Treatment and / or prevention of dengue virus infection

Abstract

The present invention relates to a compound of formula (I) for use in the prevention and / or treatment of dengue virus infection, wherein the compound of formula (I) is administered in an oral dosage form to a human in either the fed or fasting state, and the compound of formula (I) is represented by the following formula or 【Chemical 1】 JPEG2025517683000051.jpg53128 its stereoisomers, pharmaceutically acceptable salts, solvates, or polymorphs, and the compound is as follows: R 1 is H, R 2 is F, R 3 is H or CH 3 and is a compound, R 1 is H, CH 3 , or F, R 2 is OCH 3 , R 3 is H and is a compound, R 1 is H, R 2 is OCH 3 , R 3 is CH 3 and is a compound, R 1 is CH 3 , R 2 is F, R 3 is H and is a compound, R 1 is CF 3 or OCF 3 , R 2 is H, R 3 is H and is a compound, R 1 is OCF 3 , R 2 is OCH 3 , R 3 is H and is a compound, R 1 is OCF 3 , R 2 is H, R 3 is CH 3 and is a compound, relates to a compound selected from the group of.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the priority of U.S. Provisional Patent Application No. 63 / 341,074, filed on May 12, 2022, the entire content of which is hereby expressly incorporated by reference herein.

[0002] (Field of the Invention) The present invention relates to the use of substituted indole derivatives in the manufacture of pharmaceutical preparations for the treatment and / or prevention of dengue virus infections, and to the administration of pharmaceutical preparations to subjects in need thereof, either in a fed or fasting state. The present invention further provides a method for the treatment and / or prevention of dengue virus infections.

Background Art

[0003] Dengue is caused by any of four antigenically distinct DENV serotypes (DENV - 1, DENV - 2, DENV - 3, and DENV - 4) belonging to the genus Flavivirus of the family Flaviviridae. DENV is a human pathogen that is transmitted via the bite of an infected female mosquito of the Aedes genus. Dengue is endemic in more than 125 countries and has re - emerged as an epidemic in Puerto Rico, American Samoa, and the U.S. Virgin Islands. Currently, approximately half of the world's population is at risk of DENV infection. According to the World Health Organization (WHO), dengue is among the top 10 global health threats in 2019.

[0004] Dengue is widespread throughout the tropics, with regional variations in the risk of being affected by rainfall, temperature, and rapid urbanization. The exponential increase in the number of dengue cases reflects the global spread of the vector mosquitoes, which is caused by climate change, and, more importantly, by population growth, urbanization, and globalization.

[0005] The actual number of dengue cases is underreported, and many cases are misclassified as other febrile diseases such as malaria. It is estimated that there are 390 million DENV infections worldwide each year, of which 96 million (including all severities of the disease) are clinically manifested. On average, about 500,000 dengue cases per year require hospitalization due to severe and life-threatening disease, and up to 25,000 patients die from dengue. Therefore, there is a need to develop anti-DENV molecules for the prevention and treatment of dengue.

[0006] Currently, there is no dengue-specific treatment available, so clinical treatment is essentially mainly supportive.

[0007] In recent years, drugs developed for prophylactic use have been gradually attracting attention as a promising alternative for preventing dengue. Prevention can be beneficial for travelers to dengue-endemic areas (e.g., aid workers, tourists, business and military travelers), as well as for vulnerable populations living in endemic areas. By preventing viremia and / or reducing the viral load, it is possible to significantly reduce dengue-related morbidity and mortality, or even prevent illness and death. In addition, effective and safe dengue antiviral compounds may also have use as therapeutic agents.

[0008] WO 2016 / 180696 discloses compounds for the prevention and treatment of dengue virus infections. However, there is a high unmet medical need for agents that enable the treatment or prevention of dengue disease (also called dengue) in animals, and more specifically in humans.

[0009] For prophylaxis, the dosing regimen should be made as efficient as possible and as safe as possible to ensure maximum treatment compliance. For example, once-daily dosing (QD) has several advantages such as a smaller peak-to-trough ratio, the effect of food intake not being decisive, and the pill burden on the patient being able to be reduced. However, QD can also impose restrictions on treatment compliance. Once-weekly dosing (Q7D) can be a viable option that may lead to favorable treatment compliance, but it may be accompanied by certain restrictions, such as a higher peak-to-trough ratio, the potential for a higher pill burden on the patient, and a greater role in food intake.

Summary of the Invention

[0010] The present invention relates to a compound of formula (I) for use in the prevention and / or treatment of dengue virus infection. The compound of formula (I) is administered in an oral dosage form to a human subject either in a fed state or a fasting state, and the compound of formula (I) is represented by the following formula or

[0011]

Chemical

[0012] Embodiments of the present invention include compounds administered as an oral dosage form to a human in a fed state, preferably, the human is in a fed state before or simultaneously with the administration of the oral dosage form.

[0013] Further embodiments of the present invention include compounds administered as a solid dosage form comprising a pharmaceutical formulation, the formulation preferably comprising a cellulose derivative such as hydroxypropyl methylcellulose (HPMC) or a methacrylic acid copolymer, or a combination thereof.

[0014] The present invention also provides a pharmaceutical formulation for use in the prevention and / or treatment of dengue virus infection, the formulation comprising a) a compound of formula (I) above, and b1) a methacrylic acid copolymer, or b2) a cellulose derivative such as hydroxypropyl methylcellulose (HPMC), and This pharmaceutical preparation is administered orally to humans who are either in a fed state or a fasting state. The humans are at risk of being infected with dengue virus or are infected with dengue virus.

[0015] The present invention also relates to such pharmaceutical preparations and / or solid dosage forms for use in the treatment and / or prevention of dengue virus infections.

Brief Description of the Drawings

[0016] The following detailed description is presented by way of example and is not intended to limit the present invention to the specific embodiments described. It can be best understood in conjunction with the accompanying drawings.

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[0017] The first graph (captioned "450 / 900 BID2d / Q7D") corresponds to Panel I, i.e., the administration of LD 450 mg of compound (a) twice a day (BID) on the 1st and 2nd days, and then MD 900 mg once a week (Q7D) on the 3rd, 10th, 17th, and 24th days.

[0018] The second graph (captioned "450 / 450 BID2d / Q3D-Q4D") corresponds to Panel II, i.e., the administration of LD 450 mg of compound (a) twice a day (BID) on the 1st and 2nd days, and then MD 450 mg once every 3 days (Q3D) or once every 4 days (Q4D) on the 3rd, 6th, 10th, 13th, 17th, 20th, 24th, and 27th days.

[0019] The third graph (captioned "150 / 300BID2d / Q7D") corresponds to Panel III, i.e., the administration of LD 150 mg of compound (a) twice a day (BID) on the 1st and 2nd days, and then MD 300 mg once a week (Q7D) on the 3rd, 10th, 17th, and 24th days.

[0020] The fourth graph (entitled "150 / 150 BID2d / Q3D-Q4D") corresponds to Panel IV, i.e., administration of 150 mg of compound (a) twice a day (BID) on Days 1 and 2, followed by administration of 150 mg once every three days (Q3D) or once every four days (Q4D) on Days 3, 6, 10, 13, 17, 20, 24, and 27.

Mode for Carrying Out the Invention

[0021] The present disclosure can be more fully understood by reference to the following description, which includes the following glossary and illustrative examples. It is also understood that certain features of the pharmaceutical formulations and methods of the present disclosure, which are described herein in the context of separate aspects, can be provided in combination in a single aspect. Conversely, various features of the pharmaceutical formulations and methods of the present disclosure, which are described herein in the context of a single aspect for the sake of brevity, may be provided separately or in any partial combination.

[0022] Some of the quantitative expressions described herein are not modified by the term "about". Whether or not the term "about" is explicitly used, all of the amounts described herein are intended to refer to the actual values, and also to approximations of such values reasonably inferred based on the ordinary skill in the art, including approximations of such values due to experimental and / or measurement conditions of such actual values. As used herein, the term "about" or "approximately" when referring to a numerical value or range allows for some variability in that value or range, e.g., within 10% (i.e., ±10%), within 5% (i.e., ±5%), or within 2.5% (i.e., ±2.5%) of the recited value or the limiting values of the recited range.

[0023] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of those words, such as "comprising" and "comprises", mean "including but not limited to" and are not intended to (and do not) exclude other elements.

[0024] The recitation of numerical ranges by endpoints includes all integers and, where appropriate, rational numbers included within that range (e.g., 1 to 5 can include 1, 2, 3, 4 when referring to, for example, the number of elements, and can also include 1.5, 2, 2.75, and 3.80 when referring to, for example, measured values). The listing of endpoints also includes the endpoint values themselves (e.g., 1.0 to 5.0 includes both 1.0 and 5.0). Any numerical range recited in this specification is intended to include all sub-ranges subsumed therein.

[0025] All references cited in this application are hereby incorporated by reference in their entirety. In particular, the teachings of all references specifically mentioned herein are incorporated by reference.

[0026] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, although they may. Furthermore, the particular feature, structure, or characteristic may be combined in any suitable manner in one or more embodiments, as will be apparent to those skilled in the art from this disclosure. Additionally, some embodiments described herein include some features of other embodiments but not others, and combinations of features of different embodiments are intended to be within the scope of the invention and to form different embodiments, as will be understood by those skilled in the art.

[0027] As used herein, the terms "treat", "treating", or "treatment" with respect to any disease, medical condition, syndrome, or disorder, in one embodiment, refer to ameliorating the disease, medical condition, syndrome, or disorder (i.e., slowing or arresting or reducing the onset of at least one of the disease or its clinical symptoms). In another embodiment, "treat", "treating", or "treatment" refer to alleviating or improving at least one physical parameter, including physical parameters that may not be recognizable to the patient. In a further embodiment, "treat", "treating", or "treatment" refer to modulating a disease, condition, syndrome, or disorder, either physically (e.g., stabilization of recognizable symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treat", "treating", or "treatment" refer to preventing or delaying the occurrence or onset or progression of a disease, condition, syndrome, or disorder.

[0028] As used herein, the terms "prevent", "prevention", "preventing" refer to reducing the risk of contracting or developing a given disease, condition, syndrome, or disorder, or of recurrence, or of alleviating or suppressing such a disease, condition, syndrome, or disorder, in a subject who is not ill but who is in the vicinity of, or who may be exposed to, a subject having a disease, condition, syndrome, or disorder.

[0029] As used herein, the term "dengue virus" refers to a single-stranded positive-sense RNA virus of the family Flaviviridae. Four different but closely related serotypes of flavivirus dengue, so-called DENV-1, -2, -3, and -4, are known. Flaviviruses transmitted by mosquitoes or ticks cause life-threatening infections in humans such as encephalitis and hemorrhagic fever.

[0030] As used herein, the term "dengue virus infection" refers to at least one condition, syndrome, symptom, disorder, and / or disease caused by the dengue virus.

[0031] The term "fasting state" or "fasting condition" is used herein to refer to a subject, preferably a human subject, who has not eaten for at least 4 hours prior to the time of interest, such as the time of administration of the compound of formula (I). In one embodiment, a subject in a fasting state, preferably a human subject, has not eaten for at least 0.25 hour (h: hour), preferably at least 0.5 h, preferably at least 1 h, preferably at least 2 h, preferably at least 3 h, preferably at least 5 h, preferably at least 6 h, preferably at least 7 h, preferably at least 8 h, preferably at least 9 h, preferably at least 10 h, preferably at least 11 h, preferably at least 12 h, preferably at least 8 h to a maximum of 12 h, more preferably at least 10 h, or any sub-range thereof, prior to administration of the compound of formula (I). In one embodiment, a subject in a fasting state, preferably a human subject, has not eaten for at least 0.25 hour (h: hour), 0.5 h, 1 h, 2 h, 3 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h or 12 h, preferably at least 8 h to 12 h, more preferably at least 10 h, or any sub-range thereof, prior to administration of the compound of formula (I). In some embodiments, the "fasting state" means that the subject, preferably a human subject, has not eaten for at least 0.25 hour (h: hour), preferably at least 0.For 5 h, preferably at least 1 h, preferably at least 2 h, preferably at least 3 h, preferably at least 5 h, preferably at least 6 h, preferably at least 7 h, preferably at least 8 h, preferably at least 9 h, preferably at least 10 h, preferably at least 11 h, preferably at least 12 h, preferably at least 8 h to a maximum of 12 h, more preferably for at least 10 h, over 10 kilocalories, preferably over 20 kilocalories, preferably over 30 kilocalories, preferably over 40 kilocalories, preferably over 50 kilocalories (kcal, Calories, Cal), or any sub-range thereof, or over 10 kcal, preferably over 20 kcal, preferably over 30 kcal, preferably over 40 kcal, preferably over 50 kcal, it means not ingesting. In some embodiments, "fasting state" means that the subject, preferably a human subject, before administration of the compound of formula (I), for at least 0.25 hours (h: hour), 0.5 h, 1 h, 2 h, 3 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h or 12 h, preferably at least 8 h to 12 h, more preferably for at least 10 h, 10 kilocalories, 20 kilocalories, 30 kilocalories, 40 kilocalories or 50 kilocalories (kcal, Calories, Cal), or any sub-range thereof, or over 10 kcal, over 20 kcal, over 30 kcal, over 40 kcal, or over 50 kcal, is not ingesting. In some embodiments, "fasting state" means that the subject, preferably a human subject, at least 0.25 hours (h) before administration of the compound of formula (I), preferably at least 0.5 h before, preferably at least 1 h before, preferably at least 2 h before, preferably at least 3 h before, preferably at least 5 h before, preferably at least 6 h before, preferably at least 7 h before, preferably at least 8 h before, preferably at least 9 h before, preferably at least 10 h before, preferably at least 11 h before, preferably at least 12 h before, preferably at least 8 h to at most 12 h before, more preferably at least 10 h before, or before any arbitrary partial range thereof, having ingested at most 10 kcal, preferably at most 20 kcal, preferably at most 30 kcal, preferably at most 40 kcal, preferably at most 50 kcal, preferably at most 100 kcal, preferably at most 150 kcal, preferably at most 200 kcal, preferably at most 250 kcal, preferably at most 300 kcal, or any arbitrary partial range thereof. In some embodiments, "fasting state" means that the subject, preferably a human subject, has ingested at most 10 kcal, 20 kcal, 30 kcal, 40 kcal, 50 kcal, 100 kcal, 150 kcal, 200 kcal, 250 kcal, 300 kcal, or any arbitrary partial range thereof, at least 0.25 hours (h: hour) before, 0.5 h before, 1 h before, 2 h before, 3 h before, 5 h before, 6 h before, 7 h before, 8 h before, 9 h before, 10 h before, 11 h before, or 12 h before the administration of the compound of formula (I), preferably at least 8 h to 12 h before, more preferably at least 10 h before. In some embodiments, "fasting state" means that the subject, preferably a human subject, has ingested at most 10 kcal, preferably at most 20 kcal, preferably at most 30 kcal, preferably at most 40 kcal, preferably at most 50 kcal, preferably at most 100 kcal, preferably at most 150 kcal, preferably at most 200 kcal, preferably at most 250 kcal, preferably at most 300 kcal, or any arbitrary partial range thereof, and at most 0.1 g of fat, preferably at most 0.2 g, preferably at most 0.3 g, preferably at most 0.4 g, preferably at most 0.5 g, preferably at most 0.6 g, preferably at most 0.7 g, preferably at most 0.8 g, preferably at most 0.9 g of fat, or up to 1 g of fat, preferably up to 2 g, preferably up to 3 g, preferably up to 4 g, preferably up to 5 g of fat, or up to 6 g of fat, preferably up to 7 g, preferably up to 8 g, preferably up to 9 g, preferably up to 10 g of fat, or up to 11 g of fat, for example up to 12 g, for example up to 13 g, for example up to 14 g, for example up to 15 g of fat, or up to 16 g of fat, for example up to 17 g, for example up to 18 g, for example up to 19 g, for example up to 20 g of fat, or up to 21 g of fat, for example up to 22 g, for example up to 23 g, for example up to 24 g, for example up to 25 g of fat, or up to 26 g of fat, for example up to 27 g, for example up to 28 g, for example up to 29 g, for example up to 30 g of fat, or up to 31 g of fat, for example up to 32 g, for example up to 33 g, for example up to 34 g, for example up to 35 g of fat, or up to 36 g of fat, for example up to 37 g, for example up to 38 g, for example up to 39 g, for example up to 40 g of fat, or up to 41 g of fat, for example up to 42 g, for example up to 43 g, for example up to 44 g, for example up to 45 g of fat, or any specific amount or range included therein, is taken at least 0.25 hours (h: hour) before, preferably at least 0.5 h before, preferably at least 1 h before, preferably at least 2 h before, preferably at least 3 h before, preferably at least 5 h before, preferably at least 6 h before, preferably at least 7 h before, preferably at least 8 h before, preferably at least 9 h before, preferably at least 10 h before, preferably at least 11 h before, preferably at least 12 h before, preferably at least 8 h to up to 12 h before, more preferably at least 10 h before, or before any sub - range thereof. In some embodiments, "fasting state" means that a subject, preferably a human subject, consumes up to 10 kcal, 20 kcal, 30 kcal, 40 kcal, 50 kcal, 100 kcal, 150 kcal, 200 kcal, 250 kcal, 300 kcal or any sub - range thereof, and up to 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g or 0.9 g of fat, or up to 1 g, 2 g, 3 g, 4 g or 5 g of fat, or up to 6 g, 7 g, 8 g, 9 g or 10 g of fat, or up to 11 g, 12 g, 13 g, 14 g or 15 g of fat, or up to 16 g, 17 g, 18 g, 18 g, 19 g or 20 g of fat, or up to 21 g, 22 g, 23 g, 24 g or 25 g of fat, or up to 26 g, 27 g, 28 g, 29 g or 30 g of fat, or up to 31 g, 32 g, 33 g, 34 g, or 35 g of fat, or up to 36 g, 37 g, 38 g, 39 g, or 40 g of fat, or up to 41 g, 42 g, 43 g, 44 g, or 45 g of fat, or any specific amount or range included therein, is ingested at least 0.25 hours (h: hour) before, 0.5 h before, 1 h before, 2 h before, 3 h before, 5 h before, 6 h before, 7 h before, 8 h before, 9 h before, 10 h before, 11 h or 12 h before the administration of the compound of formula (I), preferably at least 8 h to 12 h before, more preferably at least 10 h before, or before any sub-range thereof. In some embodiments, a "fasting state" means that a subject, preferably a human subject, has up to 10 kcal, preferably up to 20 kcal, preferably up to 30 kcal, preferably up to 40 kcal, preferably up to 50 kcal, preferably up to 100 kcal, preferably up to 150 kcal, preferably up to 200 kcal, preferably up to 250 kcal, preferably up to 300 kcal, or any sub-range thereof, and up to 0.1 g of fat, preferably up to 0.2 g, preferably up to 0.3 g, preferably up to 0.4 g, preferably up to 0.5 g, preferably up to 0.6 g, preferably up to 0.7 g, preferably up to 0.8 g, preferably up to 0.9 g of fat, or at most 1 g of fat, preferably at most 2 g, preferably at most 3 g, preferably at most 4 g, preferably at most 5 g of fat, or at most 6 g of fat, preferably at most 7 g, preferably at most 8 g, preferably at most 9 g, preferably at most 10 g of fat, or at most 11 g of fat, preferably at most 12 g, preferably at most 13 g, preferably at most 14 g, preferably at most 15 g of fat, or at most 16 g of fat, preferably at most 17 g, preferably at most 18 g, preferably at most 19 g, preferably at most 20 g of fat, or at most 21 g of fat, preferably at most 22 g, preferably at most 23 g, preferably at most 24 g, preferably at most 25 g of fat, or any specific amount or range contained therein, is ingested at least 0.25 hours (h: hour) before administration of the compound of formula (I), preferably at least 0.5 h before, preferably at least 1 h before, preferably at least 2 h before, preferably at least 3 h before, preferably at least 5 h before, preferably at least 6 h before, preferably at least 7 h before, preferably at least 8 h before, preferably at least 9 h before, preferably at least 10 h before, preferably at least 11 h before, preferably at least 12 h before, preferably at least 8 h to at most 12 h before, more preferably at least 10 h before, or before any sub-range thereof. In some embodiments, "fasting state" means that a subject, preferably a human subject, has at most 10 kcal, 20 kcal, 30 kcal, 40 kcal, 50 kcal, 100 kcal, 150 kcal, 200 kcal, 250 kcal, 300 kcal or any sub-range therein, and at most 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g or 0.9 g of fat, or at most 1 g, 2 g, 3 g, 4 g or 5 g of fat, or at most 6 g, 7 g, 8 g, 9 g or 10 g of fat, or at most 11 g, 12 g, 13 g, 14 g or 15 g of fat, or at most 16 g, 17 g, 18 g, 18 g, 19 g or 20 g of fat, or at most 21 g, 22 g, 23 g, 24 g or 25 g of fat,. Or any specific amount or range included therein is ingested at least 0.25 hours (h: hour) before, 0.5 h before, 1 h before, 2 h before, 3 h before, 5 h before, 6 h before, 7 h before, 8 h before, 9 h before, 10 h before, 11 h or 12 h before the administration of the compound of formula (I), preferably at least 8 h to 12 h before, more preferably at least 10 h before, or before any sub-range thereof. In some embodiments, "fasting state" means that the subject, preferably a human subject, has a maximum of 0.1 g of fat, preferably a maximum of 0.2 g, preferably a maximum of 0.3 g, preferably a maximum of 0.4 g, preferably a maximum of 0.5 g, preferably a maximum of 0.6 g, preferably a maximum of 0.7 g, preferably a maximum of 0.8 g, preferably a maximum of 0.9 g of fat, or a maximum of 1 g of fat, preferably a maximum of 2 g, preferably a maximum of 3 g, preferably a maximum of 4 g, preferably a maximum of 5 g of fat, or a maximum of 6 g of fat, preferably a maximum of 7 g, preferably a maximum of 8 g, preferably a maximum of 9 g, preferably a maximum of 10 g of fat, or a maximum of 11 g of fat, preferably a maximum of 12 g, preferably a maximum of 13 g, preferably a maximum of 14 g, preferably a maximum of 15 g of fat, or a maximum of 16 g of fat, preferably a maximum of 17 g, preferably a maximum of 18 g, preferably a maximum of 19 g, preferably a maximum of 20 g of fat, or a maximum of 21 g of fat, preferably a maximum of 22 g, preferably a maximum of 23 g, preferably a maximum of 24 g, preferably a maximum of 25 g of fat, or any specific amount or range included therein is ingested at least 0.25 hours (h: hour) before the administration of the compound of formula (I), preferably at least 0.5 h before, preferably at least 1 h before, preferably at least 2 h before, preferably at least 3 h before, preferably at least 5 h before, preferably at least 6 h before, preferably at least 7 h before, preferably at least 8 h before, preferably at least 9 h before, preferably at least 10 h before, preferably at least 11 h before, preferably at least 12 h before, preferably at least 8 h to a maximum of 12 h before, more preferably at least 10 h before, or before any sub-range thereof. In some embodiments, "fasting state" means that the subject, preferably a human subject, has a maximum of 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g or 0.9 g of fat, or up to 1 g, 2 g, 3 g, 4 g or 5 g of fat, or up to 6 g, 7 g, 8 g, 9 g or 10 g of fat, or up to 11 g, 12 g, 13 g, 14 g or 15 g of fat, or up to 16 g, 17 g, 18 g, 18 g, 19 g or 20 g of fat, or up to 21 g, 22 g, 23 g, 24 g or 25 g of fat, or any specific amount or range included therein, is taken at least 0.25 hours (h: hour) before, 0.5 h before, 1 h before, 2 h before, 3 h before, 5 h before, 6 h before, 7 h before, 8 h before, 9 h before, 10 h before, 11 h or 12 h before the administration of the compound of formula (I), preferably at least 8 h to 12 h before, more preferably at least 10 h before, or before any sub-range thereof. In some embodiments, a "fasting state" means that a subject, preferably a human subject, has up to 0.1 g of fat, preferably up to 0.2 g, preferably up to 0.3 g, preferably up to 0.4 g, preferably up to 0.5 g, preferably up to 0.6 g, preferably up to 0.7 g, preferably up to 0.8 g, preferably up to 0.9 g of fat, or at most 1 g of fat, preferably at most 2 g, preferably at most 3 g, preferably at most 4 g, preferably at most 5 g of fat, or at most 6 g of fat, preferably at most 7 g, preferably at most 8 g, preferably at most 9 g, preferably at most 10 g of fat, or at most 11 g of fat, preferably at most 12 g, preferably at most 13 g, preferably at most 14 g, preferably at most 15 g of fat, or at most 16 g of fat, preferably at most 17 g, preferably at most 18 g, preferably at most 19 g, preferably at most 20 g of fat, or at most 21 g of fat, preferably at most 22 g, preferably at most 23 g, preferably at most 24 g, preferably at most 25 g of fat, or at most 26 g of fat, preferably at most 27 g, preferably at most 28 g, preferably at most 29 g, preferably at most 30 g of fat, or at most 31 g of fat, preferably at most 32 g, preferably at most 33 g, preferably at most 34 g, preferably at most 35 g of fat, or at most 36 g of fat, preferably at most 37 g, preferably at most 38 g, preferably at most 39 g, preferably at most 40 g of fat, or at most 41 g of fat, preferably at most 42 g, preferably at most 43 g, preferably at most 44 g, preferably at most 45 g of fat, or any specific amount or range included therein, is ingested at least 0.25 hours (h: hour) before administration of the compound of formula (I), preferably at least 0.5 h before, preferably at least 1 h before, preferably at least 2 h before, preferably at least 3 h before, preferably at least 5 h before, preferably at least 6 h before, preferably at least 7 h before, preferably at least 8 h before, preferably at least 9 h before, preferably at least 10 h before, preferably at least 11 h before, preferably at least 12 h before, preferably at least 8 h to at most 12 h before, more preferably at least 10 h before, or before any sub-range thereof. In some embodiments, "fasting state" means that the subject, preferably a human subject, has at most 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g or 0.9 g of fat, or up to 1 g, 2 g, 3 g, 4 g or 5 g of fat, or up to 6 g, 7 g, 8 g, 9 g or 10 g of fat, or up to 11 g, 12 g, 13 g, 14 g or 15 g of fat, or up to 16 g, 17 g, 18 g, 18 g, 19 g or 20 g of fat, or up to 21 g, 22 g, 23 g, 24 g or 25 g of fat, or up to 26 g, 27 g, 28 g, 29 g or 30 g of fat, or up to 31 g, 32 g, 33 g, 34 g, or 35 g of fat, or up to 36 g, 37 g, 38 g, 39 g, or 40 g of fat, or up to 41 g, 42 g, 43 g, 44 g, or 45 g of fat, or any specific amount or range included therein, is ingested at least 0.25 hours (h: hour) before, 0.5 h before, 1 h before, 2 h before, 3 h before, 5 h before, 6 h before, 7 h before, 8 h before, 9 h before, 10 h before, 11 h or 12 h before the administration of the compound of formula (I), preferably at least 8 h to 12 h before, more preferably at least 10 h before, or before any sub-range thereof.

[0032] As used herein, the terms "fed state" or "feeding condition" are used herein to refer to a subject, preferably a human subject, who has eaten less than 4 hours or at most 4 hours before the time of interest, such as at the time of administration of a compound of formula (I). In one embodiment, a subject in a fed state has eaten at most 5 minutes (min), preferably at most 10 min, preferably at most 0.25 hours (h), preferably at most 0.5 h, preferably at most 1 h, preferably at most 2 h, preferably at most 3 h, preferably at most 4 h, preferably at most 5 h, preferably at most 6 h, preferably at most 7 h, preferably at most 8 h, preferably at most 9 h, preferably at most 10 h, preferably at most 11 h, preferably at most 12 h, preferably at least 0 min to at most 2 h, preferably at least 5 min to at most 2 h, more preferably at least 0.25 h to at most 1 h before administration of the compound of formula (I). In one embodiment, a subject in a fed state has eaten at most 5 minutes (min), 10 min, 0.25 hours (h), 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h or 12 h before administration of the compound of formula (I), preferably 0 min to 2 h or 5 min to 2 h, more preferably 0.25 h to 1 h before. In some embodiments, the term "fed state" refers to, for example, at most 5 minutes (min), preferably at most 10 min, preferably at most 0.25 hours (h), preferably at most 0.5 h, preferably at most 1 h, preferably at most 2 h, preferably at most 3 h, preferably at most 4 h, preferably at most 5 h, preferably at most 6 h, preferably at most 7 h, preferably at most 8 h, preferably at most 9 h, preferably at most 10 h, preferably at most 11 h, preferably at most 12 h, preferably at least 0 min to at most 2 h, preferably at least 5 min to at most 2 h, more preferably at least 0.Means a human subject who has ingested at least 10 kcal, preferably at least 20 kcal, preferably at least 30 kcal, preferably at least 40 kcal, preferably at least 50 kcal, preferably at least 100 kcal, preferably at least 150 kcal, preferably at least 200 kcal, preferably at least 250 kcal, preferably at least 300 kcal, preferably at least 350 kcal, preferably at least 400 kcal, preferably at least 450 kcal, preferably at least 500 kcal or more, or any partial range thereof, 25 h to 1 h before the maximum. In some embodiments, the term "feeding state" refers to a human subject who has ingested at least 10 kcal, 20 kcal, 30 kcal, 40 kcal, 50 kcal, 100 kcal, 150 kcal, 200 kcal, 250 kcal, 300 kcal, 350 kcal, 400 kcal, 450 kcal, or 500 kcal or more, or any partial range thereof, at, for example, up to 5 minutes (min), 10 min, 0.25 hours (h), 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h or 12 h before the maximum administration of the compound of formula (I), preferably from 0 min to 2 h or from 5 min to 2 h before, more preferably from 0.25 h to 1 h before. In some embodiments, the term "feeding state" refers to at least 0.1 g of fat, preferably at least 0.2 g, preferably at least 0.3 g, preferably at least 0.4 g, preferably at least 0.5 g, preferably at least 0.6 g, preferably at least 0.7 g, preferably at least 0.8 g, preferably at least 0.9 g of fat, preferably at least 1 g of fat, preferably at least 2 g, preferably at least 3 g, preferably at least 4 g, preferably at least 5 g, preferably at least 6 g, preferably at least 7 g, preferably at least 8 g, preferably at least 9 g, preferably at least 10 g, preferably at least 11 g, preferably at least 12 g, preferably at least 13 g, preferably at least 14 g, preferably at least 15 g of fat, preferably at least 16 g of fat, preferably at least 17 g, preferably at least 18 g, preferably at least 19 g, preferably at least 20 g of fat, preferably at least 21 g of fat, preferably at least 22 g, preferably at least 23 g, preferably at least 24 g, preferably at least 25 g of fat, preferably at least 26 g of fat, preferably at least 27 g, preferably at least 28 g, preferably at least 29 g, preferably at least 30 g of fat, preferably at least 31 g of fat, preferably at least 32 g, preferably at least 33 g, preferably at least 34 g, preferably at least 35 g of fat, preferably at least 36 g of fat, preferably at least 37 g, preferably at least 38 g, preferably at least 39 g, preferably at least 40 g of fat, preferably at least 41 g of fat, preferably at least 42 g, preferably at least 43 g, preferably at least 44 g, preferably at least 45 g of fat, preferably at least 46 g of fat, preferably at least 47 g, preferably at least 48 g, preferably at least 49 g, preferably at least 50 g of fat, preferably at least 51 g of fat, 52 g, preferably at least 53 g, preferably at least 54 g, preferably at least 55 g of fat, preferably at least 56 g of fat, preferably at least 57 g, preferably at least 58 g, preferably at least 59 g, preferably at least 60 g of fat, or any specific amount or range included therein, for example, up to 5 minutes (min) before administration of the compound of formula (I), preferably up to 10 min before, preferably up to 0.25 hours (h) before, preferably up to 0.Subjects who have ingested 5 h ago, preferably up to 1 h ago, preferably up to 2 h ago, preferably up to 3 h ago, preferably up to 4 h ago, preferably up to 5 h ago, preferably up to 6 h ago, preferably up to 7 h ago, preferably up to 8 h ago, preferably up to 9 h ago, preferably up to 10 h ago, preferably up to 11 h ago, preferably up to 12 h ago, preferably at least 0 min to up to 2 h ago, preferably at least 5 min to up to 2 h ago, more preferably at least 0.25 h to up to 1 h ago, preferably human subjects. In some embodiments, the term "fed state" means at least 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g or 0.9 g of fat, preferably at least 1 g, 2 g, 3 g, 4 g or 5 g of fat, preferably at least 6 g, 7 g, 8 g, 9 g or 10 g of fat, preferably at least 11 g, 12 g, 13 g, 14 g or 15 g of fat, preferably at least 16 g, 17 g, 18 g, 18 g, 19 g, or 20 g of fat, preferably at least 21 g, 22 g, 23 g, 24 g, or 25 g of fat, preferably at least 26 g, 27 g, 28 g, 29 g, or 30 g of fat, preferably at least 31 g, 32 g, 33 g, 34 g, or 35 g of fat, preferably at least 36 g, 37 g, 38 g, 39 g, or 40 g of fat, preferably at least 41 g, 42 g, 43 g, 44 g, or 45 g of fat, preferably at least 46 g, 47 g, 48 g, 49 g, or 50 g of fat, preferably at least 51 g, 52 g, 53 g, 54 g, or 55 g of fat, preferably at least 56 g, 57 g, 58 g, 59 g, or 60 g of fat, or any specific amount or range included therein, prior to administration of the compound of formula (I), for example, up to 5 minutes (min: minute) ago, 10 min ago, 0.25 hours (h: hour) ago, 0.5 h ago, 1 h ago, 2 h ago, 3 h ago, 4 h ago, 5 h ago, 6 h ago, 7 h ago, 8 h ago, 9 h ago, 10 h ago, 11 h or 12 h ago, preferably 0 min to 2 h or 5 min to 2 h ago, more preferably 0.Refers to a subject who has ingested 25 h to 1 h prior, preferably a human subject. In some embodiments, the term "fed state" means at least 21 g of fat, preferably at least 22 g, preferably at least 23 g, preferably at least 24 g, preferably at least 25 g of fat, preferably at least 26 g of fat, preferably at least 27 g, preferably at least 28 g, preferably at least 29 g, preferably at least 30 g of fat, preferably at least 31 g of fat, preferably at least 32 g, preferably at least 33 g, preferably at least 34 g, preferably at least 35 g of fat, preferably at least 36 g of fat, preferably at least 37 g, preferably at least 38 g, preferably at least 39 g, preferably at least 40 g of fat, preferably at least 41 g of fat, preferably at least 42 g, preferably at least 43 g, preferably at least 44 g, preferably at least 45 g of fat, preferably at least 46 g of fat, preferably at least 47 g, preferably at least 48 g, preferably at least 49 g, preferably at least 50 g of fat, preferably at least 51 g of fat, preferably at least 52 g, preferably at least 53 g, preferably at least 54 g, preferably at least 55 g of fat, preferably at least 56 g of fat, preferably at least 57 g, preferably at least 58 g, preferably at least 59 g, preferably at least 60 g of fat, or any specific amount or range included therein, for example, up to 5 minutes (min: minute) before administration of the compound of formula (I), preferably up to 10 min before, preferably up to 0.25 hour (h: hour) before, preferably up to 0.5 h before, preferably up to 1 h before, preferably up to 2 h before, preferably up to 3 h before, preferably up to 4 h before, preferably up to 5 h before, preferably up to 6 h before, preferably up to 7 h before, preferably up to 8 h before, preferably up to 9 h before, preferably up to 10 h before, preferably up to 11 h before, preferably up to 12 h before, preferably at least 0 min to up to 2 h before, preferably at least 5 min to up to 2 h before, more preferably at least 0.Subjects who have ingested within 1 hour prior to 25 h, preferably human subjects. In some embodiments, the term "fed state" means at least 21 g, 22 g, 23 g, 24 g or 25 g of fat, preferably at least 26 g, 27 g, 28 g, 29 g, or 30 g of fat, preferably at least 31 g, 32 g, 33 g, 34 g, or 35 g of fat, preferably at least 36 g, 37 g, 38 g, 39 g, or 40 g of fat, preferably at least 41 g, 42 g, 43 g, 44 g, or 45 g of fat, preferably at least 46 g, 47 g, 48 g, 49 g, or 50 g of fat, preferably at least 51 g, 52 g, 53 g, 54 g, or 55 g of fat, preferably at least 56 g, 57 g, 58 g, 59 g, or 60 g of fat, or any specific amount or range included therein, for example, of the administration of the compound of formula (I). Subjects who have ingested up to 5 minutes (min: minute) ago, 10 minutes ago, 0.25 hours (h: hour) ago, 0.5 h ago, 1 h ago, 2 h ago, 3 h ago, 4 h ago, 5 h ago, 6 h ago, 7 h ago, 8 h ago, 9 h ago, 10 h ago, 11 h or 12 h ago, preferably 0 minutes to 2 h or 5 minutes to 2 h ago, more preferably 0.25 h to 1 h ago, preferably human subjects. In some embodiments, the term "feeding state" means at least 10 kcal, preferably at least 20 kcal, preferably at least 30 kcal, preferably at least 40 kcal, preferably at least 50 kcal, preferably at least 100 kcal, preferably at least 150 kcal, preferably at least 200 kcal, preferably at least 250 kcal, preferably at least 300 kcal, preferably at least 350 kcal, preferably at least 400 kcal, preferably at least 450 kcal, preferably at least 500 kcal or more, or any sub-range thereof, and at least 0.1 g of fat, preferably at least 0.2 g, preferably at least 0.3 g, preferably at least 0.4 g, preferably at least 0.5 g, preferably at least 0.6 g, preferably at least 0.7 g, preferably at least 0.8 g, preferably at least 0.9 g, preferably at least 1 g, preferably at least 2 g, preferably at least 3 g, preferably at least 4 g, preferably at least 5 g, preferably at least 6 g, preferably at least 7 g, preferably at least 8 g, preferably at least 9 g, preferably at least 10 g, preferably at least 11 g, preferably at least 12 g, preferably at least 13 g, preferably at least 14 g, preferably at least 15 g of fat, preferably at least 16 g of fat, preferably at least 17 g, preferably at least 18 g, preferably at least 19 g, preferably at least 20 g of fat, preferably at least 21 g of fat, preferably at least 22 g, preferably at least 23 g, preferably at least 24 g, preferably at least 25 g of fat, preferably at least 26 g of fat, preferably at least 27 g, preferably at least 28 g, preferably at least 29 g, preferably at least 30 g of fat, preferably at least 31 g of fat, preferably at least 32 g, preferably at least 33 g, preferably at least 34 g, preferably at least 35 g of fat, preferably at least 36 g, preferably at least 37 g, preferably at least 38 g, preferably at least 39 g, preferably at least 40 g of fat, preferably at least 41 g, preferably at least 42 g, preferably at least 43 g, preferably at least 44 g, preferably at least 45 g of fat, preferably at least 46 g, preferably at least 47 g, preferably at least 48 g, preferably at least 49 g, preferably at least 50 g of fat, preferably at least 51 g, preferably at least 52 g, preferably at least 53 g, preferably at least 54 g, preferably at least 55 g of fat, preferably at least 56 g, preferably at least 57 g, preferably at least 58 g, preferably at least 59 g, preferably at least 60 g of fat, or any specific amount or range included therein, for example, up to 5 minutes (min) before the administration of the compound of formula (I), preferably up to 10 min before, preferably up to 0.25 hours (h) before, preferably up to 0.5 h ago, preferably up to 1 h ago, preferably up to 2 h ago, preferably up to 3 h ago, preferably up to 4 h ago, preferably up to 5 h ago, preferably up to 6 h ago, preferably up to 7 h ago, preferably up to 8 h ago, preferably up to 9 h ago, preferably up to 10 h ago, preferably up to 11 h ago, preferably up to 12 h ago, preferably at least 0 min to up to 2 h ago, preferably at least 5 min to up to 2 h ago, more preferably at least 0.25 h to up to 1 h ago, and is preferably a human subject who has ingested. In some embodiments, the term "fed state" means at least 10 kcal, 20 kcal, 30 kcal, 40 kcal, 50 kcal, 100 kcal, 150 kcal, 200 kcal, 250 kcal, 300 kcal, 350 kcal, 400 kcal, 450 kcal or 500 kcal or more, or any sub-range therein, and at least 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g or 0.9 g of fat, preferably at least 1 g, 2 g, 3 g, 4 g or 5 g of fat, preferably at least 6 g, 7 g, 8 g, 9 g or 10 g of fat, preferably at least 11 g, 12 g, 13 g, 14 g or 15 g of fat, preferably at least 16 g, 17 g, 18 g, 18 g, 19 g or 20 g of fat, preferably at least 21 g, 22 g, 23 g, 24 g or 25 g of fat, preferably at least 26 g, 27 g, 28 g, 29 g or 30 g of fat, preferably at least 31 g, 32 g, 33 g, 34 g or 35 g of fat, preferably at least 36 g, 37 g, 38 g, 39 g or 40 g of fat, preferably at least 41 g, 42 g, 43 g, 44 g or 45 g of fat, preferably at least 46 g, 47 g, 48 g, 49 g or 50 g of fat, preferably at least 51 g, 52 g, 53 g, 54 g or 55 g of fat, preferably at least 56 g, 57 g, 58 g, 59 g or 60 g of fat, or any specific amount or range included therein, for example, up to 5 minutes (min: minute) before, 10 min before, 0.25 hour (h: hour) before, 0.5 h ago, 1 h ago, 2 h ago, 3 h ago, 4 h ago, 5 h ago, 6 h ago, 7 h ago, 8 h ago, 9 h ago, 10 h ago, 11 h or 12 h ago, preferably 0 minutes to 2 h or 5 minutes to 2 h ago, more preferably 0.Means a subject who has ingested 25 h to 1 h before, preferably a human subject. In some embodiments, the term "feeding state" means at least 10 kcal, preferably at least 20 kcal, preferably at least 30 kcal, preferably at least 40 kcal, preferably at least 50 kcal, preferably at least 100 kcal, preferably at least 150 kcal, preferably at least 200 kcal, preferably at least 250 kcal, preferably at least 300 kcal, preferably at least 350 kcal, preferably at least 400 kcal, preferably at least 450 kcal, preferably at least 500 kcal or more, or any partial range therein, and at least 21 g of fat, preferably at least 22 g, preferably at least 23 g, preferably at least 24 g, preferably at least 25 g of fat, preferably at least 26 g, preferably at least 27 g, preferably at least 28 g, preferably at least 29 g, preferably at least 30 g of fat, preferably at least 31 g, preferably at least 32 g, preferably at least 33 g, preferably at least 34 g, preferably at least 35 g of fat, preferably at least 36 g, preferably at least 37 g, preferably at least 38 g, preferably at least 39 g, preferably at least 40 g of fat, preferably at least 41 g, preferably at least 42 g, preferably at least 43 g, preferably at least 44 g, preferably at least 45 g of fat, preferably at least 46 g, preferably at least 47 g, preferably at least 48 g, preferably at least 49 g, preferably at least 50 g of fat, preferably at least 51 g, preferably at least 52 g, preferably at least 53 g, preferably at least 54 g, preferably at least 55 g of fat, preferably at least 56 g, preferably at least 57 g, preferably at least 58 g, preferably at least 59 g, preferably at least 60 g of fat, or any specific amount or range included therein, for the administration of the compound of formula (I), for example, up to 5 minutes (min: minute) before, preferably up to 10 min before, preferably up to 0.Subjects who have ingested 25 hours (h: hour) ago, preferably up to 0.5 h ago, preferably up to 1 h ago, preferably up to 2 h ago, preferably up to 3 h ago, preferably up to 4 h ago, preferably up to 5 h ago, preferably up to 6 h ago, preferably up to 7 h ago, preferably up to 8 h ago, preferably up to 9 h ago, preferably up to 10 h ago, preferably up to 11 h ago, preferably up to 12 h ago, preferably at least 0 min to up to 2 h ago, preferably at least 5 min to up to 2 h ago, more preferably at least 0.25 h to up to 1 h ago, preferably human subjects. In some embodiments, the term "fed state" means at least 10 kcal, 20 kcal, 30 kcal, 40 kcal, 50 kcal, 100 kcal, 150 kcal, 200 kcal, 250 kcal, 300 kcal, 350 kcal, 400 kcal, 450 kcal or 500 kcal or more, or any sub-range therein, and at least 21 g, 22 g, 23 g, 24 g, or 25 g of fat, preferably at least 26 g, 27 g, 28 g, 29 g, or 30 g of fat, preferably at least 31 g, 32 g, 33 g, 34 g, or 35 g of fat, preferably at least 36 g, 37 g, 38 g, 39 g, or 40 g of fat, preferably at least 41 g, 42 g, 43 g, 44 g, or 45 g of fat, preferably at least 46 g, 47 g, 48 g, 49 g, or 50 g of fat, preferably at least 51 g, 52 g, 53 g, 54 g, or 55 g of fat, preferably at least 56 g, 57 g, 58 g, 59 g, or 60 g of fat, or any specific amount or range included therein, of the administration of the compound of formula (I), for example, up to 5 minutes (min: minute) ago, 10 min ago, 0.25 hours (h: hour) ago, 0.5 h ago, 1 h ago, 2 h ago, 3 h ago, 4 h ago, 5 h ago, 6 h ago, 7 h ago, 8 h ago, 9 h ago, 10 h ago, 11 h or 12 h ago, preferably 0 min to 2 h or 5 min to 2 h ago, more preferably 0.25 h to 1 h ago, preferably human subjects..

[0033] As used herein, a "standard diet" (standard breakfast or standard dinner) contains approximately 21 g of fat, 67 g of carbohydrates, and 19 g of protein, and has approximately 533 kcal. Preferably, the standard diet contains at least 15 g to a maximum of 40 g of fat, preferably at least 16 g to a maximum of 38 g of fat, preferably at least 17 g to a maximum of 35 g of fat, preferably at least 17 g to a maximum of 33 g of fat, preferably at least 18 g to a maximum of 31 g of fat, preferably at least 18 g to a maximum of 30 g of fat, preferably at least 19 g to a maximum of 27 g of fat.

[0034] A "high-fat high-calorie diet" (high-fat high-calorie breakfast or high-fat high-calorie dinner) contains approximately 500 - 600 kcal of fat (56 - 67 g of fat), 250 kcal of carbohydrates, 150 kcal of protein, and a total of 900 - 1000 kcal. Preferably, the high-fat high-calorie diet contains at least 35 g to a maximum of 80 g of fat, preferably at least 40 g to a maximum of 75 g of fat, preferably at least 45 g to a maximum of 70 g of fat, preferably at least 50 to a maximum of 75 g of fat, preferably at least 50 g to a maximum of 70 g of fat, preferably 50 g to a maximum of 60 g of fat.

[0035] A "low-fat low-calorie diet" (low-fat low-calorie breakfast or low-fat low-calorie dinner) contains approximately 2.5 g of fat, 247 kcal, or approximately 9 g of fat, 330 kcal. Preferably, the low-fat low-calorie diet contains at least 0.1 g to a maximum of 15 g of fat, preferably at least 0.3 g to a maximum of 13 g of fat, preferably at least 0.5 g to a maximum of 10 g of fat, preferably at least 0.8 g to a maximum of 9 g of fat, preferably at least 0.9 g to a maximum of 8 g of fat, preferably at least 1.0 g to a maximum of 8 g of fat, preferably at least 1.2 g to a maximum of 7 g of fat.

[0036] "Low-fat high-calorie diet" (low-fat high-calorie breakfast or low-fat high-calorie dinner) contains about 4.2 g of fat, 911 kcal, or about 0.95 g of fat, 406 kcal. Preferably, the low-fat low-calorie diet contains at least 0.1 g of fat to a maximum of 15 g of fat, preferably at least 0.3 g of fat to a maximum of 13 g of fat, preferably at least 0.5 g of fat to a maximum of 10 g of fat, preferably at least 0.8 g of fat to a maximum of 9 g of fat, preferably at least 0.9 g of fat to a maximum of 8 g of fat, preferably at least 1.0 g of fat to a maximum of 8 g of fat, preferably at least 1.2 g of fat to a maximum of 7 g of fat.

[0037] "Standard normal-fat diet" (standard normal-fat breakfast or standard normal-fat dinner) contains approximately 21 g of fat, 67 g of carbohydrates, 19 g of protein, and amounts to about 533 kcal. Examples of the standard normal-fat diet include 4 slices of bread, 2 slices of ham or cheese, butter, jelly, and 1 cup or 2 cups (up to 355 mL) of decaffeinated coffee or tea with milk and / or sugar added. Preferably, the standard normal-fat diet contains at least 15 g of fat to a maximum of 40 g of fat, preferably at least 16 g of fat to a maximum of 38 g of fat, preferably at least 17 g of fat to a maximum of 35 g of fat, preferably at least 17 g of fat to a maximum of 33 g of fat, preferably at least 18 g of fat to a maximum of 31 g of fat, preferably at least 18 g of fat to a maximum of 30 g of fat, preferably at least 19 g of fat to a maximum of 27 g of fat. As used herein, the term "oral dosage form" refers to a pharmaceutical formulation containing a specific amount (dose) of a compound of formula (I), particularly compound (a), or a stereoisomer, pharmaceutically acceptable salt and / or solvate and / or polymorph thereof as the active ingredient, and an inactive ingredient (pharmaceutically acceptable excipient), and formulated into a specific form suitable for oral administration and oral drug delivery such as tablets, capsules, or liquid oral formulations. In one embodiment, the composition is in the form of a tablet that can be scored.

[0038] As used herein, the term "administer" refers to introducing an agent or active ingredient, such as a compound of formula (I), to a subject, preferably a human subject. The related terms "administering" and "administration" (and grammatical equivalents) refer to both direct administration, which can be administration to a subject by a medical professional or self-administration by the subject, and / or indirect administration, which can be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and / or provides a prescription for the drug to the patient.

[0039] With respect to use in medicine, the compounds of formula (I) described herein, particularly the co-crystals or salts of compound (a), refer to non-toxic "pharmaceutically acceptable salts". "Pharmaceutically acceptable" means approved or approvable by a federal or state government regulatory agency, or the corresponding agency in a country other than the United States, or may mean described in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals, more specifically, humans.

[0040] However, other salts may be useful for the preparation of the compound of formula (I), particularly compound (a) or its pharmaceutically acceptable salt forms. Suitable pharmaceutically acceptable salts of the compound of formula (I), particularly compound (a), include, for example, acid addition salts that can be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. Further, when the compound of formula (I), particularly compound (a) has an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts such as sodium salts or potassium salts, alkaline earth metal salts such as calcium salts or magnesium salts, and salts formed with suitable organic ligands such as quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartrates, borates, bromides, calcium edetates, camsylates, carbonates, chlorides, clubranates, citrates, dihydrochlorides, edetates, edisylicates, estrates, esilates, fumarates, gluceptates, gluconates, glutamates, glycolylarsanilates, hexylresorcinates, hydrabamines, hydrobromides, hydrochlorides, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, laurates, malates, maleates, mandelates, mesylates, methyl bromides, methyl nitrates, methyl sulfates, mucates, napsylates, nitrates, N-methylglucamine ammonium salts, oleates, pamoates (embonates), palmitates, pantothenates, phosphates / diphosphates, polygalacturonates, salicylates, stearates, sulfates, basic acetates, succinates, tannates, tartrates, theocluates, tosylates, triethiodides, valerates, and combinations of one or more of these.

[0041] Representative acids and bases that can be used in the preparation of pharmaceutically acceptable salts include acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and acids including combinations of one or more of these; and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine, tromethamine, zinc hydroxide, and combinations of one or two or more of these.

[0042] When the compounds of formula (I), in particular compound (a), have at least one chiral center, as a result they can exist as enantiomers. When the compounds have two or more chiral centers, they can additionally exist as diastereomers. It should be understood that all such isomers and their mixtures are included within the scope of the present invention. Furthermore, some of the compounds can exist as polymorphs and are therefore intended to be included in the present invention. In addition, some of the compounds can form solvates (i.e., hydrates) with water or solvates with organic solvents, and such solvates are also intended to be included within the scope of the present invention. Those skilled in the art will understand that the term "compound" as used herein refers to solvated compounds of formula (I) (especially solvates of compound (a)), hydrated compounds of formula (I) (especially hydrates of compound (a)), and hydrated and solvated compounds of formula (I) (for example, compounds of formula (I) in the form of solvates of water and organic solvents, especially compound (a) in the form of solvates of water and organic solvents).

[0043] When a mixture of stereoisomers results from a process for preparing the compounds of formula (I), in particular compound (a), these isomers can be separated by conventional techniques such as preparative chromatography. The compounds may be prepared as racemates or the individual enantiomers can also be prepared by either enantioselective synthesis or resolution. The compounds can be resolved into their component enantiomers by standard techniques such as forming diastereomeric pairs by forming salts with an optically active acid such as, for example, (-)-di-p-toluoyl-d-tartaric acid and / or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. These compounds can also be resolved by formation of diastereomeric esters or amides followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using a chiral stationary phase or an isochiral column.

[0044] In one embodiment of the pharmaceutical preparation of the present invention, the compound of formula (I) is a compound comprising, consisting of, and / or consisting essentially of the (+)-enantiomer, and this compound is substantially free of the (−)-isomer. In this context, being substantially free of means that the (−)-isomer calculated by the following formula

[0045]

Number

[0046] In another embodiment of the pharmaceutical preparation of the present invention, the compound of formula (I) is a compound comprising, consisting of, and consisting essentially of the (−)-enantiomer, and this compound is substantially free of the (+)-isomer. In this context, being substantially free of means that the (+)-isomer calculated by the following formula

[0047]

Number

[0048] In any process for preparing the compounds of the various embodiments of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the related molecules. This can be achieved by conventional protecting group means such as those described in Protective Groups in Organic Chemistry, Second Edition, J.F.W. McOmie, Plenum Press, 1973, T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. The protecting groups can be removed using methods well known in the art at a convenient subsequent stage.

[0049] The compounds of formula (I), particularly compound (a), can exist in unsolvated form and solvated forms, such as hydrates, organic solvates, or combinations of organic solvates and hydrates.

[0050] As used herein, the term "solvate" means a solvate addition form containing one or more solvents, either in stoichiometric or non-stoichiometric amounts. Some compounds have a tendency to trap solvent molecules in a crystalline solid state in a certain molar ratio, thereby forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. In certain embodiments, the solvate formed can be a combination of an organic solvate and a hydrate. A hydrate is one or more water molecules and water in its molecular state as H 2Formed by combination with one of the substances held as O, such combinations can form one or more hydrates. In hydrates, water molecules are bonded via secondary valences by intermolecular forces, particularly hydrogen bridges. Solid hydrates contain water in stoichiometric ratios as so-called water of crystallization, where the water molecules need not be equivalent with respect to their bonding states. Examples of hydrates include sesquihydrates, monohydrates, dihydrates, or trihydrates. Similarly suitable are hydrates of salts of the compounds used herein.

[0051] When a compound crystallizes from a solution or slurry, it may crystallize in various spatial lattice arrangements (this property is called "polymorphism") and form crystals with various crystal morphologies, each of which is known as a "polymorph". "Polymorph" as used herein refers to the crystal form of the compound of formula (I), where the molecules are located at three-dimensional lattice points. The various polymorphs of the compound of formula (I) may differ from each other in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystal form, accumulation pattern, fluidity, and / or solid-state stability, etc.

[0052] The compounds of formula (I) can be administered as crystalline or amorphous products. They can be obtained, for example, as solid plugs, powders, or thin films by methods such as precipitation, crystallization, freeze-drying, spray-drying, or evaporation-drying. They can be administered alone, or in combination with one or more of the other compounds described herein, or in combination with one or more other drugs. Generally, they are administered as formulations in combination with one or more pharmaceutically acceptable excipients. The choice of pharmaceutically acceptable excipients depends largely on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0053] Unless otherwise specified, the terms "wt%" and "weight percent" are used interchangeably to refer to the concentration of a component (e.g., a pharmaceutically acceptable excipient or an active pharmaceutical ingredient) relative to the weight of a pharmaceutical formulation.

[0054] The average molecular weight may refer to, for example, the number average molecular weight or the weight average molecular weight. The average molecular weight can be measured, for example, using gel permeation chromatography.

[0055] The term "subject" refers to an animal, preferably a mammal, most preferably a human, that is the subject of treatment, observation, or testing. In one embodiment, the subject is a human. In some embodiments, the subject is a human diagnosed with a medical condition, disorder, or disease caused by dengue virus, or a dengue virus infection. In one embodiment, the subject is a human diagnosed with a medical condition, syndrome, disorder, or disease caused by dengue virus. In some embodiments, the subject is a human who has not been diagnosed with a medical condition, disorder, or disease caused by dengue virus, nor a dengue virus infection, and is being prophylactically treated. In one embodiment, the subject is a human who has not been diagnosed with a medical condition, syndrome, disorder, or disease caused by dengue virus and is being prophylactically treated.

[0056] The term "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that induces a biological or medical response, including a decrease or inhibition of the activity of an enzyme or protein, or an improvement in symptoms, alleviation of a medical condition, slowing or delaying of disease progression, or prevention of a disease, in a subject, biological sample, tissue system, animal, or human, as desired by a researcher, veterinarian, physician, or other clinician.

[0057] Preferably, the term "therapeutically effective amount" can refer to the implementation of an administration regimen to a subject, preferably a human subject, to achieve a specific plasma concentration level or exposure amount of an active compound or pharmaceutical agent that is expected to result in a level effective for the treatment or prevention of dengue virus or a dengue virus infection in the subject.

[0058] Preferably, the term "therapeutically effective amount" can refer to an amount of a compound, formulation, or oral dosage form that, when administered to a subject, preferably a human subject, is effective to at least partially alleviate, suppress, prevent, treat, and / or ameliorate a condition, disorder, symptom, or disease caused by dengue virus.

[0059] As used herein, the term "dengue virus replication inhibitor" refers to an agent that inhibits or reduces at least one of the conditions, symptoms, syndromes, disorders, and / or diseases caused by dengue virus.

[0060] As used herein, unless otherwise noted, the terms "affect" or "be affected" (when referring to a disease, syndrome, condition, or disorder affected by inhibition of dengue virus replication) include reducing the frequency and / or severity of one or more symptoms or signs of the above-mentioned disease, syndrome, condition, or disorder, and / or preventing the occurrence of one or more symptoms or signs of the above-mentioned disease, syndrome, condition, or disorder.

[0061] As used herein, the term "C max " refers to the maximum (peak) plasma concentration of a particular compound observed in a subject after administration of a dose of that compound to the subject.

[0062] As used herein, the term "AUC" refers to the area under the concentration-time curve, which is a measure of exposure to the compound of interest and is the integral of the concentration-time curve after a single dose or at steady state. AUC is expressed in units of μg * hr / L (μg × hr / L).

[0063] As used herein, the term "adverse event" (AE) refers to any adverse medical event in a subject, preferably a human subject, to whom a pharmaceutical formulation according to the invention has been administered. An AE is not necessarily causally related to the administration of the pharmaceutical formulation according to the invention. Thus, an AE can be any unfavorable and unintended sign (including abnormal findings), symptom, or disease that is temporarily associated with the use of the pharmaceutical formulation and is directly related to that pharmaceutical formulation. This includes any onset that is a new onset or a worsening in severity or frequency from a baseline condition, or an abnormal result of a diagnostic procedure that includes an abnormality in a laboratory test.

[0064] As used herein, the term "adverse event occurring under treatment" refers to any adverse event that is causally related to the administration of a pharmaceutical formulation according to the invention.

[0065] As used herein, "pharmaceutically acceptable excipient" is an inactive ingredient in a pharmaceutical formulation. Examples of excipients include diluents, wetting agents (e.g., surfactants), binders, lubricants, lubricants, disintegrants, fillers, surfactants, and the like.

[0066] As used herein, a "disintegrant agent" or "disintegrant" is an excipient that hydrates a pharmaceutical formulation and aids in the dispersion of a tablet. Examples of disintegrants include croscarmellose sodium 5, crospovidone (i.e., crosslinked polyvinyl N-pyrrolidone), sodium starch glycolate, or any combination thereof.

[0067] As used herein, a "diluent" or "filler" is an excipient that adds bulk to a pharmaceutical formulation. Examples of diluents include lactose, sorbitol, cellulose, calcium phosphate, starch, sugars (e.g., mannitol, sucrose, etc.) or any combination thereof.

[0068] As used herein, "wetting agent" or "surfactant" is an excipient that imparts enhanced solubility and / or wettability to a pharmaceutical formulation. Examples of wetting agents include sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polyoxyethylene 20 sorbitan monooleate (i.e., polysorbate 20) (e.g., Tween™ or Tween 20), Soluplus®, or any combination thereof.

[0069] As used herein, "binder" is an excipient that imparts enhanced cohesive strength or tensile strength (e.g., hardness) to a pharmaceutical formulation. Examples of binders include dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose, and modified cellulose (e.g., hydroxymethyl cellulose).

[0070] As used herein, "lubricant" is an excipient that imparts enhanced flow properties to a pharmaceutical formulation. Examples of lubricants include colloidal silica and / or talc.

[0071] As used herein, "colorant" is an excipient that imparts a desired color to a pharmaceutical formulation. Examples of colorants include commercially available pigments such as FD&C Blue #1 aluminum lake, FD&C Blue #2, other FD&C Blue colors, titanium dioxide, iron oxide, and / or combinations thereof. Other colorants include commercially available pigments such as FD&C Green #3.

[0072] As used herein, "lubricant" is an excipient added to a pharmaceutical formulation that is compressed into tablets. The lubricant aids in the compression of granules into tablets and the ejection of the pharmaceutical formulation tablets from the die press. Examples of lubricants include magnesium stearate, stearic acid (stearin), hydrogenated oils, sodium stearyl fumarate, or any combination thereof.

[0073] Preferred descriptions (features) and embodiments of the pharmaceutical formulations, uses and processes of the present invention are described below. Each description and embodiment of the present invention so defined can be combined with any other description and / or embodiment unless clearly indicated otherwise. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature(s) or description indicated as being preferred or advantageous. In this regard, the present invention is particularly captured by any one of the following numbered aspects and embodiments, or any combination of any one or more of the following numbered aspects and embodiments with any other description and / or embodiment.

[0074] 1. A compound of formula (I) for use in the prevention and / or treatment of dengue virus infection, wherein the compound of formula (I) is administered in an oral dosage form to a human subject either in a fed state or a fasting state, and the compound of formula (I) is represented by the following formula, or

[0075]

Chemical formula

[0076] [Chemical formula] or a stereoisomer, pharmaceutically acceptable salt, solvate, or polymorph thereof, for use in accordance with any one of descriptions 1 to 54. 56. The oral dosage form is 1) at least one loading period in which at least one dose (A) of the compound of formula (I) is administered over a period of at least once a day for at least one day, 2) at least one maintenance period starting on the day following the last day of administration of dose (A) or the last day of the loading period, during which at least one dose (B) of the compound of formula (I) is administered at least once every two weeks, at least twice a week, at least twice a week, or at least once a day for at least one day, at least one maintenance period, and a dosing regimen comprising either dose (A) is higher or lower than dose (B), a compound for use in accordance with any one of descriptions 1 to 55, administered according to the dosing regimen. Preferably, dose (A) is higher than dose (B). 57. The oral dosage form is 1) at least one loading period in which at least one dose (A) of the compound of formula (I) is administered over a period of at least once a day, up to 20 days, preferably up to 19 days, preferably up to 18 days, preferably up to 17 days, preferably up to 16 days, preferably up to 15 days, preferably up to 14 days, preferably up to 13 days, preferably up to 12 days, preferably up to 11 days, preferably up to 10 days, preferably up to 9 days, preferably up to 8 days, preferably up to 7 days, preferably up to 6 days, preferably up to 5 days, preferably up to 4 days, preferably up to 3 days, preferably up to 2 days, preferably up to 1 day, or any specific amount or range included therein, at least one loading period, 2) At least one maintenance period that starts on the day after the last day of administration of dose (A) or the last day of the loading dose period, during which at least one dose (B) of the compound of formula (I) is administered at least once every two weeks, at least once a week, preferably at least twice a week, preferably at least once a day, for a period of at least 1 day to a maximum of 12 months, preferably a maximum of 9 months, preferably a maximum of 6 months, preferably a maximum of 3 months, preferably a maximum of 1.5 months, preferably a maximum of 40 days, preferably a maximum of 39 days, preferably a maximum of 38 days, preferably a maximum of 37 days, preferably a maximum of 36 days, preferably a maximum of 35 days, preferably a maximum of 30 days, preferably a maximum of 28 days, preferably a maximum of 21 days, preferably a maximum of 14 days, preferably a maximum of 7 days, preferably a maximum of 5 days, or any specific amount or range included therein, at least one maintenance period, A dosing regimen comprising Either dose (A) is higher or lower than dose (B), A compound for use according to any one of descriptions 1 to 56, administered according to the dosing regimen. Preferably, dose (A) is higher than dose (B). 58. The oral dosage form is 1) At least one loading dose period during which at least one dose (A) of the compound of formula (I) is administered at least once a day for a period of up to 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day, or any specific amount or range included therein, at least one loading dose period, 2) At least one maintenance period that begins on the day after the last day of administration of dose (A) or the last day of the loading dose period, during which at least one dose (B) of the compound of formula (I) is administered at least once every two weeks, at least once a week, at least twice a week or at least once a day, for a period of at least 1 day to a maximum of 12 months, 9 months, 6 months, 3 months, 1.5 months, 40 days, 39 days, 38 days, 37 days, 36 days, 35 days, 30 days, 28 days, 21 days, 14 days, 7 days, 5 days, or any specific amount or range included therein, at least one maintenance period, A dosing regimen comprising Either dose (A) is higher than dose (B) or lower than dose (B), A compound for use according to any one of descriptions 1 to 57, administered according to the dosing regimen. Preferably, dose (A) is higher than dose (B). 59. The oral dosage form is 1) At least one loading dose period in which at least one dose (A) of the compound of formula (I) is administered at least once a day, preferably at least twice a day, preferably at least three times a day, or preferably at least four times a day, for a period of at least 1 day to a maximum of 20 days, preferably at least 2 days to a maximum of 19 days, preferably at least 3 days to a maximum of 18 days, preferably at least 4 days to a maximum of 17 days, preferably at least 5 days to a maximum of 16 days, preferably at least 6 days to a maximum of 15 days, preferably at least 7 days to a maximum of 14 days, preferably at least 8 days to a maximum of 13 days, preferably at least 9 days to a maximum of 12 days, preferably at least 10 days to a maximum of 11 days, or any specific amount or range included therein, at least one loading dose period, 2) At least one maintenance period that begins on the day following the last day of administration of dose (A) or the last day of the loading dose period, during which at least one dose (B) of the compound of formula (I) is administered at least once every two weeks, preferably at least once a week, preferably at least twice a week, preferably at least twice a day, preferably at least twice a day, preferably at least three times a day, preferably at least four times a day, for a period of at least 1 day to a maximum of 12 months, at least 2 days to a maximum of 6 months, preferably at least 3 days to a maximum of 3 months, preferably at least 1 day to a maximum of 30 days, preferably at least 5 days to a maximum of 28 days, preferably at least 10 days to a maximum of 26 days, or any specific amount or range included therein, at least one maintenance period comprising an administration regimen, wherein either dose (A) is higher or lower than dose (B), A compound for use according to any one of descriptions 1 to 58, administered according to the administration regimen. Preferably, dose (A) is higher than dose (B). 60. The dose (A) of the compound of formula (I) is within the range of 50 mg to 1200 mg, preferably 100 mg to 1100 mg, preferably 150 mg to 900 mg, preferably 50 mg to 800 mg, preferably 60 mg to 700 mg, preferably 70 mg to 650 mg, preferably 80 mg to 600 mg, preferably 90 mg to 550 mg, preferably 100 mg to 500 mg, or any specific amount or range included therein, a compound for use according to any one of descriptions 56 to 59. 61. The compound for use according to any one of descriptions 56 - 60, wherein the dose (A) of the compound of formula (I) is from 5 mg to 1500 mg, preferably from 10 mg to 1400 mg, preferably from 20 mg to 1300 mg, preferably from 25 mg to 1200 mg, preferably from 30 mg to 1100 mg, preferably from 35 mg to 1000 mg, preferably from 15 mg to 1450 mg, preferably from 15 mg to 1100 mg, preferably from 25 mg to 1000 mg, preferably from 10 mg to 900 mg, preferably from 15 mg to 900 mg, preferably from 20 mg to 900 mg, preferably from 30 mg to 900 mg, preferably from 35 mg to 800 mg, preferably from 50 mg to 800 mg, or within any specific amount or range included therein. 62. The compound for use according to any one of descriptions 56 - 61, wherein the dose (A) of the compound of formula (I) is administered at least once a day, preferably at least twice a day. 63. The compound for use according to any one of descriptions 56 - 62, wherein the dose (B) of the compound of formula (I) is from 5 mg to 1500 mg, preferably from 25 mg to 1200 mg, preferably from 50 mg to 1100 mg, preferably from 100 mg to 1000 mg, preferably from 150 mg to 900 mg, preferably from 5 mg to 500 mg, preferably from 5 mg to 450 mg, preferably from 5 mg to 400 mg, preferably from 5 mg to 350 mg, preferably from 10 mg to 300 mg, preferably from 15 mg to 250 mg, preferably from 20 mg to 230 mg, preferably from 30 mg to 250 mg, preferably from 35 mg to 200 mg, preferably from 50 mg to 450 mg, or within any specific amount or range included therein. 64. The compound for use according to any one of descriptions 56 - 63, wherein the dose (B) of the compound of formula (I) is administered at least once every two weeks, preferably at least once a week, preferably at least twice a week, preferably at least once a day, preferably at least twice a day. Preferably, the dose (B) is administered once a day. 65. The dose (B) of the compound of formula (I) is administered at least once every two weeks, preferably at least once a week, preferably at least twice a week, preferably at least twice a week, preferably at least twice a day, preferably at least three times a day, preferably at least four times a day, for a period of at least 1 day to a maximum of 12 months, at least 2 days to a maximum of 6 months, preferably at least 3 days to a maximum of 3 months, preferably at least 1 day to a maximum of 30 days, preferably for a period of at least 5 days to a maximum of 28 days, preferably for a period of at least 10 days to a maximum of 26 days, or in any specific amount or range included therein, for use according to any one of descriptions 56 to 64. 66. The dose (A) of the compound of formula (I) is administered at least once a day, preferably at least twice a day, preferably at least three times a day, or preferably at least four times a day, for a period of at least 1 day to a maximum of 20 days, preferably at least 2 days to a maximum of 19 days, preferably at least 3 days to a maximum of 18 days, preferably at least 4 days to a maximum of 17 days, preferably at least 5 days to a maximum of 16 days, preferably at least 6 days to a maximum of 15 days, preferably at least 7 days to a maximum of 14 days, preferably at least 8 days to a maximum of 13 days, preferably at least 9 days to a maximum of 12 days, preferably at least 10 days to a maximum of 11 days, or in any specific amount or range included therein, for use according to any one of descriptions 56 to 65. 67. The dose (A) of the compound of formula (I) is administered at least once a day, preferably at least twice a day, preferably at least three times a day, or preferably at least four times a day, for a period of at least 1 day to a maximum of 20 days, preferably at least 2 days to a maximum of 19 days, preferably at least 3 days to a maximum of 18 days, preferably at least 4 days to a maximum of 17 days, preferably at least 5 days to a maximum of 16 days, preferably at least 6 days to a maximum of 15 days, preferably at least 7 days to a maximum of 14 days, preferably at least 8 days to a maximum of 13 days, preferably at least 9 days to a maximum of 12 days, preferably at least 10 days to a maximum of 11 days, or in any specific amount or range included therein, For the use according to any one of paragraphs 56 - 66, the dosage (A) of the compound of formula (I) is within the range of 50 mg to 1200 mg, preferably 100 mg to 1100 mg, preferably 150 mg to 900 mg, preferably 50 mg to 800 mg, preferably 60 mg to 700 mg, preferably 70 mg to 650 mg, preferably 80 mg to 600 mg, preferably 90 mg to 550 mg, preferably 100 mg to 500 mg, or any specific amount or range included therein. 68. The dosage (A) of the compound of formula (I) is administered at least once a day, preferably at least twice a day, preferably at least three times a day, or preferably at least four times a day, over a period of at least 1 day to a maximum of 20 days, preferably at least 2 days to a maximum of 19 days, preferably at least 3 days to a maximum of 18 days, preferably at least 4 days to a maximum of 17 days, preferably at least 5 days to a maximum of 16 days, preferably at least 6 days to a maximum of 15 days, preferably at least 7 days to a maximum of 14 days, preferably at least 8 days to a maximum of 13 days, preferably at least 9 days to a maximum of 12 days, preferably at least 10 days to a maximum of 11 days, or in any specific amount or range included therein. For the use according to any one of paragraphs 56 - 67, the dosage (A) of the compound of formula (I) is within the range of 5 mg to 1500 mg, preferably 10 mg to 1400 mg, preferably 20 mg to 1300 mg, preferably 25 mg to 1200 mg, preferably 30 mg to 1100 mg, preferably 35 mg to 1000 mg, preferably 15 mg to 1450 mg, preferably 15 mg to 1100 mg, preferably 25 mg to 1000 mg, preferably 10 mg to 900 mg, preferably 15 mg to 900 mg, preferably 20 mg to 900 mg, preferably 30 mg to 900 mg, preferably 35 mg to 800 mg, preferably 50 mg to 800 mg, or any specific amount or range included therein. The dosage (B) of the compound of formula (I) is administered at least once every two weeks, preferably at least once a week, preferably at least twice a week, preferably at least twice a week, preferably at least twice a day, preferably at least three times a day, preferably at least four times a day, for a period of at least 1 day to a maximum of 12 months, at least 2 days to a maximum of 6 months, preferably at least 3 days to a maximum of 3 months, preferably at least 1 day to a maximum of 30 days, preferably for a period of at least 5 days to a maximum of 28 days, preferably for a period of at least 10 days to a maximum of 26 days, or in any specific amount or range included therein, The dosage (B) of the compound of formula (I) is 5 mg to 1500 mg, preferably 25 mg to 1200 mg, preferably 50 mg to 1100 mg, preferably 100 mg to 1000 mg, preferably 150 mg to 900 mg, preferably 5 mg to 500 mg, preferably 5 mg to 450 mg, preferably 5 mg to 400 mg, preferably 5 mg to 350 mg, preferably 10 mg to 300 mg, preferably 15 mg to 250 mg, preferably 20 mg to 230 mg, preferably 30 mg to 250 mg, preferably 35 mg to 200 mg, preferably 50 mg to 450 mg, or within any specific amount or range included therein, a compound for use according to any one of descriptions 56 to 68. 70. A pharmaceutical preparation for use in the prevention and / or treatment of dengue virus infection, the preparation comprising a) a compound of formula (I) and b1) a methacrylic acid copolymer, or b2) a cellulose derivative, such as methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose (NaCMC) or hydroxypropylmethylcellulose (HPMC), or a combination thereof, a pharmaceutical preparation. Preferably, the cellulose derivative is HPMC, The pharmaceutical preparation is administered to a human subject either in the fed state or in the fasting state, Formula (I) is represented by the following formula, or

[0077] [Chemical formula] its stereoisomers, pharmaceutically acceptable salts, solvates, or polymorphs, and the compound is R 1 is H, R 2 is F, R 3 is H or CH 3 is a compound of R 1 is H, CH 3 or F, R 2 is OCH 3 and R 3 is H is a compound of R 1 is H, R 2 is OCH 3 and R 3 is CH 3 is a compound of R 1 is CH 3 and R 2 is F, R 3 is H is a compound of R 1 is CF 3 or OCF 3 and R 2 is H, R 3 is H is a compound of R 1 is OCF 3 and R 2 is OCH 3 and R 3 is H is a compound of R 1 is OCF 3 and R 2 is H, R 3 is CH 3 is a compound of is selected from the group of 71. A pharmaceutical preparation is administered in an oral dosage form to a human subject in a fed state, preferably, the human subject in a fed state is consuming a standard normal fat diet, a high-fat high-calorie diet, a low-fat low-calorie diet, or a low-fat high-calorie diet, a pharmaceutical preparation for use according to description 70. 72. A human subject is infected with dengue virus or at risk of being infected with dengue virus, a pharmaceutical preparation for use according to any one of descriptions 70 to 71. 73. A human subject is in a fed state before or simultaneously with the administration of the oral dosage form, a pharmaceutical preparation for use according to any one of descriptions 70 or 72. 74. A pharmaceutical preparation is administered to a human subject in a fed state, and the human in a fed state has eaten less than 4 hours before, preferably less than 3 hours before, preferably less than 2 hours before, preferably less than 1 hour before, preferably less than 30 minutes before, preferably less than 15 minutes before, preferably less than 10 minutes before the time of administering the pharmaceutical preparation, and preferably the pharmaceutical preparation is administered within 30 minutes of eating at most, preferably within 25 minutes of eating at most, preferably within 20 minutes of eating at most, preferably within 15 minutes of eating at most, preferably within 10 minutes of eating at most, preferably within 5 minutes of eating at most, preferably simultaneously with eating, a pharmaceutical preparation for use according to any one of descriptions 70 to 73. 75. The pharmaceutical preparation is administered orally, a pharmaceutical preparation for use according to any one of descriptions 70 to 74. 76. The pharmaceutical preparation is administered in the morning, a pharmaceutical preparation for use according to any one of descriptions 70 to 75. The oral dosage form can be administered simultaneously with or after the first meal, the second meal, or the third meal of the day. A human in a feeding state consumes at least 0.1 g of fat, preferably at least 0.2 g, preferably at least 0.3 g, preferably at least 0.4 g, preferably at least 0.5 g, preferably at least 0.6 g, preferably at least 0.7 g, preferably at least 0.8 g, preferably at least 0.9 g of fat, preferably at least 1 g of fat, preferably at least 2 g, preferably at least 3 g, preferably at least 4 g, preferably at least 5 g of fat, preferably at least 6 g of fat, preferably at least 7 g, preferably at least 8 g, preferably at least 9 g, preferably at least 10 g of fat, preferably at least 11 g of fat, preferably at least 12 g, preferably at least 13 g, preferably at least 14 g, preferably at least 15 g of fat, preferably at least 16 g of fat, preferably at least 17 g, preferably at least 18 g, preferably at least 19 g, preferably at least 20 g of fat, preferably at least 21 g of fat, preferably at least 22 g, preferably at least 23 g, preferably at least 24 g, preferably at least 25 g of fat, preferably at least 26 g of fat, preferably at least 27 g, preferably at least 28 g, preferably at least 29 g, preferably at least 30 g of fat, preferably at least 31 g of fat, preferably at least 32 g, preferably at least 33 g, preferably at least 34 g, preferably at least 35 g of fat, preferably at least 36 g of fat, preferably at least 37 g, preferably at least 38 g, preferably at least 39 g, preferably at least 40 g of fat, preferably at least 41 g of fat, preferably at least 42 g, preferably at least 43 g, preferably at least 44 g, preferably at least 45 g of fat, preferably at least 46 g of fat, preferably at least 47 g, preferably at least 48 g, preferably at least 49 g, preferably at least 50 g of fat, preferably at least 51 g of fat, 52 g, preferably at least 53 g, preferably at least 54 g, preferably at least 55 g of fat, preferably at least 56 g of fat, preferably at least 57 g, preferably at least 58 g, preferably at least 59 g, preferably at least 60 g of fat, or a food containing any specific amount or range included therein, a compound for use according to any one of descriptions 70 to 76. A human in a feeding state consumes at least 0.1 g of fat, preferably at least 0.2 g, preferably at least 0.3 g, preferably at least 0.4 g, preferably at least 0.5 g, preferably at least 0.6 g, preferably at least 0.7 g, preferably at least 0.8 g, preferably at least 0.Consuming a food containing 9 g of fat, preferably at least 1 g of fat, preferably at least 2 g, preferably at least 3 g, preferably at least 4 g, preferably at least 5 g of fat, preferably at least 6 g of fat, preferably at least 7 g, preferably at least 8 g, preferably at least 9 g, preferably at least 10 g of fat, preferably at least 11 g of fat, preferably at least 12 g, preferably at least 13 g, preferably at least 14 g, preferably at least 15 g of fat, preferably at least 16 g of fat, preferably at least 17 g, preferably at least 18 g, preferably at least 19 g, preferably at least 20 g of fat, preferably at least 21 g of fat, preferably at least 22 g, preferably at least 23 g, preferably at least 24 g, preferably at least 25 g of fat, preferably at least 26 g of fat, preferably at least 27 g, preferably at least 28 g, preferably at least 29 g, preferably at least 30 g of fat, preferably at least 31 g of fat, preferably at least 32 g, preferably at least 33 g, preferably at least 34 g, preferably at least 35 g of fat, preferably at least 36 g of fat, preferably at least 37 g, preferably at least 38 g, preferably at least 39 g, preferably at least 40 g of fat, preferably at least 41 g of fat, preferably at least 42 g, preferably at least 43 g, preferably at least 44 g, preferably at least 45 g of fat, preferably at least 46 g of fat, preferably at least 47 g, preferably at least 48 g, preferably at least 49 g, preferably at least 50 g of fat, preferably at least 51 g of fat, 52 g, preferably at least 53 g, preferably at least 54 g, preferably at least 55 g of fat, preferably at least 56 g of fat, preferably at least 57 g, preferably at least 58 g, preferably at least 59 g, preferably at least 60 g of fat, or any specific amount or range contained therein. A human has eaten within less than 4 hours, preferably less than 3 hours, preferably less than 2 hours, preferably less than 1 hour, preferably less than 30 minutes, preferably less than 15 minutes, preferably less than 10 minutes before administration of a compound of formula I, and preferably an oral dosage form is administered within at most 30 minutes, preferably within at most 25 minutes, preferably within at most 20 minutes, preferably within at most 15 minutes, preferably within at most 10 minutes, preferably within at most 5 minutes of eating after administration of a compound of formula I such as compound (a), and preferably a compound of formula I such as compound (a), preferably the compound of formula I is administered simultaneously with eating, a pharmaceutical preparation for use according to any one of descriptions 70 to 77. 79. A pharmaceutical preparation for use according to any one of descriptions 70 to 78, wherein a human in a fed state has eaten food containing at least 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g or 0.9 g of fat, preferably at least 1 g, 2 g, 3 g, 4 g or 5 g of fat, preferably at least 6 g, 7 g, 8 g, 9 g or 10 g of fat, preferably at least 11 g, 12 g, 13 g, 14 g or 15 g of fat, preferably at least 16 g, 17 g, 18 g, 18 g, 19 g, or 20 g of fat, preferably at least 21 g, 22 g, 23 g, 24 g, or 25 g of fat, preferably at least 26 g, 27 g, 28 g, 29 g, or 30 g of fat, preferably at least 31 g, 32 g, 33 g, 34 g, or 35 g of fat, preferably at least 36 g, 37 g, 38 g, 39 g, or 40 g of fat, preferably at least 41 g, 42 g, 43 g, 44 g, or 45 g of fat, preferably at least 46 g, 47 g, 48 g, 49 g, or 50 g of fat, preferably at least 51 g, 52 g, 53 g, 54 g, or 55 g of fat, preferably at least 56 g, 57 g, 58 g, 59 g, or 60 g of fat, or any specific amount or range included therein. A pharmaceutical preparation for use according to any one of descriptions 70 to 79, wherein a human in a feeding state is ingesting food having a specific amount or range of total energy numbers of at least 10 kcal, preferably at least 20 kcal, preferably at least 30 kcal, preferably at least 40 kcal, preferably at least 50 kcal, preferably at least 60 kcal, preferably at least 70 kcal, preferably at least 80 kcal, preferably at least 90 kcal, preferably at least 100 kcal, preferably at least 110 kcal, preferably at least 120 kcal, preferably at least 130 kcal, preferably at least 140 kcal, preferably at least 150 kcal, preferably at least 160 kcal, preferably at least 170 kcal, preferably at least 180 kcal, preferably at least 190 kcal, preferably at least 200 kcal, preferably at least 210 kcal, preferably at least 220 kcal, preferably at least 230 kcal, preferably at least 240 kcal, preferably at least 250 kcal, preferably at least 260 kcal, preferably at least 270 kcal, preferably at least 280 kcal, preferably at least 290 kcal, preferably at least 300 kcal, preferably at least 310 kcal, preferably at least 320 kcal, preferably at least 330 kcal, preferably at least 340 kcal, preferably at least 350 kcal, preferably at least 360 kcal, preferably at least 370 kcal, preferably at least 380 kcal, preferably at least 390 kcal, preferably at least 400 kcal, preferably at least 410 kcal, preferably at least 420 kcal, preferably at least 430 kcal, preferably at least 440 kcal, preferably at least 450 kcal, preferably at least 460 kcal, preferably at least 470 kcal, preferably at least 480 kcal, preferably at least 490 kcal, preferably at least 500 kcal.Preferably, a human in a feeding state is consuming food having a total energy number of up to 1500 kcal, preferably up to 1400 kcal, preferably up to 1300 kcal, preferably up to 1200 kcal, preferably up to 1110 kcal, preferably up to 1000 kcal, preferably up to 980 kcal, preferably up to 960 kcal, preferably up to 940 kcal, preferably up to 920 kcal, preferably up to 810 kcal, preferably up to 820 kcal, preferably up to 830 kcal, preferably up to 840 kcal, preferably up to 850 kcal, preferably up to 860 kcal, preferably up to 870 kcal, preferably up to 880 kcal, preferably up to 890 kcal, preferably up to 900 kcal, preferably up to 710 kcal, preferably up to 720 kcal, preferably up to 730 kcal, preferably up to 740 kcal, preferably up to 750 kcal, preferably up to 760 kcal, preferably up to 770 kcal, preferably up to 780 kcal, preferably up to 790 kcal, preferably up to 800 kcal, preferably up to 610 kcal, preferably up to 620 kcal, preferably up to 630 kcal, preferably up to 640 kcal, preferably up to 650 kcal, preferably up to 660 kcal, preferably up to 670 kcal, preferably up to 680 kcal, preferably up to 690 kcal, preferably up to 700 kcal, preferably up to 510 kcal, preferably up to 520 kcal, preferably up to 530 kcal, preferably up to 540 kcal, preferably up to 550 kcal, preferably up to 560 kcal, preferably up to 570 kcal, preferably up to 580 kcal, preferably up to 590 kcal, preferably up to 600 kcal, or any specific amount or range of total energy numbers included therein. A pharmaceutical preparation for use according to any one of descriptions 70 to 80, wherein a human in a feeding state is ingesting food having at least 10 kcal, 20 kcal, 30 kcal, 40 kcal or 50 kcal, preferably at least 60 kcal, 70 kcal, 80 kcal, 90 kcal or 100 kcal, preferably at least 110 kcal, 120 kcal, 130 kcal, 140 kcal or 150 kcal, preferably at least 160 kcal, 170 kcal, 180 kcal, 190 kcal or 200 kcal, preferably at least 210 kcal, 220 kcal, 230 kcal, 240 kcal, 250 kcal, 260 kcal, 270 kcal, 280 kcal, 290 kcal or 300 kcal, preferably at least 310 kcal, 320 kcal, 330 kcal, 340 kcal, 350 kcal, 360 kcal, 370 kcal, 380 kcal, 390 kcal or 400 kcal, preferably at least 410 kcal, 420 kcal, 430 kcal, 440 kcal, 450 kcal, 460 kcal, 470 kcal, 480 kcal, 490 kcal or 500 kcal, or any specific amount or range of total energy numbers included therein.Preferably, a human in a feeding state is ingesting food having a total energy number of up to 1500 kcal, 1400 kcal, 1300 kcal, 1200 kcal or 1110 kcal, preferably up to 1000 kcal, 980 kcal, 960 kcal, 940 kcal or 920 kcal, preferably up to 810 kcal, 820 kcal, 830 kcal, 840 kcal or 850 kcal, preferably up to 860 kcal, 870 kcal, 880 kcal, 890 kcal or 900 kcal, preferably up to 710 kcal, 720 kcal, 730 kcal, 740 kcal, 750 kcal, 760 kcal, 770 kcal, 780 kcal, 790 kcal or 800 kcal, preferably up to 610 kcal, 620 kcal, 630 kcal, 640 kcal, 650 kcal, 660 kcal, 670 kcal, 680 kcal, 690 kcal or 700 kcal, preferably up to 510 kcal, 520 kcal, 530 kcal, 540 kcal, 550 kcal, 560 kcal, 570 kcal, 580 kcal, 590 kcal or 600 kcal, or any specific amount or range thereof included. 82. The pharmaceutical preparation contains a cellulose derivative (such as HPMC), preferably, the compound of formula (I) and hydroxypropylmethylcellulose are in a ratio of 4:1 w / w to 1:5 w / w of the compound of formula (I): cellulose derivative, preferably 3.5:1 w / w to 1:4.5 w / w of the compound of formula (I): cellulose derivative, preferably 3:1 w / w to 1:4 w / w of the compound of formula (I): cellulose derivative, preferably 2.5:1 w / w to 1:3.5 w / w of the compound of formula (I): cellulose derivative, preferably 2:1 w / w to 1:3 w / w of the compound of formula (I): cellulose derivative, preferably 2.5:1 w / w to 1:2.5 w / w of the compound of formula (I): cellulose derivative, preferably 2:1 w / w to 1:2 w / w of the compound of formula (I): cellulose derivative, preferably 1.5:1 w / w to 1:1.5 w / w, or in a ratio included between any two ratios mentioned herein, or in a range or sub-range of ratios between any two ratios mentioned herein, and is present in an oral dosage form, a pharmaceutical preparation for use according to any one of descriptions 70 to 81. 83. The pharmaceutical preparation contains a cellulose derivative, preferably hydroxypropylmethylcellulose having a viscosity in the range of 3 to 5000 mPa·s, preferably 3 to 500 mPa·s, preferably 3 to 50 mPa·s in a 2 wt% H2O solution at 25°C, for the use according to any one of descriptions 70 to 82. Preferably, the cellulose derivative is hydroxypropylmethylcellulose selected from HPMC E5, HPMC E6, HPMC E15, HPMC E50, and mixtures thereof. 84. The pharmaceutical preparation contains a methacrylic acid copolymer, preferably the compound of formula (I) and the methacrylic acid copolymer are in a ratio of 4:1 w / w to 1:9 w / w, preferably 3.9:1 w / w to 1:8 w / w, preferably 3.8:1 w / w to 1:7 w / w, 3.7:1 w / w to 1:6 w / w, preferably 3.6:1 w / w to 1:5 w / w, preferably 3.5:1 w / w to 1:4.5 w / w, preferably 3:1 w / w to 1:4 w / w, preferably 2.5:1 w / w to 1:3.5 w / w, preferably 2:1 w / w to 1:3 w / w, preferably 2.5:1 w / w to 1:2.5 w / w, preferably 2:1 w / w to 1:2 w / w, preferably 1.5:1 w / w to 1:1.5 w / w, or in a ratio included between any two ratios mentioned herein, or in a range or sub-range of ratios between any two ratios mentioned herein, present in a solid dosage form, for the use according to any one of descriptions 70 to 83. 85. The pharmaceutical preparation is selected from the group consisting of a methacrylic acid copolymer, a copolymer of methacrylic acid and methyl methacrylate, a copolymer of methacrylic acid and ethyl acrylate, and mixtures thereof, for the use according to any one of descriptions 70 to 84. 86. The pharmaceutical preparation contains, with respect to the total weight of the preparation, up to 50 wt%, preferably up to 40 wt%, preferably up to 30 wt%, preferably up to 25 wt%, preferably up to 20 wt%, or any specific amount or range included therein, of the compound of formula (I), for the use according to any one of descriptions 70 to 85. 87. A pharmaceutical preparation contains a compound of formula (I) in an amount of 0.1% to 50% by weight, preferably 1% to 40% by weight, more preferably 2.5% to 30% by weight, most preferably 5% to 25% by weight, or any specific amount or range thereof contained therein, based on the total weight of the preparation, for use as described in any one of paragraphs 70 to 86. 88. A pharmaceutical preparation further contains one or more pharmaceutically acceptable excipients selected from the group consisting of preferably disintegrants, binders, diluents, lubricants, stabilizers, wetting agents, glidants, osmotic agents, colorants, plasticizers, coatings, fillers, surfactants, and mixtures thereof, for use as described in any one of paragraphs 70 to 87. 89. A pharmaceutical preparation further contains one or more pharmaceutically acceptable excipients, preferably the preparation contains one or more pharmaceutically acceptable excipients in an amount of up to 95% by weight, up to 90% by weight, up to 80% by weight, based on the total weight of the preparation, preferably up to 70% by weight, preferably up to 60% by weight, based on the total weight of the preparation, for use as described in any one of paragraphs 70 to 88. 90. A pharmaceutical preparation further contains one or more diluents, preferably the preparation contains a diluent in an amount of up to 95% by weight, preferably up to 80% by weight, preferably up to 75% by weight, based on the total weight of the preparation, and / or the preparation contains a diluent in an amount of at least 5% by weight, preferably at least 10% by weight, preferably at least 15% by weight, based on the total weight of the preparation, for use as described in any one of paragraphs 70 to 89. 91. A pharmaceutical preparation further contains one or more disintegrants, preferably the preparation contains a disintegrant in an amount of up to 30% by weight, preferably up to 20% by weight, preferably up to 15% by weight, preferably up to 10% by weight, based on the total weight of the preparation, and / or the preparation contains a disintegrant in an amount of at least 1% by weight, preferably at least 2.5% by weight, preferably at least 5% by weight, preferably at least 8% by weight, based on the total weight of the preparation, for use as described in any one of paragraphs 70 to 90. 92. The pharmaceutical preparation further comprises one or more binders, preferably the preparation comprises a binder of at most 50% by weight, preferably at most 45% by weight, preferably at most 40% by weight, more preferably at most 35% by weight, based on the total weight of the preparation, and / or the preparation comprises a binder of at least 5% by weight, preferably at least 10% by weight, preferably at least 15% by weight, more preferably at least 20% by weight, most preferably 25% by weight, based on the total weight of the preparation, a pharmaceutical preparation for use according to any one of descriptions 70 to 91. 93. The preparation further comprises one or more lubricants, preferably the preparation comprises a lubricant of at most 5.5% by weight, preferably at most 3.5% by weight, preferably at most 2% by weight, based on the total weight of the preparation, and / or the preparation comprises a lubricant of at least 0.5% by weight, preferably at least 1% by weight, preferably at least 1.5% by weight, based on the total weight of the preparation, a pharmaceutical preparation for use according to any one of descriptions 70 to 92. 94. The pharmaceutical preparation further comprises one or more wetting agents, preferably the preparation comprises a wetting agent of at most 5.5% by weight, preferably at most 3.5% by weight, preferably at most 2% by weight, based on the total weight of the preparation, and / or the preparation comprises a wetting agent of at least 0.5% by weight, preferably at least 1% by weight, preferably at least 1.5% by weight, based on the total weight of the preparation, a pharmaceutical preparation for use according to any one of descriptions 70 to 93. 95. The pharmaceutical preparation further comprises one or more lubricants, preferably the preparation comprises a lubricant of at most 10% by weight, preferably at most 8% by weight, preferably at most 5% by weight, based on the total weight of the preparation, and / or the preparation comprises a lubricant of at least 0.1% by weight, preferably at least 1% by weight, preferably at least 2% by weight, based on the total weight of the preparation, a pharmaceutical preparation for use according to any one of descriptions 70 to 94. 96. The pharmaceutical preparation comprises a plurality of granules forming an internal phase of the granules of the preparation and one or more pharmaceutically acceptable excipients forming an external phase of the granules of the preparation, a pharmaceutical preparation for use according to any one of descriptions 70 to 95. 97. A pharmaceutical preparation for use according to any one of descriptions 70 to 96, wherein the pharmaceutical preparation contains an internal phase of granules of at least 15% by weight, preferably at least 20% by weight, preferably at least 28% by weight, preferably at least 34% by weight, based on the weight of the pharmaceutical preparation. 98. A pharmaceutical preparation for use according to any one of descriptions 70 to 97, wherein the pharmaceutical preparation contains an internal phase of granules of at most 99% by weight, preferably at most 93% by weight, preferably at most 85% by weight, preferably at most 80% by weight, preferably at most 74% by weight, preferably at most 73% by weight, preferably at most 67% by weight, preferably at most 63% by weight, preferably at most 60% by weight, preferably at most 53% by weight, based on the weight of the pharmaceutical preparation. 99. A pharmaceutical preparation for use according to any one of descriptions 70 to 98, wherein the pharmaceutical preparation contains an internal phase of granules containing from 1% to 70% by weight of the compound of formula (I), preferably from 2% to 60% by weight, preferably from 3% to 55% by weight, preferably from 4% to 50% by weight, preferably from 5% to 45% by weight, preferably from 5% to 40% by weight, preferably from 10% to 35% by weight, preferably from 15% to 30% by weight, based on the total weight of the pharmaceutical preparation. 100. A pharmaceutical preparation for use according to any one of descriptions 70 to 99, wherein the pharmaceutical preparation contains an internal phase of granules containing from 5% to 60% by weight, preferably from 8% to 50% by weight, preferably from 15% to 45% by weight, of a methacrylic acid copolymer, a cellulose derivative, or a mixture thereof, based on the total weight of the pharmaceutical preparation. Preferably, the cellulose derivative is hydroxypropyl methylcellulose. 101. A pharmaceutical preparation for use according to any one of descriptions 70 to 100, wherein the pharmaceutical preparation contains an internal phase of granules containing from 5% to 60% by weight, preferably from 10% to 60% by weight, preferably from 10% to 50% by weight, preferably from 15% to 50% by weight, of a filler, based on the total weight of the pharmaceutical preparation. 102. The pharmaceutical preparation contains an inner phase of granules containing 1% to 10% by weight, preferably 1% to 9% by weight, preferably 1.7% to 8% by weight of a disintegrant based on the total weight of the pharmaceutical preparation, and is the pharmaceutical preparation for use according to any one of descriptions 70 to 101. 103. The pharmaceutical preparation contains an inner phase of granules containing 0.1% to 5% by weight, preferably 0.2% to 4.7% by weight, preferably 0.5% to 4.5% by weight of a lubricant based on the total weight of the pharmaceutical preparation, and is the pharmaceutical preparation for use according to any one of descriptions 70 to 102. 104. The pharmaceutical preparation contains an inner phase of granules containing 0.1% to 5% by weight, preferably 0.2% to 4.7% by weight, preferably 0.5 to 4.5% by weight of a surfactant based on the total weight of the pharmaceutical preparation, and is the compound for use according to any one of descriptions 70 to 103. 105. The pharmaceutical preparation contains an inner phase of granules containing 0.1% to 3% by weight, preferably 0.2% to 2.7% by weight, preferably 0.5 to 2.5% by weight of a lubricant based on the total weight of the pharmaceutical preparation, and is the compound for use according to any one of descriptions 70 to 104. 106. The pharmaceutical preparation is (i) 5% to 45% by weight, preferably 5% to 40% by weight, preferably 10% to 35% by weight, preferably 15% to 30% by weight of the compound of formula (I) based on the weight of the pharmaceutical preparation, and (ii) 5% to 60% by weight, preferably 8% to 50% by weight, preferably 15% to 45% by weight of a methacrylic acid copolymer or hydroxypropylmethylcellulose based on the weight of the pharmaceutical preparation, and (iii) 5% to 60% by weight, preferably 10% to 60% by weight, preferably 10% to 50% by weight, preferably 15% to 50% by weight of a filler based on the weight of the pharmaceutical preparation, and Optionally (iv) 1% to 10% by weight, preferably 1% to 9% by weight, preferably 1.7% to 8% by weight of a disintegrant based on the weight of the pharmaceutical preparation, and Optionally (v) 0.1% to 5% by weight, preferably 0.2% to 4.7% by weight, preferably 0.5 to 4.5% by weight of a lubricant based on the weight of the pharmaceutical preparation, and Optionally, (vi) 0.1% to 5% by weight, preferably 0.2% to 4.7% by weight, preferably 0.5% to 4.5% by weight of a surfactant based on the weight of the pharmaceutical preparation, and Optionally, (vii) 0.1% to 30% by weight, preferably 0.2% to 2.7% by weight, preferably 0.5% to 2.5% by weight of a lubricant based on the weight of the pharmaceutical preparation, and a granular inner phase containing the same, a pharmaceutical preparation for use according to any one of descriptions 70 to 105. 107. A pharmaceutical preparation, wherein the pharmaceutical preparation contains at least 5% by weight of an outer granular phase based on the weight of the pharmaceutical preparation, preferably at least 7% by weight, preferably at least 10% by weight, preferably at least 15% by weight, preferably at least 20% by weight, preferably at least 28% by weight, preferably at least 34% by weight of an outer granular phase based on the total weight of the pharmaceutical preparation, a compound for use according to any one of descriptions 70 to 106. 108. A pharmaceutical preparation, wherein the pharmaceutical preparation contains a maximum of 74% by weight of an outer granular phase based on the weight of the pharmaceutical preparation, preferably a maximum of 73% by weight, preferably a maximum of 67% by weight, preferably a maximum of 63% by weight, preferably a maximum of 53% by weight, preferably a maximum of 40% by weight of an outer granular phase based on the total weight of the pharmaceutical preparation, a pharmaceutical preparation according to any one of descriptions 70 to 107. 109. A pharmaceutical preparation, wherein the pharmaceutical preparation contains an outer granular phase containing 0.1% to 5% by weight of a disintegrant, preferably 0.2% to 4.7% by weight, preferably 0.5% to 3.5% by weight of a disintegrant based on the weight of the pharmaceutical preparation, a pharmaceutical preparation according to any one of descriptions 70 to 108. 110. A pharmaceutical preparation, wherein the pharmaceutical preparation contains an outer granular phase containing 0.1% to 3% by weight of a lubricant, preferably 0.2% to 2.7% by weight, preferably 0.5% to 2.5% by weight of a lubricant based on the weight of the pharmaceutical preparation, a pharmaceutical preparation for use according to any one of descriptions 70 to 109. 111. A pharmaceutical preparation contains an external granule phase comprising a filler in an amount of 0.1% to 55% by weight, preferably 0.2% to 50% by weight, preferably 0.3% to 45% by weight, preferably 0.4% to 40% by weight, preferably 0.5% to 35% by weight, preferably 0.6% to 30% by weight, preferably 0.7% to 25% by weight, preferably 0.8% to 20% by weight, preferably 1% to 15% by weight, preferably 1.3% to 12% by weight, preferably 2% to 10% by weight, preferably 2.5% to 9% by weight, preferably 3% to 8% by weight, preferably 4% to 7% by weight, preferably 5% to 6% by weight based on the weight of the pharmaceutical preparation, and is for use as described in any one of paragraphs 70 to 110. 112. The pharmaceutical preparation (a) a disintegrant in an amount of 0.1% to 5% by weight, preferably 0.2% to 4.7% by weight, preferably 0.5% to 3.5% by weight, more preferably 1% to 3% by weight based on the weight of the pharmaceutical preparation, and (b) a lubricant in an amount of preferably 0.1% to 3.0% by weight, preferably 0.2% to 2.7% by weight, preferably 0.5% to 2.5% by weight based on the weight of the pharmaceutical preparation, and (c) a filler in an amount of 1% to 15% by weight, preferably 1.3% to 12% by weight, preferably 2.5% to 8% by weight, more preferably 3 to 5% by weight based on the weight of the pharmaceutical preparation, and contains an external granule phase, and is for use as described in any one of paragraphs 70 to 111. 113. The pharmaceutical preparation for use as described in any one of paragraphs 70 to 112, wherein the pharmaceutical preparation is a tablet. 114. A pharmaceutical preparation, preferably a tablet, contains at least 0.1 mg of the compound of formula (I), preferably at least 0.5 mg, preferably at least 1 mg, preferably at least 2 mg, preferably at least 3 mg, preferably at least 4 mg, preferably at least 5 mg, preferably at least 6 mg, preferably at least 7 mg, preferably at least 8 mg, preferably at least 9 mg, preferably at least 10 mg, preferably at least 15 mg, preferably at least 20 mg, preferably at least 25 mg, preferably at least 30 mg, preferably at least 35 mg of the compound of formula (I), for use as described in any one of paragraphs 70 - 113. 115. A pharmaceutical preparation, preferably a tablet, contains 0.5 - 1500 mg of the compound of formula (I), preferably 1 - 1400 mg of the compound of formula (I), preferably 2 - 1300 mg of the compound of formula (I), preferably 3 - 1200 mg of the compound of formula (I), preferably 40 - 1250 mg of the compound of formula (I); preferably 5 - 1000 mg of the compound of formula (I), preferably 6 - 1000 mg of the compound of formula (I), preferably 7 - 1300 mg of the compound of formula (I), preferably 8 - 1200 mg of the compound of formula (I), preferably 9 - 1000 mg of the compound of formula (I), preferably 10 - 950 mg of the compound of formula (I), preferably 15 - 900 mg of the compound of formula (I), preferably 20 - 800 mg of the compound of formula (I), preferably 25 - 700 mg of the compound of formula (I), preferably 30 - 600 mg of the compound of formula (I), preferably 35 - 500 mg of the compound of formula (I), preferably 37 - 400 mg of the compound of formula (I), preferably 38 - 300 mg of the compound of formula (I), preferably 40 - 250 mg of the compound of formula (I), preferably 10 - 200 mg of the compound of formula (I), preferably 10 - 100 mg of the compound of formula (I), preferably 10 - 50 mg of the compound of formula (I), or any specific amount or range of the compound of formula (I) contained therein, for use as described in any one of paragraphs 70 - 114. 116. By oral administration of the pharmaceutical preparation, the maximum concentration (C of the compound of formula (I) in the plasma of a subject, preferably a human subject max) is at least 10 μg / L, preferably at least 20 μg / L, preferably at least 30 μg / L, preferably at least 40 μg / L, preferably at least 50 μg / L, preferably at least 100 μg / L, preferably at least 150 μg / L, preferably 50 μg / L to 5000 μg / L, preferably 60 μg / L to 4800 μg / L, preferably 70 μg / L to 4700 μg / L, preferably 80 μg / L to 4600 μg / L, preferably 90 μg / L to 4300 μg / L, preferably 100 μg / L to 4000 μg / L, or any specific amount or range included therein, a pharmaceutical preparation for use according to any one of paragraphs 70 to 115. 117. By oral administration of the pharmaceutical preparation to a human in a fed state, the maximum concentration (C of the compound of formula (I) in the plasma of the subject, preferably a human subject max ) is at least 50 μg / L, preferably at least 100 μg / L, preferably at least 150 μg / L, preferably 50 μg / L to 5000 μg / L, preferably 70 μg / L to 4800 μg / L, preferably 80 μg / L to 4700 μg / L, preferably 90 μg / L to 4600 μg / L, preferably 100 μg / L to 4300 μg / L, preferably 130 μg / L to 4000 μg / L, or any specific amount or range included therein. A pharmaceutical preparation for use according to any one of paragraphs 70 to 116. 118. The pharmaceutical preparation is orally administered to a human at least once a day, for example at least twice a day, at least three times a day, for example at least four times a day, a pharmaceutical preparation for use according to any one of paragraphs 70 to 117. 119. The pharmaceutical preparation is orally administered to a human subject once or twice a day, a pharmaceutical preparation for use according to any one of paragraphs 70 to 118. 120. A pharmaceutical preparation for use according to any one of descriptions 70 to 119, wherein the amount of the compound contained in the preparation and administered in one day or 24 hours (daily dose) is administered to a subject, preferably a human subject, in a single oral dosage form or in two, three or four oral dosage forms. For example, when the oral dosage form is a tablet, the daily dose can be administered to the subject in one tablet or in two, three or four tablets. 121. The compound of formula (I) is

[0078]

Chemical formula

[0079]

Chemical formula

[0080] The present invention provides a compound of formula (I) for use in the prevention and / or treatment of dengue virus infection, which compound is administered orally to a human in either a fed or fasting state, and formula (I) is represented by the following formula, or

[0081]

Chemical formula

[0082] In some embodiments, the oral dosage form is a solid dosage form formulated in a pharmaceutical preparation containing a cellulose derivative such as hydroxypropyl methylcellulose (HPMC) or a methacrylic acid copolymer, or a combination thereof.

[0083] The present invention also provides a compound of formula (I) for use in the prevention and / or treatment of dengue virus infection, which compound is administered in an oral dosage form to a human in either the fed or fasted state, and formula (I) is represented by the following formula, or

[0084]

Chemical formula

[0085] In some embodiments, a human subject in a fed state is consuming a standard normal-fat diet, a high-fat high-calorie diet, a low-fat low-calorie diet, or a low-fat high-calorie diet.

[0086] In some embodiments, a compound of formula (I) is administered to an individual at risk of infection with dengue virus. This individual can be one who lives in or is traveling to a dengue-endemic area. A compound of formula (I) can also be administered to an individual already infected with dengue virus. In some embodiments, a human subject is infected with dengue virus or is at risk of infection with dengue virus.

[0087] In some embodiments, adverse events manifested under treatment related to administration of a compound of formula (I), particularly compound (a), are observed in up to 30% of subjects, particularly human subjects, in a fasting or fed state, preferably in up to 25% of subjects, preferably in up to 20% of subjects, preferably in up to 19% of subjects, preferably in up to 18% of subjects, preferably in up to 17% of subjects, preferably in up to 15% of subjects, preferably in up to 14% of subjects, preferably in up to 13% of subjects, in a fasting or fed state.

[0088] In some embodiments, adverse events manifested under treatment related to administration of a compound of formula (I), particularly compound (a), are observed in up to 30% of subjects, particularly human subjects, in a fasting or fed state, and the adverse events manifested under this treatment are grade 2 or less. The adverse events manifested under treatment related to administration of a compound of formula (I), particularly compound (a), are observed in up to 25% of subjects, preferably in up to 20% of subjects, preferably in up to 19% of subjects, preferably in up to 18% of subjects, preferably in up to 17% of subjects, preferably in up to 15% of subjects, preferably in up to 14% of subjects, preferably in up to 13% of subjects, in a fasting or fed state, and the adverse events manifested under this treatment are grade 2 or less.

[0089] In some embodiments, adverse events are observed in up to 30% of subjects, particularly human subjects, in a fasting or fed state under treatment related to administration of a compound of formula (I), particularly compound (a), and in up to 25%, preferably up to 20%, preferably up to 19% of the subject, preferably up to 18% of the subject, preferably up to 17% of the subject, preferably up to 15% of the subject, preferably up to 14% of the subject, preferably up to 13% of subjects in a fed state under treatment related to administration of a compound of formula (I), particularly compound (a).

[0090] In some embodiments, adverse events are observed in up to 30% of subjects, particularly human subjects, in a fasting or fed state under treatment related to administration of a compound of formula (I), particularly compound (a), and these adverse events are grade 2 or lower. In up to 25%, preferably up to 20%, preferably up to 19% of the subject, preferably up to 18% of the subject, preferably up to 17% of the subject, preferably up to 15% of the subject, preferably up to 14% of subjects in a fed state under treatment related to administration of a compound of formula (I), particularly compound (a), adverse events are observed and these adverse events are grade 2 or lower. In some embodiments, adverse events are observed in up to 30% of subjects, particularly human subjects, in a fasting or fed state under treatment related to administration of a compound of formula (I), particularly compound (a), and in up to 25%, preferably up to 20%, preferably up to 19% of the subject, preferably up to 18% of the subject, preferably up to 17% of the subject, preferably up to 15% of the subject, preferably up to 14% of the subject, preferably up to 13% of subjects in a fasting state under treatment related to administration of a compound of formula (I), particularly compound (a).

[0091] In some embodiments, adverse events were observed in up to 30% of subjects, particularly human subjects, in a fasting or fed state, under treatment related to administration of a compound of formula (I), particularly compound (a), and the adverse events observed under this treatment were grade 2 or less, and in up to 25%, preferably up to 20%, preferably up to 19%, preferably up to 18%, preferably up to 17%, preferably up to 15%, preferably up to 14% of subjects in a fasting state, adverse events were observed under treatment related to administration of a compound of formula (I), particularly compound (a), and the adverse events observed under this treatment were grade 2 or less.

[0092] The present invention also provides a compound of formula (I) for use in the prevention and / or treatment of dengue virus infection, which compound is administered in an oral dosage form to a human in either a fed or fasting state, and formula (I) is represented by the following formula, or

[0093]

Chemical formula

[0094] The present invention also provides a compound of formula (I) for use in the prevention and / or treatment of dengue virus infection, which compound is administered orally to a human in either a fed or fasting state, and formula (I) is represented by the following formula, or

[0095]

Chemical formula

[0096] The present invention also includes a pharmaceutical preparation for use in the prevention and / or treatment of dengue virus infection, which preparation comprises 11) a) a compound of formula (I) as described herein, and b1) a methacrylic acid copolymer, or b2) a cellulose derivative such as hydroxypropyl methylcellulose (HPMC), and the pharmaceutical preparation is administered in an oral dosage form to a human being in either a fed or fasted state, who is at risk of being infected with dengue virus or already infected with dengue virus.

[0097] In some embodiments, the oral dosage form and / or pharmaceutical preparation according to the present invention comprises a compound of formula (I) as described herein and hydroxypropyl methylcellulose.

[0098] In some embodiments, the pharmaceutical preparation according to the present invention and / or the oral dosage form comprising a compound of formula (I) according to the present invention is used for the prevention and / or treatment of dengue virus infection. In some embodiments, the pharmaceutical preparation and / or oral dosage form comprises 1) at least one loading period in which at least one dose (A) of the compound of formula (I) is administered at least once a day for at least a one-day period, and 2) at least one maintenance period which starts on the day after the last day of administration of dose (A) or the last day of the loading administration period and in which at least one dose (B) of the compound of formula (I) is administered at least once every two weeks, preferably at least once a week, preferably at least twice a week, preferably at least once a day, for at least a one-day period, and the dosage regimen is such that dose (A) is either higher or lower than dose (B), and is administered according to the dosage regimen. Preferably, dose (A) is higher than dose (B).

[0099] In some embodiments, either dosage (A) or dosage (B) can vary over the entire number of days of the loading period or the maintenance period, such as increasing and / or decreasing over the entire number of days of the loading period or the maintenance period. For example, either dosage (A) or dosage (B) remains unchanged for the first 1 day, preferably the first 2 days, preferably the first 3 days, preferably the first 4 days, preferably the first 5 days, preferably the first 6 days, preferably the first 7 days, preferably the first 8 days, preferably the first 9 days, preferably the first 10 days, preferably the first 11 days, preferably the first 12 days, preferably the first 13 days, preferably the first 14 days, preferably the first 15 days, preferably the first 16 days, preferably the first 17 days, preferably the first 18 days, preferably the first 19 days, preferably the first 20 days, preferably the first 21 days, preferably the first 22 days, preferably the first 23 days, preferably the first 24 days, preferably the first 25 days, preferably the first 26 days, preferably the first 27 days, preferably the first 28 days, preferably the first 29 days, preferably the first 30 days, preferably the first 31 days, preferably the first 32 days, preferably the first 33 days, preferably the first 34 days, preferably the first 35 days, preferably the first 36 days, preferably the first 37 days, preferably the first 38 days, preferably the first 39 days, preferably the first 40 days, or more, and then, for the remaining days of the same period, the dosage can be lower and / or higher than that (e.g., bi-weekly dosage, twice-a-week dosage, twice-a-week dosage, daily dosage). For example, either dosage (A) or dosage (B) remains unchanged for the first 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, or more, and then, for the remaining days of the same period, the dosage can be lower and / or higher than that (e.g., bi-weekly dosage, twice-a-week dosage, twice-a-week dosage, daily dosage).The remaining days of each period can be 1 day, preferably 2 days, preferably 3 days, preferably 4 days, preferably 5 days, preferably 6 days, preferably 7 days, preferably 8 days, preferably 9 days, preferably 10 days, preferably 11 days, preferably 12 days, preferably 13 days, preferably 14 days, preferably 15 days, preferably 16 days, preferably 17 days, preferably 18 days, preferably 19 days, preferably 20 days, preferably 21 days, preferably 22 days, preferably 23 days, preferably 24 days, preferably 25 days, preferably 26 days, preferably 27 days, preferably 28 days, preferably 29 days, preferably 30 days, preferably 31 days, preferably 32 days, preferably 33 days, preferably 34 days, preferably 35 days, preferably 36 days, preferably 37 days, preferably 38 days, preferably 39 days, preferably 40 days, preferably 41 days, preferably 42 days, preferably 43 days, preferably 44 days, preferably 45 days, preferably 46 days, preferably 47 days, preferably 48 days, preferably 49 days, preferably 50 days, preferably 51 days, preferably 52 days, preferably 53 days, preferably 54 days, preferably 55 days, preferably 56 days, preferably 57 days, preferably 58 days, preferably 59 days, preferably 60 days, or more. The remaining days of each period can be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, or more.The pharmaceutical preparation and / or oral dosage form can also be administered at least once a week, preferably at least twice a week, preferably at least once every two weeks, preferably at least once every three weeks, preferably at least once every four weeks, preferably at least once a month, preferably at least once every two months, preferably at least once every three months, preferably at least once every four months, preferably at least once every five months, preferably at least once every six months, preferably at least once a year. The pharmaceutical preparation and / or oral dosage form can also be administered daily for 1 day, preferably 2 days, preferably 3 days, preferably 4 days, preferably 5 days, preferably 6 days, preferably 7 days, preferably 8 days, preferably 9 days, preferably 10 days, preferably 11 days, preferably 12 days, preferably 13 days, preferably 14 days, preferably 15 days, preferably 16 days, preferably 17 days, preferably 18 days, preferably 19 days, preferably 20 days, preferably 21 days, preferably 22 days, preferably 23 days, preferably 24 days, preferably 25 days, preferably 26 days, preferably 27 days, preferably 28 days, preferably 29 days, preferably 30 days, preferably 31 days, preferably 32 days, preferably 33 days, preferably 34 days, preferably 35 days, preferably 36 days, preferably 37 days, preferably 38 days, preferably 39 days, preferably 40 days, preferably 41 days, preferably 42 days, preferably 43 days, preferably 44 days, preferably 45 days, preferably 46 days, preferably 47 days, preferably 48 days, preferably 49 days, preferably 50 days, preferably 51 days, preferably 52 days, preferably 53 days, preferably 54 days, preferably 55 days, preferably 56 days, preferably 57 days, preferably 58 days, preferably 59 days, preferably 60 days, or more, and then at least twice a week, preferably at least twice a week, preferably at least once every two weeks, preferably at least once every three weeks, preferably at least once every four weeks or once a month, preferably at least once every two months, preferably at least once every three months, preferably at least once every four months, preferably at least once every five months, preferably at least once every six months, preferably at least once a year.The pharmaceutical preparation or oral dosage form may also be administered daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 days or more, and then administered at least once a week, at least twice a week, at least once every two weeks, at least once every three weeks, at least once every four weeks or once a month, at least once every two months, at least once every three months, at least once every four months, at least once every five months, at least once every six months, or at least once a year.

[0100] In some embodiments, the pharmaceutical preparation according to the present invention contains a crystallization rate inhibitor. The term "crystallization rate inhibitor" refers to an excipient, such as a polymer excipient, added to the preparation for the purpose of suppressing the crystallization of the API when the preparation is administered to a subject. The crystallization rate inhibitor can be used to improve the bioavailability of the API when the crystal form is significantly lower compared to the amorphous state / dissolved state. The crystallization rate inhibitor may also be referred to as a crystallization inhibitor or a stabilizer.

[0101] In one embodiment, the crystallization rate inhibitor is selected from polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA), poly(meth)acrylate polymer (e.g., methacrylic acid-methyl methacrylate copolymer), cyclodextrin or cyclodextrin derivative (e.g., (2-hydroxypropyl)-β-cyclodextrin (HPBCD)), hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, poly(vinyl alcohol), poloxamer (e.g., poloxamer 188, poloxamer 338, or poloxamer 407), and combinations thereof.

[0102] In one embodiment, the crystallization rate inhibitor is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, polyvinylpyrrolidone (PVP), and polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA), and combinations thereof. In a further embodiment, the crystallization rate inhibitor is selected from hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA). PVPVA can be a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a mass ratio of 6:4 (PVPVA64).

[0103] Examples of the name and abbreviation of polyvinylpyrrolidone-vinyl acetate copolymer include, but are not limited to, PVPVA, PVP-Vac-copolymer, and poly(1-vinylpyrrolidone-co-vinyl acetate).

[0104] Examples of the name and abbreviation of the copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a mass ratio of 6:4 (PVPVA64) include, but are not limited to, copovidone, copovidam, and copovidone. Examples of commercially available PVPVA64 are Kollidon® VA64, Kollidon® VA64 Fine, Luviskol VA64®, and Plasdone S-630®.

[0105] Examples of the name and abbreviation of polyvinylpyrrolidone include, but are not limited to, PVP, povidone, and crospovidone. Crospovidone is a cross-linked homopolymer of vinylpyrrolidone. An example of commercially available PVP is Plasdone® K-12.

[0106] Hydroxypropyl methylcellulose, also known as hypromellose (HPMC), is anhydroglucose in which some of the hydroxyl groups are substituted with methyl groups to form a methyl ether moiety and others are substituted with hydroxypropyl or methoxypropyl groups to form a hydroxypropyl ether or methoxypropyl ether moiety.

[0107] Hydroxypropyl methylcellulose polymer (HPMC) is available in various viscosity grades from several suppliers, such as from Dow Chemical Co. under the trade name Methocel®, and from Shin Etsu under the trade name Metolose®. Non-limiting examples of low-viscosity polymers include Methocel E5®, Methocel E6®, Methocel E-15LV®, Methocel E50LV®, Methocel K100LV®, and Methocel F50LV®, and their 2% aqueous solutions have viscosities of approximately 5 mPas, 6 mPas, 15 mPas, 50 mPas, 100 mPas, and 50 mPas, respectively, at 25°C. Non-limiting examples of medium-viscosity HPMC include Methocel E4M® and Methocel K4M, and their 2% aqueous solutions have a viscosity of 4,000 mPas at 25°C. Examples of high-viscosity HPMC include Methocel K15M® and Methocel K100M®, and their 2% aqueous solutions have viscosities of 15,000 mPas and 100,000 mPas at 25°C.

[0108] In some embodiments, the hydroxypropyl methylcellulose has a viscosity of 3 to 5000 mPa·s (at 25°C)2 It can have a viscosity within the range of 2% in water, and can be selected from the group including HPMC E5, HPMC E6, HPMC E15, HPMC E50, HPMC K4M, HPMC K15M, HPMC-AS, and mixtures thereof. In some embodiments, the hydroxypropyl methylcellulose has a viscosity within the range of 3 to 500 mPa·s (H at 25°C 2 It can have a viscosity within the range of 2% in water, and can be selected from the group including HPMC E5, HPMC E6, HPMC E15, HPMC E50, and mixtures thereof. In some embodiments, the hydroxypropyl methylcellulose has a viscosity within the range of 3 to 50 mPa·s (H at 25°C 2 It can have a viscosity within the range of 2% in water, and can be selected from the group including HPMC E5, HPMC E6, HPMC E15, HPMC E50, and mixtures thereof.

[0109] As used herein, the term "methacrylic acid copolymer" preferably refers to a copolymer of acrylic acid and / or methacrylic acid / ester (for example, a compound sold under the trade name Eudragit®). Eudragit® is commercially available, for example, from Evonik Healthcare & Nutrition GmbH (Essen, Germany).

[0110] Various types of methacrylic acid copolymers can be used, including poly(methacrylic acid co-methyl methacrylate) 1:1 (such as Eudragit® L-100, Eudragit® L12.5, etc.), poly(methacrylic acid co-methyl methacrylate) 1:2 (for example, Eudragit® S-100, Eudragit® S12,5, Eudragit® FS30D), poly(methacrylic acid co-ethyl acrylate) 1:1 (for example, Eudragit® L30D55, Eudragit® L100-55), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1 (such as Eudragit® RS30D, etc.), poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (such as Eudragit® RL30D, etc.), poly(ethyl acrylate co-methyl methacrylate) 2:1 (such as Eudragit® NM 30D or Eudragit NE 30D, etc.), a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate in a ratio of 2:1:1 (Eudragit® E-100), and combinations thereof.

[0111] In some embodiments, the methacrylic acid copolymer is selected from the group consisting of a copolymer of methacrylic acid and methyl methacrylate, a copolymer of methacrylic acid and ethyl acrylate, and mixtures thereof.

[0112] In some embodiments, the methacrylic acid copolymer is a copolymer of methacrylic acid and methyl methacrylate. Preferably, the ratio of methacrylic acid to methyl methacrylate in the copolymer is 0.5:2 to 2:0.5, preferably 0.8:1 to 1.2:1 (for example, 1:1).

[0113] In some embodiments, the methacrylic acid copolymer is poly(methacrylic acid-co-methyl methacrylate) 1:1 (EUDRAGIT® L100, CAS number: 25086-15-1).

[0114] In some embodiments, the oral dosage form and / or pharmaceutical formulation according to the invention comprises a) a compound of formula (I) as defined above herein, preferably

[0115] [Chemical formula] or a stereoisomer, pharmaceutically acceptable salt, solvate, or polymorph thereof, and b1) a methacrylic acid copolymer, or b2) a cellulose derivative such as hydroxypropyl methylcellulose (HPMC).

[0116] The oral dosage form and / or pharmaceutical formulation of the invention may contain, based on the total weight of the formulation, up to 50% by weight of the compound of formula (I), preferably up to 40% by weight, preferably up to 35% by weight, preferably up to 30% by weight, preferably up to 25% by weight of the compound of formula (I). The pharmaceutical formulation may contain, based on the total weight of the formulation, at least 0.1% by weight of the compound of formula (I), preferably at least 0.5% by weight, preferably at least 1% by weight, preferably at least 5% by weight, preferably at least 10% by weight, preferably at least 15% by weight, preferably at least 17% by weight, or preferably at least 20% by weight of the compound of formula (I). The pharmaceutical formulation may contain, based on the total weight of the formulation, from 0.1% to 45% by weight of the compound of formula (I), preferably from 0.5% to 40% by weight, preferably from 1% to 40% by weight, preferably from 5% to 35% by weight, preferably from 10% to 35% by weight of the compound of formula (I).

[0117] The oral dosage form and / or pharmaceutical preparation of the present invention may contain from 0.1 mg to 3000 mg of the compound of formula (I), preferably from 1 mg to 2000 mg of the compound of formula (I), preferably from 5 mg to 1500 mg of the compound of formula (I), preferably from 5 to 1000 mg of the compound of formula (I), preferably from 10 to 1100 mg of the compound of formula (I), preferably from 15 to 950 mg of the compound of formula (I), preferably from 20 to 900 mg of the compound of formula (I), or any specific amount or range contained therein.

[0118] The oral dosage form and / or pharmaceutical preparation of the present invention from 20 mg to 6000 mg of a methacrylic acid copolymer, preferably from 30 mg to 4000 mg of a methacrylic acid copolymer, preferably from 40 mg to 2000 mg of a methacrylic acid copolymer, preferably from 50 mg to 1500 mg of a methacrylic acid copolymer, preferably from 60 mg to 1000 mg of a methacrylic acid copolymer, preferably from 70 mg to 1000 mg of a methacrylic acid copolymer, preferably from 80 mg to 600 mg of a methacrylic acid copolymer, or any specific amount or range contained therein, or from 20 mg to 6000 mg of hydroxypropylmethylcellulose, preferably from 30 mg to 4000 mg of hydroxypropylmethylcellulose, preferably from 40 mg to 2000 mg of hydroxypropylmethylcellulose, preferably from 50 mg to 1500 mg of hydroxypropylmethylcellulose, preferably from 60 mg to 1000 mg of hydroxypropylmethylcellulose, preferably from 70 mg to 1000 mg of hydroxypropylmethylcellulose, preferably from 80 mg to 600 mg of hydroxypropylmethylcellulose, or any specific amount or range contained therein.

[0119] The oral dosage form and / or pharmaceutical preparation of the present invention may further comprise one or more diluents, and the preparation comprises 20 mg to 7500 mg of diluent, preferably 30 mg to 6500 mg, preferably 40 mg to 4500 mg, preferably 50 mg to 2500 mg, preferably 60 mg to 2000 mg, preferably 80 mg to 1000 mg, preferably 90 mg to 550 mg, or any specific amount or range of diluent included therein.

[0120] The oral dosage form and / or pharmaceutical preparation of the present invention may further comprise one or more surfactants, and the preparation comprises 0.5 mg to 300 mg of surfactant, preferably 0.6 mg to 250 mg, preferably 0.8 mg to 200 mg, preferably 1 mg to 150 mg, preferably 1.2 mg to 100 mg, preferably 1.5 mg to 80 mg, preferably 2 mg to 30 mg, or any specific amount or range of surfactant included therein.

[0121] The oral dosage form and / or pharmaceutical preparation of the present invention may further comprise one or more disintegrants, and the preparation comprises 3 mg to 900 mg of disintegrant, preferably 4 mg to 850 mg, preferably 5 mg to 600 mg, preferably 6 mg to 500 mg, preferably 7 mg to 400 mg, preferably 7.5 mg to 200 mg, preferably 8 mg to 100 mg, or any specific amount or range of disintegrant included therein.

[0122] The oral dosage form and / or pharmaceutical preparation of the present invention may further comprise one or more lubricants, and the preparation comprises 1 mg to 400 mg of lubricant, preferably 2 mg to 350 mg, preferably 3 mg to 300 mg, preferably 4 mg to 200 mg, preferably 5 mg to 100 mg, preferably 6 mg to 50 mg, preferably 8.5 mg to 35 mg, or any specific amount or range of lubricant included therein.

[0123] The oral dosage form and / or pharmaceutical preparation of the present invention may further contain one or more lubricants, and the preparation contains 0.5 mg to 200 mg of lubricant, preferably 1 mg to 150 mg, preferably 3 mg to 100 mg, preferably 4 mg to 90 mg, preferably 7 mg to 90 mg, preferably 8 mg to 80 mg, preferably 10 mg to 50 mg, or any specific amount or range of lubricant included therein.

[0124] The oral dosage form and / or pharmaceutical preparation of the present invention With respect to the total weight of the preparation, up to 60% by weight, preferably mostly 50% by weight, preferably up to 45% by weight, preferably up to 40% by weight, preferably up to 35% by weight of a methacrylic acid copolymer, or With respect to the total weight of the preparation, it may contain up to 60% by weight, preferably mostly 50% by weight, preferably up to 45% by weight, preferably up to 40% by weight, preferably up to 35% by weight of hydroxypropyl methylcellulose.

[0125] The oral dosage form and / or pharmaceutical preparation of the present invention With respect to the total weight of the preparation, at least 0.2% by weight, preferably at least 1% by weight, preferably at least 5% by weight, preferably at least 10% by weight, preferably at least 20% by weight of a methacrylic acid copolymer, or With respect to the total weight of the preparation, it may contain at least 0.2% by weight, preferably at least 1% by weight, preferably at least 5% by weight, preferably at least 10% by weight, preferably at least 20% by weight of hydroxypropyl methylcellulose.

[0126] The oral dosage form and / or pharmaceutical preparation according to the present invention With respect to the total weight of the preparation, 0.2% by weight to 60% by weight, preferably 1% by weight to 50% by weight, preferably 5% by weight to 40% by weight of a methacrylic acid copolymer, or With respect to the total weight of the preparation, it may contain 0.2% by weight to 60% by weight, preferably 1% by weight to 50% by weight, preferably 5% by weight to 40% by weight of hydroxypropyl methylcellulose.

[0127] In some embodiments, the compound of formula (I) and the methacrylic acid copolymer are present in the oral dosage forms and / or pharmaceutical formulations of the present invention in a ratio of 4:1 w / w, preferably 3.8:1 w / w, preferably 3.5:1 w / w, preferably 3.3:1 w / w, preferably 3:1 w / w, preferably 2.8:1 w / w, preferably 2.5:1 w / w, preferably 2.3:1 w / w, preferably 2:1 w / w, preferably 1.8:1 w / w, preferably 1.5:1 w / w, preferably 1:5 w / w, preferably 1:4.8 w / w, preferably 1:4.5 w / w, preferably 1:4.3 w / w, preferably 1:4 w / w, preferably 1:3.8 w / w, preferably 1:3.5 w / w, preferably 1:3.3 w / w, preferably 1:3 w / w, preferably 1:2.8 w / w, preferably 1:2.5 w / w, preferably 1:2.3 w / w, preferably 1:2 w / w, preferably 1:1.5 w / w, preferably 1:1.2 w / w, or in a ratio comprised between any two ratios mentioned herein, or in a range or sub-range of ratios between any two ratios mentioned herein.

[0128] In some embodiments, the compound of formula (I) and hydroxypropyl methylcellulose are present in the oral dosage forms and / or pharmaceutical formulations of the present invention at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 4:1 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 3.8:1 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 3.5:1 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 3.3:1 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 3:1 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 2.8:1 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 2.5:1 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 2.3:1 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 2:1 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 1.8:1 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 1.5:1 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 1:5 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 1:4.8 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 1:4.5 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 1:4.3 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 1:4 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 1:3.8 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 1:3.5 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 1:3.3 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 1:3 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 1:2.8 w / w, preferably at a ratio of the compound of formula (I):hydroxypropyl methylcellulose of 1:2.A compound of formula (I) in a ratio of 5 w / w: hydroxypropyl methylcellulose; preferably in a ratio of 1:2.3 w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably in a ratio of 1:2 w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably in a ratio of 1:1.5 w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably in a ratio of 1:1.2 w / w of the compound of formula (I): hydroxypropyl methylcellulose, or in a ratio included between any two of the ratios described herein, or in a range or sub-range of a ratio between any two ratios mentioned herein.

[0129] The oral dosage forms and / or pharmaceutical formulations of the present invention may further comprise one or more pharmaceutically acceptable excipients described in more detail herein. Pharmaceutically acceptable excipients include, but are not limited to, disintegrants, binders, diluents, lubricants, stabilizers, osmotic agents, colorants, plasticizers, coatings, fillers, surfactants, and the like. Further suitable pharmaceutical excipients and their properties can be found in Handbook of Pharmaceutical Excipients, Edited by R.C. Rowe, P.J. Sheskey & P.J. Weller, 6th Edition (published by Pharmaceutical Press, a division of the Royal Pharmaceutical Society of Great Britain).

[0130] Diluents (or fillers) useful in the present invention include microcrystalline cellulose (e.g., Avicel® PH 102, Avicel® PH 101, Ceolus UF, Ceolus KG, or Ceolus PH), silicified microcrystalline cellulose, lactose, sorbitol, cellulose, calcium phosphate, starch (e.g., partially or fully alpha - modified corn starch), sugars or lactose (e.g., mannitol, sucrose, etc.), or any combination thereof. Non - limiting examples of microcrystalline cellulose include commercially available Avicel® series such as microcrystalline cellulose having a particle size of 100 μm (e.g., Avicel® PH 102). Commercially available Ceolus of UF, KG, or PH grade is also included as microcrystalline cellulose. Other non - limiting examples of diluents include silicified microcrystalline cellulose such as the commercially available Prosolv® series (e.g., Prosolv® SMCC 50 and SMCC HD90). Lactose monohydrate is included as the lactose suitable for the present invention. The amount of diluent relative to the total weight of the pharmaceutical preparation can be 5 wt% to 95 wt%, preferably 20 wt% to 80 wt%, preferably 25 wt% to 50 wt%, preferably 30 wt% to 48 wt%, preferably 30 wt% to 52 wt%, preferably 35 wt% to 52 wt%, preferably 40 wt% to 50 wt%. For example, the diluent in the pharmaceutical preparation can contain microcrystalline cellulose, silicified microcrystalline cellulose, and partially or fully alpha - modified corn starch having a combined (or total) concentration of 5 wt% to 95 wt%, preferably 20 wt% to 80 wt%, preferably 25 wt% to 50 wt%, preferably 30 wt% to 48 wt%, preferably 30 wt% to 52 wt%, preferably 35 wt% to 52 wt%, preferably 30 wt% to 45 wt%, preferably 32.5 wt% to 45 wt% with respect to the pharmaceutical preparation.

[0131] Disintegrants promote the dispersion of pharmaceutical formulations. Non-limiting examples of disintegrants useful in the present invention include croscarmellose (e.g., croscarmellose sodium), crospovidone, sodium starch glycolate (e.g., sodium starch glycolate), and any combination thereof. Other examples of disintegrants include croscarmellose sodium (e.g., Ac-Di-Sol®) and sodium starch glycolate. The pharmaceutical formulations of the present invention may contain one or more disintegrants at a combined (or total) concentration of 1% to 10% by weight, preferably 5% to 9% by weight, preferably 6% to 8% by weight, preferably 6.5% to 7.5% by weight, preferably 6.75% to 7.25% by weight, preferably 3% to 7% by weight, preferably 1% to 7% by weight, or preferably 1.2% to 8.2% by weight of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation contains 2% to 8% (e.g., 2.5% to 7.5%) by weight, preferably 3% to 6% by weight, more preferably 4% to 5% by weight of a disintegrant (e.g., crospovidone) based on the weight of the pharmaceutical formulation.

[0132] The binder may include agents used when producing granules of the pharmaceutical active ingredient by mixing the binder with a diluent and the pharmaceutical active ingredient. Non-limiting examples of binders useful in the present invention include polyvinylpyrrolidone, sugars, modified celluloses (e.g., hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), and hydroxyethylcellulose (HEC)), and any combination thereof. Other examples of binders include polyvinylpyrrolidone (PVP). Examples of HPC include low-viscosity polymers, HPC-SL. PVP can be characterized by the "K value", a useful measure of the viscosity of the polymer composition. PVP can be commercially available under the trade names Povidone® K12, Povidone® K17, Povidone® K25, Povidone® K30, Povidone® K60, and Povidone® K90 (e.g., Tokyo Chemical Industry Co., Ltd.). Specific examples of PVP include soluble spray-dried PVP. Another example is PVP having an average molecular weight of 3,000 to 4,000, such as Povidone® K12 having an average molecular weight of 4,000. PVP can be used either in a wet or dry state. The pharmaceutical formulation of the present invention may contain one or more binders at a combined (or total) concentration of 0.1 wt% to 50 wt%, preferably 0.5 wt% to 43 wt%, preferably 2 wt% to 45 wt%, preferably 5 wt% to 40 wt%, preferably 10 wt% to 35 wt%, preferably 15 wt% to 30 wt%, preferably 20 wt% to 25 wt% based on the weight of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation contains 0.5 wt% to 2 wt% (e.g., 1.5 wt% to 2 wt% or 1.75 wt% to 2.25 wt%) of a binder (e.g., hydroxypropylmethylcellulose) based on the pharmaceutical formulation.

[0133] The lubricant functions, for example, to improve the compression and ejection of pharmaceutical formulations from a die press. Non-limiting examples of lubricants useful in the present invention include magnesium stearate, stearic acid (stearin), hydrogenated oil, sodium stearyl fumarate, compritol (glyceryl behenate), and any combination thereof. In one example, the lubricant comprises sodium stearyl fumarate. In another example, the lubricant comprises magnesium stearate. The pharmaceutical formulation of the present invention may comprise one or more lubricants at a combined (or total) concentration of 0.10 wt% to 10 wt%, preferably 0.5 wt% to 6 wt%, preferably 0.8 wt% to 3.5 wt%, preferably 1 wt% to 3 wt%, preferably 1.50 wt% to 5.5 wt%, preferably 2 wt% to 4 wt%, or preferably 0.25 wt% to 5.25 wt% based on the weight of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises 0.5 wt% to 5.5 wt%, preferably 1 wt% to 2.5 wt% of a lubricant (e.g., magnesium stearate).

[0134] One or more wetting agents can be used in the oral dosage form and / or pharmaceutical formulation of the present invention. Wetting agents suitable for the present invention generally enhance the solubility of pharmaceutical formulations. Examples of wetting agents include surfactants such as nonionic surfactants and anionic surfactants. Non-limiting examples of surfactants useful in the present invention include sodium lauryl sulfate (SLS), polyoxyethylene sorbitan fatty acids (e.g., polysorbate 20 (e.g., TWEEN 20 (trademark))), sorbitan fatty acid esters (e.g., Spans (registered trademark)), sodium dodecylbenzenesulfonate (SDBS), sodium dioctyl sulfosuccinate (docusate), sodium dioxycholate (DOSS), sorbitan monostearate, sorbitan tristearate, sodium N-lauroyl sarcosinate, sodium oleate, sodium myristate, sodium stearate, sodium palmitate, gelucire (registered trademark) 44 / 14, ethylenediaminetetraacetic acid (EDTA), vitamin E d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), lecithin, 15MW677 - 692, monosodium glutamate monohydrate, labrasol, PEG8 caprylic / capric glyceride, transcutol, diethylene glycol monoethyl ether, solutol (registered trademark) HS-15, Soluplus (registered trademark), polyethylene glycol / hydroxystearate, taurocholic acid, copolymers of polyoxypropylene and polyoxyethylene (e.g., poloxamers such as pluronic (registered trademark) L61, pluronic (registered trademark) F68, pluronic (registered trademark) F108, and pluronic (registered trademark) F127, which are also known and commercially available as pluronic (registered trademarks)), saturated polyglycolized glycerides (gelucirs (registered trademark)), and any combination thereof. Other examples include sodium lauryl sulfate, which is an anionic surfactant, and a copolymer of polyoxypropylene and polyoxyethylene, which is a nonionic surfactant.Examples of copolymers of polyoxypropylene and polyoxyethylene include poloxamers such as polyoxypropylene with a molecular weight of 1,800 g / mol and poloxamer (e.g., poloxamer 188) having a polyoxyethylene content of 80%. The pharmaceutical formulation of the present invention may contain one or more wetting agents having a combined (or total) concentration of 0.25% to 10% by weight, preferably 0.25% to 5.75% by weight, preferably 0.50% to 5% by weight, preferably 1% to 3% by weight, or preferably 1.50% to 2% by weight, based on the weight of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation contains a wetting agent (e.g., sodium lauryl sulfate) at a concentration of 0.25% to 5.00% by weight (e.g., 0.35% to 4.50% by weight).

[0135] Lubricants enhance the flow properties of the formulation during processing into the final drug product form. Non-limiting examples of lubricants useful in the present invention include silicon dioxide (e.g., colloidal fumed silica, colloidal anhydrous silica), and / or talc. Specific examples of lubricants include colloidal fumed silica (e.g., Aerosil® 200). The pharmaceutical formulation of the present invention may contain one or more lubricants at a concentration of 0.10% to 10% by weight, preferably 1% to 8% by weight, preferably 2% to 7.5% by weight, preferably 3% to 5% by weight, based on the weight of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation contains a lubricant in an amount of 0.10% to 5% by weight (e.g., 0.75% to 3.25% by weight) based on the weight of the pharmaceutical formulation. In other embodiments, the pharmaceutical formulation contains fumed silica in an amount of 0.10% to 2% by weight (e.g., 0.75% to 1.5% by weight) based on the weight of the pharmaceutical formulation.

[0136] In some embodiments, the oral dosage form according to the present invention is a solid dosage form formulated into a pharmaceutical preparation, and preferably, the solid dosage form is a tablet. The tablet dosage form of the present invention may further include a coating. Suitable coatings include film-forming polymers such as cellulose derivatives (e.g., HPC (such as hydroxypropyl cellulose), HPMC (hydroxypropoxymethyl cellulose), MC (methyl cellulose), HPMCAS (hydroxypropoxymethyl cellulose acetate succinate)), dextrin, starch, natural gums (e.g., gum arabic), xanthan, alginates, polyvinyl alcohol, polymethacrylates and their derivatives (e.g., Eudragit®), which can be applied to the tablets as solutions or suspensions by various conventional methods in the pharmaceutical field, such as film coating. Coatings that may further include one or more adjuvants (e.g., hydrophilic agents, plasticizers, surfactants, dyes, and white pigments (e.g., titanium dioxide)) in addition to any film-forming polymer present are typically applied as solutions / suspensions.

[0137] In some embodiments, the oral dosage form according to the present invention is formulated into a pharmaceutical preparation comprising a plurality of granules forming the inner phase of the granules of the preparation and one or more pharmaceutically acceptable excipients forming the outer phase of the granules of the preparation. Preferably, the oral dosage form is a tablet, and the tablet comprises an inner phase of granules and an outer phase of granules.

[0138] As used herein, the term "inner phase of granules" refers to the components of the preparation that are present with the granules. As used herein, the term "outer phase of granules" refers to the components of the preparation that are outside the granules.

[0139] In some embodiments, the inner phase of the granules of the pharmaceutical preparation according to the present invention comprises a pharmaceutical active ingredient and one or a combination of a methacrylic acid copolymer or a cellulose derivative (such as methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose (NaCMC) or hydroxypropylmethylcellulose (HPMC)). In some embodiments, the inner phase of the granules of the pharmaceutical preparation according to the present invention, a pharmaceutical active ingredient, one or a combination of a methacrylic acid copolymer or hydroxypropylmethylcellulose (HPMC: hydroxypropyl methylcellulose), and one or more pharmaceutically acceptable excipients selected from disintegrants, binders, diluents, lubricants, stabilizers, wetting agents, lubricants, osmotic agents, colorants, plasticizers, coating agents, fillers and surfactants.

[0140] In some embodiments, the pharmaceutical preparation comprises an inner phase of granules of at least 15% by weight, at least 20% by weight, preferably at least 25% by weight, preferably at least 28% by weight, preferably at least 30% by weight, preferably at least 34% by weight, preferably at least 40% by weight, preferably at least 45% by weight, preferably at least 50% by weight, preferably at least 55% by weight, preferably at least 60% by weight, preferably at least 65% by weight, based on the total weight of the pharmaceutical preparation. In some embodiments, the pharmaceutical preparation comprises an inner phase of granules of at most 99% by weight, preferably at most 95% by weight, preferably at most 93% by weight, preferably at most 90% by weight, preferably at most 85% by weight, preferably at most 80% by weight, preferably at most 75% by weight, preferably at most 74% by weight, preferably at most 73% by weight, preferably at most 70% by weight, preferably at most 67% by weight, preferably at most 63% by weight, preferably at most 60% by weight, preferably at most 53% by weight, based on the total weight of the pharmaceutical preparation.

[0141] In some embodiments, the pharmaceutical formulation comprises an inner granule phase comprising an API in an amount of preferably 1% to 70% by weight, preferably 2% to 69% by weight, preferably 3% to 68% by weight, preferably 4% to 67% by weight, preferably 5% to 66% by weight, preferably 6% to 65% by weight, preferably 10% to 64% by weight, preferably 15% to 60% by weight, preferably 20% to 55% by weight, preferably 25% to 50% by weight, preferably 30% to 45% by weight, preferably 35% to 40% by weight, based on the total weight of the pharmaceutical formulation.

[0142] In some embodiments, the oral dosage form is formulated into a pharmaceutical formulation comprising an inner granule phase comprising a methacrylic acid copolymer or hydroxypropyl methylcellulose, or a combination thereof, in an amount of 5% to 60% by weight, preferably 7% to 55% by weight, preferably 8% to 50% by weight, preferably 17% to 45% by weight, preferably 15% to 45% by weight, based on the total weight of the pharmaceutical formulation.

[0143] In some embodiments, the oral dosage form comprises an inner granule phase comprising a filler in an amount of 5% to 60% by weight, preferably 10% to 60% by weight, preferably 12% to 60% by weight, preferably 15% to 50% by weight, preferably 18% to 45% by weight, based on the total weight of the pharmaceutical formulation.

[0144] In some embodiments, the oral dosage form comprises an inner granule phase comprising a disintegrant in an amount of 1% to 10% by weight, preferably 1% to 9% by weight, preferably 1.7% to 8% by weight, preferably 1.6% to 7.5% by weight, preferably 2% to 5% by weight, based on the total weight of the pharmaceutical formulation.

[0145] In some embodiments, the oral dosage form is formulated into a pharmaceutical formulation comprising an inner granule phase comprising a lubricant in an amount of 0.1% to 5% by weight, preferably 0.2% to 4.7% by weight, preferably 0.5% to 4.5% by weight, preferably 0.8% to 4% by weight, preferably 1% to 3.5% by weight, based on the total weight of the pharmaceutical formulation.

[0146] In some embodiments, the oral dosage form is formulated into a pharmaceutical preparation comprising an inner granule phase containing a surfactant in an amount of 0.1% to 5% by weight, preferably 0.2% to 4.7% by weight, preferably 0.5% to 4.5% by weight, preferably 0.6% to 4.5% by weight, preferably 0.8% to 4.0% by weight, preferably 1% to 3.5% by weight, based on the total weight of the pharmaceutical preparation.

[0147] In some embodiments, the oral dosage form is formulated into a pharmaceutical preparation comprising an inner granule phase containing a lubricant in an amount of 0.1% to 3% by weight, preferably 0.2% to 2.7% by weight, preferably 0.5% to 2.5% by weight, preferably 0.7% to 2% by weight, based on the total weight of the pharmaceutical preparation.

[0148] In some embodiments, the oral dosage form is formulated into a pharmaceutical preparation comprising an outer granule phase in an amount of at least 5% by weight, preferably at least 7% by weight, preferably at least 10% by weight, preferably at least 15% by weight, preferably at least 20% by weight, preferably at least 25% by weight, preferably at least 28% by weight, preferably at least 30% by weight, preferably at least 34% by weight, preferably at least 35% by weight, based on the total weight of the pharmaceutical preparation. In some embodiments, the pharmaceutical preparation comprises an outer granule phase in an amount of up to 75% by weight, preferably up to 74% by weight, preferably up to 73% by weight, preferably up to 70% by weight, preferably up to 67% by weight, preferably up to 63% by weight, preferably up to 65% by weight, preferably up to 60% by weight, preferably up to 55% by weight, preferably up to 53% by weight, preferably up to 40% by weight, based on the total weight of the pharmaceutical preparation. In some embodiments, the pharmaceutical preparation comprises an outer granule phase in an amount of at least 15% to up to 75% by weight, preferably at least 25% to up to 70% by weight, preferably at least 30% to up to 65% by weight, preferably at least 35% to up to 60% by weight, preferably at least 35% to up to 70% by weight, based on the total weight of the pharmaceutical preparation.

[0149] In some embodiments, the oral dosage form is formulated into a pharmaceutical preparation comprising an inner granule phase of at least 15 wt%, at least 20 wt%, preferably at least 25 wt%, preferably at least 28 wt%, preferably at least 30 wt%, preferably at least 34 wt%, preferably at least 35 wt% based on the total weight of the pharmaceutical preparation. In some embodiments, the pharmaceutical preparation comprises an inner granule phase of up to 99 wt%, up to 93 wt%, preferably up to 85 wt%, preferably up to 80 wt%, preferably up to 75 wt%, preferably up to 74 wt%, preferably up to 73 wt%, preferably up to 70 wt%, preferably up to 67 wt%, preferably up to 65 wt%, preferably up to 63 wt%, preferably up to 60 wt%, preferably up to 55 wt%, preferably up to 53 wt% based on the total weight of the pharmaceutical preparation. In some embodiments, the pharmaceutical preparation comprises an inner granule phase of at least 15 wt% to up to 75 wt%, preferably at least 25 wt% to up to 70 wt%, preferably at least 30 wt% to up to 65 wt%, preferably at least 35 wt% to up to 60 wt%, preferably at least 35 wt% to up to 70 wt% based on the total weight of the pharmaceutical preparation.

[0150] In some embodiments, the oral dosage form is (i) from 5 wt% to 45 wt%, preferably from 10 wt% to 40 wt%, preferably from 15 wt% to 35 wt% of an API, based on the total weight of the pharmaceutical preparation, and (ii) from 5 wt% to 60 wt%, preferably from 10 wt% to 50 wt%, preferably from 15 wt% to 55 wt% of a methacrylic acid copolymer or hydroxypropylmethylcellulose, or a combination thereof, based on the total weight of the pharmaceutical preparation, and (iii) from 5 wt% to 60 wt%, preferably from 10 wt% to 50 wt%, preferably from 15 wt% to 40 wt% of a filler (e.g., mannitol, microcrystalline cellulose), based on the total weight of the pharmaceutical preparation, and (iv) 1% to 10% by weight, preferably 1.5% to 9% by weight, more preferably 1.5% to 8% by weight, of a disintegrant (such as croscarmellose sodium) based on the total weight of the pharmaceutical preparation, and (v) 0.1% to 5% by weight, preferably 0.2% to 4.5% by weight, more preferably 0.5% to 4% by weight, of a lubricant (such as colloidal silica) based on the total weight of the pharmaceutical preparation, and (vi) 0.1% to 5% by weight, preferably 0.2% to 4.5% by weight, more preferably 0.5% to 4% by weight, of a surfactant (such as sodium lauryl sulfate) based on the total weight of the pharmaceutical preparation, and (vii) 0.1% to 3% by weight, preferably 0.2% to 2.5% by weight, more preferably 0.5% to 2% by weight, of a lubricant (such as magnesium stearate) based on the total weight of the pharmaceutical preparation, and It is formulated into a pharmaceutical preparation containing a granule inner phase containing the above.

[0151] In some embodiments, the oral dosage form is formulated into a pharmaceutical preparation containing an outer granule phase containing 0.1% to 5.0% by weight, preferably 0.2% to 4.7% by weight, more preferably 0.5% to 4.5% by weight, more preferably 1% to 3.5% by weight, more preferably 1.5% to 3% by weight, of a disintegrant based on the total weight of the pharmaceutical preparation.

[0152] In some embodiments, the oral dosage form is formulated into a pharmaceutical preparation containing an outer granule phase containing 0.1% to 3% by weight, preferably 0.2% to 2.7% by weight, more preferably 0.5% to 2.5% by weight, more preferably 0.8% to 2% by weight, of a lubricant based on the total weight of the pharmaceutical preparation.

[0153] In some embodiments, the oral dosage form is formulated into a pharmaceutical preparation comprising an outer granule phase containing a filler in an amount of 0.1 wt% to 55 wt%, preferably 0.2 wt% to 50 wt%, preferably 0.3 wt% to 45 wt%, preferably 0.4 wt% to 40 wt%, preferably 0.5 wt% to 35 wt%, preferably 0.6 wt% to 30 wt%, preferably 0.7 wt% to 25 wt%, preferably 0.8 wt% to 20 wt%, preferably 1 wt% to 15 wt%, preferably 1.3 wt% to 12 wt%, preferably 2 wt% to 10 wt%, preferably 2.5 wt% to 9 wt%, preferably 3 wt% to 8 wt%, preferably 4 wt% to 7 wt%, preferably 5 wt% to 6 wt% based on the total weight of the pharmaceutical preparation.

[0154] In some embodiments, the oral dosage form (a) a disintegrant (e.g., croscarmellose sodium) in an amount of 0.1 wt% to 5.0 wt%, preferably 0.2 wt% to 4.5 wt%, preferably 0.5 wt% to 3 wt% based on the total weight of the pharmaceutical preparation, and (b) a lubricant (e.g., magnesium stearate) in an amount of 0.1 wt% to 3 wt%, preferably 0.2 wt% to 2.5 wt%, preferably 0.5 wt% to 2 wt% based on the total weight of the pharmaceutical preparation, and (c) a filler (e.g., hydroxypropylmethylcellulose) in an amount of 1 wt% to 15 wt%, preferably 1.5 wt% to 10 wt%, preferably 2 wt% to 8 wt% based on the total weight of the pharmaceutical preparation, and is formulated into a pharmaceutical preparation comprising an outer granule phase containing the same.

[0155] In some embodiments, the oral dosage form of the present invention is formulated into a pharmaceutical preparation comprising an inner granule phase and an outer granule phase, and the preparation comprises an inner granule phase of 50 mg to 17000 mg, preferably 80 mg to 10000 mg, preferably 100 mg to 5000 mg, preferably 120 mg to 3000 mg, preferably 150 mg to 2500 mg, preferably 200 mg to 2000 mg, preferably 250 mg to 1200 mg, or any specific amount or range included therein.

[0156] In some embodiments, the oral dosage form of the present invention is formulated into a pharmaceutical preparation comprising an inner granule phase and an outer granule phase, and the preparation comprises an outer granule phase of 4 mg to 1500 mg, preferably 6 mg to 1000 mg, preferably 8 mg to 500 mg, preferably 10 mg to 300 mg, preferably 15 mg to 250 mg, preferably 20 mg to 200 mg, preferably 30 mg to 100 mg, or any specific amount or range included therein.

[0157] In some embodiments, the oral dosage form is formulated into a pharmaceutical preparation comprising an inner granule layer containing 1 mg to 2000 mg, preferably 5 mg to 1500 mg, preferably 5 mg to 1000 mg, preferably 10 mg to 500 mg, preferably 15 mg to 400 mg, preferably 20 mg to 350 mg of the compound of formula (I), or any specific amount or range included therein.

[0158] In some embodiments, the oral dosage form is formulated into a pharmaceutical preparation comprising 20 mg to 6000 mg, preferably 30 mg to 4000 mg, preferably 40 mg to 2000 mg, preferably 70 mg to 1000 mg of one of methacrylic acid copolymers or hydroxypropylmethylcellulose or a combination thereof, or any specific amount or range included therein.

[0159] In some embodiments, the oral dosage form is formulated into a pharmaceutical preparation comprising an inner granule phase containing 10 mg to 6500 mg, preferably 12 mg to 5000 mg, preferably 15 mg to 4000 mg, preferably 15 mg to 2000 mg, preferably 18 mg to 1000 mg, preferably 18 mg to 500 mg of a diluent / filler, or any specific amount or range included therein.

[0160] In some embodiments, the oral dosage form is formulated into a pharmaceutical preparation comprising a surfactant in an amount of 0.5 mg to 300 mg, preferably 0.6 mg to 250 mg, preferably 0.8 mg to 200 mg, preferably 1 mg to 150 mg, preferably 1.2 mg to 100 mg, preferably 1.5 mg to 80 mg, preferably 2 mg to 30 mg, or an inner phase of granules containing any specific amount or range contained therein.

[0161] In some embodiments, the oral dosage form is formulated into a pharmaceutical preparation comprising a disintegrant in an amount of 2 mg to 720 mg, preferably 4 mg to 650 mg, preferably 5 mg to 400 mg, preferably 6 mg to 300 mg, preferably 7 mg to 200 mg, preferably 7.5 mg to 100 mg, preferably 8 mg to 60 mg, or an inner phase of granules containing any specific amount or range contained therein.

[0162] In some embodiments, the oral dosage form is formulated into a pharmaceutical preparation comprising a lubricant in an amount of 1 mg to 400 mg, preferably 2 mg to 350 mg, preferably 3 mg to 300 mg, preferably 4 mg to 200 mg, preferably 5 mg to 100 mg, preferably 6 mg to 50 mg, preferably 8.5 mg to 35 mg, or an inner phase of granules containing any specific amount or range contained therein.

[0163] In some embodiments, the oral dosage form is formulated into a pharmaceutical preparation comprising a lubricant in an amount of 0.3 mg to 90 mg, preferably 0.5 mg to 70 mg, preferably 0.6 mg to 50 mg, preferably 0.7 mg to 25 mg, preferably 0.8 mg to 10 mg, or an inner phase of granules containing any specific amount or range contained therein.

[0164] In some embodiments, the oral dosage form is (i) an API in an amount of 1 mg to 2000 mg, preferably 5 mg to 1500 mg, preferably 5 mg to 1000 mg, preferably 10 mg to 500 mg, preferably 15 mg to 400 mg, preferably 20 mg to 350 mg, (ii) One of methacrylic acid copolymers, hydroxypropyl methylcellulose, or a combination thereof, in an amount of 20 mg to 6000 mg, preferably 30 mg to 4000 mg, preferably 40 mg to 2000 mg, preferably 70 mg to 1000 mg, (iii) A diluent / filler (e.g., mannitol, microcrystalline cellulose) in an amount of 10 mg to 6500 mg, preferably 12 mg to 5000 mg, preferably 15 mg to 4000 mg, preferably 15 mg to 2000 mg, preferably 18 mg to 1000 mg, preferably 18 mg to 500 mg, (iv) A disintegrant (e.g., croscarmellose sodium) in an amount of 2 mg to 720 mg, preferably 4 mg to 650 mg, preferably 5 mg to 400 mg, preferably 6 mg to 300 mg, preferably 7 mg to 200 mg, preferably 7.5 mg to 100 mg, preferably 8 mg to 60 mg, (v) A lubricant (e.g., colloidal silicon dioxide) in an amount of 1 mg to 400 mg, preferably 2 mg to 350 mg, preferably 3 mg to 300 mg, preferably 4 mg to 200 mg, preferably 5 mg to 100 mg, preferably 6 mg to 50 mg, preferably 8.5 mg to 35 mg, (vi) A surfactant (e.g., sodium lauryl sulfate) in an amount of 0.5 mg to 300 mg, preferably 0.6 mg to 250 mg, preferably 0.8 mg to 200 mg, preferably 1 mg to 150 mg, preferably 1.2 mg to 100 mg, preferably 1.5 mg to 80 mg, preferably 2 mg to 30 mg, and (vii) A lubricant (e.g., magnesium stearate) in an amount of 0.3 mg to 90 mg, preferably 0.5 mg to 70 mg, preferably 0.6 mg to 50 mg, preferably 0.7 mg to 25 mg, preferably 0.8 mg to 10 mg is formulated into a pharmaceutical preparation, which contains a granule internal phase containing the above components.

[0165] In some embodiments, the oral dosage form is formulated into a pharmaceutical preparation comprising an outer granule phase containing a disintegrant in an amount of 0.6 mg to 180 mg, preferably 1 mg to 100 mg, preferably 2 mg to 80 mg, preferably 3 mg to 50 mg, preferably 5 mg to 20 mg.

[0166] In some embodiments, the oral dosage form is formulated into a pharmaceutical preparation comprising an outer granule phase containing a diluent / filler in an amount of 3.5 mg to 1100 mg, preferably 5 mg to 500 mg, preferably 10 mg to 250 mg, preferably 15 mg to 100 mg, preferably 25 mg to 90 mg.

[0167] In some embodiments, the oral dosage form is formulated into a pharmaceutical preparation comprising an outer granule phase containing a lubricant in an amount of 0.3 mg to 90 mg, preferably 0.5 mg to 70 mg, preferably 1 mg to 50 mg, preferably 1.5 mg to 20 mg, preferably 2 mg to 10 mg.

[0168] In some embodiments, the oral dosage form is (a) a disintegrant (e.g., croscarmellose sodium) in an amount of 0.6 mg to 180 mg, preferably 1 mg to 100 mg, preferably 2 mg to 80 mg, preferably 3 mg to 50 mg, preferably 5 mg to 20 mg, (b) a lubricant (e.g., magnesium stearate) in an amount of 0.3 mg to 90 mg, preferably 0.5 mg to 70 mg, preferably 1 mg to 50 mg, preferably 1.5 mg to 20 mg, preferably 2 mg to 10 mg, and (c) a diluent / filler (e.g., hydroxypropyl methylcellulose) in an amount of 3.5 mg to 1100 mg, preferably 5 mg to 500 mg, preferably 10 mg to 250 mg, preferably 15 mg to 100 mg, preferably 25 mg to 90 mg, and is formulated into a pharmaceutical preparation comprising an outer granule phase containing the same.

[0169] One of ordinary skill in the art will readily recognize that suitable pharmaceutically acceptable excipients are selected such that they are compatible with other excipients and do not bind to or cause degradation of the pharmaceutical active ingredient (e.g., the compound of formula (I)).

[0170] It will be understood that any of the above descriptions of the components of the pharmaceutical formulation can be applied to any of the other aspects and embodiments of the present invention.

[0171] The present invention provides a compound of formula (I) as described herein for use in the prevention and / or treatment of dengue virus infection, which is included in a pharmaceutical formulation administered either in the fed state or the fasting state. Preferably, the compound is administered to a human who is at risk of being infected with dengue virus or who is already infected with dengue virus.

[0172] In some embodiments, the compound of formula (I) is in an amorphous form or in a dissolved state (i.e., molecular dispersion) in the pharmaceutical formulation.

[0173] In a further embodiment of the present invention, the compound of formula (I) is

[0174]

Chemical formula

[0175]

Chemical formula

[0176] The present invention also includes a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

[0177] The present invention also includes the compound of formula (I) in an amorphous state or in a dissolved state (i.e., molecular dispersion), or its enantiomer, diastereomer or pharmaceutically acceptable salt form.

[0178] In particular, the starting material in the process for preparing the pharmaceutical formulations described herein is the compound of formula (I), or its enantiomer, diastereomer, solvate or pharmaceutically acceptable salt form, and the final pharmaceutical formulation or solid dosage form as defined herein is the compound of formula (I) in an amorphous form or in a dissolved state, or its enantiomer, diastereomer or pharmaceutically acceptable salt form.

[0179] In a preferred embodiment, the compound of formula (I) is

[0180]

Chemical formula

[0181] The compound of formula (I) can be compound (a), or a solvate or pharmaceutically acceptable salt form thereof. The compound of formula (I) can be compound (a) or a pharmaceutically acceptable salt form thereof. The compound of formula (I) can be compound (a) in a solvated form, such as a monohydrate. The compound of formula (I) can be compound (a) solvated with an organic solvent and water, such as a solvate and hydrate. Preferably, the compound of formula (I) is compound (a). Preferably, the compound of formula (I) is the (+)-enantiomer of compound (a). Preferably, the compound of formula (I) is the (S)-enantiomer of compound (a). Preferably, the compound of formula (I) is compound (a) in an anhydrous form. Preferably, the compound of formula (I) is compound (a) in an amorphous form. Preferably, the compound of formula (I) is compound (a) or a pharmaceutically acceptable salt form thereof in an amorphous form or in a dissolved state. Preferably, the compound of formula (I) is compound (a) in an amorphous form or in a dissolved state. Preferably, the compound of formula (I) is the (S)-enantiomer of compound (a) in an amorphous form. Preferably, the compound of formula (I) is the (S)-enantiomer of compound (a) in an anhydrous form.

[0182] In some embodiments, the compound of formula (I) is enantiomer 9A, wherein, 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.09 (s, 3H) 3.73 (s, 3H) 3.99 (s, 3H) 6.26 (d, J = 7.9 Hz, 1H) 6.55 - 6.62 (m, 2H) 6.91 (t, J = 1.5 Hz, 1H) 6.98 (dd, J = 8.4, 2.0 Hz, 1H) 7.07 (d, J = 7.9 Hz, 1H) 7.13 (d, J = 2.0 Hz, 1H) 7.21 (dd, J = 8.8, 1.8 Hz, 1H) 7.36 (d, J = 8.4 Hz, 1H) 7.59 (d, J = 8.8 Hz, 1H) 8.07 (d, J = 0.9 Hz, 1H) 8.55 (s, 1H) 12.29 (br s, 1H).

[0183] In some embodiments, the compound of formula (I) is enantiomer 9B, Here, 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.09 (s, 3H) 3.73 (s, 3H) 3.99 (s, 3H) 6.26 (d, J = 7.9 Hz, 1H) 6.56 - 6.62 (m, 2H) 6.92 (t, J = 2.0 Hz, 1H) 6.98 (dd, J = 8.1, 2.0 Hz, 1H) 7.07 (d, J = 7.9 Hz, 1H) 7.13 (d, J = 2.0 Hz, 1H) 7.22 (dd, J = 8.8, 1.8 Hz, 1H) 7.36 (d, J = 8.4 Hz, 1H) 7.59 (d, J = 8.8 Hz, 1H) 8.07 (d, J = 0.9 Hz, 1H) 8.55 (s, 1H) 12.30 (br s, 1H).

[0184] The compound of formula (I) can be synthesized according to the procedures disclosed in International Publication No. WO 2016 / 180696 (which is hereby incorporated by reference in its entirety).

[0185] The compound of formula (I) for use in the present invention can be synthesized according to the general synthetic methods described below and exemplified in the following schemes and examples. Since the schemes are illustrative, the present invention should not be construed as being limited by the chemical reactions and conditions described in these schemes and examples. Compounds similar to the target compounds of these examples can be prepared according to similar routes. The compounds of the present disclosure are useful as pharmaceuticals as described herein. The various starting materials used in the schemes and examples are either commercially available or can be prepared by methods well within the skill of those in the art.

[0186] The synthesis of the compound of general formula (I) can be carried out as outlined in Scheme 1. 2-(4-Chloro-2-methoxyphenyl)acetic acid (II) can be converted to the corresponding 2-(4-chloro-2-methoxyphenyl)acetyl chloride (III) using a chlorinating agent such as thionyl chloride. The Friedel-Crafts reaction of the acid chloride III with a substituted indole of general formula IV can be carried out, for example, in CH 2 Cl 2In a suitable solvent such as 1,2-dichloroethane, for example, Et 2 AlCl or TiCl 4 such as a Lewis acid reagent is used, typically (but not exclusively) under suitable reaction conditions including cooling, to obtain a 3-acylated indole of general formula V. The introduction of the aniline moiety at the α-position to the carbonyl moiety of the compound of general formula V is carried out in a suitable solvent such as THF (tetrahydrofuran), for example, by brominating V with a reagent such as phenyltrimethylammonium tribromide to obtain a compound of general formula VI, and then, for example, in a suitable solvent such as CH 3 CN, typically using a base such as TEA or DIPEA, and reacting the compound of general formula VI with 3-methoxy-5-(methylsulfonyl)aniline (VII), to carry out a reaction sequence to obtain the compound of general formula I as a racemic mixture. The chiral resolution of the compound of general formula (I) can be carried out, for example, by chiral chromatography to obtain enantiomer A and enantiomer B of general formula (I).

[0187] [Chemical formula]

[0188] In some cases, the synthesis of the intermediate of general formula V by a Friedel-Crafts synthetic approach benefits from the presence of a protecting group (PG) on the indole-N during the Friedel-Crafts reaction step, as outlined in Scheme 2. For this purpose, the substituted indole of general formula IV can first be converted to an N-protected intermediate of general formula VIII, such as an N-tosylated intermediate (PG = Ts) of general formula VIII, using a reagent such as tosyl chloride in the presence of a base (such as sodium hydride). The Friedel-Crafts reaction of the substituted indole of general formula IV with the acid chloride III is carried out in a suitable solvent (such as CH 2 Cl 2 or 1,2-dichloroethane) with a Lewis acid reagent (such as Et 2 AlCl or TiCl 4) can be carried out under suitable reaction conditions, typically (but not exclusively) including cooling, to give the 3-acylated N-protected indoles of general formula IX. Removal of the indole-N protecting group PG of the intermediate of general formula IX can be carried out using a reagent such as LiOH (when PG = Ts) at a suitable reaction temperature in a solvent mixture (e.g., THF / water), thereby giving the 3-acylated indoles of general formula V.

[0189]

Chemical formula

[0190] As another approach, the intermediate of general formula V can also be prepared as outlined in Scheme 3. That is, the N-Boc protected substituted indole-3-carbaldehyde of general formula X is reacted with morpholine in a suitable solvent such as a mixture of water and a water-miscible organic solvent (e.g., dioxane, etc.) in the presence of reagents such as sodium cyanide and sodium bisulfite to convert it to the corresponding Strecker-type intermediate of general formula XI. Alkylation of the compound of general formula XI with 4-chloro-2-methoxy-benzyl chloride can be carried out in a suitable solvent such as DMF in the presence of a base such as potassium hexamethyldisilazane to give the compound of general formula XII. When the compound of general formula XII is subjected to suitable aqueous acidic hydrolysis conditions (e.g., treatment with aqueous hydrochloric acid at high temperature), the intermediate of general formula V is obtained.

[0191]

Chemical formula

[0192] In certain embodiments, the compound of formula (I) is compound (a), or a stereoisomer, pharmaceutically acceptable salt, solvate or polymorph thereof.

[0193] The present invention also provides a compound of formula (I) as described herein, which is included in a pharmaceutical formulation to be administered as a solid dosage form as described herein.

[0194] The dosage form can be an oral dosage form (e.g., a capsule for oral administration). Alternatively, the oral dosage form can be an enteral dosage form. Alternatively, the solid dosage form can be a tablet.

[0195] The solid dosage form (e.g., a tablet) as described herein contains from 0.1 mg to 3000 mg of the compound of formula (I), preferably from 1 mg to 2000 mg of the compound of formula (I), preferably from 5 mg to 1500 mg of the compound of formula (I), preferably from 5 mg to 1000 mg of the compound of formula (I), preferably from 10 mg to 1100 mg of the compound of formula (I), preferably from 15 mg to 950 mg of the compound of formula (I), preferably from 20 mg to 900 mg of the compound of formula (I), or can contain any specific amount or range included therein.

[0196] The solid dosage form (e.g., a tablet) as described herein can contain from 0.5 mg to 2000 mg of the compound of formula (I), or any specific amount or range included therein.

[0197] In some embodiments, the solid dosage form can contain from 0.5 mg to 1800 mg, preferably from 1 mg to 1600 mg, preferably from 2 mg to 1500 mg, preferably from 3 mg to 1450 mg, preferably from 3 mg to 1300 mg, preferably from 4 mg to 1200 mg, preferably from 5 mg to 1100 mg, preferably from 6 mg to 1000 mg, preferably from 6 mg to 900 mg, preferably from 7 mg to 800 mg, preferably from 8 mg to 700 mg, preferably from 9 mg to 600 mg, preferably from 10 mg to 500 mg, preferably from 11 mg to 400 mg, preferably from 12 mg to 300 mg, preferably from 13 mg to 200 mg, preferably from 14 mg to 100 mg, preferably from 15 mg to 50 mg, or any specific amount or range included therein, and preferably, the compound of formula (I) is compound (a) shown below

[0198] [Chemical formula] is as follows.

[0199] Preferably, the compound of formula (I) is the (+)-enantiomer of compound (a), preferably the (S)-enantiomer of compound (a).

[0200] The solid dosage form may contain at least 2 mg, preferably at least 10 mg, preferably at least 15 mg, preferably at least 20 mg, preferably at least 30 mg, preferably at least 40 mg of compound (a).

[0201] In a specific embodiment, the solid dosage form is a tablet, a) a compound of formula (I); and b1) a methacrylic acid copolymer, or b2) a cellulose derivative such as hydroxypropyl methylcellulose (HPMC), and is a tablet containing the same.

[0202] In a specific embodiment, the solid dosage form is a tablet, a) a compound of formula (I); and b1) a methacrylic acid copolymer, or b2) a cellulose derivative such as hydroxypropyl methylcellulose (HPMC), and is a tablet containing the same. c) one or more pharmaceutically acceptable excipients selected from disintegrants, binders, diluents, lubricants, stabilizers, wetting agents, lubricants, osmotic agents, colorants, plasticizers, coatings, fillers, and surfactants.

[0203] In a specific embodiment, the solid dosage form is a tablet containing the pharmaceutical preparation of the present invention.

[0204] In one embodiment, the solid dosage form is a pharmaceutical formulation comprising at least 5 mg of a compound of formula (I), preferably at least 10 mg, preferably at least 15 mg, preferably at least 20 mg, preferably at least 25 mg, preferably at least 30 mg, preferably at least 35 mg, preferably at least 40 mg of a compound of formula (I), preferably wherein the compound of formula (I) is

[0205] [Chemical formula] or a pharmaceutically acceptable salt form thereof, and comprises a pharmaceutical formulation.

[0206] For oral administration, the solid dosage form is particularly provided in the form of tablets containing at least 1 mg of a compound of formula (I), preferably at least 10 mg, preferably at least 15 mg, preferably at least 20 mg, preferably at least 25 mg, preferably at least 30 mg, preferably at least 40 mg, particularly 15 mg to 2500 mg of a compound of formula (I).

[0207] It will be understood that any of the above descriptions regarding the solid dosage form may apply to any of the other aspects and embodiments of the present invention.

[0208] As an advantage, the compound of formula (I) may be administered in a single daily dose or in divided doses where the total daily dose is divided into two, three, four, or five doses per day.

[0209] In some embodiments, the compound of formula (I) is administered either in the fed state or the fasted state.

[0210] It will be understood that any of the above descriptions regarding the oral dosage form may apply to any of the other aspects and embodiments of the present invention.

[0211] The present invention also relates to a process for preparing a pharmaceutical formulation described herein, a) Dissolving the compound of formula (I) in a solvent to form a solution; b) Mixing a methacrylic acid copolymer or hydroxypropylmethylcellulose or a combination thereof with the solution formed in step a), thereby obtaining a mixture; c) Spray-drying the mixture to obtain a solid dispersion; d) Optionally, blending the solid dispersion with at least one pharmaceutically acceptable excipient, and a process for obtaining the pharmaceutical formulation described herein is also provided.

[0212] As used herein, the term "solid dispersion" means a dispersion of an API (e.g., the compound of formula (I)) in a solid matrix, wherein the matrix comprises a small molecule or a polymer, or a combination thereof.

[0213] The pharmaceutical formulation according to the invention comprises a solid dispersion in which the matrix is a polymer, which polymer is selected from methacrylic acid copolymers, or cellulose derivatives such as methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose (NaCMC) or hydroxypropylmethylcellulose (HPMC), or a combination thereof. Preferably, the cellulose derivative is HPMC.

[0214] The invention also provides a process for preparing the solid dosage form described herein, a) Dissolving the compound of formula (I) in a solvent to form a solution; b) Mix a methacrylic acid copolymer, or a cellulose derivative such as methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose (NaCMC) or hydroxypropylmethylcellulose, or a combination thereof, with the solution formed in step a), thereby obtaining a mixture, and optionally further stirring the mixture; c) Spray-drying the mixture to obtain a solid dispersion; d) Optionally, blending the solid dispersion with one or more pharmaceutically acceptable excipients, wherein, for example, the pharmaceutically acceptable excipients can be selected from the group comprising fillers, surfactants, disintegrants, lubricants, glidants and mixtures thereof; e) Compressing the blend into tablets, which comprises providing the solid dosage form described herein.

[0215] In some embodiments, the process for preparing the solid dosage form described herein a) Dissolving a compound of formula (I) in a solvent to form a solution; b) Mixing a methacrylic acid copolymer or hydroxypropylmethylcellulose or a combination thereof with the solution formed in step a), thereby obtaining a mixture, and optionally further stirring the mixture; c) Spray-drying the mixture to obtain a solid dispersion; d) Blending the solid dispersion with at least one filler, at least one surfactant, at least one disintegrant, at least one lubricant and at least one glidant; e) Granulating the blend; f) Blending the mixture obtained in step e) with at least one disintegrant, filler and at least one glidant; g) Compressing the blend into tablets, which comprises providing the solid dosage form described herein.

[0216] In some embodiments, the solid dispersion can be obtained using hot melt extrusion. In some embodiments, the step of granulating the blend is carried out using a roller compactor or by slugging.

[0217] Another aspect of the present invention provides a packaged pharmaceutical formulation for use in the prevention and / or treatment of dengue virus infection, which pharmaceutical formulation is administered in an oral dosage form to a human subject in either a fed or fasted state, preferably a fed state, and which pharmaceutical formulation is any of the formulations described herein (e.g., tablets) sealed in a blister film, the blister film comprising a formulation holding layer configured to hold one or more pharmaceutical formulations (e.g., tablets) and a sealing layer covering the holding layer and configured to seal the pharmaceutical formulation within the holding layer, the sealing layer comprising an aluminum foil and a desiccant material. As used herein, the term "desiccant material" refers to any hygroscopic substance useful as a desiccant. Examples of desiccant materials include, but are not limited to, silica (e.g., silica gel), activated carbon, calcium sulfate, calcium chloride, and zeolite materials.

[0218] In some embodiments, the holding layer comprises one or more chambers, each chamber being configured to hold one or more pharmaceutical formulations (e.g., any of the pharmaceutical formulations described herein (e.g., one or more tablets)), and each chamber being sealed by the sealing layer. In some embodiments, the holding layer comprises a transparent or opaque material (e.g., a transparent or opaque polyethylene material). In some embodiments, the sealing layer completely overlaps the holding layer and any chambers provided in the holding layer.

[0219] Examples of commercially available blister films useful in the present invention include Dessiflex Plus and Dessiflex Ultra available from Amcor plc. In some embodiments, the packaged pharmaceutical formulation consists of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 - 4, 2 - 10, or 1 - 10) tablets sealed in a blister film, and the blister film includes one card. The stability and shelf life of the pharmaceutical formulations of the present invention are improved by using the blister film packaging of the present invention in which the sealing layer contains a desiccant material as compared to packaging the pharmaceutical formulation in a blister film having a sealing layer lacking a desiccant material (e.g., Aclar 400 blister film).

[0220] Another aspect of the present invention provides a kit for use in the prevention and / or treatment of dengue virus infection, the kit being administered in an oral dosage form to a human subject either in a fed or fasting state, preferably in a fed state, and comprising a packaged pharmaceutical formulation such as any of the packaged pharmaceutical formulations described herein, and instructions for administration of the packaged pharmaceutical formulation.

[0221] It will be understood that any of the above considerations regarding solid dosage forms and processes for their preparation may be applied to any embodiment of the prevention and / or treatment methods described herein.

[0222] The present invention further encompasses methods for treating, ameliorating, and / or preventing diseases, syndromes, conditions affected by inhibition of dengue virus replication, most preferably in a human subject.

[0223] This method includes administering to a subject a therapeutically effective amount of a compound of formula (I) described herein, such as compound (a), or a pharmaceutical formulation and / or solid dosage form comprising a compound of formula (I) according to any dosing regimen described herein. The subject is at risk of infection with dengue virus or is infected with dengue virus.

[0224] One embodiment of the present invention is a method for preventing dengue virus infection in a human subject in need thereof, comprising administering to the subject a therapeutically effective...

Claims

1. A compound of formula (I) for use in the prevention and / or treatment of dengue virus infection, wherein the compound of formula (I) is administered orally to a person in a feeding or fasting state, and the compound of formula (I) is represented by the following formula, or 【Chemistry 1】 The stereoisomer, pharmaceutically acceptable salt, solvate, or polymorph of the compound is as follows: R １ H is R ２ F is R ３ is H or CH ３ The compound, R １ is H, CH ３ , or F, and R ２ is OCH ３ , and R ３ is H, a compound R １ H is R ２ ga OCH ３ And R ３ CH ３ The compound, R １ CH ３ And R ２ F is R ３ A compound in which H R １ ga CF ３ or OCF ３ And R ２ H is R ３ A compound in which H R １ OCF ３ And R ２ ga OCH ３ And R ３ A compound in which H R １ OCF ３ And R ２ H is R ３ CH ３ The compound, A compound selected from the group.

2. The compound for use according to claim 1, wherein the compound is administered in oral form to a human being in a feeding state.

3. The compound for use according to claim 2, wherein the human is in a state of feeding before or at the same time as the administration of the oral dosage form.

4. The compound for use according to claim 1, wherein the person has ingested the compound up to three hours prior to the administration of the oral dosage form.

5. The compound for use according to claim 1, wherein the oral dosage form is administered to the human at least once a day, at least twice a day, at least three times a day, or at least four times a day.

6. The compound for use according to claim 1, wherein the oral dosage form is a solid dosage form.

7. The aforementioned oral dosage form is 1) At least one loading dose (A) of the compound of formula (I) is administered at least once a day for a period of at least one day, 2) At least one maintenance period, which begins on the last day of administration of dose (A) or the day following the last day of the loading period, during which at least one dose (B) of the compound of formula (I) is administered at least once a day for at least one day. A dosage regimen that includes, Dose (A) is either higher or lower than dose (B), preferably dose (A) is higher than dose (B). Administered according to the administration regimen. The compound for use according to claim 1.

8. The compound for use according to claim 1, wherein the oral dosage form is a solid dosage form comprising a cellulose derivative having a viscosity in the range of 3 to 5000 mPa·s in a 2% by weight H2O solution at 25°C, and is selected from the group comprising HPMC E5, HPMC E6, HPMC E15, HPMC E50, HPMC K4M, HPMC-AS and any combination thereof.

9. The oral dosage form is formulated into a pharmaceutical preparation containing 0.5 mg to 1500 mg of the compound of formula (I), preferably the preparation contains 1 mg to 1000 mg of the compound of formula (I), and preferably the preparation contains 2 mg to 900 mg of the compound of formula (I). The compound for use according to claim 1.

10. The compound of formula (I) above, 【Chemistry 2】 The pharmaceutical preparation according to claim 1, or a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a polymorph thereof.

11. A pharmaceutical preparation for use in the prevention and / or treatment of dengue virus infection, wherein the preparation is a) Compound of formula (I) and b1) Methacrylic acid copolymer, or b2) Hydroxypropyl methylcellulose (HPMC), The preparation contains, and the preparation is administered orally to a person who is either fed or fasting, and formula (I) is represented by the following formula, or 【Transformation 3】 The stereoisomer, pharmaceutically acceptable salt, solvate, or polymorph of the compound is as follows: R １ H is R ２ F is R ３ is H or CH ３ The compound, R １ H, CH ３ , or F, R ２ ga OCH ３ And R ３ A compound in which H R １ H is R ２ ga OCH ３ And R ３ CH ３ The compound, R １ CH ３ And R ２ F is R ３ A compound in which H R １ ga CF ３ or OCF ３ And R ２ H is R ３ A compound in which H R １ OCF ３ And R ２ ga OCH ３ And R ３ A compound in which H R １ OCF ３ And R ２ H is R ３ CH ３ The compound, A pharmaceutical preparation selected from the group.

12. The pharmaceutical preparation for use according to claim 11, wherein the pharmaceutical preparation is administered in oral form to a human being in a feeding state.

13. The pharmaceutical formulation for use according to claim 11, wherein the human is in a state of feeding before or during administration of the oral dosage form.

14. The pharmaceutical formulation for use according to claim 11, wherein the human being is in a feeding state and has eaten up to 3 hours prior to the time of administration of the oral dosage form.

15. The aforementioned oral dosage form is 1) At least one loading dose (A) of the compound of formula (I) is administered at least once a day for a period of at least one day, 2) At least one maintenance period, which begins on the last day of administration of dose (A) or the day following the last day of the loading period, during which at least one dose (B) of the compound of formula (I) is administered at least once a day for at least one day. A dosage regimen that includes, Dose (A) is either higher or lower than dose (B), preferably dose (A) is higher than dose (B). Administered according to the administration regimen. A pharmaceutical preparation for use according to claim 11.

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