature between 18°C ​​and 28°C, and humidity between 30% and 80% RH.

[0031] The term "active pharmaceutical ingredient" (or "API") refers to a compound or molecule in a pharmaceutical composition that has a specific biological activity. In a particular embodiment, the term "API" refers to (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine). The API described herein has a chiral center and may be present in the form of an optically pure enantiomer, a mixture of enantiomers (such as, for example, a racemic mixture), an optically pure diastereomer, a mixture of diastereomers, a diastereomer racemic mixture, or a mixture of diastereomer racemic mixtures. When a chiral center is present in the chemical structure, it means that all stereoisomers associated with that chiral center are included in this disclosure. In certain embodiments, the API described herein is a pure enantiomer, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine.

[0032] The term "crystalline form" refers to the crystalline structure in which a compound (or its salts or solvates) can crystallize in different crystalline stacks, all having the same elemental composition. Different crystalline forms typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can cause one crystalline form to dominate. Crystalline polymorphs of a compound can be prepared by crystallization under different conditions.

[0033] "Pharmaceutical composition" and "pharmaceutical formulation" (or "formulation") refer to a formulation in which the biologically effective active ingredient contained therein is permitted and which does not contain any additional components that would have unacceptable toxicity to a subject to whom the composition will be administered. The term "pharmaceuticalally acceptable" means that a substance that can be used to prepare a pharmaceutical composition has the following properties: generally safe, non-toxic, neither biologically nor otherwise undesirable, and acceptable for both veterinary and human pharmaceutical use.

[0034] "Crystallization" and "recrystallization" are used interchangeably; they refer to methods in which a compound dissolved or suspended in a solvent system results in a stable polymorph or crystalline form of the compound. For example, the crystallization step can be accomplished by forming crystals using a solvent and an antisolvent.

[0035] The term "(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine" refers to a compound having Chemical Abstracts Service registration number 2414056-31-6 and having the chemical structure of formula (I): (I) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine) is interchangeable with compounds of formula (I). Unless otherwise indicated herein, “(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine” should be understood to include any pharmaceutically acceptable form, solvate, salt, and polymorphic form (including cocrystals or cocrystals of salts) of the compound or stereoisomer, and its isotopically labeled version. (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has been shown to be a potent ErbB2 (HER2) inhibitor that can cross the blood-brain barrier (BBB) ​​and exhibits high selectivity for wild-type EGFR to minimize EGFR-mediated diarrhea and rash. In particular, it has been shown to be useful for the treatment of ErbB2-positive BC patients with or without brain metastases. (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine and methods for preparing and using the compound are described in WO 2020 / 057511.

[0036] In specific embodiments, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is a solid in crystalline or amorphous form, more particularly in crystalline form, and even more particularly in the form of fumarate type A, fumarate type B, fumarate type C, fumarate type E, free base type A, free base type B, free base type C, free base type D, free base type E, free base type F, free base type G, HCl salt type A, HCl salt type B, methanesulfonate type A, methanesulfonate type B, phosphate type A, L-tartrate type A, or adipate type A The most distinctive type is fumarate type A. Fumarate type A of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has been disclosed along with its preparation method in WO 2023 / 066296 and is referred to as "fumarate type A".

[0037] The scope of this document also includes pharmaceutical compositions comprising solvates, salts, and polymorphic forms of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or its stereoisomers, as well as isotopically labeled versions. Specifically, in this disclosure, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine refers to fumarate type A. Fumarate type A is (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate (1 / 1.5), as shown below: "Fumarate Type A" refers to the crystalline form of compound (I), fumarate type A, characterized by an X-ray powder diffraction pattern containing at least peaks at 2θ (± 0.2°) 6.9 and 11.5; typically, characterized by an X-ray powder diffraction pattern containing at least peaks at 2θ (± 0.2°) 5.8, 6.9, 11.5, 12.1, and 17.7; more typically, characterized by an X-ray powder diffraction pattern containing at least peaks at 2θ (± 0.2°) 5.8, 6.9, 11.5, 12.1, 17.7, 20.8, and 24.0; more typically, characterized by an X-ray powder diffraction pattern containing at least peaks at 2θ (± 0.2°) 5.8, 6.9, 11.5, 12.1, 17.7, 18.9, 20.8, 23.1, 23.7, and 24.0. X-ray powder diffraction pattern of the peak at 28.8°C. In some embodiments, the crystalline form of the compound of formula (I) is provided herein as fumarate type A, characterized by a differential scanning calorimeter peak phase transition temperature of about 167.6°C.

[0038] As used herein, the term "eutectic" refers to a crystalline material composed of two or more different molecules associated in the same lattice by nonionic and noncovalent bonds, one of which is an API.

[0039] As used herein, the term "salt" refers to any of a number of compounds obtained by replacing some or all of the hydrogen acids of an acid to form an ionic or electrovalent compound.

[0040] As used herein, the term "eutectic salt" refers to a crystalline form in which the salt-forming API and co-formations (or vice versa) are associated in the same lattice through nonionic and noncovalent bonds.

[0041] The term “(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoropiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine” or “4-quinazolineamine, 5-[[(4R)-3,3-difluoro-4-piperidinyl]oxy]-6-methoxy-N-[3-methyl-4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)phenyl]” refers to a compound having Chemical Abstracts Service registration number 2414057-05-7 and having the chemical structure of formula (II): (II).

[0042] The method for preparing compound (II) is described in WO 2020 / 057511. Surprisingly, compound (II) was found to be an active metabolite of compound (II).

[0043] The term "chiral center" refers to a carbon atom bonded to four different substituents. The term "chirality" refers to the ability to not overlap with its mirror image, while the term "chirality" refers to an embodiment that can overlap with its mirror image. Chiral molecules are optically active, meaning they are capable of rotating the plane of plane-polarized light.

[0044] The stereochemical definitions and conventions used in this article generally follow SP Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. Substituents attached to the chiral center are ordered according to the Cahn, Ingold, and Prelog order (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511). The prefixes D and L or (+) and (-) are used to indicate the rotation of a compound with respect to plane-polarized light, where (-) or L indicates that the compound is levorotatory. Compounds with the (+) or D prefix are dextrorotatory.

[0045] The terms “pharmaceuticalally acceptable excipient,” “pharmaceuticalally acceptable carrier,” and “therapeutic inert excipient” are used interchangeably and refer to any pharmaceutically acceptable component in a pharmaceutical composition that is not therapeutically active and is non-toxic to the subject to which it is administered, such as disintegrants, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents, lubricants, or combinations thereof used in the formulation of pharmaceutical products.

[0046] The interchangeable terms "filler" or "diluent" refer to a relatively inert substance in the form of granules, powders, beads, flakes, or spheres that improves the physical properties of a pharmaceutical composition or increases its volume or weight. Fillers, in particular, refer to excipients that fill the volume of a tablet or capsule, thereby facilitating its manufacture and use by the consumer. Suitable diluents include, for example, pharmaceutically acceptable fillers such as microcrystalline cellulose (e.g., Avicel). ® Microcrystalline cellulose coated with colloidal silica, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugars, sucrose, glucose, sugar alcohols, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate (i.e., Fujicalin), calcium sulfate, and combinations thereof. A specific example of a filler is anhydrous dicalcium phosphate.

[0047] The terms "individual" or "subject" refer to a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., human and non-human primates, such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the individual or subject is a human.

[0048] "Patient" (or "patients") means a person (such as a man or woman) who has been diagnosed with cancer, particularly if the cancer is ErbB2 positive, more particularly if the cancer is selected from breast cancer, stomach cancer, bile duct cancer, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer, and uterine cancer, and most particularly if the cancer is selected from breast cancer, stomach cancer, bile duct cancer, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer, and uterine cancer, and is ErbB2 positive.

[0049] "HER2-expressing cancer" refers to cancer cells or tumor cells that have the HER2 protein on their cell surface.

[0050] "HER2-positive cancer" or "HER2-overexpressing cancer" can be defined as cancer in which cancer cells or tumor cells have significantly higher levels of HER2 on their surface compared to non-cancer cells of the same tissue type. This overexpression may be caused by gene amplification or increased transcription or translation.

[0051] “HER ligand overexpression cancer” refers to cancer that produces significantly higher levels of HER2 ligand compared to non-cancerous cells of the same tissue type. As used herein, “HER ligand” refers to a polypeptide that binds to and / or activates the HER receptor. Examples include, but are not limited to: epidermal growth factor (EGF), transforming growth factor α (TGF-α), bimodalin, β-cytokinin, heparin-binding epidermal growth factor (HBEGF), cytokinin, epidermodynamicin, neuromodulatory protein-2 (NRG-2), NRG-3, NRG-4, or cripto (CR-1). HER ligands that bind EGFR include EGF, TGF-α, bimodalin, β-cytokinin, HBEGF, and epidermodynamicin.

[0052] The expression or overexpression of the HER receptor or HER ligand can be determined in diagnostic or prognostic assays by assessing elevated levels of HER proteins present on the cell surface (e.g., via immunohistochemistry; IHC). Alternatively, or additionally, the level of nucleic acid encoding HER in cells can be measured, for example via fluorescence in situ hybridization (FISH; see WO98 / 45479, October 1998), Southern blotting, or polymerase chain reaction (PCR) techniques, such as real-time quantitative PCR (RT-PCR). HER receptor overexpression can also be studied by measuring exfoliated antigens (e.g., HER extracellular domains) in biological fluids such as serum (see, for example, U.S. Patent No. 4,933,294, published June 12, 1990; WO91 / 1005264, published April 18, 1991; U.S. Patent No. 5,401,638, published March 28, 1995; and Sias et al., J. Immunol. Methods 132: 73-80 (1990)). In addition to the above assays, skilled practitioners can utilize various in vivo assays. For example, cells in a patient's body can be exposed to antibodies, optionally labeled with a detectable marker (e.g., a radioisotope), and the binding of the antibody to the patient's cells can be assessed, for example, by external radiographic scanning or by analyzing biopsy samples obtained from patients previously exposed to the antibody.

[0053] The expression or overexpression of the HER receptor or HER ligand can be determined in diagnostic or prognostic assays by evaluating elevated levels of HER or HER ligand in biological samples (such as cancer cells) from a subject to be treated. Various methods can be used. For example, the test biological sample can be exposed to an anti-HER2 antibody that binds to and detects the expressed HER2 protein. Alternatively, methods such as qPCR, reverse transcriptase PCR, microarrays, SAGE, FISH, etc., can be used to detect HER2 at the nucleic acid expression level. HER receptor overexpression can also be investigated by measuring exfoliated antigens (e.g., HER extracellular domains) in biological fluids such as serum (see, for example, U.S. Patent No. 4,933,294; WO91 / 05264; U.S. Patent No. 5,401,638; and Sias et al. J. Immunol. Methods 132: 73-80 (1990)). In some embodiments, the test sample is derived from cancer cells or tissue, or tumor-infiltrating immune cells.

[0054] The term “solvent” in this document refers to a molecular complex comprising a compound of formula (I) and one or more solvent molecules (e.g., ethanol) in stoichiometric or non-stoichiometric amounts.

[0055] The term "therapeutic effective amount" means the amount of a compound or molecule of this disclosure that, when administered to a subject, (i) treats or prevents a particular disease, condition, or disorder; (ii) reduces, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder; or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. Therapeutic effective amounts will vary depending on the compound, the state of the disease being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0056] The term "treating" or "treatment" of a disease state includes suppressing the disease state, that is, preventing the development of the disease state or its clinical symptoms, or alleviating the disease state, that is, causing the disease state or its clinical symptoms to temporarily or permanently subside.

[0057] “XRPD” refers to the analytical method of X-ray powder diffraction. Repeatability of angular values ​​is within 2θ ± 0.2°. The term “approximately” given in conjunction with angular values ​​indicates repeatability within 2θ ± 0.2°. Relative XRPD peak intensity depends on many factors, such as structure factor, temperature factor, crystallinity, polarization factor, multiplicity, and Lorentz factor. Relative intensity can vary significantly between different measurements due to the preferred orientation effect. According to USP 941 (US Pharmacopoeia, 37th edition, General Chapter 941), the relative intensity between two samples of the same material can vary significantly due to the “preferred orientation” effect. Anisotropic materials with preferred orientation will result in anisotropic distributions of properties such as modulus, strength, ductility, toughness, electrical conductivity, thermal expansion, etc., as described by Kocks UF et al. (Texture and Anisotropy: Preferred Orientations in Polycrystals and Their Effect on Materials Properties, Cambridge University Press, 2000). In XRPD and Raman spectroscopy, preferred orientation leads to changes in intensity distribution. The preferred orientation effect is particularly pronounced in crystalline APIs with relatively large grain sizes.

[0058] "Binder" refers to a substance that binds pharmaceutical ingredients together. Binders ensure that pharmaceutical particles are formed with the required mechanical strength and provide volume for low-activity-dose tablets, capsules, or any other form. Suitable binders include hydroxypropyl methylcellulose, polyvinylpyrrolidone, carboxylated polymethylene, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethyl starch, starch, or mixtures thereof. Specific examples of binders described herein are polyvinylpyrrolidone (PVP; e.g., povidone K30), hydroxypropyl methylcellulose (HPMC; e.g., METHOCEL™ E5), and hydroxypropyl cellulose (HPC; e.g., Klucel). TM Hydroxypropyl cellulose (HPC), and proteins such as gelatin. In a specific embodiment, the binder is hydroxypropyl cellulose (HPC; for example, Klucel). TM Hydroxypropyl cellulose).

[0059] A "capsule" refers to a conventional hard drug capsule intended for oral administration to humans or animals. The capsule consists of two coaxial, telescopingly connected parts called the capsule body and the capsule cap. Typically, the capsule cap and capsule body have sidewalls, an open end, and a closed end. The length of the sidewall of each of these components is usually greater than the capsule diameter. The capsule cap and capsule body are telescopingly connected together so that their sidewalls partially overlap to form a hard capsule shell.

[0060] "Enteric-coated capsules" refer to capsules as defined above, wherein the capsule is not dissolved by gastric juices but is dissolved by intestinal juices, resulting in a delayed or targeted release of the capsule's contents in the intestine. Examples of enteric-coated capsules are enteric-coated empty gelatin capsules or enteric-coated empty hydroxypropyl methylcellulose capsules. Examples of enteric coating materials are cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMC P), polyvinyl alcohol phthalate (PVAP), or polyacrylic acid (Eudragit E100, RL / RS, EPO, NE / RD). A specific example of an enteric-coated capsule is an empty hydroxypropyl methylcellulose capsule coated with hydroxypropyl methylcellulose phthalate. Another specific example of an enteric-coated capsule is an empty gelatin capsule coated with hydroxypropyl methylcellulose phthalate.

[0061] "Disintegrant" refers to a substance that swells and dissolves upon contact with a solvent, causing the solid to break down into smaller parts and dissolve more quickly. Examples of disintegrants are sodium carboxymethyl starch or cross-linked polymers such as cross-linked polyvinylpyrrolidone (crosspovidone), cross-linked carboxymethyl cellulose (cross-linked sodium carboxymethyl cellulose), or combinations thereof; in a particular embodiment, the disintegrant is sodium cross-linked carboxymethyl cellulose.

[0062] "Glide aid" refers to a substance that, when added to a powder, improves the flowability of the powder, such as by reducing interparticle friction. Exemplary glide aids include, but are not limited to, colloidal silica, colloidal silica (e.g., AEROSIL). ® 200), fumed silica (e.g., CAB-O-SIL®M-5P), magnesium trisilicate, powdered cellulose, talc, starch, magnesium aluminum silicate, and combinations thereof. A specific example of a flow aid is colloidal silica, and more particularly, colloidal silica.

[0063] "Lubricant" refers to an excipient that prevents ingredients from clumping together and adhering to the capsule filling machine. Lubricants also ensure that formation and spraying can occur with low friction between the active ingredient and the capsule wall. Examples of lubricants include poloxamer, polyethylene glycol, polyoxyethylene stearate, polyvinyl alcohol, talc, glyceryl silicate stearate, magnesium stearate, sodium stearate fumarate, or mixtures thereof. A specific example is magnesium stearate.

[0064] All the embodiments provided herein can be used in combination.

[0065] In one embodiment, the pharmaceutical composition provided herein comprises: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (b) at least one filler, and (c) At least one flow aid.

[0066] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (b) at least one filler, (c) at least one gliding agent, and (d) At least one disintegrant.

[0067] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (b) at least one filler, (c) At least one gliding agent, (d) at least one disintegrant, and (e) At least one adhesive.

[0068] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (b) at least one filler, (c) At least one gliding agent, (d) At least one disintegrant, (e) at least one adhesive, and (f) At least one lubricant.

[0069] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (1) Intraparticle components, which include: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (b) at least one filler, (c) At least one gliding agent, (d) at least one disintegrant, and (e) at least one adhesive, (2) Extraparticle components, which include: (a) At least one lubricant.

[0070] Specific embodiments relate to pharmaceutical compositions as described above, comprising between 30% and 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, more particularly between 50% and 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, and most particularly 70 ± 10% by weight. (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof.

[0071] Specific embodiments relate to pharmaceutical compositions as described above, comprising between 30% and 95% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, more particularly between 50% and 85% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, and most particularly 70 ± 10% by weight. The fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumarate, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A.

[0072] Specific embodiments relate to pharmaceutical compositions as described above, wherein the filler is between 4% by weight and 69% by weight, more particularly between 10% by weight and 50% by weight, and most particularly between 20 ± 10% by weight.

[0073] Specific embodiments relate to pharmaceutical compositions as described above, wherein the filler is between 4% by weight and 69% by weight, more particularly between 10% by weight and 50% by weight, and most particularly between 12 ± 2% by weight.

[0074] Specific embodiments relate to pharmaceutical compositions as described above, wherein the binder is a binder between 1% by weight and 5% by weight, more particularly between 2% by weight and 4% by weight, and most particularly 3 ± 0.5% by weight.

[0075] Specific embodiments relate to pharmaceutical compositions as described above, which comprise a binder between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly 3 ± 0.5% by weight.

[0076] Specific embodiments relate to pharmaceutical compositions as described above, wherein the disintegrant is between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly between 6 ± 2% by weight.

[0077] Specific embodiments relate to pharmaceutical compositions as described above, comprising between 0.5% by weight and 15% by weight of a disintegrant, more particularly between 3% by weight and 10% by weight of a disintegrant, and most particularly 8 ± 2% by weight of a disintegrant.

[0078] The pharmaceutical composition described above, wherein the gliding agent is between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly between 2 ± 0.5% by weight.

[0079] Specific embodiments relate to pharmaceutical compositions as described above, comprising between 0.5% by weight and 10% by weight of a gliding agent, more particularly between 1% by weight and 3% by weight of a gliding agent, and most particularly 2 ± 0.5% by weight of a gliding agent.

[0080] Specific embodiments relate to pharmaceutical compositions as described above, wherein the lubricant is a lubricant in amounts between 0.25% by weight and 5% by weight, more particularly between 0.5% by weight and 2.5% by weight, and most particularly between 1.5 ± 0.5% by weight.

[0081] Specific embodiments relate to pharmaceutical compositions as described above, comprising between 0.25% by weight and 5% by weight of a lubricant, more particularly between 0.5% by weight and 2.5% by weight of a lubricant, and most particularly 1.5 ± 0.5% by weight of a lubricant.

[0082] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (a) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, most particularly 70% by weight. ±10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (b) at least one filler in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, most particularly 20 ± 10% by weight, and (c) Disintegrants in amounts between 0.5% and 15% by weight, more particularly between 3% and 10% by weight, and most particularly between 8 ± 2% by weight; The total amount of the ingredients shall not exceed 100% w / w.

[0083] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (a) Fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine between 30 wt% and 95 wt%, more particularly between 50 wt% and 85 wt% of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine), most particularly between 70 ± 10 wt%. The fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most notably wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) fillers between 4% by weight and 69% by weight, more particularly between 10% by weight and 50% by weight, most particularly between 12 ± 2% by weight, and (c) Disintegrants in amounts between 0.5% and 15% by weight, more particularly between 3% and 10% by weight, and most particularly between 8 ± 2% by weight. The total amount of the ingredients shall not exceed 100% w / w.

[0084] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (a) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, most particularly 70% by weight. ±10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (b) at least one filler in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, and most particularly between 20 ± 10% by weight. (c) Disintegrants in amounts between 0.5% and 15% by weight, more particularly between 3% and 10% by weight, and most particularly between 8 ± 2% by weight, and (d) At least one flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight of a flow aid. The total amount of the ingredients shall not exceed 100% w / w.

[0085] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (a) Fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine between 30 wt% and 95 wt%, more particularly between 50 wt% and 85 wt% of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine), most particularly between 70 ± 10 wt%. The fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) Fillers in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, and most particularly between 12 ± 2% by weight. (c) Disintegrants in amounts between 0.5% and 15% by weight, more particularly between 3% and 10% by weight, and most particularly between 8 ± 2% by weight, and (d) A flow aid between 0.5% and 10% by weight, more particularly between 1% and 3% by weight, and most particularly 2 ± 0.5% by weight. The total amount of the ingredients shall not exceed 100% w / w.

[0086] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (a) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, most particularly 70% by weight. ±10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (b) at least one filler in amounts between 4% by weight and 69% by weight, more particularly between 10% by weight and 50% by weight, and most particularly between 20 ± 10% by weight. (c) At least one disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight. (d) At least one flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight of the flow aid, and (e) at least one adhesive in amounts between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly 3 ± 0.5% by weight. The total amount of the ingredients shall not exceed 100% w / w.

[0087] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (a) Fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine between 30 wt% and 95 wt%, more particularly between 50 wt% and 85 wt% of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine), most particularly between 70 ± 10 wt%. The fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) The filler in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, and most particularly between 12 ± 2% by weight. (c) 0.5% to 15% by weight of the disintegrant, more particularly 3% to 10% by weight of the disintegrant, and most particularly 8 ± 2% by weight of the disintegrant. (d) 0.5% to 10% by weight of the flow aid, more particularly between 1% and 3% by weight of the flow aid, and most particularly 2 ± 0.5% by weight of the flow aid, and (e) the adhesive in amounts between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly between 3 ± 0.5% by weight. The total amount of the ingredients shall not exceed 100% w / w.

[0088] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (a) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, most particularly 70% by weight. ±10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (b) at least one filler in amounts between 4% by weight and 69% by weight, more particularly between 10% by weight and 50% by weight, and most particularly between 20 ± 10% by weight. (c) At least one disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight. (d) At least one flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight of the flow aid. (e) at least one adhesive in amounts between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly 3 ± 0.5% by weight of the adhesive, and (f) at least one lubricant in amounts between 0.25% by weight and 5% by weight, more particularly between 0.5% by weight and 2.5% by weight, and most particularly 1.5 ± 0.5% by weight of the lubricant. The total amount of the ingredients shall not exceed 100% w / w.

[0089] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (a) Fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine between 30 wt% and 95 wt%, more particularly between 50 wt% and 85 wt% of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine), most particularly between 70 ± 10 wt%. The fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) The filler in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, and most particularly between 12 ± 2% by weight. (c) 0.5% to 15% by weight of the disintegrant, more particularly 3% to 10% by weight of the disintegrant, and most particularly 8 ± 2% by weight of the disintegrant. (d) The flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly between 2 ± 0.5% by weight. (e) the adhesive in amounts between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly 3 ± 0.5% by weight, and (f) The lubricant in amounts between 0.25% by weight and 5% by weight, more particularly between 0.5% by weight and 2.5% by weight, and most particularly between 1.5 ± 0.5% by weight. The total amount of the ingredients shall not exceed 100% w / w.

[0090] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (1) Intraparticle components, which include: (a) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, most particularly 70% by weight. ±10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (b) at least one filler in amounts between 4% by weight and 69% by weight, more particularly between 10% by weight and 50% by weight, and most particularly between 20 ± 10% by weight. (c) At least one disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight. (d) At least one flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight of the flow aid, and (e) at least one adhesive in amounts between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly 3 ± 0.5% by weight. (2) Extraparticle components, which include: (a) at least one lubricant in amounts between 0.25% by weight and 5% by weight, more particularly between 0.5% by weight and 2.5% by weight, and most particularly 1.5 ± 0.5% by weight of the lubricant. The total amount of the ingredients shall not exceed 100% w / w.

[0091] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (1) Intraparticle components, which include: (a) Fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine between 30 wt% and 95 wt%, more particularly between 50 wt% and 85 wt% of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine), most particularly between 70 ± 10 wt%. The fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) The filler in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, and most particularly between 12 ± 2% by weight. (c) 0.5% to 15% by weight of the disintegrant, more particularly 3% to 10% by weight of the disintegrant, and most particularly 8 ± 2% by weight of the disintegrant. (d) 0.5% to 10% by weight of the flow aid, more particularly between 1% and 3% by weight of the flow aid, and most particularly 2 ± 0.5% by weight of the flow aid, and (e) the adhesive in amounts between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly between 3 ± 0.5% by weight. (2) Extraparticle components, which include: (f) The lubricant in amounts between 0.25% by weight and 5% by weight, more particularly between 0.5% by weight and 2.5% by weight, and most particularly between 1.5 ± 0.5% by weight. The total amount of the ingredients shall not exceed 100% w / w.

[0092] Specific embodiments relate to pharmaceutical compositions as described above, comprising: Specific embodiments relate to pharmaceutical compositions as described above, comprising: (a) 70 ± 10 wt% of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most notably wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) 12 ± 2% by weight of filler, (c) 8 ± 2% by weight of disintegrant, (d) 2 ± 0.5% by weight of gliding agent, (e) 3 ± 0.5% by weight of adhesive, and (f) 1.5 ± 0.5% by weight of lubricant, The total amount of the ingredients shall not exceed 100% by weight.

[0093] Specific embodiments relate to pharmaceutical compositions as described above, which consist of the following: (a) 70 ± 10 wt% of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) 12 ± 2% by weight of the filler, (c) 8 ± 2% by weight of the disintegrant, (d) 2 ± 0.5% by weight of this gliding agent, (e) 3 ± 0.5% by weight of the adhesive, and (f) 1.5 ± 0.5% by weight of this lubricant, The total amount of the components is equal to 100 by weight.

[0094] Specific embodiments relate to pharmaceutical compositions as described above, wherein the pharmaceutical composition comprises 50 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine).

[0095] Specific embodiments relate to pharmaceutical compositions as described above, wherein (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is 50 mg.

[0096] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (a) 50 ± 5 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof. (b) 20 ± 10% by weight of filler, (c) 3 ± 0.5% by weight of adhesive, (d) 8 ± 2% by weight of disintegrant, (e) 2 ± 0.5% by weight of a gliding agent, and (f) 1.5 ± 0.5% by weight of lubricant.

[0097] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (a) 65 ± 5 mg of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a 1:1.5 ratio. The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most notably wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) 12 ± 2% by weight of filler, (c) 3 ± 0.5% by weight of adhesive, (d) 8 ± 2% by weight of disintegrant, (e) 2 ± 0.5% by weight of a gliding agent, and (f) 1.5 ± 0.5% by weight of lubricant, The total amount of the ingredients shall not exceed 100% by weight.

[0098] Specific embodiments relate to pharmaceutical compositions as described above, wherein the pharmaceutical composition comprises 200 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine).

[0099] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (a) 200 ± 20 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof. (b) 20 ± 10% by weight of filler, (c) 3 ± 0.5% by weight of adhesive, (d) 8 ± 2% by weight of disintegrant, (e) 2 ± 0.5% by weight of a gliding agent, and (f) 1.5 ± 0.5% by weight of lubricant.

[0100] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (a) 260 ± 20 mg of fumarate of (R)-N-(4-([1,2,4]triazol[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazol[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) 12 ± 2% by weight of filler, (c) 3 ± 0.5% by weight of adhesive, (d) 8 ± 2% by weight of disintegrant, (e) 2 ± 0.5% by weight of a gliding agent, and (f) 1.5 ± 0.5% by weight of lubricant, The total amount of the ingredients shall not exceed 100% by weight.

[0101] Specific embodiments relate to pharmaceutical compositions as described above, comprising compounds of formula (II). (II), particularly having less than 0.1% of compound (II), and more particularly having between 1 ppb and 100 ppm of compound (II).

[0102] Specific embodiments relate to pharmaceutical compositions as described above, wherein (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is a fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, particularly having a 1:1.5 ratio of [compound of formula (I): fumaric acid]. The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, most particularly fumarate type A.

[0103] Specific embodiments relate to pharmaceutical compositions as described above that comprise a single active pharmaceutical ingredient (API), particularly wherein the single API is (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, and more particularly wherein the single API is (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate.

[0104] Specific embodiments relate to pharmaceutical compositions as described above, wherein the pharmaceutical ingredient (API) has a particle size (Dv(90)) of less than 95.5 µm.

[0105] Specific embodiments relate to pharmaceutical compositions as described above, comprising between 30% and 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, more particularly between 50% and 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, and most particularly 70 ± 10% by weight. (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate.

[0106] Specific embodiments relate to pharmaceutical compositions as described above, wherein the pharmaceutical composition comprises 70 ± 10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate.

[0107] Specific embodiments relate to pharmaceutical compositions as described above, wherein the pharmaceutical composition comprises 70 ± 10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid.

[0108] Specific embodiments relate to pharmaceutical compositions as described above, wherein the pharmaceutical composition comprises 70 ± 10% by weight of fumarate type A.

[0109] Specific embodiments relate to pharmaceutical compositions as described above, wherein the pharmaceutical composition comprises 65 ± 5 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid.

[0110] Specific embodiments relate to pharmaceutical compositions as described above, wherein the pharmaceutical composition comprises 65 ± 5 mg of fumarate type A.

[0111] Specific embodiments relate to pharmaceutical compositions as described above, wherein the pharmaceutical composition comprises 260 ± 20 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid.

[0112] Specific embodiments relate to pharmaceutical compositions as described above, wherein the pharmaceutical composition comprises 260 ± 20 mg of fumarate type A.

[0113] Specific embodiments relate to pharmaceutical compositions as described above, wherein the filler is selected from microcrystalline cellulose (e.g., Avicel®), microcrystalline cellulose coated with colloidal silica, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate (i.e., Fujicalin), calcium sulfate, and combinations thereof.

[0114] Specific embodiments relate to pharmaceutical compositions as described above, wherein the filler is anhydrous dicalcium phosphate, particularly wherein the anhydrous dicalcium phosphate has an average particle size of 115 µm, and most particularly, the anhydrous dicalcium phosphate is Fujicalin® SG.

[0115] Specific embodiments relate to pharmaceutical compositions as described above, wherein the binder is selected from hydroxypropyl methylcellulose (e.g., METHOCEL™ E5), hydroxypropyl cellulose (e.g., Klucel™ hydroxypropyl cellulose), polyvinylpyrrolidone (PVP, such as povidone K30), sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and proteins such as gelatin, or mixtures thereof.

[0116] Specific embodiments relate to pharmaceutical compositions as described above, wherein the binder is hydroxypropyl cellulose (CAS: 9004-64-20), particularly wherein the hydroxypropyl cellulose has a low viscosity of 100-1000 mpa.s (e.g., Klucel™ hydroxypropyl cellulose E).

[0117] Specific embodiments relate to pharmaceutical compositions as described above, wherein the disintegrant is selected from sodium carboxymethyl starch or crosslinked polymers such as crosslinked polyvinylpyrrolidone (Copovidone), crosslinked carboxymethyl cellulose (e.g., crosslinked sodium carboxymethyl cellulose), and mixtures thereof.

[0118] Specific embodiments relate to pharmaceutical compositions as described above, wherein the disintegrant is croscarmellose sodium, and particularly wherein croscarmellose sodium has a drying loss of ≤10%.

[0119] Specific embodiments relate to pharmaceutical compositions as described above, wherein the disintegrant is croscarmellose sodium, which is present in an amount greater than 2% by weight and less than or equal to about 10% by weight.

[0120] Specific embodiments relate to pharmaceutical compositions as described above, wherein the disintegrant is croscarmellose sodium, which is present in an amount of 8 ± 2% by weight.

[0121] Specific embodiments relate to pharmaceutical compositions as described above, wherein the gliding agent is selected from colloidal silica, colloidal silica (e.g., AEROSIL® 200), fumed silica (e.g., CAB-O-SIL® M-5P), talc, starch, magnesium aluminum silicate, hydrophilic fumed silica, and mixtures thereof.

[0122] Specific embodiments relate to pharmaceutical compositions as described above, wherein the gliding agent is colloidal silica, particularly wherein the colloidal silica has a specific surface area of ​​200 m². 2 / g of hydrophilic fumed silica (e.g., CAS 7631-86-9), and more particularly colloidal silica as AEROSIL. ® 200 Pharma.

[0123] Specific embodiments relate to pharmaceutical compositions as described above, wherein the lubricant is selected from poloxamer, polyethylene glycol, polyoxyethylene stearate, polyvinyl alcohol, talc, glyceryl silica stearate, magnesium stearate, sodium stearate fumarate, or mixtures thereof.

[0124] Specific embodiments relate to pharmaceutical compositions as described above, wherein the lubricant is magnesium stearate.

[0125] Specific embodiments relate to pharmaceutical compositions as described above, wherein the lubricant has a bulk density of 0.05 g / cm³. 3 Up to 0.30 g / cm 3 Magnesium stearate (e.g., CAS 557-04-0), wherein magnesium stearate is based on a plant-derived product used in pharmaceutical products.

[0126] Specific embodiments relate to pharmaceutical compositions as described above, wherein: (a) The filler is anhydrous dicalcium phosphate (e.g., Fujicalin SG). (b) The disintegrant is croscarmellose sodium. (c) The flow aid is colloidal silica (e.g., AEROSIL). ® 200), and (d) The adhesive is hydroxypropyl cellulose (e.g., EXF type). (e) The lubricant is magnesium stearate.

[0127] Specific embodiments relate to pharmaceutical compositions as described above, comprising: (a) 70 ± 10 wt% of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most notably wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) 12 ± 2% by weight of filler, wherein the filler is anhydrous dicalcium phosphate (e.g., Fujicalin SG). (c) 8 ± 2% by weight of a disintegrant, wherein the disintegrant is croscarmellose sodium. (d) 2 ± 0.5% by weight of a flow aid, wherein the flow aid is colloidal silica (e.g., AEROSIL). ® 200), (e) 3 ± 0.5% by weight of an adhesive, wherein the adhesive is hydroxypropyl cellulose (e.g., EXF type), and (f) 1.5 ± 0.5% by weight of a lubricant, wherein the lubricant is magnesium stearate. The total amount of the ingredients shall not exceed 100% by weight.

[0128] Specific embodiments relate to pharmaceutical compositions as described above, wherein the pharmaceutical composition is prepared by a method including a wet granulation step (e.g., manufacturing method C).

[0129] Specific embodiments relate to pharmaceutical compositions as described above, wherein the pharmaceutical composition is prepared by a method including a wet granulation step, wherein the method includes the following steps: (a) When present, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof (e.g., fumarate), fillers, binders, disintegrants, and flow aids are sieved. (b) Dissolve the adhesive in water. (c) When present, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof (e.g., fumarate), filler, disintegrant, and glidant are mixed, optionally in a wet granulation pan. (d) Add solution b) to mixture c) and perform high-shear granulation to produce wet granules. (e) Dry wet granules, (f) Grinding the dried particles from step (e), and (g) Optionally, when present, the particles from step (f) are blended with a lubricant.

[0130] Specific embodiments relate to pharmaceutical compositions as described above, wherein: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine or a pharmaceutically acceptable salt thereof (e.g., fumarate) is (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, more particularly wherein (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most notably wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) Fillers as defined herein, such as anhydrous dicalcium phosphate (e.g., Fujicalin SG). (c) Disintegrants as defined herein, such as croscarmellose sodium, (d) A flow aid as defined herein, such as colloidal silica (e.g., AEROSIL). ® 200), (e) Adhesives as defined herein, such as hydroxypropyl cellulose (e.g., EXF type), and (f) Lubricants as defined herein, such as magnesium stearate.

[0131] Specific embodiments relate to pharmaceutical compositions as described above, wherein (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof (e.g., fumarate) is processed by using a jet milling method or a recrystallization method.

[0132] Specific embodiments relate to pharmaceutical compositions as described above, wherein (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof (e.g., fumarate) has a particle size (Dv(90)) of not more than 95.5 µm.

[0133] Specific embodiments relate to pharmaceutical compositions as described above, wherein: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof (e.g., fumarate) having a particle size not greater than 95.5 µm (Dv(90)), and (b) wherein the disintegrant is croscarmellose sodium, which is present in an amount greater than 2% by weight and less than or equal to about 10% by weight, and more particularly wherein the disintegrant is croscarmellose sodium, which is present in an amount of 8 ± 2% by weight.

[0134] In one embodiment, this document provides a capsule comprising the pharmaceutical composition as described above.

[0135] Specific embodiments relate to capsules as described above, comprising pharmaceutical compositions as described above, wherein the capsule is an enteric-coated capsule, and particularly wherein the capsule is an oral enteric-coated capsule.

[0136] Specific embodiments relate to capsules as described above, comprising the pharmaceutical composition described above, wherein the capsule is a pH-dependent enteric-coated empty gelatin capsule, most particularly comprising gelatin and hydroxypropyl methylcellulose phthalate.

[0137] Specific embodiments relate to capsules as described above, comprising the pharmaceutical composition described above, wherein the capsule is a pH-dependent enteric-coated empty hydroxypropyl methylcellulose capsule comprising hydroxypropyl methylcellulose and hydroxypropyl methylcellulose acetate succinate.

[0138] In one embodiment, this document also provides a kit comprising: a pharmaceutical composition as described above, in capsule form, particularly enteric-coated capsule form, the pharmaceutical composition comprising a therapeutically effective amount of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine; prescription information, also known as “instructions for use”; blister packs or bottles (HDPE or glass), particularly moisture-proof primary packaging, more particularly Alu / Alu Blister or plastic bottle containing desiccant; and container, in particular where the prescription information specifically includes advice to the patient regarding the administration of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine.

[0139] In one embodiment, this document also provides a method for manufacturing particles comprising (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine as described above, a filler, a binder, and a flow aid, the method comprising the following steps: (a) The (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, fillers, binders, disintegrants, and flow aids are sieved, wherein the fillers, binders, disintegrants, and flow aids are as defined herein. (b) Dissolve the adhesive in water, wherein the adhesive is as defined herein, thereby obtaining solution b). (c) Mixing (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, the filler, the disintegrant, and the flow aid, optionally in a wet granulator pot. (d) Add solution b) to mixture c) and perform high-shear granulation to produce wet granules. (e) Dry wet granules, (f) Grinding the dried particles from step (e), and (g) Optionally, the particles from step (f) are blended with the extraparticle portion (e.g., lubricant).

[0140] Specific embodiments relate to a method for manufacturing particles comprising (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof (e.g., fumarate), fillers, binders, disintegrants, and flow aids, the method comprising the steps of: (a) Sieve (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof (e.g., fumarate), fillers, binders, disintegrants and flow aids. (b) Dissolve the adhesive in water to obtain solution b). (c) Mixing (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof (e.g., fumarate), fillers, disintegrants, and gliding agents, optionally in a wet granulator pot, (d) Add solution b) to mixture c) and perform high-shear granulation to produce wet granules. (e) Dry the wet granules. (f) Grinding the dried particles from step (e), and (g) Optionally, the particles from step (f) are blended with the extraparticle portion (e.g., lubricant).

[0141] Specific embodiments relate to the methods described above, wherein: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof (e.g., fumarate) is (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl) Fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most notably wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) Fillers as defined herein, such as anhydrous dicalcium phosphate (e.g., Fujicalin SG). (c) Disintegrants as defined herein, such as croscarmellose sodium, (d) A flow aid as defined herein, such as colloidal silica (e.g., AEROSIL). ® 200), (e) Adhesives as defined herein, such as hydroxypropyl cellulose (e.g., EXF type), and (f) Lubricants as defined herein, such as magnesium stearate.

[0142] Specific embodiments relate to the method as described above, which further includes filling the mixture obtained in step g) as described above into capsules, wherein the capsules are as defined above.

[0143] Specific embodiments involve the method as described above, which further includes packaging the capsule in a bottle.

[0144] Specific embodiments involve the method as described above, wherein (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof (e.g., fumarate) is treated by using a jet milling method or a recrystallization method.

[0145] Specific embodiments involve the method as described above, wherein (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof (e.g., fumarate) has a particle size (Dv (90)) of not more than 95.5 µm.

[0146] Specific embodiments relate to pharmaceutical compositions as described above, comprising (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, which may be administered to an individual at any suitable dose (e.g., to achieve a therapeutically effective dose), particularly a suitable dose for a therapeutically effective dose of about 200 mg to 2000 mg daily (daily dose calculated based on free base), more particularly 200 mg to 1800 mg daily, and most particularly about 400 mg to 1600 mg daily.

[0147] In one embodiment, the pharmaceutical composition described above is used to treat cancers including, but not limited to, the following: circulatory system cancers, such as heart cancers (sarcomas [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma), mediastinum and pleura, and other intrathoracic organs, vascular tumors, and tumor-associated vascular tissues; respiratory system cancers, such as nasal cavity and middle ear, paranasal sinuses, larynx, trachea, bronchi, and lungs, such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogenic cancers, etc. Cancers (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal system, such as esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), stomach, pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma) (e.g., fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract, e.g., kidneys (adenocarcinoma, Wilms' tumor [nephroblastoma], lymphoma, leukemia), bladder and / or urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminomatous seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma); liver, e.g., hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, liver cell carcinoma. Cytomas, hemangiomas, pancreatic endocrine tumors (such as pheochromocytomas, insulinomas, vasoactive intestinal peptide tumors, islet cell tumors, and glucagonomas); bones, such as osteosarcomas, fibrosarcomas, malignant fibrous histiocytomas, chondrosarcomas, Ewing's sarcoma, malignant lymphomas (reticular cell sarcomas), multiple myeloma, malignant giant cell tumors, chordomas, osteochondromas (osteochondrogenic exostosis), benign chondromas, chondroblastomas, chondromycinoid fibromas, osteoid osteomas, and giant cell tumors; the nervous system, such as the central nervous system (CNS). Tumors, primary CNS lymphomas, skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);Reproductive system diseases, such as gynecological diseases, uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell carcinoma, Sertoli-Leydig cell carcinoma). The female reproductive organs include: cytomas, dysgerminomas, malignant teratomas; vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)); fallopian tubes (cancer); and other sites related to the female reproductive organs; placenta, penis, prostate, testes; and other sites related to the male reproductive organs; hematopoietic system, such as blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; oral cavity, such as lips, tongue, gums, floor of mouth, palate, and other parts of the oral cavity. Parts of the parotid gland and other parts of the salivary glands, tonsils, oropharynx, nasopharynx, piriform sinus, hypopharynx, and lips, other parts of the oral cavity and pharynx; skin, such as malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid; adrenal glands: neuroblastoma; and other tissues, including connective tissue and soft tissue, retroperitoneum and peritoneum, eye, intraocular melanoma and adnexa, breast, head and / or neck, anal region, thyroid gland, parathyroid glands, adrenal glands and other endocrine glands and related structures, secondary and unspecified malignant tumors of lymph nodes, secondary malignant tumors of the respiratory and digestive systems, and secondary malignant tumors of other sites.

[0148] Specific embodiments relate to a pharmaceutical composition as described above for use in treating cancers, including but not limited to: circulatory system cancers such as heart (sarcomas [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma), mediastinum and pleura, and other intrathoracic organs, vascular tumors, and tumor-associated vascular tissues; respiratory tract cancers such as the nasal cavity and middle ear, paranasal sinuses, larynx, trachea, bronchi, and lungs, such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), and bronchogenic carcinomas (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma). Adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal system, such as esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), stomach, pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract, such as kidney (adenocarcinoma, Wilms' disease). Hepatoblastoma (nephroblastoma), lymphoma, leukemia), bladder and / or urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoblastoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver, such as hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pancreatic endocrine tumors (such as pheochromocytoma, pancreatic...). Insulinoma, vasoactive intestinal peptide tumor, islet cell tumor, and glucagonoma; skeletal tumors, such as osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor; nervous system tumors, such as the central nervous system (CNS). Tumors, primary CNS lymphomas, skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);Reproductive system diseases, such as gynecological diseases, uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell carcinoma, Sertoli-Leydig cell carcinoma). The female reproductive organs include: cytomas, dysgerminomas, malignant teratomas; vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)); fallopian tubes (cancer); and other sites related to the female reproductive organs; placenta, penis, prostate, testes; and other sites related to the male reproductive organs; hematopoietic system, such as blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; oral cavity, such as lips, tongue, gums, floor of mouth, palate, and other parts of the oral cavity. Parts of the parotid gland and other parts of the salivary glands, tonsils, oropharynx, nasopharynx, piriform sinus, hypopharynx, and lips, other parts of the oral cavity and pharynx; skin, such as malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid; adrenal glands: neuroblastoma; and other tissues, including connective tissue and soft tissue, retroperitoneum and peritoneum, eye, intraocular melanoma and adnexa, breast, head and / or neck, anal region, thyroid gland, parathyroid glands, adrenal glands and other endocrine glands and related structures, secondary and unspecified malignant tumors of lymph nodes, secondary malignant tumors of the respiratory and digestive systems, and secondary malignant tumors of other sites.

[0149] Specific embodiments relate to pharmaceutical compositions as described above for use in the treatment of HER2-related cancers.

[0150] Specific embodiments relate to pharmaceutical compositions as described above for use in treating cancer, or pharmaceutical compositions as described above for use in treatment methods as described above, wherein the cancer is selected from cancers expressing HER2, HER2-positive cancers, or HER ligand-overexpressing cancers.

[0151] Specific embodiments relate to pharmaceutical compositions as described above for use in the treatment methods described above, wherein the cancer is HER2-positive cancer.

[0152] Specific embodiments relate to pharmaceutical compositions as described above for use in treating cancer, or pharmaceutical compositions as described above for use in treatment methods as described above, wherein the cancer is selected from breast cancer, gastric cancer, biliary tract cancer, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer, and uterine cancer, and more particularly wherein the cancer is selected from breast cancer, gastric cancer, colorectal cancer, or NSCLC.

[0153] Specific embodiments relate to pharmaceutical compositions as described above for use in the treatment methods described above, wherein the cancer is a metastasis of the cancer specified in any of the foregoing embodiments.

[0154] Specific embodiments relate to the pharmaceutical composition described above for use in the treatment methods described above, wherein the metastasis is a brain metastasis.

[0155] Specific embodiments relate to pharmaceutical compositions as described above for use in treating cancer, or pharmaceutical compositions as described above for use in treatment methods as described above, wherein the cancer is breast cancer with brain metastases.

[0156] Specific embodiments relate to the use of the pharmaceutical compositions described above in the preparation of a medicament for treating cancer, including but not limited to: circulatory system cancers, such as heart cancers (sarcomas [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma), mediastinum and pleura, and other intrathoracic organs, vascular tumors, and tumor-associated vascular tissues; respiratory tract cancers, such as the nasal cavity and middle ear, paranasal sinuses, larynx, trachea, bronchi, and lungs, such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), and bronchogenic carcinomas (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma). Cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal system, such as esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), stomach, pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract, such as kidney (adenocarcinoma, Wilms' disease). Hepatoblastoma (nephroblastoma), lymphoma, leukemia), bladder and / or urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoblastoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver, such as hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pancreatic endocrine tumors (such as pheochromocytoma, pancreatic...). Insulinoma, vasoactive intestinal peptide tumor, islet cell tumor, and glucagonoma; skeletal tumors, such as osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor; nervous system tumors, such as the central nervous system (CNS). Tumors, primary CNS lymphomas, skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);Reproductive system diseases, such as gynecological diseases, uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell carcinoma, Sertoli-Leydig cell carcinoma). The female reproductive organs include: cytomas, dysgerminomas, malignant teratomas; vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)); fallopian tubes (cancer); and other sites related to the female reproductive organs; placenta, penis, prostate, testes; and other sites related to the male reproductive organs; hematopoietic system, such as blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; oral cavity, such as lips, tongue, gums, floor of mouth, palate, and other parts of the oral cavity. Parts of the parotid gland and other parts of the salivary glands, tonsils, oropharynx, nasopharynx, piriform sinus, hypopharynx, and lips, other parts of the oral cavity and pharynx; skin, such as malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid; adrenal glands: neuroblastoma; and other tissues, including connective tissue and soft tissue, retroperitoneum and peritoneum, eye, intraocular melanoma and adnexa, breast, head and / or neck, anal region, thyroid gland, parathyroid glands, adrenal glands and other endocrine glands and related structures, secondary and unspecified malignant tumors of lymph nodes, secondary malignant tumors of the respiratory and digestive systems, and secondary malignant tumors of other sites.

[0157] Specific embodiments relate to the use of the pharmaceutical composition described above in the preparation of a medicament for treating HER2-related cancers.

[0158] Specific embodiments relate to the use of the pharmaceutical composition as described above in the preparation of a medicament for treating cancer, or the use of the pharmaceutical composition as described above in the preparation of a medicament as described above, wherein the cancer is selected from cancers expressing HER2, HER2-positive cancers, or HER ligand-overexpressing cancers.

[0159] Specific embodiments relate to the use of the pharmaceutical composition as described above in the preparation of the medicament as described above, wherein the cancer is HER2-positive cancer.

[0160] Specific embodiments relate to the use of the pharmaceutical composition as described above in the preparation of a medicament for treating cancer, or the use of the pharmaceutical composition as described above in the preparation of a medicament as described above, wherein the cancer is selected from breast cancer, gastric cancer, biliary tract cancer, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer, and uterine cancer, and more particularly wherein the cancer is selected from breast cancer, gastric cancer, colorectal cancer, or NSCLC.

[0161] Specific embodiments relate to the use of the pharmaceutical composition as described above in the preparation of the medicament as described above, wherein the cancer is metastasis of the cancer specified in any of the foregoing embodiments.

[0162] Specific embodiments relate to the use of the pharmaceutical composition as described above in the preparation of the medicament as described above, wherein the transfer is a brain transfer.

[0163] Specific embodiments relate to the use of the pharmaceutical composition as described above in the preparation of a medicament for treating cancer, or the use of the pharmaceutical composition as described above in the preparation of a medicament as described above, wherein the cancer is brain metastasis of breast cancer.

[0164] Specific embodiments relate to a method for treating cancer, the method comprising administering a pharmaceutical composition as described above, wherein the cancers include, but are not limited to, cancers of the following: circulatory system, such as the heart (sarcomas [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma), mediastinum and pleura, and other intrathoracic organs, vascular tumors, and tumor-associated vascular tissue; respiratory tract, such as the nasal cavity and middle ear, paranasal sinuses, larynx, trachea, bronchi, and lungs, such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated small cell carcinoma, etc.). Large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal system, such as esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), stomach, pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract, such as kidney (adenocarcinoma, Wilms' disease). Hepatoblastoma (nephroblastoma), lymphoma, leukemia), bladder and / or urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoblastoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver, such as hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pancreatic endocrine tumors (such as pheochromocytoma, pancreatic...). Insulinoma, vasoactive intestinal peptide tumor, islet cell tumor, and glucagonoma; skeletal tumors, such as osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor; nervous system tumors, such as the central nervous system (CNS). Tumors, primary CNS lymphomas, skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);Reproductive system diseases, such as gynecological diseases, uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell carcinoma, Sertoli-Leydig cell carcinoma). The female reproductive organs include: cytomas, dysgerminomas, malignant teratomas; vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)); fallopian tubes (cancer); and other sites related to the female reproductive organs; placenta, penis, prostate, testes; and other sites related to the male reproductive organs; hematopoietic system, such as blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; oral cavity, such as lips, tongue, gums, floor of mouth, palate, and other parts of the oral cavity. Parts of the parotid gland and other parts of the salivary glands, tonsils, oropharynx, nasopharynx, piriform sinus, hypopharynx, and lips, other parts of the oral cavity and pharynx; skin, such as malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid; adrenal glands: neuroblastoma; and other tissues, including connective tissue and soft tissue, retroperitoneum and peritoneum, eye, intraocular melanoma and adnexa, breast, head and / or neck, anal region, thyroid gland, parathyroid glands, adrenal glands and other endocrine glands and related structures, secondary and unspecified malignant tumors of lymph nodes, secondary malignant tumors of the respiratory and digestive systems, and secondary malignant tumors of other sites.

[0165] Specific embodiments relate to a method for treating HER2-related cancers, the method comprising administering a pharmaceutical composition as described above.

[0166] Specific embodiments relate to a method for treating cancer, the method comprising administering a pharmaceutical composition as described above or a treatment method as described above, wherein the cancer is selected from cancers expressing HER2, HER2-positive cancers, or HER-ligand-overexpressing cancers.

[0167] Specific embodiments relate to the treatment methods described above, wherein the cancer is HER2-positive cancer.

[0168] Specific embodiments relate to a method for treating cancer, the method comprising administering a pharmaceutical composition as described above or a treatment method as described above, wherein the cancer is selected from breast cancer, gastric cancer, biliary tract cancer, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer, and uterine cancer, and more particularly wherein the cancer is selected from breast cancer, gastric cancer, colorectal cancer, or NSCLC.

[0169] Specific embodiments relate to treatment methods as described above, wherein the cancer is a metastasis of the cancer specified in any of the foregoing embodiments.

[0170] Specific embodiments relate to the treatment methods described above, wherein the metastasis is a brain metastasis.

[0171] Specific embodiments relate to a method for treating cancer, the method comprising administering a pharmaceutical composition as described above or a treatment method as described above, wherein the cancer is a brain metastasis of breast cancer.

[0172] In one embodiment, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof optionally further comprises a diluent, such as lactose, starch, hydrolyzed starch, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, calcium hydrogen phosphate, calcium sulfate, or combinations thereof.

[0173] Other features and embodiments of this disclosure will become apparent from the following examples, which are provided to illustrate the invention and not to limit its intended scope.

[0174] Example 1: Drug-Excipient Compatibility Study A binary drug-excipient compatibility study was conducted to determine suitable excipients for the capsule formulation of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine). Pharmaceutical excipients such as fillers, binders, disintegrants, glidants, and lubricants were evaluated. The powder blend of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate and excipients was stored in glass vials for 30 days at 40°C / 75% ± 5% relative humidity (RH) (open), and relevant substances were tested. The results of the drug-excipient compatibility study are summarized in Table 1 below.

[0175] Table 1: Relevant substances for excipient compatibility studies Functional excipients hydroxypropyl cellulose, croscarmellose sodium, colloidal silica, and magnesium stearate were shown to have good compatibility with APIs.

[0176] Example 2: Evaluation of the manufacturing method of enteric-coated capsules The feasibility of preparing compositions containing (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate was evaluated using different manufacturing methods, including direct blending, high-shear wet granulation, and roller pressing dry granulation, and is summarized in Table 2 below.

[0177] Table 2: Prototype Formulations and Their Manufacturing Methods In manufacturing method A, net API is directly filled into No. 0 enteric gelatin hard capsule shells by hand.

[0178] In manufacturing method B, enteric-coated capsules are prepared using a dry blending manufacturing method followed by automated capsule filling, with the following steps: 1) Distribute the API and auxiliary materials, and then sieve them separately using a 35-mesh sieve.

[0179] 2) Blend the screened material into a suitable blender.

[0180] Blending speed: 20 rpm, time: 10 minutes.

[0181] 3) Lubricate the dry mixture. Speed: 20 rpm, Time: 3 minutes.

[0182] 4) The final dry blend is encapsulated in No. 0 enteric gelatin hard capsule shells.

[0183] Manufacturing method C is a wet granulation method, and its steps are as follows: 1) Distribute the API and auxiliary materials, and then sieve them separately using a 35-mesh sieve.

[0184] 2) Premixed sieved material. Add the binder solution (8% hydroxypropyl cellulose solution) to the granulator pot and perform high-shear granulation.

[0185] Cutter speed: 500 rpm, impeller speed: 1000 rpm, pelleting time: 5 minutes 3) Use a fluidized bed dryer to dry the wet particles. The drying parameters are as follows: inlet air temperature: 50℃-70℃, airflow velocity: 50-300 m / s. 3 / h.

[0186] 4) Pass the dried particles through a grinder set to 1,000 rpm and equipped with a 1.0 mm screen.

[0187] 5) Blend and lubricate the collected dried particles. Speed: 20 rpm, Time: 3 minutes.

[0188] 6) The lubricating blend is encapsulated in No. 0 enteric gelatin hard capsule shells.

[0189] Manufacturing method D is the dry granulation of D, and its steps are as follows: 1) Distribute the API and auxiliary materials, and then sieve them separately using a 35-mesh sieve.

[0190] 2) Blend the screened material into a suitable blender.

[0191] Blending speed: 20 rpm, time: 10 minutes.

[0192] 3) Dry granulation of the mixture is performed using a roller press platform. The pressed strip is then ground using a 1.0 mm sieve.

[0193] Pressing force: 5KN, roller speed: 10rpm, roller gap: 2mm 4) Add sieved magnesium stearate and lubricate. Speed: 20 rpm, Time: 3 minutes.

[0194] 5) The final granules are encapsulated in No. 0 enteric gelatin hard capsule shells.

[0195] Overall, the powder flowability of the API was examined by measuring the angle of repose and calculating the Karl elliptic index, and the results showed that the active pharmaceutical ingredient had low bulk density and poor flowability. Therefore, it was found difficult to directly fill 200 mg of API into size 0 capsules. Direct dry blending of API with excipients (manufacturing method B) did not show any advantage in improving the flowability and bulk density of API. However, high-shear wet granulation (manufacturing method C) and roller-based dry granulation (manufacturing method D) showed improvements in particle flowability and density for capsule filling. Considering that high drug loading may lead to adhesion problems in the roller-based method, wet granulation is the preferred manufacturing method.

[0196] Capsules prepared by different manufacturing methods (wet granulation, direct dry blending, and pure API encapsulation) were tested using FaSSIF as the dissolution medium to evaluate the effect of wet granulation on dissolution. The results are shown in Table 3.

[0197] Table 3: Dissolution curves of capsules prepared by different manufacturing methods Capsules manufactured by wet granulation showed dissolution profiles comparable to those prepared by direct dry blending and pure API encapsulation. These dissolution profiles were considered acceptable.

[0198] Example 3: Active pharmaceutical ingredient particle size assessment Generally, for drug substances with a rod-like morphology and particle size in the micrometer range, larger drug substance particle sizes improve manufacturability due to better flowability. However, larger drug substance particle sizes may reduce dissolution and negatively impact the in vivo performance of the drug substance. To determine an appropriate drug substance particle size distribution range for further research, a pharmaceutical composition comprising (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate with four different particle size distributions (PSDs) was prepared.

[0199] Table 4: Formulation components using different PSD APIs API used in E is processed using a jet milling method. APIs used in F, G, and H are all obtained using conventional recrystallization methods.

[0200] Enteric-coated capsules are prepared using a wet granulation method and then filled using an automated capsule filling machine.

[0201] Table 5: Dissolution curves of capsules using different PSD active pharmaceutical ingredients The dissolution ratio of enteric-coated capsules prepared using API with a large particle size Dv (90) of 125 µm (H) did not meet the quality standards. However, the dissolution rate of products with a particle size controlled to Dv (90) no greater than 95.5 µm met the dissolution standards. Therefore, it is recommended to use (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate with a particle size no greater than 95.5 µm (Dv (90)) for API formulations.

[0202] Example 4: Evaluation of formulation components at the level of disintegrants Pharmaceutical compositions containing different levels of the disintegrant croscarmellose sodium (0.0%, 2.0%, 5.0%, and 8.0%) of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate were prepared according to Table 6 below to investigate the effect of disintegrant levels on drug release.

[0203] Table 6: Formulation components with different disintegrant levels Enteric-coated capsules were prepared using a high-shear wet granulation method, and then filled into enteric-coated gelatin hard capsules using an automated capsule filling machine. Dissolution test results are summarized in Table 7.

[0204] Table 7: Dissolution results at different levels of disintegrants In summary, capsule products containing higher levels of disintegrants exhibited faster release. Capsule products without a disintegrant (cross-linked carboxymethyl cellulose sodium) (batch I) did not meet the dissolution quality standards. To achieve rapid release at the target absorption site in the duodenum, a disintegrant concentration greater than 2% of cross-linked carboxymethyl cellulose sodium was selected for use in capsule products.

[0205] Example 5: Evaluation of formulation components of filler type The feasibility of formulation and high-shear wet granulation methods was evaluated using a pharmaceutical composition comprising (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate and commonly used fillers microcrystalline cellulose, lactose monohydrate, and calcium hydrogen phosphate. The formulation composition is described in Table 8.

[0206] Table 8: Composition of different filler formulations Enteric-coated capsules were prepared using a high-shear wet granulation method with different fillers: microcrystalline cellulose, lactose monohydrate, and dicalcium phosphate. The particle characteristics are summarized in Table 9 below.

[0207] Table 9. Particle characteristics of different filler formulations In summary, the wet granulation method demonstrates robustness for all formulations using microcrystalline cellulose, lactose monohydrate, and dicalcium phosphate as fillers.

[0208] Example 6 Manufacturing of 50 mg and 200 mg enteric-coated capsules Table 10 shows the different strengths of capsules, 50 mg and 200 mg, based on (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate).

[0209] Table 10: Composition of 50 mg and 200 mg enteric-coated capsules 10,200 g of ordinary granules were prepared using a high-shear wet granulation method, followed by automated capsule filling. The particle sizes of the API were: Dv(10): 4.47 µm, Dv(50): 15.44 µm, and Dv(90): 40.27 µm. The high-shear wet granulation method is summarized below: 1) The API and pharmaceutical excipients were sieved using a 35-mesh sieve.

[0210] 2) In a suitable container, dissolve hydroxypropyl cellulose in purified water and stir at 1000 rpm. Obtain a clear binder solution.

[0211] 3) Then, the sieved API, dicalcium phosphate, cross-linked sodium carboxymethyl cellulose, and colloidal silica materials are transferred to a suitable 3 L wet granulator. Premix at 500 rpm for 3 min.

[0212] 4) Add the binder solution to the pellet mill pot and granulate. Impeller speed: 410 rpm, cutter speed: 1500 rpm, mixing time: 5 min.

[0213] 5) Dry the wet particles in a 10L fluidized bed dryer with the following drying parameters: inlet air temperature: 50℃-70℃, airflow velocity: 50-300 m / s. 3 / h.

[0214] 6) Pass the dried particles through a grinder set to 1,000 rpm and equipped with a 1.0 mm sieve.

[0215] 7) Collect the sieved material and then blend it with the extragranular magnesium stearate in a 5L mixer hopper. Blending speed: 15 rpm; Blending time: 5 min.

[0216] 8) The lubricating blend was filled into enteric-coated capsules No. 0 and No. 2 to obtain capsule products in 200 mg and 50 mg strengths, respectively.

[0217] The enteric-coated capsule final product is packaged in 75 ml high-density polyethylene (HDPE) bottles for solid dosage forms and sealed with an aluminum foil induction seal and a 33 mm pharmaceutical safety cap (oral solid dosage form polypropylene (PP) child safety cap).

[0218] Drug release tests were performed on 50 mg and 200 mg enteric-coated capsules in acid and buffer phases using a USP Type II paddle method under the conditions described below (bath temperature 37°C) and qualified high-performance liquid chromatography. These formulations were tested using the conditions described herein. Dissolution results are provided in Table 11 below, representing the average percentage of release of ((R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine) fumarate from the capsules.

[0219] Table 11: Dissolution curves of 50 mg and 200 mg capsules Overall, the 50 mg and 200 mg enteric-coated capsules showed good acid resistance in 0.1 N HCl solution, and no drug release was observed in the dissolution test. In the buffer stage, the product showed acceptable release profiles and met quality standards.

[0220] The acid resistance of enteric-coated capsules of formulation P in 0.1N HCl solution for 120 min was evaluated. The appearance of the enteric-coated capsules is shown in Figure 1.

[0221] Other quality properties of enteric-coated capsules are provided in Table 12. Table 12: Quality Attributes of Enteric-Coated Capsules Pharmacokinetic evaluation was performed on the 200 mg (P) enteric-coated capsule formulation in beagle dogs (n = 5).

[0222] Materials and methods for PK research The research design is as follows: Table 13: Mean plasma concentration-time data after PO administration in male beagle dogs (P, n=5) Enteric-coated capsules showed favorable pharmacokinetic characteristics and exposure in male beagle dogs.

[0223] Example 7 200 mg enteric-coated capsules Table 14 shows the 200 mg granules in enteric-coated capsules. The granules can be prepared by a method including a wet granulation step (e.g., manufacturing method C).

[0224] Table 14: Composition of 200 mg enteric-coated capsules The capsule may also have one or more of the following characteristics: 1. Salt coefficient: 722.66 (sesquifumarate) / 548.544 (free base) = 1.3174.

[0225] 2. Capsule type: Gelatin, enteric-coated.

[0226] 3. Hard capsule size: 0.

[0227] 4. Shell weight: 104.4 mg.

[0228] The following numbered embodiments also constitute a part of this disclosure: Example: Example 1: A pharmaceutical composition comprising: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (b) at least one filler, and (c) At least one flow aid.

[0229] Example 2: The pharmaceutical composition according to Example 1, comprising: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (b) at least one filler, (c) at least one gliding agent, and (d) At least one disintegrant.

[0230] Example 3: The pharmaceutical composition according to Example 1 or 2, comprising: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (b) at least one filler, (c) At least one gliding agent, (d) at least one disintegrant, and (e) At least one adhesive.

[0231] Example 4: A pharmaceutical composition according to any one of Examples 1 to 3, comprising: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (b) at least one filler, (c) At least one gliding agent, (d) At least one disintegrant, (e) at least one adhesive, and (f) At least one lubricant.

[0232] Example 5: A pharmaceutical composition according to any one of Examples 1 to 4, comprising: (1) Intraparticle components, which include: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (b) at least one filler, (c) At least one gliding agent, (d) At least one disintegrant, (e) at least one adhesive, (2) Extraparticle components, which include: (a) At least one lubricant.

[0233] Example 6: A pharmaceutical composition according to any one of Examples 1 to 5, comprising between 30% and 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, more particularly between 50% and 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, most particularly 70 ± 10% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof.

[0234] Example 7: A pharmaceutical composition according to any one of Examples 1 to 6, wherein the filler is between 4% by weight and 69% by weight, more particularly between 10% by weight and 50% by weight, and most particularly between 20 ± 10% by weight.

[0235] Example 8: A pharmaceutical composition according to any one of Examples 1 to 7, wherein the binder is between 1% by weight and 5% by weight, more particularly between 2% by weight and 4% by weight, and most particularly 3 ± 0.5% by weight.

[0236] Example 9: A pharmaceutical composition according to any one of Examples 1 to 8, wherein the disintegrant is between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly between 8 ± 2% by weight.

[0237] Example 10: A pharmaceutical composition according to any one of Examples 1 to 9, wherein the gliding agent is between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight.

[0238] Example 11: A pharmaceutical composition according to any one of Examples 1 to 10, wherein the lubricant is between 0.25% by weight and 5% by weight, more particularly between 0.5% by weight and 2.5% by weight, and most particularly 1.5 ± 0.5% by weight.

[0239] Example 12: A pharmaceutical composition according to any one of Examples 1 to 11, comprising: (a) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, most particularly 70% by weight. ±10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (b) at least one filler in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, and most particularly 20 ± 10% by weight of the filler, and (c) 0.5% to 15% by weight of the disintegrant, more particularly 3% to 10% by weight of the disintegrant, and most particularly 8 ± 2% by weight of the disintegrant. The total amount of the ingredients shall not exceed 100% w / w.

[0240] Example 13: A pharmaceutical composition according to any one of Examples 1 to 12, comprising: (a) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, most particularly 70% by weight. ±10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (b) at least one filler in amounts between 4% by weight and 69% by weight, more particularly between 10% by weight and 50% by weight, and most particularly between 20 ± 10% by weight. (c) 0.5% to 15% by weight of the disintegrant, more particularly 3% to 10% by weight of the disintegrant, and most particularly 8 ± 2% by weight of the disintegrant, and (d) At least one flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight of the flow aid. The total amount of the ingredients shall not exceed 100% w / w.

[0241] Example 14: A pharmaceutical composition according to any one of Examples 1 to 13, comprising: (a) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, most particularly 70% by weight. ±10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (b) at least one filler in amounts between 4% by weight and 69% by weight, more particularly between 10% by weight and 50% by weight, and most particularly between 20 ± 10% by weight. (c) At least one disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight. (d) At least one flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight of the flow aid, and (e) at least one adhesive in amounts between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly 3 ± 0.5% by weight. The total amount of the ingredients shall not exceed 100% w / w.

[0242] Example 15: A pharmaceutical composition according to any one of Examples 1 to 14, comprising: (a) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, most particularly 70% by weight. ±10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (b) at least one filler in amounts between 4% by weight and 69% by weight, more particularly between 10% by weight and 50% by weight, and most particularly between 20 ± 10% by weight. (c) At least one disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight. (d) At least one flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight of the flow aid. (e) at least one adhesive in amounts between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly 3 ± 0.5% by weight of the adhesive, and (f) at least one lubricant in amounts between 0.25% by weight and 5% by weight, more particularly between 0.5% by weight and 2.5% by weight, and most particularly 1.5 ± 0.5% by weight of the lubricant. The total amount of the ingredients shall not exceed 100% w / w.

[0243] Example 16: A pharmaceutical composition according to any one of Examples 1 to 15, comprising: (1) Intraparticle components, which include: (a) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, most particularly 70% by weight. ±10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (b) at least one filler in amounts between 4% by weight and 69% by weight, more particularly between 10% by weight and 50% by weight, and most particularly between 20 ± 10% by weight. (c) At least one disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight. (d) At least one flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight of the flow aid, and (e) at least one adhesive in amounts between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly 3 ± 0.5% by weight. (2) Extraparticle components, which include: (a) at least one lubricant in amounts between 0.25% by weight and 5% by weight, more particularly between 0.5% by weight and 2.5% by weight, and most particularly 1.5 ± 0.5% by weight of the lubricant. The total amount of the ingredients shall not exceed 100% w / w.

[0244] Example 17: A pharmaceutical composition according to any one of Examples 1 to 16, comprising: (a) 70 ± 10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (b) 20 ± 10% by weight of the filler, (c) 8 ± 2% by weight of the disintegrant, (d) 2 ± 0.5% by weight of this gliding agent, (e) 3 ± 0.5% by weight of the adhesive, and (f) 1.5 ± 0.5% by weight of this lubricant, The total amount of the ingredients shall not exceed 100% by weight.

[0245] Example 18: A pharmaceutical composition according to any one of Examples 1 to 17, wherein the pharmaceutical composition comprises 50 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine.

[0246] Example 19: A pharmaceutical composition according to any one of Examples 1 to 18, comprising: (a) 50 ± 5 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof. (b) 20 ± 10% by weight of filler, (c) 3 ± 0.5% by weight of adhesive, (d) 8 ± 2% by weight of disintegrant, (e) 2 ± 0.5% by weight of a gliding agent, and (f) 1.5 ± 0.5% by weight of lubricant.

[0247] Example 20: A pharmaceutical composition according to any one of Examples 1 to 17, wherein the pharmaceutical composition comprises 200 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine.

[0248] Example 21: A pharmaceutical composition according to any one of Examples 1 to 17 and 20, comprising: (a) 200 ± 20 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof. (b) 20 ± 10% by weight of filler, (c) 3 ± 0.5% by weight of adhesive, (d) 8 ± 2% by weight of disintegrant, (e) 2 ± 0.5% by weight of a gliding agent, and (f) 1.5 ± 0.5% by weight of lubricant.

[0249] Example 22: A pharmaceutical composition according to any one of Examples 1 to 21, further comprising a compound of formula (II). (II), particularly having less than 0.1% of the compound of formula (II), and more particularly having between 1 ppb and 100 ppm of the compound of formula (II).

[0250] Example 23: A pharmaceutical composition according to any one of Examples 1 to 22, wherein (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is a fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, particularly having a 1:1.5 ratio of [Compound of Formula (I): fumaric acid]. The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, most particularly fumarate type A.

[0251] Example 24: A pharmaceutical composition according to any one of Examples 1 to 23, comprising a single active pharmaceutical ingredient (API), particularly wherein the single API is a compound of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the single API is (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate.

[0252] Example 25: A pharmaceutical composition according to any one of Examples 1 to 24, comprising between 30% and 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, more particularly between 50% and 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, most particularly 70 ± 10% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate.

[0253] Example 26: A pharmaceutical composition according to any one of Examples 1 to 25, wherein the filler is selected from microcrystalline cellulose (e.g., Avicel). ® Microcrystalline cellulose coated with colloidal silica, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate (i.e., Fujicalin), calcium sulfate, and combinations thereof.

[0254] Example 27: A pharmaceutical composition according to any one of Examples 1 to 26, wherein the filler is anhydrous calcium hydrogen phosphate, particularly wherein the anhydrous calcium hydrogen phosphate has an average particle size of 115 µm, and most particularly wherein the anhydrous calcium hydrogen phosphate is Fujicalin.® SG.

[0255] Example 28: A pharmaceutical composition according to any one of Examples 1 to 27, wherein the binder is selected from hydroxypropyl methylcellulose (e.g., METHOCEL™ E5), hydroxypropyl cellulose (e.g., Klucel), etc. TM Hydroxypropyl cellulose), polyvinylpyrrolidone (PVP, such as povidone K30), sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and proteins such as gelatin, or mixtures thereof.

[0256] Example 29: A pharmaceutical composition according to any one of Examples 1 to 28, wherein the binder is hydroxypropyl cellulose (CAS: 9004-64-20), particularly wherein the hydroxypropyl cellulose has a low viscosity of 100-1000 mPa·s (e.g., Klucel). TM Hydroxypropyl cellulose (E).

[0257] Example 30: A pharmaceutical composition according to any one of Examples 1 to 29, wherein the disintegrant is sodium carboxymethyl starch or a crosslinked polymer, such as crosslinked polyvinylpyrrolidone (Copovidone), crosslinked carboxymethyl cellulose (e.g., crosslinked sodium carboxymethyl cellulose), or a mixture thereof.

[0258] Example 31: A pharmaceutical composition according to any one of Examples 1 to 30, wherein the disintegrant is croscarmellose sodium, particularly wherein the croscarmellose sodium has a drying loss of ≤10%.

[0259] Example 32: A pharmaceutical composition according to any one of Examples 1 to 31, wherein the gliding agent is selected from colloidal silica, colloidal silica (e.g., AEROSIL). ® 200), fumed silica (e.g., CAB-O-SIL®M-5P), talc, starch, magnesium aluminum silicate, hydrophilic fumed silica and mixtures thereof.

[0260] Example 33: A pharmaceutical composition according to any one of Examples 1 to 32, wherein the gliding agent is colloidal silica, particularly wherein the colloidal silica has a specific surface area of ​​200 m². 2 / g of hydrophilic fumed silica (e.g., CAS 7631-86-9), more particularly the colloidal silica being AEROSIL. ® 200 Pharma.

[0261] Example 34: A pharmaceutical composition according to any one of Examples 1 to 33, wherein the lubricant is selected from poloxamer, polyethylene glycol, polyoxyethylene stearate, polyvinyl alcohol, talc, glyceryl silica stearate, magnesium stearate, sodium stearate fumarate, or mixtures thereof.

[0262] Example 35: A pharmaceutical composition according to any one of Examples 1 to 34, wherein the lubricant has a bulk density of 0.05 g / cm³. 3 Up to 0.30 g / cm 3 Magnesium stearate (e.g., CAS 557-04-0), wherein the magnesium stearate is based on a plant-derived product for pharmaceutical use.

[0263] Example 36: A capsule comprising the pharmaceutical composition according to any one of Examples 1 to 35.

[0264] Example 37 The capsule according to Example 36, wherein the capsule is an enteric-coated capsule, and particularly wherein the capsule is an oral enteric-coated capsule.

[0265] Example 38: A capsule according to Example 36 or 37, wherein the capsule is a pH-dependent enteric-coated empty gelatin capsule, most particularly comprising gelatin and hydroxypropyl methylcellulose phthalate.

[0266] Example 39: The capsule according to Example 36 or 37, wherein the capsule is a pH-dependent enteric-coated empty hydroxypropyl methylcellulose capsule containing hydroxypropyl methylcellulose and hydroxypropyl methylcellulose acetate succinate.

[0267] Example 40: A kit comprising: a pharmaceutical composition according to any one of Examples 1 to 35 in capsule form, particularly enteric-coated capsule form, the pharmaceutical composition comprising a therapeutically effective amount of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine; prescription information, also known as “instructions for use”; blister packs or bottles (HDPE or glass), particularly moisture-proof primary packaging, more particularly Alu / Alu Blister or plastic bottle containing desiccant; and container, in particular where the prescription information specifically includes advice to the patient regarding the administration of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine.

[0268] Example 41: A method for manufacturing particles comprising (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, a filler, a binder, and a flow aid, the method comprising the following steps: (a) The (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, the filler, the binder, the disintegrant, and the flow aid are sieved. (b) The adhesive is dissolved in water, wherein the adhesive is as defined in Examples 1 to 35, thereby obtaining solution b). (c) Mixing (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, the filler, the disintegrant, and the flow aid, optionally in a wet granulator pot. (d) Add solution b) to mixture c) and perform high-shear granulation to produce wet granules. (e) Dry the wet granules. (f) Grinding the dried particles from step (e), and (g) Optionally, the particles from step (f) are blended with the extraparticle portion (e.g., lubricant).

[0269] Example 42: The method according to Example 41 further includes (h) filling the mixture obtained in step g) into capsules.

[0270] Example 43: The method according to Example 42 further includes (i) packaging the capsule in a bottle.

[0271] Example 44: A pharmaceutical composition according to any one of Examples 1 to 35, wherein the pharmaceutical composition is administered to an individual at any suitable dose (e.g., to achieve a therapeutically effective dose), particularly a suitable dose for a therapeutically effective dose of about 200 mg to 2000 mg daily (daily dose calculated based on free base), more particularly 200 mg to 1800 mg daily, and most particularly about 400 mg to 1600 mg daily.

[0272] Example 45: A pharmaceutical composition according to any one of Examples 1 to 35, for treating cancer, including but not limited to: circulatory system cancers, such as heart cancers (sarcomas [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma), mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissues; respiratory tract cancers, such as nasal cavity and middle ear, paranasal sinuses, larynx, trachea, bronchi, and lungs, such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogenic carcinomas (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma). Alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal system, such as esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), stomach, pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract, such as kidney (adenocarcinoma, Wilms' disease). Hepatoblastoma (nephroblastoma), lymphoma, leukemia), bladder and / or urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoblastoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver, such as hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pancreatic endocrine tumors (such as pheochromocytoma, pancreatic...). Insulinoma, vasoactive intestinal peptide tumor, islet cell tumor, and glucagonoma; skeletal tumors, such as osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor; nervous system tumors, such as the central nervous system (CNS). Tumors, primary CNS lymphomas, skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);Reproductive system diseases, such as gynecological diseases, uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell carcinoma, Sertoli-Leydig cell carcinoma). The female reproductive organs include: cytomas, dysgerminomas, malignant teratomas; vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)); fallopian tubes (cancer); and other sites related to the female reproductive organs; placenta, penis, prostate, testes; and other sites related to the male reproductive organs; hematopoietic system, such as blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; oral cavity, such as lips, tongue, gums, floor of mouth, palate, and other parts of the oral cavity. Parts of the parotid gland and other parts of the salivary glands, tonsils, oropharynx, nasopharynx, piriform sinus, hypopharynx, and lips, other parts of the oral cavity and pharynx; skin, such as malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid; adrenal glands: neuroblastoma; and other tissues, including connective tissue and soft tissue, retroperitoneum and peritoneum, eye, intraocular melanoma and adnexa, breast, head and / or neck, anal region, thyroid gland, parathyroid glands, adrenal glands and other endocrine glands and related structures, secondary and unspecified malignant tumors of lymph nodes, secondary malignant tumors of the respiratory and digestive systems, and secondary malignant tumors of other sites.

[0273] Terms and Conditions 1. A pharmaceutical composition comprising: (d) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (e) at least one filler, and (f) At least one gliding agent.

[0274] 2. The pharmaceutical composition according to Clause 1, comprising: (e) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (f) At least one filler, (g) at least one gliding agent, and (h) At least one disintegrant.

[0275] 3. The pharmaceutical composition according to clause 1 or 2, comprising: (f) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (g) At least one filler, (h) At least one gliding agent, (i) at least one disintegrant, and (j) At least one adhesive.

[0276] 4. The pharmaceutical composition according to any one of clauses 1 to 3, comprising: (g) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (h) At least one filler, (i) at least one gliding agent, (j) At least one disintegrant, (k) at least one adhesive, and (l) At least one lubricant.

[0277] 5. The pharmaceutical composition according to any one of clauses 1 to 4, comprising: (3) Intraparticle components, which include: (f) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (g) At least one filler, (h) At least one gliding agent, (i) at least one disintegrant, (j) at least one adhesive, (4) Extraparticle components, which include: (g) At least one lubricant.

[0278] 6. A pharmaceutical composition according to any one of Clauses 1 to 5, comprising between 30% and 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, more particularly between 50% and 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, most particularly 70 ± 10% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof.

[0279] 7. The pharmaceutical composition according to any one of Clauses 1 to 6, wherein the filler is between 4% by weight and 69% by weight, more particularly between 10% by weight and 50% by weight, and most particularly between 20% ± 10% by weight.

[0280] 8. The pharmaceutical composition according to any one of Clauses 1 to 7, wherein the binder is between 1% by weight and 5% by weight, more particularly between 2% by weight and 4% by weight, and most particularly 3 ± 0.5% by weight.

[0281] 9. The pharmaceutical composition according to any one of Clauses 1 to 8, wherein the disintegrant is between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly between 8 ± 2% by weight.

[0282] 10. The pharmaceutical composition according to any one of Clauses 1 to 9, wherein the gliding agent is between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly between 2 ± 0.5% by weight.

[0283] 11. The pharmaceutical composition according to any one of Clauses 1 to 10, wherein the lubricant is between 0.25% by weight and 5% by weight, more particularly between 0.5% by weight and 2.5% by weight, and most particularly 1.5 ± 0.5% by weight.

[0284] 12. The pharmaceutical composition according to any one of clauses 1 to 11, comprising: (d) Pharmaceutically acceptable salts of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or equivalent amounts thereof, between 30% and 95% by weight, more particularly between 50% and 85% by weight, of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or equivalent amounts thereof, most particularly 70% by weight. ±10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (e) at least one filler in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, most particularly 20 ± 10% by weight, and (f) 0.5% by weight to 15% by weight of the disintegrant, more particularly 3% by weight to 10% by weight of the disintegrant, and most particularly 8 ± 2% by weight of the disintegrant. The total amount of the ingredients shall not exceed 100% w / w.

[0285] 13. The pharmaceutical composition according to any one of clauses 1 to 12, comprising: (e) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, most particularly 70% by weight. ±10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (f) at least one filler in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, and most particularly between 20 ± 10% by weight. (g) 0.5% to 15% by weight of the disintegrant, more particularly 3% to 10% by weight of the disintegrant, and most particularly 8 ± 2% by weight of the disintegrant, and (h) at least one flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight of the flow aid. The total amount of the ingredients shall not exceed 100% w / w.

[0286] 14. The pharmaceutical composition according to any one of clauses 1 to 13, comprising: (f) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, most particularly 70% by weight. ±10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (g) at least one filler in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, and most particularly between 20 ± 10% by weight. (h) at least one disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight. (i) at least one flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight of the flow aid, and (j) at least one adhesive in an amount between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly 3 ± 0.5% by weight. The total amount of the ingredients shall not exceed 100% w / w.

[0287] 15. The pharmaceutical composition according to any one of clauses 1 to 14, comprising: (g) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, most particularly 70% by weight. ±10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (h) at least one filler in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, and most particularly between 20 ± 10% by weight. (i) at least one disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight. (j) at least one flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight of the flow aid. (k) at least one adhesive in amounts between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly 3 ± 0.5% by weight of the adhesive, and (l) at least one lubricant in an amount between 0.25% by weight and 5% by weight, more particularly in an amount between 0.5% by weight and 2.5% by weight, and most particularly in an amount of 1.5 ± 0.5% by weight. The total amount of the ingredients shall not exceed 100% w / w.

[0288] 16. The pharmaceutical composition according to any one of clauses 1 to 15, comprising: (3) Intraparticle components, which include: (f) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, most particularly 70% by weight. ±10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (g) at least one filler in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, and most particularly between 20 ± 10% by weight. (h) at least one disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight. (i) at least one flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight of the flow aid, and (j) at least one adhesive in an amount between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly 3 ± 0.5% by weight. (4) Extraparticle components, which include: (b) at least one lubricant in amounts between 0.25% by weight and 5% by weight, more particularly between 0.5% by weight and 2.5% by weight, and most particularly 1.5 ± 0.5% by weight. The total amount of the ingredients shall not exceed 100% w / w.

[0289] 17. The pharmaceutical composition according to any one of clauses 1 to 16, comprising: (g) 70 ± 10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (h) 20 ± 10% by weight of this filler, (i) 8 ± 2% by weight of the disintegrant, (j) 2 ± 0.5% by weight of this gliding agent, (k) 3 ± 0.5% by weight of the adhesive, and (l) 1.5 ± 0.5% by weight of this lubricant, The total amount of the ingredients shall not exceed 100% by weight.

[0290] 18. The pharmaceutical composition according to any one of Clauses 1 to 17, wherein the pharmaceutical composition comprises 50 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine.

[0291] 19. The pharmaceutical composition according to any one of clauses 1 to 18, comprising: (g) 50 ± 5 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof. (h) 20 ± 10% by weight of filler, (i) 3 ± 0.5% by weight of adhesive, (j) 8 ± 2% by weight of disintegrant, (k) 2 ± 0.5% by weight of gliding agent, and (l) 1.5 ± 0.5% by weight of lubricant.

[0292] 20. The pharmaceutical composition according to any one of Clauses 1 to 17, wherein the pharmaceutical composition comprises 200 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine.

[0293] 21. The pharmaceutical composition according to any one of clauses 1 to 17 and 20, comprising: (g) 200 ± 20 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof. (h) 20 ± 10% by weight of filler, (i) 3 ± 0.5% by weight of adhesive, (j) 8 ± 2% by weight of disintegrant, (k) 2 ± 0.5% by weight of gliding agent, and (l) 1.5 ± 0.5% by weight of lubricant.

[0294] 22. A pharmaceutical composition according to any one of clauses 1 to 21, further comprising a compound of formula (II). (II), particularly having less than 0.1% of the compound of formula (II), and more particularly having between 1 ppb and 100 ppm of the compound of formula (II).

[0295] 23. A pharmaceutical composition according to any one of clauses 1 to 22, wherein (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is a fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, particularly having a 1:1.5 ratio of [compound of formula (I): fumaric acid] The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, most particularly fumarate type A.

[0296] 24. A pharmaceutical composition according to any one of clauses 1 to 23, comprising a single active pharmaceutical ingredient (API), particularly wherein the single API is a compound of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the single API is (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate.

[0297] 25. A pharmaceutical composition according to any one of Clauses 1 to 24, comprising between 30% and 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, more particularly between 50% and 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, most particularly 70 ± 10% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate.

[0298] 26. The pharmaceutical composition according to any one of clauses 1 to 25, wherein the filler is selected from microcrystalline cellulose (e.g., Avicel). ® Microcrystalline cellulose coated with colloidal silica, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate (i.e., Fujicalin), calcium sulfate, and combinations thereof.

[0299] 27. The pharmaceutical composition according to any one of clauses 1 to 26, wherein the filler is anhydrous calcium hydrogen phosphate, particularly wherein the anhydrous calcium hydrogen phosphate has an average particle size of 115 µm, and most particularly wherein the anhydrous calcium hydrogen phosphate is Fujicalin. ® SG.

[0300] 28. The pharmaceutical composition according to any one of clauses 1 to 27, wherein the binder is selected from hydroxypropyl methylcellulose (e.g., METHOCEL™ E5), hydroxypropyl cellulose (e.g., Klucel), etc. TM Hydroxypropyl cellulose), polyvinylpyrrolidone (PVP, such as povidone K30), sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and proteins such as gelatin, or mixtures thereof.

[0301] 29. The pharmaceutical composition according to any one of clauses 1 to 28, wherein the binder is hydroxypropyl cellulose (CAS: 9004-64-20), particularly wherein the hydroxypropyl cellulose has a low viscosity of 100-1000 mPa·s (e.g., Klucel). TM Hydroxypropyl cellulose (E).

[0302] 30. The pharmaceutical composition according to any one of Clauses 1 to 29, wherein the disintegrant is sodium carboxymethyl starch or a cross-linked polymer, such as crospovidone, crospovidone, crospovidone (e.g., sodium crospovidone), or a mixture thereof.

[0303] 31. The pharmaceutical composition according to any one of Clauses 1 to 30, wherein the disintegrant is croscarmellose sodium, particularly wherein the croscarmellose sodium has a loss on drying of ≤10%.

[0304] 32. The pharmaceutical composition according to any one of clauses 1 to 31, wherein the gliding agent is selected from colloidal silica, colloidal silica (e.g., AEROSIL). ® 200), fumed silica (e.g., CAB-O-SIL®M-5P), talc, starch, magnesium aluminum silicate, hydrophilic fumed silica and mixtures thereof.

[0305] 33. The pharmaceutical composition according to any one of clauses 1 to 32, wherein the gliding agent is colloidal silica, particularly wherein the colloidal silica has a specific surface area of ​​200 m². 2 / g of hydrophilic fumed silica (e.g., CAS7631-86-9), more particularly the colloidal silica being AEROSIL ® 200 Pharma.

[0306] 34. The pharmaceutical composition according to any one of Clauses 1 to 33, wherein the lubricant is selected from poloxamer, polyethylene glycol, polyoxyethylene stearate, polyvinyl alcohol, talc, glyceryl silica stearate, magnesium stearate, sodium stearate fumarate, or mixtures thereof.

[0307] 35. The pharmaceutical composition according to any one of clauses 1 to 34, wherein the lubricant has a bulk density of 0.05 g / cm³. 3 Up to 0.30 g / cm 3 Magnesium stearate (e.g., CAS 557-04-0), wherein the magnesium stearate is based on a plant-derived product for pharmaceutical use.

[0308] 36. A capsule comprising a pharmaceutical composition according to any one of clauses 1 to 35.

[0309] 37. The capsule as described in Clause 36, wherein the capsule is an enteric-coated capsule, and particularly wherein the capsule is an oral enteric-coated capsule.

[0310] 38. The capsule as described in Clause 36 or 37, wherein the capsule is a pH-dependent enteric-coated empty gelatin capsule, most particularly comprising gelatin and hydroxypropyl methylcellulose phthalate.

[0311] 39. The capsule as described in Clause 36 or 37, wherein the capsule is a pH-dependent enteric-coated empty hydroxypropyl methylcellulose capsule comprising hydroxypropyl methylcellulose and hydroxypropyl methylcellulose acetate succinate.

[0312] 40. A kit comprising: a pharmaceutical composition according to any one of claims 1 to 35, in capsule form, particularly enteric-coated capsule form, the pharmaceutical composition comprising a therapeutically effective amount of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine; prescription information, also known as “instructions for use”; blister packs or bottles (HDPE or glass), particularly moisture-proof primary packaging, more particularly Alu / Alu Blister or plastic bottle containing desiccant; and container, in particular where the prescription information specifically includes advice to the patient regarding the administration of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine.

[0313] 41. A method for manufacturing particles comprising (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, a filler, a binder, and a flow aid, the method comprising the steps of: (a) The (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, the filler, the binder, the disintegrant, and the flow aid are sieved. (b) Dissolving the adhesive in water, wherein the adhesive is as defined in clauses 1 to 35, thereby obtaining solution b). (c) Mixing (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, the filler, the disintegrant, and the flow aid, optionally in a wet granulator pot. (d) Add solution b) to mixture c) and perform high-shear granulation to produce wet granules. (e) Dry the wet granules. (f) Grinding the dried particles from step (e), and (g) Optionally, the particles from step (f) are blended with the extraparticle portion (e.g., lubricant).

[0314] 42. The method according to Clause 41 further comprises (h) filling the mixture obtained in step g) into capsules.

[0315] 43. The method according to Clause 42 further comprises (i) packaging the capsule in a bottle.

[0316] 44. The pharmaceutical composition according to any one of Clauses 1 to 35, wherein the pharmaceutical composition is administered to an individual at any suitable dose (e.g., to achieve a therapeutically effective dose), particularly a suitable dose for a therapeutically effective dose of about 200 mg to 2000 mg daily (daily dose calculated based on free base), more particularly 200 mg to 1800 mg daily, and most particularly about 400 mg to 1600 mg daily.

[0317] 45. A pharmaceutical composition according to any one of Clauses 1 to 35, for the treatment of cancer, including but not limited to: circulatory system cancers, such as heart cancers (sarcomas [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma), mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissues; respiratory system cancers, such as nasal cavity and middle ear, paranasal sinuses, larynx, trachea, bronchi, and lungs, such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogenic carcinomas (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma). Alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal system, such as esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), stomach, pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract, such as kidney (adenocarcinoma, Wilms' disease). Hepatoblastoma (nephroblastoma), lymphoma, leukemia), bladder and / or urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoblastoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver, such as hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pancreatic endocrine tumors (such as pheochromocytoma, pancreatic...). Insulinoma, vasoactive intestinal peptide tumor, islet cell tumor, and glucagonoma; skeletal tumors, such as osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor; nervous system tumors, such as the central nervous system (CNS). Tumors, primary CNS lymphomas, skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);Reproductive system diseases, such as gynecological diseases, uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell carcinoma, Sertoli-Leydig cell carcinoma). The female reproductive organs include: cytomas, dysgerminomas, malignant teratomas; vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)); fallopian tubes (cancer); and other sites related to the female reproductive organs; placenta, penis, prostate, testes; and other sites related to the male reproductive organs; hematopoietic system, such as blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; oral cavity, such as lips, tongue, gums, floor of mouth, palate, and other parts of the oral cavity. Parts of the parotid gland and other parts of the salivary glands, tonsils, oropharynx, nasopharynx, piriform sinus, hypopharynx, and lips, other parts of the oral cavity and pharynx; skin, such as malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid; adrenal glands: neuroblastoma; and other tissues, including connective tissue and soft tissue, retroperitoneum and peritoneum, eye, intraocular melanoma and adnexa, breast, head and / or neck, anal region, thyroid gland, parathyroid glands, adrenal glands and other endocrine glands and related structures, secondary and unspecified malignant tumors of lymph nodes, secondary malignant tumors of the respiratory and digestive systems, and secondary malignant tumors of other sites.

Claims

1. A pharmaceutical composition comprising: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (b) at least one filler, and (c) At least one flow aid.

2. The pharmaceutical composition according to claim 1, comprising: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (b) at least one filler, (c) at least one gliding agent, and (d) At least one disintegrant.

3. The pharmaceutical composition according to claim 1 or 2, comprising: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (b) at least one filler, (c) At least one gliding agent, (d) at least one disintegrant, and (e) At least one adhesive.

4. The pharmaceutical composition according to any one of claims 1 to 3, comprising: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (b) at least one filler, (c) At least one gliding agent, (d) At least one disintegrant, (e) at least one adhesive, and (f) At least one lubricant.

5. The pharmaceutical composition according to any one of claims 1 to 4, comprising: (1) Intraparticle components, said intraparticle components comprising: (a) (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, (b) at least one filler, (c) At least one gliding agent, (d) At least one disintegrant, (e) at least one adhesive, (2) Extraparticle components, said extraparticle components comprising: (f) At least one lubricant.

6. The pharmaceutical composition according to any one of claims 1 to 5, comprising between 30% and 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, more particularly between 50% and 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof, most particularly 70 ± 10% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to any one of claims 1 to 5, comprising between 30% and 95% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, more particularly between 50% and 85% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, most particularly 70 ± 10% by weight The fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumarate, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the filler is between 4% by weight and 69% by weight, more particularly between 10% by weight and 50% by weight, and most particularly between 20 ± 10% by weight.

9. The pharmaceutical composition according to any one of claims 1 to 7, comprising between 4% and 69% by weight of the filler, more particularly between 10% and 50% by weight of the filler, and most particularly 12 ± 2% by weight of the filler.

10. The pharmaceutical composition according to any one of claims 1 to 8, wherein the binder is the binder in an amount between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly 3 ± 0.5% by weight.

11. The pharmaceutical composition according to any one of claims 1 to 7 or 9, comprising between 1% and 5% by weight of the adhesive, more particularly between 2% and 4% by weight of the adhesive, and most particularly 3 ± 0.5% by weight of the adhesive.

12. The pharmaceutical composition according to any one of claims 1 to 8 or 10, wherein the disintegrant is between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight.

13. The pharmaceutical composition according to any one of claims 1 to 7, 9 or 11, comprising between 0.5% and 15% by weight of the disintegrant, more particularly between 3% and 10% by weight of the disintegrant, and most particularly 8 ± 2% by weight of the disintegrant.

14. The pharmaceutical composition according to any one of claims 1 to 8, 10 or 12, wherein the gliding agent is between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight.

15. The pharmaceutical composition according to any one of claims 1 to 7, 9, 11 or 13, comprising between 0.5% by weight and 10% by weight of the gliding agent, more particularly between 1% by weight and 3% by weight of the gliding agent, and most particularly 2 ± 0.5% by weight of the gliding agent.

16. The pharmaceutical composition according to any one of claims 1 to 8, 10, 12 or 14, wherein the lubricant is the lubricant in an amount between 0.25% by weight and 5% by weight, more particularly in an amount between 0.5% by weight and 2.5% by weight, and most particularly in an amount of 1.5 ± 0.5% by weight.

17. The pharmaceutical composition according to any one of claims 1 to 7, 9, 11, 13 or 15, comprising between 0.25% by weight and 5% by weight of the lubricant, more particularly between 0.5% by weight and 2.5% by weight of the lubricant, and most particularly 1.5 ± 0.5% by weight of the lubricant.

18. The pharmaceutical composition according to any one of claims 1 to 17, comprising: (a) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, most particularly 70 ± 10% by weight. (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof. (b) at least one filler in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, and most particularly 20 ± 10% by weight of the filler, and (c) The disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight. The total amount of the ingredients shall not exceed 100% w / w.

19. The pharmaceutical composition according to any one of claims 1 to 17, comprising: (a) Fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine between 30 wt% and 95 wt%, more particularly between 50 wt% and 85 wt% of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine), most particularly between 70 ± 10 wt%. The fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) the filler in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, and most particularly 12 ± 2% by weight, and (c) The disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight. The total amount of the ingredients shall not exceed 100% w / w.

20. The pharmaceutical composition according to any one of claims 1 to 18, comprising: (a) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, most particularly 70 ± 10% by weight. (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof. (b) at least one filler in amounts between 4% by weight and 69% by weight, more particularly between 10% by weight and 50% by weight, and most particularly between 20 ± 10% by weight. (c) the disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight, and (d) At least one flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight of the flow aid. The total amount of the ingredients shall not exceed 100% w / w.

21. The pharmaceutical composition according to any one of claims 1 to 17 or 19, comprising: (a) Fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine between 30 wt% and 95 wt%, more particularly between 50 wt% and 85 wt% of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine), most particularly between 70 ± 10 wt%. The fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) The filler in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, and most particularly between 12 ± 2% by weight. (c) the disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight, and (d) The flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight. The total amount of the ingredients shall not exceed 100% w / w.

22. The pharmaceutical composition according to any one of claims 1 to 18 or 20, comprising: (a) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, most particularly 70 ± 10% by weight. (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof. (b) at least one filler in amounts between 4% by weight and 69% by weight, more particularly between 10% by weight and 50% by weight, and most particularly between 20 ± 10% by weight. (c) At least one disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight. (d) At least one flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight of the flow aid, and (e) at least one adhesive in amounts between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly 3 ± 0.5% by weight. The total amount of the ingredients shall not exceed 100% w / w.

23. The pharmaceutical composition according to any one of claims 1 to 17, 19 or 21, comprising: (a) Fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine between 30 wt% and 95 wt%, more particularly between 50 wt% and 85 wt% of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine), most particularly between 70 ± 10 wt%. The fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) The filler in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, and most particularly between 12 ± 2% by weight. (c) The disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight. (d) The flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight, and (e) the adhesive in amounts between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly between 3 ± 0.5% by weight. The total amount of the ingredients shall not exceed 100% w / w.

24. The pharmaceutical composition according to any one of claims 1 to 18, 20 or 22, comprising: (a) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, most particularly 70 ± 10% by weight. (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof. (b) at least one filler in amounts between 4% by weight and 69% by weight, more particularly between 10% by weight and 50% by weight, and most particularly between 20 ± 10% by weight. (c) At least one disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight. (d) At least one flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight of the flow aid. (e) at least one adhesive in amounts between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly 3 ± 0.5% by weight, and (f) at least one lubricant in amounts between 0.25% by weight and 5% by weight, more particularly between 0.5% by weight and 2.5% by weight, and most particularly between 1.5 ± 0.5% by weight. The total amount of the ingredients shall not exceed 100% w / w.

25. The pharmaceutical composition according to any one of claims 1 to 17, 19, 21 or 23, comprising: (a) Fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine between 30 wt% and 95 wt%, more particularly between 50 wt% and 85 wt% of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine), most particularly between 70 ± 10 wt%. The fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) The filler in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, and most particularly between 12 ± 2% by weight. (c) The disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight. (d) The flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight. (e) the adhesive in amounts between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly 3 ± 0.5% by weight, and (f) the lubricant in amounts between 0.25% by weight and 5% by weight, more particularly between 0.5% by weight and 2.5% by weight, and most particularly between 1.5 ± 0.5% by weight. The total amount of the ingredients shall not exceed 100% w / w.

26. The pharmaceutical composition according to any one of claims 1 to 18, 20, 22 or 24, comprising: (1) Intraparticle components, said intraparticle components comprising: (a) 30% to 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, more particularly 50% to 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof, most particularly 70 ± 10% by weight. (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof. (b) at least one filler in amounts between 4% by weight and 69% by weight, more particularly between 10% by weight and 50% by weight, and most particularly between 20 ± 10% by weight. (c) At least one disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight. (d) At least one flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight of the flow aid, and (e) at least one adhesive in amounts between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly 3 ± 0.5% by weight. (2) Extraparticle components, said extraparticle components comprising: (f) at least one lubricant in amounts between 0.25% by weight and 5% by weight, more particularly between 0.5% by weight and 2.5% by weight, and most particularly between 1.5 ± 0.5% by weight. The total amount of the ingredients shall not exceed 100% w / w.

27. The pharmaceutical composition according to any one of claims 1 to 17, 19, 21, 23 or 25, comprising: (1) Intraparticle components, said intraparticle components comprising: (a) Fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine between 30 wt% and 95 wt%, more particularly between 50 wt% and 85 wt% of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine), most particularly between 70 ± 10 wt%. The fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) The filler in amounts between 4% and 69% by weight, more particularly between 10% and 50% by weight, and most particularly between 12 ± 2% by weight. (c) The disintegrant in amounts between 0.5% by weight and 15% by weight, more particularly between 3% by weight and 10% by weight, and most particularly 8 ± 2% by weight. (d) The flow aid in amounts between 0.5% by weight and 10% by weight, more particularly between 1% by weight and 3% by weight, and most particularly 2 ± 0.5% by weight, and (e) the adhesive in amounts between 1% and 5% by weight, more particularly between 2% and 4% by weight, and most particularly between 3 ± 0.5% by weight. (2) Extraparticle components, said extraparticle components comprising: (f) the lubricant in amounts between 0.25% by weight and 5% by weight, more particularly between 0.5% by weight and 2.5% by weight, and most particularly between 1.5 ± 0.5% by weight. The total amount of the ingredients shall not exceed 100% w / w.

28. The pharmaceutical composition according to any one of claims 1 to 18, 20, 22, 24 or 26, comprising: (a) 70 ± 10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent amount of a pharmaceutically acceptable salt thereof. (b) 20 ± 10% by weight of the filler, (c) 8 ± 2% by weight of the aforementioned disintegrant, (d) 2 ± 0.5% by weight of the aforementioned flow aid, (e) 3 ± 0.5% by weight of the adhesive, and (f) 1.5 ± 0.5% by weight of the lubricant, The total amount of the ingredients shall not exceed 100% by weight.

29. The pharmaceutical composition according to any one of claims 1 to 17, 19, 21, 23, 25 or 27, comprising: (a) 70 ± 10 wt% of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) 12 ± 2% by weight of the filler, (c) 8 ± 2% by weight of the aforementioned disintegrant, (d) 2 ± 0.5% by weight of the aforementioned flow aid, (e) 3 ± 0.5% by weight of the adhesive, and (f) 1.5 ± 0.5% by weight of the lubricant, The total amount of the ingredients shall not exceed 100% by weight.

30. The pharmaceutical composition according to any one of claims 1 to 17, 19, 21, 23, 25, 27 or 29, comprising: (a) 70 ± 10 wt% of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) 12 ± 2% by weight of the filler, (c) 8 ± 2% by weight of the aforementioned disintegrant, (d) 2 ± 0.5% by weight of the aforementioned flow aid, (e) 3 ± 0.5% by weight of the adhesive, and (f) 1.5 ± 0.5% by weight of the lubricant, The total amount of the components is equal to 100 by weight.

31. The pharmaceutical composition according to any one of claims 1 to 6, 8 to 18, 20, 22, 24, 26 or 28, wherein the pharmaceutical composition comprises 50 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine).

32. The pharmaceutical composition according to any one of claims 1 to 6, 8 to 18, 20, 22, 24, 26, 28 or 31, comprising: (a) 50 ± 5 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof. (b) 20 ± 10% by weight of filler, (c) 3 ± 0.5% by weight of adhesive, (d) 8 ± 2% by weight of disintegrant, (e) 2 ± 0.5% by weight of a gliding agent, and (f) 1.5 ± 0.5% by weight of lubricant.

33. The pharmaceutical composition according to any one of claims 1 to 17, 19, 21, 23, 25, 27, 29 or 30, comprising: (a) 65 ± 5 mg of fumarate of (R)-N-(4-([1,2,4]triazol[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazol[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a 1:1.5 ratio. The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) 12 ± 2% by weight of filler, (c) 3 ± 0.5% by weight of adhesive, (d) 8 ± 2% by weight of disintegrant, (e) 2 ± 0.5% by weight of a gliding agent, and (f) 1.5 ± 0.5% by weight of lubricant, The total amount of the ingredients shall not exceed 100% by weight.

34. The pharmaceutical composition according to any one of claims 1 to 6, 8 to 18, 20, 22, 24, 26 or 28, wherein the pharmaceutical composition comprises 200 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine.

35. The pharmaceutical composition according to any one of claims 1 to 6, 8 to 18, 20, 22, 24, 26, 28 or 34, comprising: (a) 200 ± 20 mg of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or an equivalent pharmaceutically acceptable salt thereof. (b) 20 ± 10% by weight of filler, (c) 3 ± 0.5% by weight of adhesive, (d) 8 ± 2% by weight of disintegrant, (e) 2 ± 0.5% by weight of a gliding agent, and (f) 1.5 ± 0.5% by weight of lubricant.

36. The pharmaceutical composition according to any one of claims 1 to 17, 19, 21, 23, 25, 27, 29 or 30, comprising: (a) 260 ± 20 mg of fumarate of (R)-N-(4-([1,2,4]triazol[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazol[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a 1:1.5 ratio. The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) 12 ± 2% by weight of filler, (c) 3 ± 0.5% by weight of adhesive, (d) 8 ± 2% by weight of disintegrant, (e) 2 ± 0.5% by weight of a gliding agent, and (f) 1.5 ± 0.5% by weight of lubricant, The total amount of the ingredients shall not exceed 100% by weight.

37. The pharmaceutical composition according to any one of claims 1 to 36, further comprising a compound of formula (II). (II), particularly having less than 0.1% of the compound of formula (II), and more particularly having between 1 ppb and 100 ppm of the compound of formula (II).

38. The pharmaceutical composition according to any one of claims 1 to 37, wherein (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is a fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, particularly having a 1:1.5 ratio of [compound of formula (I): fumaric acid] The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, most particularly fumarate type A.

39. The pharmaceutical composition according to any one of claims 1 to 38, comprising a single active pharmaceutical ingredient (API), particularly wherein the single API is a compound of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the single API is ( R )-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate.

40. The pharmaceutical composition according to any one of claims 1 to 39, comprising between 30% and 95% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, more particularly between 50% and 85% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, most particularly 70 ± 10% by weight (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate.

41. The pharmaceutical composition according to claim 39 or 40, wherein the pharmaceutical composition comprises 70 ± 10% by weight of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate.

42. The pharmaceutical composition according to any one of claims 1 to 17, 19, 21, 23, 25, 27, 29, 30, 33, 36 or 37, comprising: (a) 70 ± 10 wt% of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, or (b) 70 ± 10% by weight of fumarate type A, or (c) 65 ± 5 mg of fumarate of (R)-N-(4-([1,2,4]triazol[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, wherein the fumarate of (R)-N-(4-([1,2,4]triazol[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, or (d) 65 ± 5 mg of fumarate type A, or (e) 260 ± 20 mg of fumarate of (R)-N-(4-([1,2,4]triazol[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, wherein the fumarate of (R)-N-(4-([1,2,4]triazol[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, or (f) 260 ± 20 mg of fumarate type A.

43. The pharmaceutical composition according to any one of claims 1 to 42, wherein the filler is selected from microcrystalline cellulose (e.g., Avicel). ® Microcrystalline cellulose coated with colloidal silica, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate (i.e., Fujicalin), calcium sulfate, and combinations thereof.

44. The pharmaceutical composition according to any one of claims 1 to 43, wherein the filler is anhydrous calcium hydrogen phosphate, particularly wherein the anhydrous calcium hydrogen phosphate has an average particle size of 115 µm, and most particularly wherein the anhydrous calcium hydrogen phosphate is Fujicalin. ® SG.

45. The pharmaceutical composition according to any one of claims 1 to 44, wherein the binder is selected from hydroxypropyl methylcellulose (e.g., METHOCEL™ E5), hydroxypropyl cellulose (e.g., Klucel), etc. TM Hydroxypropyl cellulose), polyvinylpyrrolidone (PVP, such as povidone K30), sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and proteins such as gelatin, or mixtures thereof.

46. ​​The pharmaceutical composition according to any one of claims 1 to 45, wherein the binder is hydroxypropyl cellulose (CAS: 9004-64-20), particularly wherein the hydroxypropyl cellulose has a low viscosity of 100-1000 mPa·s (e.g., Klucel). TM Hydroxypropyl cellulose (E).

47. The pharmaceutical composition according to any one of claims 1 to 46, wherein the binder is hydroxypropyl cellulose EXF type.

48. The pharmaceutical composition according to any one of claims 1 to 47, wherein the disintegrant is sodium carboxymethyl starch or a crosslinked polymer, such as crosslinked polyvinylpyrrolidone (Copovidone), crosslinked carboxymethyl cellulose (e.g., sodium crosslinked carboxymethyl cellulose), or a mixture thereof.

49. The pharmaceutical composition according to any one of claims 1 to 48, wherein the disintegrant is croscarmellose sodium, particularly wherein the croscarmellose sodium has a drying loss of ≤10%.

50. The pharmaceutical composition according to any one of claims 1 to 49, wherein the disintegrant is croscarmellose sodium, which is present in an amount greater than 2% by weight and less than or equal to about 10% by weight.

51. The pharmaceutical composition according to any one of claims 1 to 50, wherein the disintegrant is croscarmellose sodium, which is present in an amount of 8 ± 2% by weight.

52. The pharmaceutical composition according to any one of claims 1 to 51, wherein the gliding agent is selected from colloidal silica, colloidal silica (e.g., AEROSIL). ® 200), fumed silica (e.g., CAB-O-SIL®M-5P), talc, starch, magnesium aluminum silicate, hydrophilic fumed silica and mixtures thereof.

53. The pharmaceutical composition according to any one of claims 1 to 52, wherein the gliding agent is colloidal silica, particularly wherein the colloidal silica has a specific surface area of ​​200 m². 2 / g of hydrophilic fumed silica (e.g., CAS7631-86-9), more particularly the colloidal silica being AEROSIL. ® 200 Pharma.

54. The pharmaceutical composition according to any one of claims 1 to 53, wherein the lubricant is selected from poloxamer, polyethylene glycol, polyoxyethylene stearate, polyvinyl alcohol, talc, glyceryl silica stearate, magnesium stearate, sodium stearate fumarate, or mixtures thereof.

55. The pharmaceutical composition according to any one of claims 1 to 54, wherein the lubricant is magnesium stearate.

56. The pharmaceutical composition according to any one of claims 1 to 55, wherein the lubricant has a bulk density of 0.05 g / cm³. 3 Up to 0.30 g / cm 3 Magnesium stearate (e.g., CAS 557-04-0), wherein the magnesium stearate is based on a plant-derived material used in pharmaceutical products.

57. The pharmaceutical composition according to any one of claims 1 to 56, wherein: (a) The filler is anhydrous dicalcium phosphate (e.g., Fujicalin SG). (b) The disintegrant is croscarmellose sodium. (c) The flow aid is colloidal silica (e.g., AEROSIL). ® 200), and (d) The adhesive is hydroxypropyl cellulose (e.g., EXF type). (e) The lubricant is magnesium stearate.

58. The pharmaceutical composition according to any one of claims 1 to 17, 19, 21, 23, 25, 27, 29, 30, 37 or 42 to 57, comprising: (a) 70 ± 10 wt% of fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) 12 ± 2% by weight of the filler, wherein the filler is anhydrous dicalcium phosphate (e.g., Fujicalin SG). (c) 8 ± 2% by weight of the disintegrant, wherein the disintegrant is croscarmellose sodium. (d) 2 ± 0.5% by weight of the flow aid, wherein the flow aid is colloidal silica (e.g., AEROSIL). ® 200), (e) 3 ± 0.5% by weight of the adhesive, wherein the adhesive is hydroxypropyl cellulose (e.g., EXF type), and (f) 1.5 ± 0.5% by weight of the lubricant, wherein the lubricant is magnesium stearate. The total amount of the ingredients shall not exceed 100% by weight.

59. The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition is prepared by a method including a wet granulation step (e.g., manufacturing method C).

60. The pharmaceutical composition according to any preceding claim, wherein the pharmaceutical composition is prepared by a method including a wet granulation step, wherein the method includes the following steps: (a) When present, the (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or its pharmaceutically acceptable salt (e.g., fumarate), the filler, the binder, the disintegrant, and the flow aid are sieved. (b) Dissolve the adhesive in water. (c) When present, (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or its pharmaceutically acceptable salt (e.g., fumarate), the filler, the disintegrant, and the flow aid are mixed, optionally in a wet granulation pan. (d) Add solution b) to mixture c) and perform high-shear granulation to produce wet granules. (e) Dry the wet particles. (f) Grinding the dried particles from step (e), and (g) Optionally, when present, the particles from step (f) are blended with the lubricant.

61. The pharmaceutical composition according to claim 60, wherein... (a) The (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine or its pharmaceutically acceptable salt (e.g., fumarate) is (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) The filler is as defined in any one of claims 1 to 58, such as anhydrous dicalcium phosphate (e.g., Fujicalcin SG). (c) The disintegrant is as defined in any one of claims 2 to 58, such as croscarmellose sodium. (d) The flow aid as defined in any one of claims 1 to 58, such as colloidal silica (e.g., AEROSIL). ® 200), (e) The adhesive is as defined in any one of claims 3 to 58, such as hydroxypropyl cellulose (e.g., EXF type), and (f) The lubricant is as defined in any one of claims 4 to 58, such as magnesium stearate.

62. The pharmaceutical composition according to any one of claims 1 to 61, wherein the (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or its pharmaceutically acceptable salt (e.g., fumarate) is treated by means of jet milling or recrystallization.

63. The pharmaceutical composition according to any one of claims 1 to 62, wherein the (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or its pharmaceutically acceptable salt (e.g., fumarate) has a particle size (Dv (90)) of not more than 95.5 µm.

64. The pharmaceutical composition according to any one of claims 1 to 63, wherein: (a) The (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or its pharmaceutically acceptable salt (e.g., fumarate) has a particle size (Dv (90)) not greater than 95.5 µm, and (b) The disintegrant is croscarmellose sodium, which is present in an amount greater than 2% by weight and less than or equal to about 10% by weight, and more particularly the disintegrant is croscarmellose sodium, which is present in an amount of 8 ± 2% by weight.

65. A capsule comprising the pharmaceutical composition according to any one of claims 1 to 64.

66. The capsule according to claim 65, wherein the capsule is an enteric-coated capsule, and particularly wherein the capsule is an oral enteric-coated capsule.

67. The capsule according to claim 65 or 66, wherein the capsule is a pH-dependent enteric-coated empty gelatin capsule, most particularly comprising gelatin and hydroxypropyl methylcellulose phthalate.

68. The capsule according to claim 65 or 66, wherein the capsule is a pH-dependent enteric-coated empty hydroxypropyl methylcellulose capsule comprising hydroxypropyl methylcellulose and hydroxypropyl methylcellulose acetate succinate.

69. A kit comprising: a pharmaceutical composition according to any one of claims 1 to 64 in capsule form, particularly enteric-coated capsule form, said pharmaceutical composition comprising a therapeutically effective amount of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine; prescription information, also known as "instructions for use"; blister packs or bottles (HDPE or glass), particularly moisture-proof primary packaging, more particularly Alu / Alu Blister or plastic bottle containing desiccant; and container, in particular, wherein the prescription information specifically includes recommendations to the patient regarding the administration of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine.

70. A method for manufacturing particles, said particles comprising (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, a filler, a binder, and a flow aid, said method comprising the steps of: (a) The (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, the filler, the binder, the disintegrant, and the flow aid are sieved. (b) Dissolving the adhesive in water, wherein the adhesive is as defined in claims 1 to 64, to obtain solution b). (c) Mixing (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine, the filler, the disintegrant, and the flow aid, optionally in a wet granulator pot. (d) Add solution b) to mixture c) and perform high-shear granulation to produce wet granules. (e) Dry the wet particles. (f) Grinding the dried particles from step (e), and (g) Optionally, the particles from step (f) are blended with an extraparticle portion (e.g., a lubricant).

71. A method for manufacturing granules, said granules comprising (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or a pharmaceutically acceptable salt thereof (e.g., fumarate), fillers, binders, disintegrants, and flow aids, said method comprising the steps of: (a) Sieve (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or its pharmaceutically acceptable salt (e.g., fumarate), the filler, the binder, the disintegrant, and the flow aid. (b) Dissolve the adhesive in water to obtain solution b). (c) Mixing (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or its pharmaceutically acceptable salt (e.g., fumarate), the filler, the disintegrant, and the flow aid, optionally in a wet granulation pan. (d) Add solution b) to mixture c) and perform high-shear granulation to produce wet granules. (e) Dry the wet particles. (f) Grinding the dried particles from step (e), and (g) Optionally, the particles from step (f) are blended with an extraparticle portion (e.g., a lubricant).

72. The method according to claim 71, wherein: (a) The (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine or its pharmaceutically acceptable salt (e.g., fumarate) is (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine fumarate, more particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine has a ratio of 1:1.5 The ratio of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine to fumaric acid, most particularly wherein the fumarate of (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine is fumarate type A. (b) The filler is as defined in any one of claims 1 to 64, such as anhydrous dicalcium phosphate (e.g., Fujicalcin SG). (c) The disintegrant is as defined in any one of claims 2 to 64, such as croscarmellose sodium. (d) The flow aid as defined in any one of claims 1 to 64, such as colloidal silica (e.g., AEROSIL). ® 200), (e) The adhesive is as defined in any one of claims 3 to 64, such as hydroxypropyl cellulose (e.g., EXF type), and (f) The lubricant is as defined in any one of claims 4 to 64, such as magnesium stearate.

73. The method according to any one of claims 70 to 72, further comprising (h) filling the mixture obtained in step (g) into capsules.

74. The method of claim 73, further comprising (i) packaging the capsule in a bottle.

75. The method according to any one of claims 70 to 74, wherein the (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or its pharmaceutically acceptable salt (e.g., fumarate) is treated by using a jet milling method or a recrystallization method.

76. The method according to any one of claims 70 to 75, wherein the (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline-4-amine or its pharmaceutically acceptable salt (e.g., fumarate) has a particle size (Dv (90)) of not more than 95.5 µm.

77. The pharmaceutical composition according to any one of claims 1 to 64, wherein the pharmaceutical composition is administered to an individual at any suitable dose (e.g., to achieve a therapeutically effective dose), particularly a suitable dose of a therapeutically effective dose of about 200 mg to 2000 mg daily (daily dose calculated based on free base), more particularly 200 mg to 1800 mg daily, and most particularly about 400 mg to 1600 mg daily.

78. The pharmaceutical composition according to any one of claims 1 to 64, for treating cancer, said cancer including but not limited to: circulatory system cancers, such as heart cancers (sarcomas [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma), mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissues; respiratory system cancers, such as nasal cavity and middle ear, paranasal sinuses, larynx, trachea, bronchi, and lungs, such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogenic carcinomas (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), etc. Alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal system, such as esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), stomach, pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract, such as kidney (adenocarcinoma, Wilms' disease). Hepatoblastoma (nephroblastoma), lymphoma, leukemia), bladder and / or urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoblastoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver, such as hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pancreatic endocrine tumors (such as pheochromocytoma, pancreatic...). Insulinoma, vasoactive intestinal peptide tumor, islet cell tumor, and glucagonoma; skeletal tumors, such as osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor; nervous system tumors, such as the central nervous system (CNS). Tumors, primary CNS lymphomas, skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);The reproductive system, including gynecology, uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell carcinoma, Sertoli-Leydig cell carcinoma, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (cancer) and other sites related to the female reproductive organs; placenta, penis, prostate, testes and other sites related to the male reproductive organs; the hematopoietic system, including blood disorders (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative disorders). Sexually transmitted diseases, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; oral cavity, such as lips, tongue, gums, floor of mouth, palate and other parts of the oral cavity, parotid glands and other parts of the salivary glands, tonsils, oropharynx, nasopharynx, piriform sinus, hypopharynx and other parts of the lips, oral cavity and pharynx; skin, such as malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma and keloid; Adrenal gland: Neuroblastoma; And other tissues, including connective and soft tissues, retroperitoneum and peritoneum, eyes, intraocular melanomas and adnexa, breasts, head and / or neck, anal region, thyroid gland, parathyroid glands, adrenal glands and other endocrine glands and related structures, secondary and unspecified malignancies of lymph nodes, secondary malignancies of the respiratory and digestive systems, and secondary malignancies of other sites.

79. The pharmaceutical composition according to any one of claims 1 to 64, used for treating cancer, said cancer including but not limited to: circulatory system cancers, such as heart cancers (sarcomas [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma), mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissues; respiratory system cancers, such as nasal cavity and middle ear, paranasal sinuses, larynx, trachea, bronchi, and lungs, such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogenic carcinomas (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma). Alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal system, such as esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), stomach, pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyosarcoma); genitourinary tract, such as kidney (adenocarcinoma, Wilms' disease). Nephroblastoma, lymphoma, leukemia), bladder and / or urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoblastoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver, such as hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pancreatic endocrine tumors (such as pheochromocytoma, insulinoma, etc.). Vasoactive intestinal peptide tumors, islet cell tumors, and glucagonomas; skeletal tumors, such as osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondrogenic exostosis), benign chondroma, chondroblastoma, chondromycinoma, osteomyxoid fibroma, osteoid osteoma, and giant cell tumor; nervous system tumors, such as central nervous system (CNS) tumors, primary CNS tumors. Lymphoma, skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);The reproductive system, including gynecology, uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell carcinoma, Sertoli-Leydig cell carcinoma, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (cancer) and other sites related to the female reproductive organs; placenta, penis, prostate, testes and other sites related to the male reproductive organs; the hematopoietic system, including blood disorders (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative disorders). Sexually transmitted diseases, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; oral cavity, such as lips, tongue, gums, floor of mouth, palate and other parts of the oral cavity, parotid glands and other parts of the salivary glands, tonsils, oropharynx, nasopharynx, piriform sinus, hypopharynx and other parts of the lips, oral cavity and pharynx; skin, such as malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma and keloid; Adrenal gland: Neuroblastoma; And other tissues, including connective and soft tissues, retroperitoneum and peritoneum, eyes, intraocular melanomas and adnexa, breasts, head and / or neck, anal region, thyroid gland, parathyroid glands, adrenal glands and other endocrine glands and related structures, secondary and unspecified malignancies of lymph nodes, secondary malignancies of the respiratory and digestive systems, and secondary malignancies of other sites.

80. The pharmaceutical composition according to any one of claims 1 to 64, used for the treatment of HER2-related cancers.

81. A pharmaceutical composition for treating cancer according to any one of claims 1 to 64, or a pharmaceutical composition for use according to claim 80, wherein the cancer is selected from cancers expressing HER2, HER2-positive cancers, or HER ligand-overexpressing cancers.

82. The pharmaceutical composition according to claim 81, wherein the cancer is HER2-positive cancer.

83. A pharmaceutical composition for treating cancer according to any one of claims 1 to 64, or a pharmaceutical composition for use according to any one of claims 80 to 82, wherein the cancer is selected from breast cancer, gastric cancer, biliary tract cancer, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer, and uterine cancer, and more particularly wherein the cancer is selected from breast cancer, gastric cancer, colorectal cancer, or NSCLC cancer.

84. The pharmaceutical composition used according to any one of claims 80 to 83, wherein the cancer is a metastasis of the cancer specified in any one of claims 80 to 83.

85. The pharmaceutical composition according to claim 84, wherein the transfer is a brain transfer.

86. A pharmaceutical composition for treating cancer according to any one of claims 1 to 64, or a pharmaceutical composition for use according to any one of claims 80 to 85, wherein the cancer is breast cancer with brain metastasis.

87. Use of the pharmaceutical composition according to any one of claims 1 to 64 in the preparation of a medicament for treating cancer, wherein the cancer includes, but is not limited to, cancers of the following: circulatory system, such as the heart (sarcomas [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma), mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissues; respiratory tract, such as the nasal cavity and middle ear, paranasal sinuses, larynx, trachea, bronchi and lungs, such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, etc.). Adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal system, such as esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), stomach, pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract, such as kidney (adenocarcinoma, Wilm's disease). Hepatoblastoma (nephroblastoma), lymphoma, leukemia), bladder and / or urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoblastoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver, such as hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pancreatic endocrine tumors (such as pheochromocytoma, pancreatic...). Insulinoma, vasoactive intestinal peptide tumor, islet cell tumor, and glucagonoma; skeletal tumors, such as osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor; nervous system tumors, such as the central nervous system (CNS). Tumors, primary CNS lymphomas, skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);The reproductive system, including gynecology, uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell carcinoma, Sertoli-Leydig cell carcinoma, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (cancer) and other sites related to the female reproductive organs; placenta, penis, prostate, testes and other sites related to the male reproductive organs; the hematopoietic system, including blood disorders (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative disorders). Sexually transmitted diseases, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; oral cavity, such as lips, tongue, gums, floor of mouth, palate and other parts of the oral cavity, parotid glands and other parts of the salivary glands, tonsils, oropharynx, nasopharynx, piriform sinus, hypopharynx and other parts of the lips, oral cavity and pharynx; skin, such as malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma and keloid; Adrenal gland: Neuroblastoma; And other tissues, including connective and soft tissues, retroperitoneum and peritoneum, eyes, intraocular melanomas and adnexa, breasts, head and / or neck, anal region, thyroid gland, parathyroid glands, adrenal glands and other endocrine glands and related structures, secondary and unspecified malignancies of lymph nodes, secondary malignancies of the respiratory and digestive systems, and secondary malignancies of other sites.

88. Use of the pharmaceutical composition according to any one of claims 1 to 64 in the preparation of a medicament for treating HER2-related cancers.

89. Use of the pharmaceutical composition according to any one of claims 1 to 64 in the preparation of a medicament for treating cancer, or the use according to claim 88, wherein the cancer is selected from cancers expressing HER2, HER2-positive cancers, or HER ligand-overexpressing cancers.

90. The use according to claim 89, wherein the cancer is a HER2-positive cancer.

91. Use of the pharmaceutical composition according to any one of claims 1 to 64 in the preparation of a medicament for treating cancer, or use according to any one of claims 88 to 90, wherein the cancer is selected from breast cancer, gastric cancer, biliary tract cancer, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer, and uterine cancer, and more particularly wherein the cancer is selected from breast cancer, gastric cancer, colorectal cancer, or NSCLC cancer.

92. The use according to any one of claims 88 to 91, wherein the cancer is a metastasis of the cancer specified in any one of claims 88 to 91.

93. The use according to claim 92, wherein the transfer is a brain transfer.

94. Use of the pharmaceutical composition according to any one of claims 1 to 64 in the preparation of a medicament for treating cancer, or use according to any one of claims 88 to 93, wherein the cancer is brain metastasis of breast cancer.

95. A method for treating cancer, the method comprising administering a pharmaceutical composition according to any one of claims 1 to 64, wherein the cancer includes, but is not limited to, cancers of the following: circulatory system, such as the heart (sarcomas [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma), mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissues; respiratory tract, such as the nasal cavity and middle ear, paranasal sinuses, larynx, trachea, bronchi and lungs, such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveoli ( Bronchiolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal system, such as esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), stomach, pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract, such as kidney (adenocarcinoma, Wilms' disease). Hepatoblastoma (nephroblastoma), lymphoma, leukemia), bladder and / or urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoblastoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver, such as hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pancreatic endocrine tumors (such as pheochromocytoma, pancreatic...). Insulinoma, vasoactive intestinal peptide tumor, islet cell tumor, and glucagonoma; skeletal tumors, such as osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor; nervous system tumors, such as the central nervous system (CNS). Tumors, primary CNS lymphomas, skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);The reproductive system, including gynecology, uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell carcinoma, Sertoli-Leydig cell carcinoma, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (cancer) and other sites related to the female reproductive organs; placenta, penis, prostate, testes and other sites related to the male reproductive organs; the hematopoietic system, including blood disorders (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative disorders). Sexually transmitted diseases, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; oral cavity, such as lips, tongue, gums, floor of mouth, palate and other parts of the oral cavity, parotid glands and other parts of the salivary glands, tonsils, oropharynx, nasopharynx, piriform sinus, hypopharynx and other parts of the lips, oral cavity and pharynx; skin, such as malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma and keloid; Adrenal gland: Neuroblastoma; And other tissues, including connective and soft tissues, retroperitoneum and peritoneum, eyes, intraocular melanomas and adnexa, breasts, head and / or neck, anal region, thyroid gland, parathyroid glands, adrenal glands and other endocrine glands and related structures, secondary and unspecified malignancies of lymph nodes, secondary malignancies of the respiratory and digestive systems, and secondary malignancies of other sites.

96. A method for treating HER2-related cancer, the method comprising administering a pharmaceutical composition according to any one of claims 1 to 64.

97. A method for treating cancer, the method comprising administering a pharmaceutical composition according to any one of claims 1 to 64, or the method according to claim 96, wherein the cancer is selected from cancers expressing HER2, HER2-positive cancers, or HER ligand-overexpressing cancers.

98. The method of claim 97, wherein the cancer is HER2-positive cancer.

99. A method for treating cancer, the method comprising administering a pharmaceutical composition according to any one of claims 1 to 64, or the method according to any one of claims 96 to 98, wherein the cancer is selected from breast cancer, gastric cancer, biliary tract cancer, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer, and uterine cancer, and more particularly wherein the cancer is selected from breast cancer, gastric cancer, colorectal cancer, or NSCLC cancer.

100. The method according to any one of claims 96 to 99, wherein the cancer is a metastasis of the cancer specified in any one of claims 96 to 99.

101. The method of claim 100, wherein the transfer is a brain transfer.

102. A method for treating cancer, the method comprising administering a pharmaceutical composition according to any one of claims 1 to 64, or the method according to any one of claims 96 to 101, wherein the cancer is a brain metastasis of breast cancer.

103. The invention as described herein.

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