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 being in an eating state or a fasting state and wherein said compound of formula (I) corresponds to # imgabs0 # stereoisomeric form, pharmaceutically acceptable salt, solvate or polymorph thereof; the compound is selected from the group consisting of: R1 is H, R2 is F, and R3 is H or CH3, R1 is H, CH3 or F, R2 is OCH3, and R3 is H, R1 is H, R2 is OCH3, and R3 is CH3, R1 is CH3, R2 is F, and R3 is H, R1 is CF3 or OCF3, R2 is H, and R3 is H, R1 is OCF3, R2 is OCH3, and R3 is H, R1 is OCF3, R2 is H, and R3 is CH3.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 341,074, filed on May 12, 2022, the entire contents of which are expressly incorporated herein by reference. Technical Field

[0003] The present invention relates to the use of substituted indole derivatives in the manufacture of a pharmaceutical preparation for treating and / or preventing dengue virus infection, and administering the pharmaceutical preparation to a subject in need thereof in a fed state or a fasted state. The present invention also provides a method for treating and / or preventing dengue virus infection. Background Art

[0004] Dengue is caused by any of 4 antigenically distinct DENV serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) belonging to the genus Flavivirus in the family Flaviviridae. DENV is a human pathogen transmitted by the bite of infected female Aedes mosquitoes. Dengue is endemic in more than 125 countries and is also recurrent in the United States (US) territories of Puerto Rico, American Samoa, and the Virgin Islands. Approximately half of the global population is currently at risk for DENV infection. According to the World Health Organization (WHO), dengue was one of the top 10 threats to global health in 2019.

[0005] Dengue is widespread in tropical regions, with local variations in risk influenced by rainfall, temperature and rapid urbanization. The exponential growth in the number of dengue cases reflects the global spread of the mosquito vector, which is driven by climate change and, more importantly, by population growth, urbanization and globalization.

[0006] The actual number of dengue cases is underestimated and many cases are misclassified as other febrile illnesses, such as malaria. It is estimated that there are 390 million DENV infections worldwide each year, of which 96 million infections present with clinical manifestations (any disease severity). Due to severe and life-threatening illnesses, an average of about 500,000 dengue cases require hospitalization each year, and up to 25,000 patients die from dengue. Therefore, it is desirable to develop an anti-DENV molecule for the prevention and treatment of dengue.

[0007] Currently, there is no treatment available for dengue fever and therefore clinical treatment is primarily supportive in nature.

[0008] In recent years, the development of drugs for preventive use has gradually received more attention as a potential alternative for preventing dengue fever. Prevention may be beneficial for travelers to dengue fever-endemic areas (e.g., rescue workers, tourists, business travelers and military travelers, and expatriates), and for susceptible populations living in endemic areas. By preventing viremia and / or by reducing viral load, dengue fever-related morbidity and mortality can be significantly reduced or even prevented. In addition, effective and safe dengue antiviral compounds may also still have their use as therapeutic agents.

[0009] WO 2016 / 180696 discloses compounds for the prevention and treatment of dengue virus infections. However, there is still a huge unmet medical need for drugs that allow the treatment and / or prevention of dengue disease (also known as dengue fever) in animals, more specifically humans.

[0010] In terms of prevention, dosing regimens should be as streamlined and as safe as possible to ensure maximum treatment compliance. For example, daily dosing (QD) has several advantages, such as lower peak-to-trough ratios, the impact of food intake becomes less critical, and the patient's pill burden may be lower; however, QD may have limitations on treatment compliance. Weekly dosing (Q7D) may be a viable option with potentially favorable treatment compliance, but it may be associated with certain limitations, such as higher peak-to-trough ratios, a potentially higher pill burden on patients, and food intake may play a greater role. Summary of the invention

[0011] The present invention relates to a compound of formula (I) for preventing and / or treating dengue virus infection, wherein the compound of formula (I) is administered to a human subject in a fed state or a fasted state in an oral dosage form, wherein the compound of formula (I) corresponds to

[0012]

[0013] Its stereoisomeric form, pharmaceutically acceptable salt, solvate or polymorph; the compound is selected from the following group, wherein:

[0014] R1 is H, R2 is F, and R3 is H or CH3,

[0015] R1 is H, CH3 or F, R2 is OCH3, and R3 is H,

[0016] R1 is H, R2 is OCH3, and R3 is CH3,

[0017] R1 is CH3, R2 is F, and R3 is H,

[0018] R1 is CF3 or OCF3, R2 is H, and R3 is H,

[0019] R1 is OCF3, R2 is OCH3, and R3 is H,

[0020] R1 is OCF3, R2 is H, and R3 is CH3.

[0021] Embodiments of the invention include compounds administered in an oral dosage form to a human in a fed state; preferably, wherein the human is in a fed state prior to or concurrently with administration of the oral dosage form.

[0022] Additional embodiments of the invention include compounds administered as solid dosage forms comprising a pharmaceutical formulation, preferably comprising a cellulose derivative such as hydroxypropylmethylcellulose (HPMC), or a methacrylic acid copolymer, or a combination thereof.

[0023] The present invention also provides a pharmaceutical preparation for preventing and / or treating dengue virus infection, the preparation comprising

[0024] a) a compound of formula (I) as described above; and

[0025] b1) methacrylic acid copolymer, or

[0026] b2) cellulose derivatives, such as hydroxypropyl methylcellulose (HPMC);

[0027] The pharmaceutical preparation is administered in an oral dosage form to a human being in a fed state or a fasted state, wherein the human being is at risk of being infected by the dengue virus or is infected by the dengue virus.

[0028] The present invention also relates to such pharmaceutical preparations and / or solid dosage forms for treating and / or preventing dengue virus infection. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The following detailed description, which is given by way of example and is not intended to limit the invention to only the specific embodiments described, is best understood in conjunction with the accompanying drawings.

[0030] Figure 1 represents the AUC of a single 400 mg dose of compound (a) according to the present invention last Box plots of (ng h / mL) as a function of treatment, either oral solution (Treatment A) or SF1b (Treatment B) under fasting conditions.

[0031] Figure 2 represents the AUC of a single 400 mg dose of compound (a) according to the present invention lastBox plots of (ng h / mL) as a function of treatment, either oral solution (Treatment A) or SF2b (Treatment C), under fasting conditions.

[0032] Figure 3 represents the AUC of a single 800 mg dose of compound (a) (SF2a / b) according to the present invention last Box plots of (ng h / mL) as a function of treatment under fasting or fed conditions, i.e., fasting condition (Treatments D and J), standardized breakfast (Treatment E), high-fat high-calorie breakfast (Treatment K), low-fat low-calorie breakfast (Treatment L), and low-fat high-calorie breakfast (Treatment M).

[0033] Figure 4 represents the AUC of a single 200 mg dose of compound (a) (SF2a / b) according to the present invention last Box plots of (ng h / mL) as a function of treatment under fasting or fed conditions, namely fasting condition (Treatment F), standardized breakfast (Treatment G), low-fat low-calorie breakfast (Treatment N), and low-fat high-calorie breakfast (Treatment O).

[0034] Figure 5 The graph represents the mean (SD) plasma concentration (ng / mL) of compound (a) on treatment day 1 up to 12 hours. Group I corresponds to a loading dose (LD) of 450 mg of compound (a) twice daily (BID) on days 1 and 2, followed by a maintenance dose (MD) of 900 mg once a week (Q7D) on days 3, 10, 17 and 24. Group III corresponds to a loading dose of 150 mg of compound (a) twice daily (BID) on days 1 and 2, followed by a maintenance dose of 300 mg once a week (Q7D) on days 3, 10, 17 and 24.

[0035] Figure 6 The graph represents the mean (SD) plasma concentration (ng / mL) of compound (a) plotted up to 12 hours on treatment day 2. Group I corresponds to 450 mg LD of compound (a) administered twice daily (BID) on days 1 and 2, followed by 900 mg MD administered once a week on days 3, 10, 17 and 24. Group I corresponds to 150 mg LD of compound (a) administered twice daily (BID) on days 1 and 2, followed by 300 mg MD administered once a week (Q7D) on days 3, 10, 17 and 24.

[0036] Figure 7The graph represents the mean (SD) plasma concentration (ng / mL) of compound (a) plotted up to 12 hours on treatment day 3. Group I corresponds to 450 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by 900 mg MD once weekly on days 3, 10, 17 and 24. Group I corresponds to 150 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by 300 mg MD once weekly (Q7D) on days 3, 10, 17 and 24.

[0037] Figure 8 Represents a graph plotting the mean (SD) plasma concentrations (ng / mL) of compound (a) on treatment days 3 to 6 up to 72 hours. Group I corresponds to 450 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by 900 mg MD once weekly on days 3, 10, 17 and 24. Group I corresponds to 150 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by 300 mg MD once weekly (Q7D) on days 3, 10, 17 and 24.

[0038] Fig. 9 The graph represents the mean (SD) plasma concentration (ng / mL) of compound (a) plotted up to 12 hours on treatment day 24. Group I corresponds to 450 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by 900 mg MD once weekly on days 3, 10, 17 and 24. Group I corresponds to 150 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by 300 mg MD once weekly (Q7D) on days 3, 10, 17 and 24.

[0039] Fig.10 The graph represents the mean (SD) plasma concentration (ng / mL) of compound (a) plotted on treatment days 24 to 59 up to 840 hours. Group I corresponds to 450 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by 900 mg MD once weekly (Q7D) on days 3, 10, 17 and 24. Group I corresponds to 150 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by 300 mg MD once weekly (Q7D) on days 3, 10, 17 and 24.

[0040] Fig.11Represents a graph plotting the mean (SD) plasma concentration (ng / mL) of compound (a) on treatment day 1 up to 12 hours. Group II corresponds to administration of 450 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by administration of 450 mg MD every 3 days (Q3D) or every 4 days (Q4D) on days 3, 6, 10, 13, 17, 20, 24 and 27. Group IV corresponds to administration of 150 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by administration of 150 mg MD every 3 days (Q3D) or every 4 days (Q4D) on days 3, 6, 10, 13, 17, 20, 24 and 27.

[0041] Fig.12 Represents a graph plotting the mean (SD) plasma concentration (ng / mL) of compound (a) up to 12 hours on day 2 of treatment. Group II corresponds to administration of 450 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by administration of 450 mg MD once every 3 days (Q3D) or once every 4 days (Q4D) on days 3, 6, 10, 13, 17, 20, 24 and 27. Group IV corresponds to administration of 150 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by administration of 150 mg MD once every 3 days (Q3D) or once every 4 days (Q4D) on days 3, 6, 10, 13, 17, 20, 24 and 27.

[0042] Fig.13 Represents a graph plotting the mean (SD) plasma concentration (ng / mL) of compound (a) up to 12 hours on day 3 of treatment. Group II corresponds to administration of 450 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by administration of 450 mg MD once every 3 days (Q3D) or once every 4 days (Q4D) on days 3, 6, 10, 13, 17, 20, 24 and 27. Group IV corresponds to administration of 150 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by administration of 150 mg MD once every 3 days (Q3D) or once every 4 days (Q4D) on days 3, 6, 10, 13, 17, 20, 24 and 27.

[0043] Fig.14Represents a graph plotting the mean (SD) plasma concentration (ng / mL) of compound (a) on treatment days 3 to 6 up to 72 hours. Group II corresponds to administration of 450 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by administration of 450 mg MD once every 3 days (Q3D) or once every 4 days (Q4D) on days 3, 6, 10, 13, 17, 20, 24 and 27. Group IV corresponds to administration of 150 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by administration of 150 mg MD once every 3 days (Q3D) or once every 4 days (Q4D) on days 3, 6, 10, 13, 17, 20, 24 and 27.

[0044] Fig.15 Represents a graph plotting the mean (SD) plasma concentration (ng / mL) of compound (a) up to 12 hours on treatment day 27. Group II corresponds to administration of 450 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by administration of 450 mg MD once every 3 days (Q3D) or once every 4 days (Q4D) on days 3, 6, 10, 13, 17, 20, 24 and 27. Group IV corresponds to administration of 150 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by administration of 150 mg MD once every 3 days (Q3D) or once every 4 days (Q4D) on days 3, 6, 10, 13, 17, 20, 24 and 27.

[0045] Fig.16 Represents a graph plotting the mean (SD) plasma concentration (ng / mL) of compound (a) from treatment day 27 to day 62 until 840 hours. Group II corresponds to administration of 450 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by administration of 450 mg MD once every 3 days (Q3D) or once every 4 days (Q4D) on days 3, 6, 10, 13, 17, 20, 24 and 27. Group IV corresponds to administration of 150 mg LD of compound (a) twice daily (BID) on days 1 and 2, followed by administration of 150 mg MD once every 3 days (Q3D) or once every 4 days (Q4D) on days 3, 6, 10, 13, 17, 20, 24 and 27.

[0046] Fig.17 The graph shows the change in the mean plasma concentration (ng / mL) of compound (a) over time (days).

[0047] The first graph (named "450 / 900BID2d / Q7D") corresponds to Group I: 450 mg LD of compound (a) was administered twice daily (BID) on days 1 and 2, followed by 900 mg MD once a week (Q7D) on days 3, 10, 17 and 24.

[0048] The second coordinate graph (named "450 / 450BID2d / Q3D-Q4D") corresponds to Group II: 450 mg LD of compound (a) was administered twice a day (BID) on days 1 and 2, followed by 450 mg MD once every 3 days (Q3D) or once every 4 days (Q4D) on days 3, 6, 10, 13, 17, 20, 24 and 27.

[0049] The third graph (named "150 / 300BID2d / Q7D") corresponds to Group III: 150 mg LD of compound (a) was administered twice daily (BID) on days 1 and 2, followed by 300 mg MD once a week (Q7D) on days 3, 10, 17 and 24.

[0050] The fourth coordinate graph (named "150 / 150BID2d / Q3D-Q4D") corresponds to Group IV: 150 mg LD of compound (a) was administered twice a day (BID) on days 1 and 2, followed by 150 mg MD once every 3 days (Q3D) or once every 4 days (Q4D) on days 3, 6, 10, 13, 17, 20, 24 and 27. DETAILED DESCRIPTION

[0051] The present disclosure may be more fully understood by reference to the following description, including the following glossary and concluding examples. It should be understood that certain features of the disclosed pharmaceutical preparations and methods are described in the context of separate aspects for clarity, but may also be provided in a single aspect in combination. Conversely, various features of the disclosed pharmaceutical preparations and methods are described in the context of a single aspect for simplicity, and may also be provided separately or in any sub-combination.

[0052] Some quantitative expressions given herein are not qualified by the term "about". It should be understood that, whether or not the term "about" is explicitly used, each amount given herein is intended to refer to the actual given value, and is also intended to refer to the approximate value of such given value that can be reasonably inferred by a person of ordinary skill in the art, including the approximate value of such given value resulting from experimental conditions and / or measurement conditions. As used herein, the term "about" or "approximately" when referring to a numerical value or range allows a certain degree of fluctuation in the value or range, for example, within 10% (i.e., ±10%), within 5% (i.e., ±5%) or within 2.5% (i.e., ±2.5%) of the value or the limit of the range.

[0053] Throughout the description and claims of this specification, the words “include” and “comprises” and variations of these words such as “comprising” mean “including but not limited to”, and are not intended to (and do not) exclude other components.

[0054] Numerical ranges expressed by endpoints include all integers and, where appropriate, fractions contained within the range (e.g., 1 to 5 may include 1, 2, 3, 4 when referring to, for example, multiple elements, and may also include 1.5, 2, 2.75, and 3.80 when referring to, for example, measurement results). The expression 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 expressed herein is intended to include all subranges contained therein.

[0055] All references cited in this specification are hereby incorporated by reference in their entirety. In particular, the teachings of all references specifically mentioned herein are incorporated by reference.

[0056] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in conjunction with the embodiment is included in at least one embodiment of the present invention. Thus, the phrases "in one embodiment" or "in an embodiment" appearing throughout this specification do not necessarily all refer to the same embodiment, but may refer to the same embodiment. Furthermore, in one or more embodiments, the particular features, structures, or characteristics may be combined in any suitable manner, as will be apparent to those skilled in the art from this disclosure. Furthermore, while some embodiments described herein include some features but not other features included in other embodiments, the combination of features of different embodiments is meant to be within the scope of the present invention and to form different embodiments, as will be appreciated by those skilled in the art.

[0057] As used herein, the term "treatment" of any disease, condition, syndrome or disorder refers to ameliorating the disease, condition, syndrome or disorder (i.e., slowing or preventing or slowing the development of at least one of the disease or its clinical symptoms). In another embodiment, "treatment" refers to alleviating or improving at least one physical parameter, including those that the patient may not perceive. In another embodiment, "treatment" refers to regulating a disease, condition, syndrome or disorder physically (e.g., perceptible symptom stabilization), physiologically (e.g., physical parameter stabilization), or both. In yet another embodiment, "treatment" refers to preventing or delaying the onset or development or progression of a disease, condition, syndrome or disorder.

[0058] As used herein, the term "prevent" refers to reducing the risk of acquiring or developing a given disease, condition, syndrome or disorder in a subject who does not have the disease but has been or may be close to a person with the disease, or reducing or inhibiting the recurrence of the disease, condition, syndrome or disorder.

[0059] As used herein, the term "dengue virus" refers to a single positive-stranded RNA virus of the Flaviviridae family; four different but closely related serotypes of the flavivirus dengue are known, the so-called DENV-1, DENV-2, DENV-3 and DENV-4. Flaviviruses transmitted by mosquitoes or ticks cause life-threatening infections in humans, such as encephalitis and hemorrhagic fever.

[0060] As used herein, the term "dengue virus infection" refers to at least one condition, syndrome, symptom, disorder and / or disease caused by a dengue virus.

[0061] 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 a time point of interest, such as the time of administration of a compound of Formula (I). In one embodiment, a subject, preferably a human subject, in a fasting state has not eaten for at least 0.25 hours (h), preferably at least 0.5h, preferably at least 1h, preferably at least 2h, preferably at least 3h, preferably at least 5h, preferably at least 6h, preferably at least 7h, preferably at least 8h, preferably at least 9h, preferably at least 10h, preferably at least 11h, preferably at least 12h, preferably at least 8h to up to 12h, more preferably at least 10h, or any subrange thereof, prior to administration of a compound of Formula (I). In one embodiment, the subject, preferably a human subject, in a fasting state has not consumed food for at least 0.25 hours (h), 0.5h, 1h, 2h, 3h, 5h, 6h, 7h, 8h, 9h, 10h, 11h or 12h, preferably at least 8h to 12h, more preferably at least 10h, or any subrange thereof, prior to administration of the compound of Formula (I). In some embodiments, "fasting state" means that a subject, preferably a human subject, has not consumed more than 10 kilocalories (kcal, kilocalories, Cal), preferably not more than 20 kcal, preferably not more than 30 kcal, preferably not more than 40 kcal, preferably not more than 50 kcal, or any subranges thereof, or has not consumed more than 10 kcal, preferably not more than 20 kcal, preferably not more than 30 kcal, preferably not more than 40 kcal, preferably not more than 50 kcal, or any subranges thereof, at least 0.25 hours (h), 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 up to 12 h, more preferably at least 10 h before administration of the compound of formula (I). In some embodiments, "fasting state" means that the subject, preferably a human subject, has not consumed 10 kilocalories (kcal, kilocalories, Cal), 20 kcal, 30 kcal, 40 kcal or 50 kcal, or any subranges thereof, or has not consumed more than 10 kcal, 20 kcal, 30 kcal, 40 kcal or 50 kcal, or any subranges thereof, for at least 0.25 hours (h), 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 before administration of the compound of Formula (I).In some embodiments, "fasting state" means that a subject, preferably a human subject, has consumed 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 subrange thereof, at least 0.25 hours (h), 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 at most 12 h, more preferably at least 10 h, or any subrange thereof, prior to administration of a compound of Formula (I). In some embodiments, "fasting state" means that a subject, preferably a human subject, has consumed up to 10 kcal, 20 kcal, 30 kcal, 40 kcal, 50 kcal, 100 kcal, 150 kcal, 200 kcal, 250 kcal, 300 kcal, or any subrange thereof, at least 0.25 hours (h), 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 subrange thereof, prior to administration of a compound of Formula (I).In some embodiments, "fasting state" means that a subject, preferably a human subject, has consumed at most 10 kcal, preferably at most 20 kcal, preferably at most 30 kcal, at least 0.25 hours (h), 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 at most 12 h, more preferably at least 10 h, or any subrange thereof, before administration of a compound of formula (I). , 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 subrange therein, and at most 0.1 g fat, preferably at most 0.2 g fat, preferably at most 0.3 g fat, preferably at most 0.4 g fat, preferably at most 0.5 g fat, preferably at most 0.6 g fat, preferably at most 0.7 g fat, preferably at most 0.8 g fat, preferably at most 0.9 g fat; or at most 1 g fat, preferably at most 2 g fat or at most 15g fat, for example at most 16g fat, for example at most 17g fat, for example at most 18g fat, for example at most 19g fat, for example at most 20g fat; or at most 21g fat, for example at most 22g fat, for example at most 23g fat, for example at most 24g fat, for example at most 25g fat, for example at most 26g fat, for example at most 27g fat, for example at most 28g fat, for example at most 29g fat, for example at most 30g fat, for example at most 31g fat, for example at most 32g fat, for example at most 33g fat, for example at most 34g fat, for example at most 35g fat, for example at most At most 25g fat; or at most 26g fat, for example at most 27g fat, for example at most 28g fat, for example at most 29g fat, for example at most 30g fat; or at most 31g fat, for example at most 32g fat, for example at most 33g fat, for example at most 34g fat, for example at most 35g fat; or at most 36g fat, for example at most 37g fat, for example at most 38g fat, for example at most 39g fat, for example at most 40g fat; or at most 41g fat, for example at most 42g fat, for example at most 43g fat, for example at most 44g fat, for example at most 45g fat; or any specific amount or range subsumed therein.In some embodiments, "fasting state" means that a subject, preferably a human subject, has consumed at most 10 kcal, 20 kcal, 30 kcal, 40 kcal, 50 kcal, 100 kcal, 150 kcal, 200 kcal, 250 kcal, 300 kcal, or any subrange 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, 0.9 g, 10 g, 11 g, 12 g, 13 g, 14 g, 15 g, 16 g, 17 g, 18 g, 19 g, 20 g, 21 g, 22 g, 23 g, 24 g, 25 g, 26 g, 27 g, 28 g, 29 g, 30 g, 31 g, 32 g, 33 g, 34 g, 35 g, 36 g, 37 g, 38 g, 39 g, 40 g, 41 g, 42 g, 43 g, 44 g, 45 g, 46 g, 47 g, 48 g, 49 g, 50 g, g, 32g, 33g, 34g or 35g fat, or up to 36g, 37g, 38g, 39g or 40g fat, or up to 41g, 42g, 43g, 44g or 45g fat, or any specific amount or range subsumed therein.In some embodiments, "fasting state" means that a subject, preferably a human subject, has consumed 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 subrange thereof, and at most 0.1 g fat, preferably at most 0.25 h, 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 at most 12 h, more preferably at least 10 h, or any subrange thereof, before administration of a compound of formula (I). at most 0.2g fat, preferably at most 0.3g fat, preferably at most 0.4g fat, preferably at most 0.5g fat, preferably at most 0.6g fat, preferably at most 0.7g fat, preferably at most 0.8g fat, preferably at most 0.9g fat; or at most 1g fat, preferably at most 2g, preferably at most 3g, preferably at most 4g, preferably at most 5g fat; or at most 6g fat, preferably at most 7g, preferably at most 8g, preferably at most 9g, preferably at most 10g fat. Preferably, at most 10g fat; or at most 11g fat, preferably at most 12g, preferably at most 13g, preferably at most 14g, preferably at most 15g fat; or at most 16g fat, preferably at most 17g, preferably at most 18g, preferably at most 19g, preferably at most 20g fat; or at most 21g fat, preferably at most 22g, preferably at most 23g, preferably at most 24g, preferably at most 25g fat; or any specific amount or range subsumed therein.In some embodiments, "fasting state" means that a subject, preferably a human subject, has consumed at most 10 kcal, 20 kcal, 30 kcal, 40 kcal, 50 kcal, 100 kcal, 150 kcal, 200 kcal, 250 kcal, 300 kcal, 400 kcal, 500 kcal, 600 kcal, 700 kcal, 800 kcal, 900 kcal, 1000 kcal, 1500 kcal, 2000 kcal, 2500 kcal, 3000 kcal, 4000 kcal, 5000 kcal, 6000 kcal, 7000 kcal, 8000 kcal, 9000 kcal, 10000 kcal, 15000 kcal, 20000 kcal, 25000 kcal, 30000 kcal, 40000 kcal, 50000 kcal, 60000 kcal, 70000 kcal, 80000 kcal, 90000 kcal, 10000 kcal, 15000 kcal, 20000 kcal, 25000 kcal, 30000 kcal, 40000 kcal, 50000 kcal, 60000 kcal, 80000 kcal, 90000 kcal, 100000 kcal, 150000 kcal, 20000 kcal, 25000 kcal, 30000 kcal, 40000 kcal, 50000 kcal, 60000 kcal, 80000 kcal, 90000 kcal, al or any sub-range thereof, and up to 0.1g, 0.2g, 0.3g, 0.4g, 0.5g, 0.6g, 0.7g, 0.8g or 0.9g fat, or up to 1g, 2g, 3g, 4g or 5g fat, or up to 6g, 7g, 8g, 9g or 10g fat, or up to 11g, 12g, 13g, 14g or 15g fat, or up to 16g, 17g, 18g, 18g, 19g or 20g fat, or up to 21g, 22g, 23g, 24g or 25g fat, or any specific amount or range subsumed therein. In some embodiments, "fasting state" means that a subject, preferably a human subject, has consumed at most 0.1 g 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, at least 0.25 hours (h), 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 at most 12 h, more preferably at least 10 h, or any subrange therein, prior to administration of a compound of formula (I). Preferably at most 0.9g fat; or at most 1g fat, preferably at most 2g fat, preferably at most 3g fat, preferably at most 4g fat, preferably at most 5g fat; or at most 6g fat, preferably at most 7g fat, preferably at most 8g fat, preferably at most 9g fat, preferably at most 10g fat; or at most 11g fat, preferably at most 12g, preferably at most 13g, preferably at most 14g, preferably at most 15g fat; or at most 16g fat, preferably at most 17g, preferably at most 18g, preferably at most 19g, preferably at most 20g fat; or at most 21g fat, preferably at most 22g, preferably at most 23g, preferably at most 24g, preferably at most 25g fat; or any specific amount or range subsumed therein.In some embodiments, the term "fasting state" means that a subject, preferably a human subject, has ingested 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, 0.9 g, 10 g, 11 g, or 12 h, preferably at least 8 h to 12 h, more preferably at least 10 h, or any subrange therein, prior to administration of a compound of formula (I). 6g, 0.7g, 0.8g or 0.9g fat, or at most 1g, 2g, 3g, 4g or 5g fat, or at most 6g, 7g, 8g, 9g or 10g fat, or at most 11g, 12g, 13g, 14g or 15g fat, or at most 16g, 17g, 18g, 18g, 19g or 20g fat, or at most 21g, 22g, 23g, 24g or 25g fat, or any specific amount or range subsumed therein.In some embodiments, "fasting state" means that the subject, preferably a human subject, is at least 0.25 hours (h), preferably at least 0.5h, preferably at least 1h, preferably at least 2h, preferably at least 3h, preferably at least 5h, preferably at least 6h, preferably at least 7h, preferably at least 8h, preferably at least 9h, preferably at least 10h, preferably at least 11h, preferably at least 12h, preferably at least 8h to up to 12h, more preferably at least 10h before administration of the compound of formula (I), or wherein Any subrange, having consumed at most 0.1 g 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 fat; or at most 1 g fat, preferably at most 2 g fat, preferably at most 3 g fat, preferably at most 4 g fat, preferably at most 5 g fat; or at most 6 g fat, preferably at most 7 g fat, preferably at most 8 g fat, preferably at most 9 g fat. g fat, preferably at most 10g fat; or at most 11g fat, preferably at most 12g, preferably at most 13g, preferably at most 14g, preferably at most 15g fat; or at most 16g fat, preferably at most 17g, preferably at most 18g, preferably at most 19g, preferably at most 20g fat; or at most 21g fat, preferably at most 22g, preferably at most 23g, preferably at most 24g, preferably at most 25g fat; or at most 26g fat, preferably at most 27g, preferably at most 28g, preferably at most 29g, preferably at most 30g fat; or at most 31g fat, preferably at most 32g, preferably at most 33g, preferably at most 34g, preferably at most 35g fat; or at most 36g fat, preferably at most 37g, preferably at most 38g, preferably at most 39g, preferably at most 40g fat; or at most 41g fat, preferably at most 42g, preferably at most 43g, preferably at most 44g, preferably at most 45g fat; or any specific amount or range subsumed therein.In some embodiments, the term "fasting state" means that a subject, preferably a human subject, has consumed 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, 10 g, 11 g or 12 g, preferably at least 8 h to 12 h, more preferably at least 10 h, or any subrange therein, prior to administration of a compound of Formula (I). g, 32g, 33g, 34g or 35g fat, or up to 36g, 37g, 38g, 39g or 40g fat, or up to 41g, 42g, 43g, 44g or 45g fat, or any specific amount or range subsumed therein.

[0062] As used herein, the term "fed state" or "fed condition" is used herein to refer to a subject, preferably a human subject, who has eaten less than 4 hours or at most 4 hours before a time point of interest, such as 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 a compound of formula (I). In one embodiment, the subject in a fed state has eaten at most 5 minutes (min), 10 min, 0.25 hours (h), 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h or 12h, preferably 0min to 2h or 5min to 2h, more preferably 0.25h to 1h prior to administration of the compound of Formula (I). In some embodiments, the term "fed state" refers to a human subject who, for example, is fed 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 ... least 5 min to at most 5 h, preferably at most 5 h 2h, more preferably at least 0.25h to at most 1h, has ingested at least 10kcal, preferably at least 20kcal, preferably at least 30kcal, preferably at least 40kcal, preferably at least 50kcal, preferably at least 100kcal, preferably at least 150kcal, preferably at least 200kcal, preferably at least 250kcal, preferably at least 300kcal, preferably at least 350kcal, preferably at least 400kcal, preferably at least 450kcal, preferably at least 500kcal or more kcal, or any subrange thereof. In some embodiments, the term "fed state" refers to a human subject who, for example, at most 5 minutes (min), 10min, 0.25 hours (h), 0.5h (h) or more prior to administration of a compound of Formula (I).5h, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h or 12h, preferably 0min to 2h or 5min to 2h, more preferably 0.25h to 1h, at least 10kcal, 20kcal, 30kcal, 40kcal, 50kcal, 100kcal, 150kcal, 200kcal, 250kcal, 300kcal, 350kcal, 400kcal, 450kcal, 500kcal or more kcal, or any sub-range thereof, has been consumed. In some embodiments, the term "fed state" means that a subject, preferably a human subject, has consumed at least 0.1 g fat, preferably at least 0.2 g fat, preferably at least 0.3 g fat, preferably at least 0.4 g fat, preferably at least 0.5 g fat, preferably at least 0.6 g fat, preferably at least 0.7 g fat, preferably at least 0.8 g fat, preferably at least 0.9 g fat, preferably at least 10 g fat, preferably at least 11 g fat, preferably at least 12 g fat, 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 a compound of formula (I).9g fat, preferably at least 1g fat, preferably at least 2g fat, preferably at least 3g fat, preferably at least 4g fat, preferably at least 5g fat, preferably at least 6g fat, preferably at least 7g fat, preferably at least 8g fat, preferably at least 9g fat, preferably at least 10g fat, preferably at least 11g fat, preferably at least 12g fat, preferably at least 13g fat, preferably at least 14g fat, preferably at least 15g fat, preferably at least 16g fat, preferably at least 17g fat, preferably at least 18g fat, preferably at least 19g fat, preferably at least 20g fat, preferably at least 21g fat, preferably at least 22g fat, preferably at least 23g fat, preferably at least 24g fat, preferably at least 25g fat, preferably at least 26g fat, preferably at least 27g fat, preferably at least 28g fat, preferably at least 29g fat, preferably at least 30g fat, preferably at least 31g fat , preferably at least 32g fat, preferably at least 33g fat, preferably at least 34g fat, preferably at least 35g fat, preferably at least 36g fat, preferably at least 37g fat, preferably at least 38g fat, preferably at least 39g fat, preferably at least 40g fat, preferably at least 41g fat, preferably at least 42g fat, preferably at least 43g fat, preferably at least 44g fat, preferably at least 45g fat, preferably at least 46g fat, preferably at least 47g fat, preferably at least 48g fat, preferably at least 49g fat, preferably at least 50g fat, preferably at least 51g fat, preferably at least 52g fat, preferably at least 53g fat, preferably at least 54g fat, preferably at least 55g fat, preferably at least 56g fat, preferably at least 57g fat, preferably at least 58g fat, preferably at least 59g fat, preferably at least 60g fat, or any specific amount or range subsumed therein. In some embodiments, the term "fed state" means that a subject, preferably a human subject, has ingested 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 a compound of formula (I), e.g., 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, preferably 0 min to 2 h or 5 min to 2 h, more preferably 0.25 h to 1 h.9g fat, preferably at least 1g, 2g, 3g, 4g or 5g fat, preferably at least 6g, 7g, 8g, 9g or 10g fat, preferably at least 11g, 12g, 13g, 14g or 15g fat, preferably at least 16g, 17g, 18g, 18g, 19g or 20g fat, preferably at least 21g, 22g, 23g, 24g or 25g fat, preferably at least 26g, 27g, 28g, 29g or 30g fat, preferably at least 31g , 32g, 33g, 34g or 35g fat, preferably at least 36g, 37g, 38g, 39g or 40g fat, preferably at least 41g, 42g, 43g, 44g or 45g fat, preferably at least 46g, 47g, 48g, 49g or 50g fat, preferably at least 51g, 52g, 53g, 54g or 55g fat, preferably at least 56g, 57g, 58g, 59g or 60g fat, or any specific amount or range subsumed therein. In some embodiments, the term "fed state" means that the subject, preferably a human subject, has been fed for at least 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 0.5 min to at most 1 ...25h to at most 1h, at least 21g fat, preferably at least 22g fat, preferably at least 23g fat, preferably at least 24g fat, preferably at least 25g fat, preferably at least 26g fat, preferably at least 27g fat, preferably at least 28g fat, preferably at least 29g fat, preferably at least 30g fat, preferably at least 31g fat, preferably at least 32g fat, preferably at least 33g fat, preferably at least 34g fat, preferably at least 35g fat, preferably at least 36g fat, preferably at least 37g fat, preferably at least 38g fat, preferably at least 39g fat, preferably at least 40g fat, preferably at least 41g fat At least 41g fat, preferably at least 42g fat, preferably at least 43g fat, preferably at least 44g fat, preferably at least 45g fat, preferably at least 46g fat, preferably at least 47g fat, preferably at least 48g fat, preferably at least 49g fat, preferably at least 50g fat, preferably at least 51g fat, preferably at least 52g fat, preferably at least 53g fat, preferably at least 54g fat, preferably at least 55g fat, preferably at least 56g fat, preferably at least 57g fat, preferably at least 58g fat, preferably at least 59g fat, preferably at least 60g fat, or any specific amount or range subsumed therein. In some embodiments, the term "fed state" means that a subject, preferably a human subject, has consumed 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, 30 g, 31 g, 32 g, 33 g, 34 g or 36 g of fat, e.g., 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, preferably 0 min to 2 h or 5 min to 2 h, more preferably 0.25 h to 1 h, before administration of a compound of formula (I). g, 29g or 30g fat, preferably at least 31g, 32g, 33g, 34g or 35g fat, preferably at least 36g, 37g, 38g, 39g or 40g fat, preferably at least 41g, 42g, 43g, 44g or 45g fat, preferably at least 46g, 47g, 48g, 49g or 50g fat, preferably at least 51g, 52g, 53g, 54g or 55g fat, preferably at least 56g, 57g, 58g, 59g or 60g fat, or any specific amount or range subsumed therein. In some embodiments, the term "fed state" means that a subject, preferably a human subject, is, for example, up to 5 minutes (min), preferably up to 10 minutes, preferably up to 0.25 hours (h), preferably up to 0.5 hours (h) before administration of a compound of formula (I).5h, preferably at most 1h, preferably at most 2h, preferably at most 3h, preferably at most 4h, preferably at most 5h, preferably at most 6h, preferably at most 7h, preferably at most 8h, preferably at most 9h, preferably at most 10h, preferably at most 11h, preferably at most 12h, preferably at least 0min to at most 2h, preferably at least 5min to at most 2h, more preferably at least 0.25h to at most 1h, having ingested at least 10kcal, preferably at least 20kcal, preferably at least 30kcal, preferably at least 40kcal, preferably at least 50kcal, preferably at least 100kcal, 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 kcal, or any subrange therein, and at least 0.1 g fat, preferably at least 0.2 g fat, preferably at least 0.3 g fat, preferably at least 0.4 g fat, preferably at least 0.5 g fat, preferably at least 0.6 g fat, preferably at least 0.7 g fat, preferably at least 0.8 g fat, preferably at least 0.9g fat, preferably at least 1g fat, preferably at least 2g fat, preferably at least 3g fat, preferably at least 4g fat, preferably at least 5g fat, preferably at least 6g fat, preferably at least 7g fat, preferably at least 8g fat, preferably at least 9g fat, preferably at least 10g fat, preferably at least 11g fat, preferably at least 12g fat, preferably at least 13g fat, preferably at least 14g fat, preferably at least 15g fat, preferably at least 16g fat, preferably at least 17g fat, preferably at least 18g fat, preferably at least 19g fat, preferably at least 20g fat, preferably at least 21g fat, preferably at least 22g fat, preferably at least 23g fat, preferably at least 24g fat, preferably at least 25g fat, preferably at least 26g fat, preferably at least 27g fat, preferably at least 28g fat, preferably at least 29g fat, preferably at least 30g fat, preferably at least 31g fat , preferably at least 32g fat, preferably at least 33g fat, preferably at least 34g fat, preferably at least 35g fat, preferably at least 36g fat, preferably at least 37g fat, preferably at least 38g fat, preferably at least 39g fat, preferably at least 40g fat, preferably at least 41g fat, preferably at least 42g fat, preferably at least 43g fat, preferably at least 44g fat, preferably at least 45g fat, preferably at least 46g fat, preferably at least 47g fat, preferably at least 48g fat, preferably at least 49g fat, preferably at least 50g fat, preferably at least 51g fat, preferably at least 52g fat, preferably at least 53g fat, preferably at least 54g fat, preferably at least 55g fat, preferably at least 56g fat, preferably at least 57g fat, preferably at least 58g fat, preferably at least 59g fat, preferably at least 60g fat, or any specific amount or range subsumed therein. In some embodiments, the term "fed state" means that a subject, preferably a human subject, has consumed at least 10 kcal, 2 kcal, 3 kcal, 4 kcal, 5 kcal, 6 kcal, 7 kcal, 8 kcal, 9 kcal, ... 0 kcal, 30 kcal, 40 kcal, 50 kcal, 100 kcal, 150 kcal, 200 kcal, 250 kcal, 300 kcal, 350 kcal, 400 kcal, 450 kcal, 500 kcal or more kcal, or any subrange 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 0.9g fat, preferably at least 1g, 2g, 3g, 4g or 5g fat, preferably at least 6g, 7g, 8g, 9g or 10g fat, preferably at least 11g, 12g, 13g, 14g or 15g fat, preferably at least 16g, 17g, 18g, 18g, 19g or 20g fat, preferably at least 21g, 22g, 23g, 24g or 25g fat, preferably at least 26g, 27g, 28g, 29g or 30g fat, preferably at least 31g , 32g, 33g, 34g or 35g fat, preferably at least 36g, 37g, 38g, 39g or 40g fat, preferably at least 41g, 42g, 43g, 44g or 45g fat, preferably at least 46g, 47g, 48g, 49g or 50g fat, preferably at least 51g, 52g, 53g, 54g or 55g fat, preferably at least 56g, 57g, 58g, 59g or 60g fat, or any specific amount or range subsumed therein. In some embodiments, the term "fed state" means that the subject, preferably a human subject, has been fed for at least 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 0.5 min to at most 1 ...25 h to at most 1 h, having 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 kcal, or any subrange therein, and at least 21 g fat, preferably at least 22 g fat, preferably at least 23 g fat, preferably at least 24 g fat, preferably at least 25 g fat, preferably at least 26 g fat, preferably at least 27 g fat, preferably at least 28 g fat, preferably at least 29 g fat, preferably at least 30 g fat, preferably at least 31 g fat, preferably at least 32 g fat 2g fat, preferably at least 33g fat, preferably at least 34g fat, preferably at least 35g fat, preferably at least 36g fat, preferably at least 37g fat, preferably at least 38g fat, preferably at least 39g fat, preferably at least 40g fat, preferably at least 41g fat, preferably at least 42g fat, preferably at least 43g fat, preferably at least 44g fat, preferably at least 45g fat, preferably at least 46g fat, preferably at least 47g fat, preferably at least 48g fat, preferably at least 49g fat, preferably at least 50g fat, preferably at least 51g fat, preferably at least 52g fat, preferably at least 53g fat, preferably at least 54g fat, preferably at least 55g fat, preferably at least 56g fat, preferably at least 57g fat, preferably at least 58g fat, preferably at least 59g fat, preferably at least 60g fat, or any specific amount or range subsumed therein. In some embodiments, the term "fed state" means that a subject, preferably a human subject, has been fed for at least 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, preferably 0 min to 2 h or 5 min to 2 h, more preferably 0.25h to 1h, having consumed at least 10kcal, 20kcal, 30kcal, 40kcal, 50kcal, 100kcal, 150kcal, 200kcal, 250kcal, 300kcal, 350kcal, 400kcal, 450kcal, 500kcal or more kcal, or any subrange therein, and at least 21g, 22g, 23g, 24g or 25g fat, preferably at least 26g, 27g, 28g, 29g or more 30g fat, preferably at least 31g, 32g, 33g, 34g or 35g fat, preferably at least 36g, 37g, 38g, 39g or 40g fat, preferably at least 41g, 42g, 43g, 44g or 45g fat, preferably at least 46g, 47g, 48g, 49g or 50g fat, preferably at least 51g, 52g, 53g, 54g or 55g fat, preferably at least 56g, 57g, 58g, 59g or 60g fat, or any specific amount or range subsumed therein. .

[0063] As used herein, a "standardized meal" (standardized breakfast or standardized dinner) comprises approximately 21 g fat, 67 g carbohydrates, 19 g protein, and produces approximately 533 kcal calories. Preferably, the standardized meal comprises at least 15 g fat to at most 40 g fat, preferably at least 16 g fat to at most 38 g fat, preferably at least 17 g fat to at most 35 g fat, preferably at least 17 g fat to at most 33 g fat, preferably at least 18 g fat to at most 31 g fat, preferably at least 18 g fat to at most 30 g fat, preferably at least 19 g fat to at most 27 g fat.

[0064] A "high-fat, high-calorie meal" (a high-fat, high-calorie breakfast or a high-fat, high-calorie dinner) contains approximately: 500kcal to 600kcal fat (56g to 67g fat), 250kcal carbohydrates, 150kcal protein, and a total calorie count of 900kcal to 1000kcal. Preferably, a high-fat, high-calorie meal contains at least 35g fat to at most 80g fat, preferably at least 40g fat to at most 75g fat, preferably at least 45g fat to at most 70g fat, preferably at least 50g fat to at most 75g fat, preferably at least 50g fat to at most 70g fat, preferably 50g fat to at most 60g fat.

[0065] A "low-fat, low-calorie meal" (a low-fat, low-calorie breakfast or a low-fat, low-calorie dinner) contains about 2.5g fat, 247kcal, or about 9g fat, 330kcal. Preferably, a low-fat, low-calorie meal contains at least 0.1g fat to at most 15g fat, preferably at least 0.3g fat to at most 13g fat, preferably at least 0.5g fat to at most 10g fat, preferably at least 0.8g fat to at most 9g fat, preferably at least 0.9g fat to at most 8g fat, preferably at least 1.0g fat to at most 8g fat, preferably at least 1.2g fat to at most 7g fat.

[0066] "Low-fat high-calorie meal" (low-fat high-calorie breakfast or low-fat high-calorie dinner) contains about 4.2g fat, 911kcal, or about 0.95g fat, 406kcal. Preferably, the low-fat low-calorie meal contains at least 0.1g fat to at most 15g fat, preferably at least 0.3g fat to at most 13g fat, preferably at least 0.5g fat to at most 10g fat, preferably at least 0.8g fat to at most 9g fat, preferably at least 0.9g fat to at most 8g fat, preferably at least 1.0g fat to at most 8g fat, preferably at least 1.2g fat to at most 7g fat.

[0067] "Standardized normal fat meal" (standardized normal fat breakfast or standardized normal fat dinner) comprises about 21g fat, 67g carbohydrate, 19g protein, produces about 533kcal heat. An example of standardized normal fat meal is 4 slices of bread, 2 slices of ham or cheese, butter, jelly and 1 or 2 cups (maximum 355mL) of decaffeinated coffee or tea with milk and / or sugar. Preferably, standardized normal fat meal comprises at least 15g fat to at most 40g fat, preferably at least 16g fat to at most 38g fat, preferably at least 17g fat to at most 35g fat, preferably at least 17g fat to at most 33g fat, preferably at least 18g fat to at most 31g fat, preferably at least 18g fat to at most 30g fat, preferably at least 19g fat to at most 27g fat. As used herein, the term "oral dosage form" refers to a pharmaceutical preparation comprising a specified amount (dose) of a compound of formula (I), particularly compound (a), or a stereoisomeric form, a pharmaceutically acceptable salt and / or solvate and / or polymorph thereof as an active ingredient, and an inactive component (pharmaceutically acceptable excipient), which is formulated into a specific configuration suitable for oral administration and drug delivery, such as a tablet, capsule or liquid oral preparation. In one embodiment, these compositions are in the form of tablets that can be scored.

[0068] As used herein, the term "administering" refers to the introduction of a medicament or active ingredient (such as a compound of formula (I)) into a subject, preferably a human subject. The related term "administering" (and grammatical equivalents) refers to both direct administration, which can be administration to a subject by a medical professional or self-administration by a subject; and / or indirect administration, which can be the act of prescribing a drug. For example, a physician instructs a patient to self-administer a drug and / or provides a drug prescription to a patient.

[0069] For use in medicine, cocrystals or salts of compounds of formula (I) (particularly compound (a)) as disclosed herein refer to non-toxic "pharmaceutically acceptable salts". "Pharmaceutically acceptable" may mean approved or approved by a regulatory agency of a federal or state government or a corresponding agency in a country outside the United States or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, particularly humans.

[0070] However, other salts may also be used to prepare compounds of formula (I), particularly compound (a), or pharmaceutically acceptable salt forms thereof. Suitable pharmaceutically acceptable salts of compounds of formula (I), particularly compound (a), include acid addition salts, which may be formed, for example, by mixing a solution of the compound with a pharmaceutically acceptable acid solution 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. In addition, in the case where compounds of formula (I), particularly compound (a), contain an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts formed with suitable organic ligands, such as quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camphorsulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, propionate dodecyl sulfate, esylate, fumarate, glucoheptonate, gluconate, glutamate, p-alpha-hydroxyacetamidophenylarsenate, hexylresorcinate, hydrazine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothiosulfate , lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthenate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (pamoate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, toluenesulfonate, triethyl iodide, valerate, and combinations of one or more thereof.

[0071] Representative acids and bases that can be used to prepare pharmaceutically acceptable salts include acids including 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-hydroxy-ethanesulfonic 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, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, and undecylenic acid; and bases including ammonia, L-arginine, phenethylbenzylamine , benzathine, calcium hydroxide, choline, danol, 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 more thereof.

[0072] In the case where the compound of formula (I), particularly compound (a) has at least one chiral center, they can exist as enantiomers accordingly. If the compound has two or more chiral centers, they can also exist in diastereomeric forms. It should be understood that all such isomers and mixtures thereof are included within the scope of the present invention. In addition, some compounds in the compound can exist as polymorphs, and therefore are also intended to be included in the present invention. In addition, some compounds in the compound can form solvates (i.e., hydrates) with water or form solvates with organic solvents, and such solvates are also intended to be included within the scope of the present invention. It will be understood by those skilled in the art that the term "compound" as used herein is intended to include solvated compounds of formula (I) (particularly solvates of compound (a)), hydrated compounds of formula (I) (particularly hydrates of compound (a)), and hydrated and solvated compounds of formula (I) (e.g., compounds of formula (I) in the form of solvates together with water and organic solvents, particularly compounds (a) in the form of solvates together with water and organic solvents).

[0073] In the case where the method for preparing a compound of formula (I), particularly compound (a), produces a stereoisomer mixture, these isomers can be separated by conventional techniques (such as preparative chromatography). The compound can be prepared in racemic form, or can be synthesized by enantiomer specificity or prepared by splitting a single enantiomer. For example, a diastereomeric pair can be formed by standard techniques, such as by forming a salt with an optically active acid (such as (-)-di-p-toluoyl-d-tartaric acid and / or (+)-di-p-toluoyl-l-tartaric acid), then fractional crystallization and regeneration of free alkali, to split the compound into their component enantiomers. The compound can also be split by forming diastereomeric esters or amides, followed by chromatographic separation and removal of chiral auxiliary agents. Alternatively, a chiral stationary phase or a chiral column can be used to split the compound.

[0074] In one embodiment of the pharmaceutical formulation of the present invention, the compound of formula (I) is a compound comprising, consisting of and / or consisting essentially of the (+)-enantiomer, wherein the compound is essentially free of the (-)-isomer. In the context of the present invention, "essentially free" means less than about 25%, preferably less than about 10%, more preferably less than about 5%, even more preferably less than about 2%, and even more preferably less than about 1% of the (-)-isomer, which can be calculated as follows

[0075]

[0076] In another embodiment of the pharmaceutical formulation of the present invention, the compound of formula (I) is a compound comprising, consisting of, and consisting essentially of the (-)-enantiomer, wherein the compound is substantially free of the (+)-isomer. In the context of the present invention, "substantially free" means less than about 25%, preferably less than about 10%, more preferably less than about 5%, even more preferably less than about 2%, and even more preferably less than about 1% of the (+)-isomer, which can be calculated as follows

[0077]

[0078] 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 on any molecule of interest. This can be achieved by conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, Second Edition, JFWMcOmie, Plenum Press, 1973; TWGreene and PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991; and TWGreene and PGM Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. Protective groups can be removed at a convenient subsequent stage using methods known in the art.

[0079] The compounds of formula (I), in particular compound (a), can exist in unsolvated forms as well as solvated forms, such as hydrates, organic solvent solvates, or a combination of organic solvent solvates and hydrates.

[0080] As used herein, the term "solvate" means a solvent addition form containing one or more solvents in stoichiometric or non-stoichiometric amounts. Some compounds tend to capture a fixed molar ratio of solvent molecules in a crystalline solid state, thereby forming a solvate. If 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 solvent solvate and a hydrate. Hydrates are formed by combining one or more water molecules with a substance in which water maintains its molecular state as H2O, and this combination can form one or more hydrates. In hydrates, water molecules are connected by secondary valence using intermolecular forces, particularly hydrogen bridges. Solid hydrates contain stoichiometric water, so-called crystal water, in which water molecules do not have to be equivalent in terms of their binding state. Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Hydrates of salts of compounds used herein are also applicable.

[0081] When a compound crystallizes from a solution or slurry, it can crystallize in different spatially arranged lattices (a property known as "polymorphism"), forming crystals with different crystalline forms, each of which is referred to as a "polymorph". As used herein, "polymorph" refers to a crystalline form of a compound of formula (I) in which the molecules are arranged in three-dimensional lattice sites. Different polymorphs of a compound of formula (I) may differ from one another in one or more physical properties, such as solubility and dissolution rate, true specific gravity, crystal form, accumulation pattern, flowability and / or solid state stability, among others.

[0082] The compounds of formula (I) can be administered as crystalline products or amorphous products. They can be obtained in the form of, for example, solid fillers, powders or films by methods such as precipitation, crystallization, freeze drying, spray drying or evaporative drying. They can be administered alone, or in combination with one or more other compounds described herein, or in combination with one or more other drugs. Typically, they will be administered as a formulation in combination with one or more pharmaceutically acceptable excipients. The selection of pharmaceutically acceptable excipients depends primarily on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the properties of the dosage form.

[0083] Unless otherwise indicated, the terms "wt %" and "weight percent" are used interchangeably to refer to the concentration of an ingredient (eg, a pharmaceutically acceptable excipient or an active pharmaceutical ingredient) by weight of a pharmaceutical formulation.

[0084] The average molecular weight may, for example, be referred to as number average molecular weight or weight average molecular weight. The average molecular weight may, for example, be measured using gel permeation chromatography.

[0085] The term "subject" refers to an animal that has been the object of treatment, observation or experiment, preferably a mammal, most preferably a human. In one embodiment, the subject is a human. In some embodiments, the subject is a human who has been diagnosed with a condition, disorder or disease caused by dengue virus, or has been diagnosed with a dengue virus infection. In one embodiment, the subject is a human who has been diagnosed with a condition, syndrome, disorder or disease caused by dengue virus. In some embodiments, the subject is a human who has not yet been diagnosed with a condition, disorder or disease caused by dengue virus or dengue virus infection and will be treated prophylactically. In one embodiment, the subject is a human who has not yet been diagnosed with a condition, syndrome, disorder or disease caused by dengue virus and will be treated prophylactically.

[0086] The term "therapeutically effective amount" refers to that amount of an active compound or agent that elicits the biological or medical response of a subject, biological sample, tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, including reduction or inhibition of enzyme or protein activity, or amelioration of symptoms, alleviation of a condition, slowing or delaying progression of a disease, or prevention of a disease.

[0087] Preferably, the term "therapeutically effective amount" may refer to administering a dosing regimen to a subject, preferably a human subject, to achieve a certain plasma concentration level or exposure of the active compound or agent, which will produce an effective level for treating or preventing dengue virus or dengue virus infection in the subject.

[0088] Preferably, the term "therapeutically effective amount" may refer to an amount of a compound, preparation or dosage form that, when administered to a subject, preferably a human subject, can effectively at least partially alleviate, inhibit, prevent, treat and / or improve the condition, disorder, symptom or disease caused by dengue virus.

[0089] As used herein, the term "dengue virus replication inhibitor" refers to an agent that inhibits or alleviates at least one condition, symptom, syndrome, disorder and / or disease caused by dengue virus.

[0090] Unless otherwise indicated, as used herein, the terms "affect" or "affected" (when referring to a disease, syndrome, condition or disorder affected by inhibition of dengue virus replication) include a reduction in the frequency and / or severity of one or more symptoms or clinical manifestations of the disease, syndrome, condition or disorder; and / or include preventing the development of one or more symptoms or clinical manifestations of the disease, syndrome, condition or disorder or the development of the disease, condition, syndrome or disorder.

[0091] As used herein, the term “C max ” refers to the maximum (peak) plasma concentration of a compound observed in a subject following administration of a dose of the compound to the subject.

[0092] As used herein, the term "AUC" refers to the area under the concentration-time curve, which is a measure of exposure to a compound of interest and is the integral of the concentration-time curve after a single dose or at steady state. AUC is expressed in μg*hr / L (μg×hr / L).

[0093] As used herein, the term "adverse event" (AE) refers to any untoward medical event occurring in a subject, preferably a human subject, to which a pharmaceutical preparation according to the present invention is administered. AE is not necessarily causally related to the administration of a pharmaceutical preparation according to the present invention. Therefore, AE can be any unfavorable and unexpected symptom (including abnormal findings), symptom or disease temporarily associated with the use of a pharmaceutical preparation, i.e., directly associated with the pharmaceutical preparation. This includes any new occurrence or event that is worse in severity or frequency than the baseline condition, or an abnormal result of a diagnostic procedure, including abnormal laboratory tests.

[0094] As used herein, the term "adverse event occurring during treatment" refers to any adverse event that is causally related to the administration of the pharmaceutical formulation according to the present invention.

[0095] As used herein, "pharmaceutically acceptable excipients" are inactive ingredients in pharmaceutical formulations. Examples of excipients include diluents, wetting agents (e.g., surfactants), binders, glidants, lubricants, disintegrants, fillers, surfactants, and the like.

[0096] As used herein, "disintegrant" is an excipient that hydrates the drug formulation and aids in the dispersion of the tablet. Examples of disintegrants include croscarmellose sodium, crospovidone (ie, cross-linked polyvinyl N-pyrrolidone), sodium starch glycolate, or any combination thereof.

[0097] As used herein, "diluents" or "fillers" are excipients that increase the bulk of a pharmaceutical formulation. Examples of fillers include lactose, sorbitol, cellulose, calcium phosphate, starch, sugar (e.g., mannitol, sucrose, etc.), or any combination thereof.

[0098] As used herein, a "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 TM or Tween 20), or any combination thereof.

[0099] As used herein, "binder" is an excipient that imparts enhanced cohesion 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).

[0100] As used herein, a "glidant" is an excipient that imparts enhanced flow properties to a pharmaceutical formulation. Examples of glidants include colloidal silicon dioxide and / or talc.

[0101] As used herein, a "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 pigments, titanium dioxide, iron oxide, and / or combinations thereof. Other colorants include commercially available pigments such as FD&C Green #3.

[0102] As used herein, a "lubricant" is an excipient added to a pharmaceutical formulation that is compressed into a tablet. The lubricant helps compress the granules into tablets and eject the tablets of the pharmaceutical formulation from the molding machine. Examples of lubricants include magnesium stearate, stearic acid (stearin), hydrogenated oil, sodium stearyl fumarate, or any combination thereof.

[0103] Preferred statements (features) and embodiments of the pharmaceutical preparations, uses and methods of the present invention are set forth below. Unless there is a clear statement to the contrary, each statement and embodiment of the present invention so defined may be combined with any other statement and / or embodiment. Specifically, any feature indicated as preferred or advantageous may be combined with any other feature or features or statements indicated as preferred or advantageous. To this end, the present invention is particularly captured by any one or any combination of one or more of the following numbered aspects and embodiments and any other statements and / or embodiments.

[0104] 1. A compound of formula (I) for preventing and / or treating dengue virus infection, wherein

[0105] The compound of formula (I) is administered in an oral dosage form to a human subject in a fed or fasted state, and wherein the compound of formula (I) corresponds to

[0106]

[0107] Its stereoisomeric form, pharmaceutically acceptable salt, solvate or polymorph; the compound is selected from the following group, wherein:

[0108] R1 is H, R2 is F, and R3 is H or CH3,

[0109] R1 is H, CH3 or F, R2 is OCH3, and R3 is H,

[0110] R1 is H, R2 is OCH3, and R3 is CH3,

[0111] R1 is CH3, R2 is F, and R3 is H,

[0112] R1 is CF3 or OCF3, R2 is H, and R3 is H,

[0113] R1 is OCF3, R2 is OCH3, and R3 is H,

[0114] R1 is OCF3, R2 is H, and R3 is CH3.

[0115] 2. A compound for use according to statement 1, wherein the compound is administered in an oral dosage form to a human subject in a fed state; preferably, the human subject in the fed state has consumed a standard normal fat meal, a high fat-high calorie meal, a low fat-low calorie meal, or a low fat-high calorie meal.

[0116] 3. A compound for use according to any one of statements 1 or 2, wherein the human subject is infected with or at risk of being infected with a dengue virus.

[0117] 4. A compound for use according to any one of statements 1 to 3, wherein the human subject is in a fed state prior to or while administering the oral dosage form.

[0118] 5. A compound for use according to any one of statements 1 to 4, wherein the human is in a fed state and has eaten 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 the time of administration of the oral dosage form, the oral dosage form is preferably administered within at most 30 minutes after eating, preferably within at most 25 minutes after eating, preferably within at most 20 minutes after eating, preferably within at most 15 minutes after eating, preferably within at most 10 minutes after eating, preferably within at most 5 minutes after eating, preferably while eating.

[0119] 6. The compound for use according to any one of statements 1 to 4, wherein the oral dosage form is administered in the morning. The oral dosage form may be administered at the same time as or after the first, second or third meal of the day.

[0120] 7. A compound for use according to any one of statements 1 to 5, wherein the human being in a fed state has eaten a food comprising fat in an amount of at least 0.1 g fat, preferably at least 0.2 g fat, preferably at least 0.3 g fat, preferably at least 0.4 g fat, preferably at least 0.5 g fat, preferably at least 0.6 g fat, preferably at least 0.7 g fat, preferably at least 0.8 g fat, preferably at least 0.9 g fat, preferably at least 1 g fat, preferably at least 2 g fat, preferably at least 3 g fat, preferably at least 4 g fat, preferably at least 5 g fat, preferably at least 6 g fat, preferably at least 7 g fat, preferably at least 8 g fat, preferably at least 9 g fat, preferably at least 10 g fat, preferably at least 11 g fat, preferably at least 12 g fat, preferably at least 13 g fat, preferably at least 14 g fat, preferably at least 15 g fat, preferably at least 16 g fat, preferably at least 17 g fat, preferably at least 18 g fat, preferably at least 19 g fat, preferably at least 20 g fat, preferably at least 21 g fat, preferably at least 22 g fat, preferably at least 23 g fat, preferably at least 24 g fat, preferably at least 25 g fat, preferably at least 26 g fat, preferably at least 27 g fat, preferably at least 28 g fat, preferably at least 29 g fat, preferably at least 30 g fat, preferably at least 31 g fat, preferably at least 32 g fat, preferably at least 33 g fat, preferably at least 34 g fat, preferably at least 35 g fat, preferably at least 36 g fat, preferably at least 37 g fat, preferably at least 38 g fat, preferably at least 39 g fat, preferably at least 40 g fat Preferably at least 6g fat, preferably at least 7g fat, preferably at least 8g fat, preferably at least 9g fat, preferably at least 10g fat, preferably at least 11g fat, preferably at least 12g fat, preferably at least 13g fat, preferably at least 14g fat, preferably at least 15g fat, preferably at least 16g fat, preferably at least 17g fat, preferably at least 18g fat, preferably at least 19g fat, preferably at least 20g fat, preferably at least 21g fat, preferably at least 22g fat, preferably at least 23g fat, preferably at least 24g fat, preferably at least 25g fat, preferably at least 26g fat, preferably at least 27g fat, preferably at least 28g fat, preferably at least 29g fat, preferably at least 30g fat, preferably at least 31g fat, preferably at least 32g fat, preferably at least 33g fat, preferably at least 34g fat, preferably at least 35g fat, preferably at least 36g fat, preferably at least 37g fat, preferably at least 38g fat, preferably at least 39g fat, preferably at least 40g fat, preferably at least 41g fat, preferably at least 42g fat Preferably at least 25g fat, preferably at least 26g fat, preferably at least 27g fat, preferably at least 28g fat, preferably at least 29g fat, preferably at least 30g fat, preferably at least 31g fat, preferably at least 32g fat, preferably at least 33g fat, preferably at least 34g fat, preferably at least 35g fat, preferably at least 36g fat, preferably at least 37g fat, preferably at least 38g fat, preferably at least 39g fat, preferably at least 40g fat, preferably at least 41g fat, preferably at least 42g fat, preferably at least 43g fat. fat, preferably at least 44g fat, preferably at least 45g fat, preferably at least 46g fat, preferably at least 47g fat, preferably at least 48g fat, preferably at least 49g fat, preferably at least 50g fat, preferably at least 51g fat, preferably at least 52g fat, preferably at least 53g fat, preferably at least 54g fat, preferably at least 55g fat, preferably at least 56g fat, preferably at least 57g fat, preferably at least 58g fat, preferably at least 59g fat, preferably at least 60g fat, or any specific amount or range contained therein.

[0121] 8. A compound for use according to any one of statements 1 to 7, wherein the human being in a fed state has eaten a food comprising the following amount of fat: at least 0.1 g fat, preferably at least 0.2 g fat, preferably at least 0.3 g fat, preferably at least 0.4 g fat, preferably at least 0.5 g fat, preferably at least 0.6 g fat, preferably at least 0.7 g fat, preferably at least 0.8 g fat, preferably at least 0.9 g fat, preferably at least 1 g fat, preferably at least 2 g fat, preferably at least 3 g fat, preferably at least 4 g fat, preferably at least 5 g fat, preferably at least 6 g fat, preferably at least 7 g fat, preferably at least 8 g fat, preferably at least 9 g fat, preferably at least 10 g fat, preferably at least 11 g fat, preferably at least 12 g fat, preferably at least 13 g fat, preferably at least 14 g fat, preferably at least 15 g fat, preferably at least 16 g fat, preferably at least 17 g fat, preferably at least 18 g fat, preferably at least 19 g fat, preferably at least 20 g fat, preferably at least 21 g fat, preferably at least 22 g fat, preferably at least 23 g fat, preferably at least 24 g fat, preferably at least 25 g fat, preferably at least 26 g fat, preferably at least 27 g fat, preferably at least 28 g fat, preferably at least 29 g fat, preferably at least 30 g fat, preferably at least 31 g fat, preferably at least 32 g fat, preferably at least 33 g fat, preferably at least 34 g fat, preferably at least 35 g fat, preferably at least 36 g fat, preferably at least 37 g fat, preferably at least 38 g fat, preferably at least 39 g fat, preferably at least 40 g fat Preferably at least 6g fat, preferably at least 7g fat, preferably at least 8g fat, preferably at least 9g fat, preferably at least 10g fat, preferably at least 11g fat, preferably at least 12g fat, preferably at least 13g fat, preferably at least 14g fat, preferably at least 15g fat, preferably at least 16g fat, preferably at least 17g fat, preferably at least 18g fat, preferably at least 19g fat, preferably at least 20g fat, preferably at least 21g fat, preferably at least 22g fat, preferably at least 23g fat, preferably at least 24g fat, preferably at least 25g fat, preferably at least 26g fat, preferably at least 27g fat, preferably at least 28g fat, preferably at least 29g fat, preferably at least 30g fat, preferably at least 31g fat, preferably at least 32g fat, preferably at least 33g fat, preferably at least 34g fat, preferably at least 35g fat, preferably at least 36g fat, preferably at least 37g fat, preferably at least 38g fat, preferably at least 39g fat, preferably at least 40g fat, preferably at least 41g fat, preferably at least 42g fat Preferably at least 25g fat, preferably at least 26g fat, preferably at least 27g fat, preferably at least 28g fat, preferably at least 29g fat, preferably at least 30g fat, preferably at least 31g fat, preferably at least 32g fat, preferably at least 33g fat, preferably at least 34g fat, preferably at least 35g fat, preferably at least 36g fat, preferably at least 37g fat, preferably at least 38g fat, preferably at least 39g fat, preferably at least 40g fat, preferably at least 41g fat, preferably at least 42g fat, preferably at least 43g fat. fat, preferably at least 44g fat, preferably at least 45g fat, preferably at least 46g fat, preferably at least 47g fat, preferably at least 48g fat, preferably at least 49g fat, preferably at least 50g fat, preferably at least 51g fat, preferably at least 52g fat, preferably at least 53g fat, preferably at least 54g fat, preferably at least 55g fat, preferably at least 56g fat, preferably at least 57g fat, preferably at least 58g fat, preferably at least 59g fat, preferably at least 60g fat, or any specific amount or range subsumed therein;

[0122] And wherein the human has eaten less than 4 hours before administration of the compound of formula I, has eaten 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 the administration time of the oral dosage form, and the oral dosage form is preferably administered within 30 minutes after eating, preferably within 25 minutes after eating, preferably within 20 minutes after eating, preferably within 15 minutes after eating, preferably within 10 minutes after eating, preferably within 5 minutes after eating before administration of the compound of formula I such as compound (a); preferably, the compound of formula I such as compound (a) is administered while eating.

[0123] 9. A compound for use according to any one of statements 1 to 8, wherein the human being in a fed state has eaten a food comprising 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 fat, preferably at least 1 g, 2 g, 3 g, 4 g or 5 g fat, preferably at least 6 g, 7 g, 8 g, 9 g or 10 g fat, preferably at least 11 g, 12 g, 13 g, 14 g or 15g fat; preferably at least 16g, 17g, 18g, 18g, 19g or 20g fat, preferably at least 21g, 22g, 23g, 24g or 25g fat, preferably at least 26g, 27g, 28g, 29g or 30g fat, preferably at least 31g, 32g, 33g, 34g or 35g fat, preferably at least 36g, 37g, 38g, 39g or 40g fat, preferably at least 41g, 42g, 43g,

[0124] 44g or 45g fat, preferably at least 46g, 47g, 48g, 49g or 50g fat, preferably at least 51g, 52g, 53g, 54g or 55g fat, preferably at least 56g,

[0125] 10. The compound for use according to any one of statements 1 to 9, wherein the human being in a fed state has eaten food having a total energy count 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 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 at least 510 kcal, preferably at least 520 kcal, preferably at least 530 kcal, preferably at least 540 kcal, preferably at least 550 kcal, preferably at least 560 kcal, preferably at least 570 kcal, preferably at least 580 kcal, preferably at least 590 kcal, preferably at least 600 kcal, or any specific amount or range subsumed therein.

[0126] 11. A compound for use according to any one of statements 1 to 10, wherein the human being in a fed state has eaten food having a total energy count of at most 1500 kcal, preferably at most 1400 kcal, preferably at most 1300 kcal, preferably at most 1200 kcal, preferably at most 1110 kcal, preferably at most 1000 kcal, preferably at most 980 kcal, preferably at most 960 kcal, preferably at most 940 kcal, preferably at most 920 kcal. 0 kcal, preferably at most 810 kcal, preferably at most 820 kcal, preferably at most 830 kcal, preferably at most 840 kcal, preferably at most 850 kcal, preferably at most 860 kcal, preferably at most 870 kcal, preferably at most 880 kcal, preferably at most 890 kcal, preferably at most 900 kcal, preferably at most 710 kcal, preferably at most 720 kcal, preferably at most 730 kcal, preferably at most 740 kcal, preferably at most 750 kcal, preferably at most 760 kcal 40 kcal, preferably at most 750 kcal, preferably at most 760 kcal, preferably at most 770 kcal, preferably at most 780 kcal, preferably at most 790 kcal, preferably at most 800 kcal, preferably at most 610 kcal, preferably at most 620 kcal, preferably at most 630 kcal, preferably at most 640 kcal, preferably at most 650 kcal, preferably at most 660 kcal, preferably at most 670 kcal, preferably at most 680 kcal at most, preferably 690 kcal at most, preferably 700 kcal at most, preferably 510 kcal at most, preferably 520 kcal at most, preferably 530 kcal at most, preferably 540 kcal at most, preferably 550 kcal at most, preferably 560 kcal at most, preferably 570 kcal at most, preferably 580 kcal at most, preferably 590 kcal at most, preferably 600 kcal at most, or any specific amount or range subsumed therein.

[0127] 12. A compound for use according to any one of statements 1 to 11, wherein the human being in a fed state has consumed food having a total energy count of at least 10 kcal,

[0128] 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 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 subsumed therein. Preferably, the human being in the fed state has eaten food having a total energy count of at most 1500 kcal, 1400 kcal, 1300 kcal, 1200 kcal or 1110 kcal, preferably at most 1000 kcal, 980 kcal, 960 kcal, 940 kcal or 920 kcal, preferably at most 810 kcal, 820 kcal, 830 kcal, 840 kcal or 850 kcal, preferably at most 860 kcal, 870 kcal, 880 kcal, 890 kcal or 900 kcal, preferably at most 710 kcal, 720 kcal, 730 kcal , 740kcal, 750kcal, 760kcal, 770kcal, 780kcal, 790kcal or 800kcal, preferably at most 610kcal, 620kcal, 630kcal, 640kcal, 650kcal, 660kcal, 670kcal, 680kcal, 690kcal or 700kcal, preferably at most 510kcal, 520kcal, 530kcal, 540kcal, 550kcal, 560kcal, 570kcal, 580kcal, 590kcal or 600kcal, or any specific amount or range subsumed therein.

[0129] 13. A compound for use according to any one of statements 1 to 12, wherein the oral dosage form is a solid dosage form formulated as a pharmaceutical preparation.

[0130] 14. A compound for use according to any one of statements 1 to 13, wherein the oral dosage form is a solid dosage form and comprises a cellulose derivative such as hydroxypropylmethylcellulose (HPMC), or a methacrylic acid copolymer, or a combination thereof.

[0131] 15. A compound for use according to any one of statements 1 to 14, wherein the oral dosage form is a solid dosage form comprising a cellulose derivative; preferably, wherein the compound of formula (I) and the cellulose derivative (e.g., hydroxypropyl methylcellulose) are present in the oral dosage form in the following ratio: 4:1 w / w to 1:5 w / w of compound of formula (I):cellulose derivative, preferably 3.5:1 w / w to 1:4.5 w / w of compound of formula (I):cellulose derivative, preferably 3:1 w / w to 1:4 w / w of compound of formula (I):cellulose derivative, preferably 2.5:1 w / w to 1:5 w / w of compound of formula (I):cellulose derivative. 3.5w / w of compound of formula (I):cellulose derivative, preferably 2:1 w / w to 1:3w / w of compound of formula (I):cellulose derivative, preferably 2.5:1 w / w to 1:2.5w / w of compound of formula (I):cellulose derivative, preferably 2:1 w / w to 1:2w / w of compound of formula (I):cellulose derivative, preferably 1.5:1 w / w to 1:1.5w / w of compound of formula (I):cellulose derivative, or a ratio comprised within any two ratios mentioned herein, or a range or sub-range of ratios within any two ratios mentioned herein.

[0132] 16. A compound for use according to any one of statements 1 to 15, wherein the oral dosage form is a solid dosage form comprising a cellulose derivative, the cellulose derivative being hydroxypropylmethylcellulose (HPMC), preferably wherein the hydroxypropylmethylcellulose has a viscosity in a 2 wt% H2O solution at 25°C in the range between 3 mPa.s and 5000 mPa.s, preferably in a 2 wt% H2O solution at 25°C in the range between 3 mPa.s and 500 mPa.s, preferably in a 2 wt% H2O solution at 25°C in the range between 3 mPa.s and 50 mPa.s. Preferably, the cellulose derivative is a hydroxypropylmethylcellulose selected from HPMC E5, HPMC E6, HPMC E15, HPMC E50 and mixtures thereof.

[0133] 17. A compound for use according to any one of statements 1 to 16, wherein the oral dosage form is a solid dosage form comprising a methacrylic acid copolymer; preferably, wherein the compound of formula (I) and the methacrylic acid copolymer are present in the solid dosage form in the following ratio: 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 a ratio comprised within any two ratios mentioned herein, or a range or sub-range of ratios within any two ratios mentioned herein.

[0134] 18. A compound for use according to any one of statements 1 to 17, wherein the oral dosage form is a solid dosage form comprising a copolymer selected from the group consisting of copolymers of methacrylic acid and methyl methacrylate, copolymers of methacrylic acid and ethyl acrylate, and mixtures thereof.

[0135] 19. A compound for use according to any one of statements 1 to 18, wherein the oral dosage form is formulated as a pharmaceutical formulation comprising up to 50% by weight, preferably up to 40% by weight, preferably up to 30% by weight, preferably up to 25% by weight, preferably up to 20% by weight, of a compound of formula (I) relative to the total weight of the formulation, or any specific amount or range contained therein.

[0136] 20. A compound for use according to any one of statements 1 to 19, wherein the solid dosage form is formulated in a pharmaceutical formulation comprising 0.1 wt% to 50 wt% of the compound of formula (I) relative to the total weight of the formulation, preferably 1 wt% to 40 wt%, more preferably 2.5 wt% to 30 wt%, most preferably 5 wt% to 25 wt% relative to the total weight of the formulation or any specific amount or range of the compound of formula (I) contained therein.

[0137] 21. A compound for use according to any one of statements 1 to 20, wherein the oral dosage form is formulated in a pharmaceutical formulation, which further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of disintegrants, binders, diluents, lubricants, stabilizers, wetting agents, glidants, osmotic agents, colorants, plasticizers, coating agents, fillers, surfactants, and mixtures thereof.

[0138] 22. A compound for use according to any one of statements 1 to 21, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising one or more pharmaceutically acceptable excipients; wherein the formulation comprises at most 95% by weight, at most 90% by weight, at most 80% by weight, preferably at most 70% by weight, preferably at most 60% by weight of the one or more pharmaceutically acceptable excipients relative to the total weight of the formulation;

[0139] And / or wherein the formulation comprises at least 10 wt.-%, preferably at least 20 wt.-%, preferably at least 30 wt.-% of the one or more pharmaceutically acceptable excipients relative to the total weight of the formulation.

[0140] 23. A compound for use according to any one of statements 1 to 22, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising one or more diluents; preferably wherein the formulation comprises at most 95% by weight, preferably at most 80% by weight, preferably at most 75% by weight of the diluent relative to the total weight of the formulation; and /

[0141] Or wherein the formulation comprises at least 5 wt.-%, preferably at least 10 wt.-%, preferably at least 15 wt.-% of said diluent relative to the total weight of the formulation.

[0142] 24. A compound for use according to any one of statements 1 to 23, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising one or more disintegrants; preferably wherein the formulation comprises up to 30% by weight, preferably up to 20% by weight, preferably up to 15% by weight, preferably up to 10% by weight of the disintegrant relative to the total weight of the formulation; and / or wherein the formulation comprises at least 1% by weight, preferably at least 2.5% by weight, preferably at least 5% by weight, preferably at least 8% by weight of the disintegrant relative to the total weight of the formulation.

[0143] 25. A compound for use according to any one of statements 1 to 24, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising one or more binders; preferably wherein the formulation comprises up to 50 wt.-%, preferably up to 45 wt.-%, preferably up to 40 wt.-%, more preferably up to 35 wt.-% of the binder relative to the total weight of the formulation; and / or wherein the formulation comprises at least 5 wt.-%, preferably at least 10 wt.-%, preferably at least 15 wt.-%, more preferably at least 20 wt.-%, most preferably 25 wt.-% of the binder relative to the total weight of the formulation.

[0144] 26. A compound for use according to any one of statements 1 to 25, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising one or more lubricants; preferably wherein the formulation comprises up to 5.5 wt.-%, preferably up to 3.5 wt.-%, preferably up to 2 wt.-% of the lubricant relative to the total weight of the formulation; and / or wherein the formulation comprises at least 0.5 wt.-%, preferably at least 1 wt.-%, preferably at least 1.5 wt.-% of the lubricant relative to the total weight of the formulation.

[0145] 27. A compound for use according to any one of statements 1 to 26, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising one or more wetting agents; preferably wherein the formulation comprises up to 5.5 wt. %, preferably up to 3.5 wt. %, preferably up to 2 wt. % of the wetting agent relative to the total weight of the formulation; and / or wherein the formulation comprises at least 0.5 wt. %, preferably at least 1 wt. %, preferably at least 1.5 wt. % of the wetting agent relative to the total weight of the formulation.

[0146] 28. A compound for use according to any one of statements 1 to 27, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising one or more glidants; preferably wherein the formulation comprises up to 10 wt.-%, preferably up to 8 wt.-%, preferably up to 5 wt.-% of the glidant relative to the total weight of the formulation; and / or wherein the formulation comprises at least 0.1 wt.-%, preferably at least 1 wt.-%, preferably at least 2 wt.-% of the glidant relative to the total weight of the formulation.

[0147] 29. A compound for use according to any one of statements 1 to 28, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising a plurality of particles forming an intragranular phase of the formulation, and one or more pharmaceutically acceptable excipients forming an extragranular phase of the formulation.

[0148] 30. A compound for use according to any one of statements 1 to 29, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising at least 15.0 wt. % of intragranular phase, based on the weight of the pharmaceutical formulation; preferably at least 20.0 wt. %, preferably at least 28.0 wt. %, preferably at least 34.0 wt. % of intragranular phase, based on the weight of the pharmaceutical formulation.

[0149] 31. A compound for use according to any one of statements 1 to 30, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising up to 99.0 wt. % of intragranular phase, based on the weight of the pharmaceutical formulation; preferably up to 93.0 wt. %, preferably up to 85.0 wt. %, preferably up to 80.0 wt. %, preferably up to 74.0 wt. %, preferably up to 73.0 wt. %, preferably up to 67.0 wt. %, preferably up to 63.0 wt. %, preferably up to 60.0 wt. %, preferably up to 53.0 wt. % of intragranular phase, based on the weight of the pharmaceutical formulation.

[0150] 32. A compound for use according to any one of statements 1 to 31, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising an intragranular phase comprising 1.0 wt% to 70.0 wt% of the compound of formula (I) based on the weight of the pharmaceutical formulation; preferably 2.0 wt% to 60.0 wt%, preferably 3.0 wt% to 55.0 wt%, preferably 4.0 wt% to 50.0 wt%, preferably 5.0 wt% to 45.0 wt%, preferably 5.0 wt% to 40.0 wt%, preferably 10.0 wt% to 35.0 wt%, preferably 15.0 wt% to 30.0 wt% of the compound of formula (I) based on the total weight of the pharmaceutical formulation.

[0151] 33. A compound for use according to any one of statements 1 to 32, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising (a) an active pharmaceutical ingredient (API); and (b) 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), or a combination thereof. Preferably, the cellulose derivative is HPMC;

[0152] The API is a compound of formula (I); preferably compound (a).

[0153] 34. A compound for use according to any one of statements 1 to 33, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising an intragranular phase comprising 5 to 60 wt%, preferably 8 to 50 wt%, preferably 15 to 45 wt% of a methacrylic acid copolymer, a cellulose derivative or a mixture thereof, based on the total weight of the pharmaceutical formulation. Preferably, the cellulose derivative is hydroxypropyl methylcellulose.

[0154] 35. A compound for use according to any one of statements 1 to 34, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising an intragranular phase comprising 5 to 60 wt %, preferably 10 to 60 wt %, preferably 10 to 50 wt %, preferably 15 to 50 wt % of filler, based on the total weight of the pharmaceutical formulation.

[0155] 36. A compound for use according to any one of statements 1 to 35, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising an intragranular phase comprising 1 wt% to 10 wt%, preferably 1 wt% to 9 wt%, preferably 1.7 wt% to 8 wt% of a disintegrant, based on the total weight of the pharmaceutical formulation.

[0156] 37. A compound for use according to any one of statements 1 to 36, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising an intragranular phase comprising 0.1 wt% to 5 wt%, preferably 0.2 wt% to 4.7 wt%, preferably 0.5 wt% to 4.5 wt% of a glidant, based on the total weight of the pharmaceutical formulation.

[0157] 38. A compound for use according to any one of statements 1 to 37, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising an intragranular phase comprising 0.1 wt% to 5 wt%, preferably 0.2 wt% to 4.7 wt%, preferably 0.5 wt% to 4.5 wt% of a surfactant based on the total weight of the pharmaceutical formulation.

[0158] 39. A compound for use according to any one of statements 1 to 28, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising an intragranular phase comprising 0.1 wt% to 3 wt%, preferably 0.2 wt% to 2.7 wt%, preferably 0.5 wt% to 2.5 wt% of a lubricant, based on the total weight of the pharmaceutical formulation.

[0159] 40. A compound for use according to any one of statements 1 to 39, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising an intragranular phase comprising:

[0160] (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 a compound of formula (I), based on the weight of the pharmaceutical preparation;

[0161] (ii) 5 to 60 wt%, preferably 8 to 50 wt%, preferably 15 to 45 wt% of methacrylic acid copolymer or hydroxypropyl methylcellulose, based on the weight of the pharmaceutical formulation; and

[0162] Optionally (iii) 5 to 60 wt%, preferably 10 to 60 wt%, preferably 10 to 50 wt%, preferably 15 to 50 wt%, based on the weight of the pharmaceutical formulation, of a filler;

[0163] Optionally (iv) 1 to 10 wt %, preferably 1 to 9 wt %, preferably 1.7 to 8 wt % of a disintegrant, based on the weight of the pharmaceutical formulation;

[0164] Optionally (v) 0.1 wt% to 50 wt%, preferably 0.2 wt% to 4.7 wt%, preferably 0.5 wt% to 4.5 wt% of a glidant, based on the weight of the pharmaceutical formulation;

[0165] Optionally (vi) 0.1 wt% to 5 wt%, preferably 0.2 wt% to 4.7 wt%, preferably 0.5 wt% to 4.5 wt% of a surfactant, based on the weight of the pharmaceutical formulation; and

[0166] Optionally (vii) 0.1 wt% to 3 wt%, preferably 0.2 wt% to 2.7 wt%, preferably 0.5 wt% to 2.5 wt% of a lubricant, based on the weight of the pharmaceutical formulation.

[0167] 41. A compound for use according to any one of statements 1 to 40, wherein the oral dosage form is formulated as a pharmaceutical preparation comprising at least

[0168] 5% by weight of the extragranular phase; based on the total weight of the pharmaceutical preparation, preferably at least

[0169] 7 wt.-%, preferably at least 10 wt.-%, preferably at least 15 wt.-%, preferably at least 20 wt.-%, preferably at least 28 wt.-%, preferably at least 34 wt.-% of extragranular phase.

[0170] 42. A compound for use according to any one of statements 1 to 41, wherein the oral dosage form is formulated as a pharmaceutical preparation comprising at most

[0171] 74% by weight of the extragranular phase; preferably up to

[0172] 73 wt.-%, preferably at most 67 wt.-%, preferably at most 63 wt.-%, preferably at most 53 wt.-%, preferably at most 40 wt.-% of extragranular phase.

[0173] 43. A compound for use according to any one of statements 1 to 42, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising an extragranular phase comprising 0.1 wt% to 5 wt% of a disintegrant, based on the weight of the pharmaceutical formulation; preferably 0.2 wt% to 4.7 wt%, preferably 0.5 wt% to 3.5 wt% of a disintegrant, based on the total weight of the pharmaceutical formulation.

[0174] 44. A compound for use according to any one of statements 1 to 43, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising an extragranular phase comprising 0.1 wt% to 3 wt% lubricant by weight of the pharmaceutical formulation; preferably 0.2 wt% to 2.7 wt%, preferably 0.5 wt% to 2.5 wt% lubricant by total weight of the pharmaceutical formulation.

[0175] 45. A compound for use according to any one of statements 1 to 44, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising an extragranular phase comprising 0.1 wt% to 55 wt% of filler based on the weight of the pharmaceutical formulation; preferably 0.2 wt% to 50 wt%, preferably 0.2 wt% to 50 wt%, based on the total weight of the pharmaceutical formulation.

[0176] 0.3 wt % to 45 wt %, preferably 0.4 wt % to 40 wt %, preferably

[0177] 0.5 wt % to 35 wt %, preferably 0.6 wt % to 30 wt %, preferably

[0178] 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 %

[0179] % to 8 wt. %, preferably 4 to 7 wt. %, preferably 5 to 6 wt. % filler.

[0180] 46. ​​A compound for use according to any one of statements 1 to 45, wherein the oral dosage form is formulated in a pharmaceutical formulation comprising an extragranular phase comprising:

[0181] (a) 0.1 wt % to 5 wt % of a disintegrant based on the weight of the pharmaceutical formulation;

[0182] Preferably 0.2 wt% to 4.7 wt%, preferably 0.5 wt% to 3.5 wt%, more preferably 1 wt% to 3 wt% of a disintegrant, based on the total weight of the pharmaceutical formulation;

[0183] (b) 0.1 wt % to 3.0 wt % of a lubricant, based on the weight of the pharmaceutical formulation;

[0184] Preferably 0.2 wt% to 2.7 wt%, preferably 0.5 wt% to 2.5 wt% of a lubricant, based on the total weight of the pharmaceutical formulation; and

[0185] 1 to 15% by weight of a filler based on the weight of the pharmaceutical preparation;

[0186] Preferably 1.3 wt% to 12 wt%, preferably 2.5 wt% to 8 wt%, more preferably 3 wt% to 5 wt% filler based on the total weight of the pharmaceutical formulation.

[0187] 47. A compound for use according to any one of Statements 1 to 46, wherein the oral dosage form is a tablet.

[0188] 48. A compound for use according to any one of statements 1 to 47, wherein the oral dosage form is a solid dosage form, preferably a tablet, comprising 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).

[0189] 49. A compound for use according to any one of statements 1 to 48, wherein the oral dosage form is a solid dosage form, preferably a tablet, the tablet preferably comprising 0.5 mg to 1500 mg of the compound of formula (I), preferably comprising 1 mg to 1400 mg of the compound of formula (I), preferably comprising 2 mg to 1300 mg of the compound of formula (I), preferably comprising 3 mg to 1200 mg of the compound of formula (I), preferably comprising 4 mg to 1250 mg of the compound of formula (I)

[0190] The compound preferably contains 5 mg to 1000 mg of the compound of formula (I), preferably contains 6 mg to 1000 mg of the compound of formula (I), preferably contains 7 mg to 1300 mg of the compound of formula (I), preferably contains 8 mg to 1200 mg of the compound of formula (I), preferably contains 9 mg to 1000 mg of the compound of formula (I), preferably contains 10 mg to 950 mg of the compound of formula (I), preferably contains 15 mg to 900 mg of the compound of formula (I), preferably contains 20 mg to 800 mg of the compound of formula (I), preferably contains 25 mg to 700 mg of the compound of formula (I). The invention relates to a pharmaceutical composition comprising: ...

[0191] 50. A compound for use according to any one of statements 1 to 49, wherein oral administration of the oral dosage form results in a maximum concentration (C 20 ) 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 25 μg / L to 10,000 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 subsumed therein.

[0192] 51. A compound for use according to any one of statements 1 to 50, wherein oral administration of the oral dosage form to a human in a fed state results in a maximum concentration (C 20 ) 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 25 μg / L to 10,000 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.

[0193] 52. A compound for use according to any one of statements 1 to 51, wherein the oral dosage form is administered to the human subject at least once a day, such as at least twice a day, at least three times a day, such as at least four times a day.

[0194] 53. A compound for use according to any one of Statements 1 to 52, wherein the oral dosage form is administered to the human subject once a day or twice a day.

[0195] 54. A compound for use according to any one of statements 1 to 53, wherein the amount of compound administered in one day or 24 hours (daily dose) is administered to the subject, preferably a human subject, in a single oral dosage form, or in two, three or four oral dosage forms. For example, where the oral dosage form is a tablet, the daily dose can be administered to the subject in the form of one, two, three or four tablets.

[0196] 55. A compound for use according to any one of Statements 1 to 54, wherein the formula (I)

[0197] The compounds are:

[0198]

[0199] or a stereoisomeric form, a pharmaceutically acceptable salt, a solvate or a polymorph thereof.

[0200] 56. A compound for use according to any one of statements 1 to 55, wherein the oral dosage form is administered according to a dosing regimen comprising:

[0201] 1) at least one loading phase during which at least one dose (A) of a compound of formula (I) is administered at least once a day over a period of at least one day; and

[0202] 2) at least one maintenance period starting from the last day of administration of dose (A) or the day after the last day of the loading period, during which at least one dose (B) of a 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 over a period of at least one day;

[0203] wherein the dose (A) is higher or lower than the dose (B). Preferably, the dose (A)

[0204] Higher than dose (B).

[0205] 57. A compound for use according to any one of statements 1 to 56, wherein the oral dosage form is administered according to a dosing regimen comprising:

[0206] 1) at least one loading phase during which at least one dose (A) of a compound of formula (I) is administered at least once a day within the following time periods: up to 20 days,

[0207] Preferably at most 19 days, preferably at most 18 days, preferably at most 17 days,

[0208] Preferably at most 16 days, preferably at most 15 days, preferably at most 14 days,

[0209] Preferably at most 13 days, preferably at most 12 days, preferably at most 11 days,

[0210] Preferably at most 10 days, preferably at most 9 days, preferably at most 8 days, preferably at most 7 days, preferably at most 6 days, preferably at most 5 days, preferably at most 4 days, preferably at most 3 days, preferably at most 2 days, preferably at most

[0211] 1 day, or any specific amount or range subsumed therein; and

[0212] 2) at least one maintenance period starting from the day after the last day of administration of dose (A) or the last day of the loading period, during which at least one dose (B) of a 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 within the following period: at least one day to up to 12 months, preferably up to 9 months, preferably up to 6 months, preferably up to 3 months, preferably up to 1.5 months, preferably up to 40 days, preferably up to 39 days, preferably up to 38 days, preferably up to 37 days, preferably up to 36 days, preferably up to 35 days, preferably up to 30 days, preferably up to 28 days, preferably up to 21 days, preferably up to 14 days, preferably up to 7 days, preferably up to 5 days, or any specific amount or range subsumed therein;

[0213] wherein the dose (A) is higher or lower than the dose (B). Preferably, the dose (A)

[0214] Higher than dose (B).

[0215] 58. A compound for use according to any one of statements 1 to 57, wherein the oral dosage form is administered according to a dosing regimen comprising:

[0216] 1) at least one loading phase during which at least one dose (A) of a compound of formula (I) is administered at least once a day within the following time periods: up to 20 days,

[0217] 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days,

[0218] 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 subsumed therein; and

[0219] 2) at least one maintenance period starting from the last day of administration of dose (A) or the day after the last day of the loading period, during which at least one dose (B) 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 within the following time period:

[0220] Compound: at least one day to up to 12 months, 9 months, 6 months, 3 months,

[0221] 1.5 months, 40 days, 39 days, 38 days, 37 days, 36 days, 35 days, 30 days,

[0222] 28 days, 21 days, 14 days, 7 days, 5 days, or any specific amount or range subsumed therein;

[0223] wherein the dose (A) is higher or lower than the dose (B). Preferably, the dose (A)

[0224] Higher than dose (B).

[0225] 59. A compound for use according to any one of statements 1 to 58, wherein the oral dosage form is administered according to a dosing regimen comprising:

[0226] 1) at least one loading phase during which at least one dose (A) of a 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 within a period of at least 1 day to at most 20 days, preferably at least 2 days to at most 19 days, preferably at least 3 days to at most 18 days, preferably at least 4 days to at most 17 days, preferably at least 5 days to at most 16 days, preferably at least 6 days to at most 15 days, preferably at least 7 days to at most 14 days, preferably at least 8 days to at most 13 days, preferably at least 9 days to at most 12 days, preferably at least 10 days to at most 11 days, or any specific amount or range subsumed therein; and

[0227] 2) at least one maintenance period starting from the last day of administration of dose (A) or the day after the last day of the loading period, during which at least one dose (B) of a 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 at least three times a day, preferably at least four times a day within the following time period: at least 1 day to at most 12 months, at least 2 days to at most 6 months, preferably at least 3 days to at most 3 months, preferably at least 1 day to at most 30 days, preferably at least 5 days to at most 28 days, preferably at least 10 days to at most 26 days, or any specific amount or range subsumed therein;

[0228] wherein the dose (A) is higher or lower than the dose (B). Preferably, the dose (A)

[0229] Higher than dose (B).

[0230] 60. A compound for use according to any one of statements 56 to 59, wherein the dose (A) of the compound of formula (I) is in the range of 50 mg to 1200 mg, preferably in the range of 100 mg to

[0231] 1100mg, preferably in the range of 150mg to 900mg, preferably in the range of

[0232] In the range of 50 mg to 800 mg, preferably in the range of 60 mg to 700 mg, preferably in the range of 70 mg to 650 mg, preferably in the range of 80 mg to 600 mg, preferably in the range of 90 mg to 550 mg, preferably in the range of 100 mg to 500 mg, or any specific amount or range subsumed therein.

[0233] 61. A compound for use according to any one of statements 56 to 60, wherein the dose (A) of the compound of formula (I) is in the range of 5 mg to 1500 mg, preferably in the range of 10 mg to

[0234] 1400mg, preferably in the range of 20mg to 1300mg, preferably in the range of

[0235] Preferably, the range of the present invention is 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 subsumed therein.

[0236] 62. A compound for use according to any one of statements 56 to 61, wherein the dose (A) of the compound of formula (I) is administered at least once a day, preferably at least twice a day.

[0237] 63. A compound for use according to any one of statements 56 to 62, wherein the dose (B) of the compound of formula (I) is in the range of 5 mg to 1500 mg, preferably in the range of 25 mg to

[0238] 1200mg range, preferably 50mg to 1100mg range, preferably

[0239] In the range of 100 mg to 1000 mg, preferably in the range of 150 mg to 900 mg, preferably in the range of 5 mg to 500 mg, preferably in the range of 5 mg to 450 mg, preferably in the range of 5 mg to 400 mg, preferably in the range of 5 mg to 350 mg, preferably in the range of 10 mg to 300 mg, preferably in the range of 15 mg to 250 mg, preferably in the range of 20 mg to 230 mg, preferably in the range of 30 mg to 250 mg, preferably in the range of 35 mg to 200 mg, preferably in the range of 50 mg to 450 mg, or any specific amount or range subsumed therein.

[0240] 64. A compound for use according to any one of statements 56 to 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, dose (B) is administered once a day.

[0241] 65. A compound for use according to any one of statements 56 to 64, wherein a 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 at least three times a day, preferably at least four times a day within the following period: at least 1 day to at most 12 months, at least 2 days to at most 6 months, preferably at least 3 days to at most 3 months, preferably at least 1 day to at most 30 days, preferably at least 5 days to at most 28 days, preferably at least 10 days to at most 26 days, or any specific amount or range subsumed therein.

[0242] 66. A compound for use according to any one of statements 56 to 65, wherein a dose of formula (I) (A) 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 within the following period:

[0243] Compound: at least 1 day to at most 20 days, preferably at least 2 days to at most 19 days, preferably at least 3 days to at most 18 days, preferably at least 4 days to at most 17 days, preferably at least 5 days to at most 16 days, preferably at least 6 days to at most 15 days, preferably at least 7 days to at most 14 days, preferably at least 8 days to at most 13 days, preferably at least 9 days to at most 12 days, preferably at least 10 days to at most 11 days, or any specific amount or range subsumed therein.

[0244] 67. A compound for use according to any one of statements 56 to 66, wherein a dose of formula (I) (A) 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 within the following period:

[0245] Compound: at least 1 day to at most 20 days, preferably at least 2 days to at most 19 days, preferably at least 3 days to at most 18 days, preferably at least 4 days to at most 17 days, preferably at least 5 days to at most 16 days, preferably at least 6 days to at most 15 days, preferably at least 7 days to at most 14 days, preferably at least 8 days to at most 13 days, preferably at least 9 days to at most 12 days, preferably at least 10 days to at most 11 days, or any specific amount or range subsumed therein;

[0246] And wherein the dose (A) of the compound of formula (I) is in the range of 50 mg to 1200 mg, preferably in the range of 100 mg to 1100 mg, preferably in the range of 150 mg to 900 mg, preferably in the range of 50 mg to 800 mg, preferably in the range of 60 mg to 700 mg, preferably in the range of 70 mg to 650 mg, preferably in the range of 80 mg to 600 mg, preferably in the range of 90 mg to 550 mg, preferably in the range of 100 mg to 500 mg, or any specific amount or range subsumed therein.

[0247] 68. A compound for use according to any one of statements 56 to 67, wherein a dose of formula (I) (A) 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 within the following period:

[0248] Compound: at least 1 day to at most 20 days, preferably at least 2 days to at most 19 days, preferably at least 3 days to at most 18 days, preferably at least 4 days to at most 17 days, preferably at least 5 days to at most 16 days, preferably at least 6 days to at most 15 days, preferably at least 7 days to at most 14 days, preferably at least 8 days to at most 13 days, preferably at least 9 days to at most 12 days, preferably at least 10 days to at most 11 days, or any specific amount or range subsumed therein;

[0249] and wherein the dose (A) of the compound of formula (I) is in the range of 5 mg to 1500 mg, preferably in the range of 10 mg to 1400 mg, preferably in the range of 20 mg to 1300 mg, preferably in the range of 25 mg to 1200 mg, preferably in the range of 30 mg to

[0250] 1100mg range, preferably 35mg to 1000mg range, preferably

[0251] In the range of 15 mg to 1450 mg, preferably in the range of 15 mg to 1100 mg, preferably in the range of 25 mg to 1000 mg, preferably in the range of 10 mg to 900 mg, preferably in the range of 15 mg to 900 mg, preferably in the range of 20 mg to 900 mg, preferably in the range of 30 mg to 900 mg, preferably in the range of 35 mg to 800 mg, preferably in the range of 50 mg to 800 mg, or any specific amount or range subsumed therein.

[0252] 69. A compound for use according to any one of statements 56 to 68, wherein a 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 at least three times a day, preferably at least four times a day within the following period: at least 1 day to at most 12 months, at least 2 days to at most 6 months, preferably at least 3 days to at most 3 months, preferably at least 1 day to at most 30 days, preferably at least 5 days to at most 28 days, preferably at least 10 days to at most 26 days, or any specific amount or range subsumed therein;

[0253] and wherein the dose (B) of the compound of formula (I) is in the range of 5 mg to 1500 mg, preferably in the range of 25 mg to 1200 mg, preferably in the range of 50 mg to 1100 mg, preferably in the range of 100 mg to 1000 mg, preferably in the range of 150 mg to

[0254] 900mg, preferably in the range of 5mg to 500mg, preferably in the range of 5mg to

[0255] In the range of 450mg, preferably in the range of 5mg to 400mg, preferably in the range of 5mg to

[0256] Preferably, the range of 10 to 350 mg is preferably within the range of 10 to 300 mg, preferably within the range of 15 to 250 mg, preferably within the range of 20 to 230 mg, preferably within the range of 30 to 250 mg, preferably within the range of 35 to 200 mg, preferably within the range of 50 to 450 mg, or any specific amount or range subsumed therein.

[0257] 70. A pharmaceutical preparation for preventing and / or treating dengue virus infection, the preparation comprising

[0258] a) a compound of formula (I); and

[0259] b1) methacrylic acid copolymer, or

[0260] b2) cellulose derivatives, such as methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (NaCMC) or hydroxypropyl methyl cellulose (HPMC) or combinations thereof. Preferably, the cellulose derivative is HPMC;

[0261] wherein the pharmaceutical formulation is administered to a human subject in a fed state or a fasted state;

[0262] Wherein formula (I) corresponds to

[0263]

[0264] Its stereoisomeric form, pharmaceutically acceptable salt, solvate or polymorph; the compound is selected from the following group, wherein:

[0265] R1 is H, R2 is F, and R3 is H or CH3,

[0266] R1 is H, CH3 or F, R2 is OCH3, and R3 is H,

[0267] R1 is H, R2 is OCH3, and R3 is CH3,

[0268] R1 is CH3, R2 is F, and R3 is H,

[0269] R1 is CF3 or OCF3, R2 is H, and R3 is H,

[0270] R1 is OCF3, R2 is OCH3, and R3 is H,

[0271] R1 is OCF3, R2 is H, and R3 is CH3.

[0272] 71. A pharmaceutical formulation for use according to statement 70, wherein the pharmaceutical formulation is administered in an oral dosage form to a human subject in a fed state; preferably, the human subject in the fed state has consumed a standard normal fat meal, a high fat-high calorie meal, a low fat-low calorie meal, or a low fat-high calorie meal.

[0273] 72. A pharmaceutical formulation for use according to any one of statements 70 or 71, wherein the human subject is infected with or at risk of being infected with a dengue virus.

[0274] 73. A pharmaceutical formulation for use according to any one of statements 70 or 72, wherein the human subject is in a fed state prior to or while administering the oral dosage form.

[0275] 74. A pharmaceutical formulation for use according to any one of statements 70 to 73, wherein the pharmaceutical formulation is administered to a human subject in a fed state, and wherein the human in the fed state has eaten 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 the time of administration of the pharmaceutical formulation, and the pharmaceutical formulation is preferably administered within at most 30 minutes after eating, preferably within at most 25 minutes after eating, preferably within at most 20 minutes after eating, preferably within at most 15 minutes after eating, preferably within at most 10 minutes after eating, preferably within at most 5 minutes after eating, preferably while eating.

[0276] 75. A pharmaceutical preparation for use according to any one of statements 70 to 74, wherein the pharmaceutical preparation is administered orally.

[0277] 76. A pharmaceutical preparation for use according to any one of statements 70 to 75, wherein the pharmaceutical preparation is administered in the morning. The oral dosage form may be administered with or after the first, second or third meal of the day.

[0278] 77. A pharmaceutical formulation for use according to any one of statements 70 to 76, wherein the human being in a fed state has eaten food comprising the following amount of fat: at least 0.1 g fat, preferably at least 0.2 g fat, preferably at least 0.3 g fat, preferably at least 0.4 g fat, preferably at least 0.5 g fat, preferably at least 0.6 g fat, preferably at least 0.7 g fat, preferably at least 0.8 g fat, preferably at least 0.9 g fat, preferably at least 1 g fat, preferably at least 2 g fat, preferably at least 3 g fat, preferably at least 4 g fat, preferably at least 5 g fat. g fat, preferably at least 6 g fat, preferably at least 7 g fat, preferably at least 8 g fat, preferably at least 9 g fat, preferably at least 10 g fat, preferably at least 11 g fat, preferably at least 12 g fat, preferably at least 13 g fat, preferably at least 14 g fat, preferably at least 15 g fat, preferably at least 16 g fat, preferably at least 17 g fat, preferably at least 18 g fat, preferably at least 19 g fat, preferably at least 20 g fat, preferably at least 21 g fat, preferably at least 22 g fat, preferably at least 23 g fat, preferably at least 24 g fat , preferably at least 25g fat, preferably at least 26g fat, preferably at least 27g fat, preferably at least 28g fat, preferably at least 29g fat, preferably at least 30g fat, preferably at least 31g fat, preferably at least 32g fat, preferably at least 33g fat, preferably at least 34g fat, preferably at least 35g fat, preferably at least 36g fat, preferably at least 37g fat, preferably at least 38g fat, preferably at least 39g fat, preferably at least 40g fat, preferably at least 41g fat, preferably at least 42g fat, preferably at least 43g fat. g fat, preferably at least 44g fat, preferably at least 45g fat, preferably at least 46g fat, preferably at least 47g fat, preferably at least 48g fat, preferably at least 49g fat, preferably at least 50g fat, preferably at least 51g fat, preferably at least 52g fat, preferably at least 53g fat, preferably at least 54g fat, preferably at least 55g fat, preferably at least 56g fat, preferably at least 57g fat, preferably at least 58g fat, preferably at least 59g fat, preferably at least 60g fat, or any specific amount or range subsumed therein.

[0279] 78. A pharmaceutical formulation for use according to any one of statements 70 to 77, wherein the human being in a fed state has eaten food comprising the following amount of fat: at least 0.1 g fat, preferably at least 0.2 g fat, preferably at least 0.3 g fat, preferably at least 0.4 g fat, preferably at least 0.5 g fat, preferably at least 0.6 g fat, preferably at least 0.7 g fat, preferably at least 0.8 g fat, preferably at least 0.9 g fat, preferably at least 1 g fat, preferably at least 2 g fat, preferably at least 3 g fat, preferably at least 4 g fat, preferably at least 5 g fat. g fat, preferably at least 6 g fat, preferably at least 7 g fat, preferably at least 8 g fat, preferably at least 9 g fat, preferably at least 10 g fat, preferably at least 11 g fat, preferably at least 12 g fat, preferably at least 13 g fat, preferably at least 14 g fat, preferably at least 15 g fat, preferably at least 16 g fat, preferably at least 17 g fat, preferably at least 18 g fat, preferably at least 19 g fat, preferably at least 20 g fat, preferably at least 21 g fat, preferably at least 22 g fat, preferably at least 23 g fat, preferably at least 24 g fat , preferably at least 25g fat, preferably at least 26g fat, preferably at least 27g fat, preferably at least 28g fat, preferably at least 29g fat, preferably at least 30g fat, preferably at least 31g fat, preferably at least 32g fat, preferably at least 33g fat, preferably at least 34g fat, preferably at least 35g fat, preferably at least 36g fat, preferably at least 37g fat, preferably at least 38g fat, preferably at least 39g fat, preferably at least 40g fat, preferably at least 41g fat, preferably at least 42g fat, preferably at least 43g fat. g fat, preferably at least 44g fat, preferably at least 45g fat, preferably at least 46g fat, preferably at least 47g fat, preferably at least 48g fat, preferably at least 49g fat, preferably at least 50g fat, preferably at least 51g fat, preferably at least 52g fat, preferably at least 53g fat, preferably at least 54g fat, preferably at least 55g fat, preferably at least 56g fat, preferably at least 57g fat, preferably at least 58g fat, preferably at least 59g fat, preferably at least 60g fat, or any specific amount or range subsumed therein;

[0280] And wherein the human has eaten less than 4 hours before administration of the compound of formula I, has eaten 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 the administration time of the oral dosage form, and the oral dosage form is preferably administered within 30 minutes after eating, preferably within 25 minutes after eating, preferably within 20 minutes after eating, preferably within 15 minutes after eating, preferably within 10 minutes after eating, preferably within 5 minutes after eating before administration of the compound of formula I such as compound (a); preferably the compound of formula I such as compound (a), preferably the compound of formula I is administered while eating.

[0281] 79. A pharmaceutical preparation for use according to any one of statements 70 to 78, wherein the human being in a fed state has consumed a food containing fat in an amount of at least 0.1 g, 0.2 g,

[0282] 0.3g, 0.4g, 0.5g, 0.6g, 0.7g, 0.8g or 0.9g fat, preferably at least 1g,

[0283] 2g, 3g, 4g or 5g fat, preferably at least 6g, 7g, 8g, 9g or 10g fat, preferably at least 11g, 12g, 13g, 14g or 15g fat; preferably at least 16g, 17g, 18g, 19g or 20g fat, preferably at least 21g, 22g, 23g, 24g, 25g or 26g fat.

[0284] 23g, 24g or 25g fat, preferably at least 26g, 27g, 28g, 29g or 30g fat; preferably at least 31g, 32g, 33g, 34g or 35g fat, preferably at least 36g, 37g, 38g, 39g or 40g fat, preferably at least 41g, 42g, 43g,

[0285] 44g or 45g fat, preferably at least 46g, 47g, 48g, 49g or 50g fat, preferably at least 51g, 52g, 53g, 54g or 55g fat, preferably at least 56g,

[0286] 57g, 58g, 59g or 60g fat, or any specific amount or range contained therein. 80. A pharmaceutical preparation for use according to any one of statements 70 to 79, wherein the human being in a fed state has eaten food having a total energy count 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

[0287] 110 kcal, preferably at least 120 kcal, preferably at least 130 kcal, preferably at least

[0288] 140 kcal, preferably at least 150 kcal, preferably at least 160 kcal, preferably at least

[0289] 170 kcal, preferably at least 180 kcal, preferably at least 190 kcal, preferably at least

[0290] 200 kcal, preferably at least 210 kcal, preferably at least 220 kcal, preferably at least

[0291] 230 kcal, preferably at least 240 kcal, preferably at least 250 kcal, preferably at least

[0292] 260 kcal, preferably at least 270 kcal, preferably at least 280 kcal, preferably at least

[0293] 290 kcal, preferably at least 300 kcal, preferably at least 310 kcal, preferably at least

[0294] 320 kcal, preferably at least 330 kcal, preferably at least 340 kcal, preferably at least

[0295] 350 kcal, preferably at least 360 kcal, preferably at least 370 kcal, preferably at least

[0296] 380 kcal, preferably at least 390 kcal, preferably at least 400 kcal, preferably at least

[0297] 410 kcal, preferably at least 420 kcal, preferably at least 430 kcal, preferably at least

[0298] 440 kcal, preferably at least 450 kcal, preferably at least 460 kcal, preferably at least

[0299] 470 kcal, preferably at least 480 kcal, preferably at least 490 kcal, preferably at least

[0300] 500kcal, or any specific amount or range subsumed therein. Preferably the human being in the fed state has eaten food having a total energy count of at most 1500 kcal, preferably at most 1400 kcal, preferably at most 1300 kcal, preferably at most 1200 kcal, preferably at most 1110 kcal, preferably at most 1000 kcal, preferably at most 980 kcal, preferably at most 960 kcal, preferably at most 940 kcal, preferably at most 920 kcal, preferably at most 810 kcal, preferably at most 820 kcal, preferably at most 830 kcal, preferably at most 840 kcal, preferably at most 850 kcal, preferably at most 860 kcal, preferably at most 870 kcal, preferably at most 880 kcal, preferably at most 890 kcal, preferably at most 900 kcal, preferably at most 710 kcal, preferably at most 720 kcal, preferably at most 730 kcal, preferably at most 740 kcal, preferably at most kcal at most, preferably at most 510 kcal, preferably at most 520 kcal, preferably at most 530 kcal, preferably at most 540 kcal, preferably at most 550 kcal, preferably at most 560 kcal, preferably at most 570 kcal, preferably at most 580 kcal, preferably at most 590 kcal, preferably at most 600 kcal, or any specific amount or range subsumed therein.

[0301] 81. A pharmaceutical preparation for use according to any one of statements 70 to 80, wherein the human being in a fed state has eaten food having a total energy count of at least 10 kcal,

[0302] 20kcal, 30kcal, 40kcal or 50kcal, preferably at least 60kcal, 70kcal,

[0303] 80kcal, 90kcal or 100kcal, preferably at least 110kcal, 120kcal,

[0304] 130 kcal, 140 kcal or 150 kcal, preferably at least 160 kcal, 170 kcal,

[0305] 180 kcal, 190 kcal or 200 kcal, preferably at least 210 kcal, 220 kcal,

[0306] 230kcal, 240kcal, 250kcal, 260kcal, 270kcal, 280kcal,

[0307] 290kcal or 300kcal, preferably at least 310kcal, 320kcal, 330kcal,

[0308] 340kcal, 350kcal, 360kcal, 370kcal, 380kcal, 390kcal or

[0309] 400 kcal, preferably at least 410 kcal, 420 kcal, 430 kcal, 440 kcal,

[0310] 450kcal, 460kcal, 470kcal, 480kcal, 490kcal or 500kcal, or

[0311] Preferably, the human being in the fed state has consumed food having a total energy count of at most 1500 kcal, 1400 kcal,

[0312] 1300 kcal, 1200 kcal or 1110 kcal, preferably at most 1000 kcal, 980 kcal,

[0313] 960 kcal, 940 kcal or 920 kcal, preferably at most 810 kcal, 820 kcal,

[0314] 830 kcal, 840 kcal or 850 kcal, preferably at most 860 kcal, 870 kcal,

[0315] kcal, 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 subsumed therein.

[0316] 82. A pharmaceutical formulation for use according to any one of statements 70 to 81, wherein the pharmaceutical formulation comprises a cellulose derivative (such as HPMC); preferably, wherein the compound of formula (I) and the hydroxypropyl methylcellulose are present in the oral dosage form in the following ratios: 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 compound of formula (I):cellulose derivative, preferably 2:1 w / w to 1:3 w / w of compound of formula (I):cellulose derivative, preferably 2.5:1 w / w to 1:2.5 w / w of compound of formula (I):cellulose derivative, preferably 2:1 w / w to 1:2 w / w of compound of formula (I):cellulose derivative, preferably 1.5:1 w / w to 1:1.5 w / w of compound of formula (I):cellulose derivative, or a ratio comprised within any two ratios mentioned herein, or a range or sub-range of ratios within any two ratios mentioned herein.

[0317] 83. A pharmaceutical formulation for use according to any one of statements 70 to 82, wherein the pharmaceutical formulation comprises a cellulose derivative, preferably wherein the hydroxypropyl methylcellulose has a viscosity in a 2 wt% H2O solution at 25° C. in the range between 3 mPa.s and 5000 mPa.s, preferably in a 2 wt% H2O solution at 25° C. in the range between 3 mPa.s and 500 mPa.s, preferably in a 2 wt% H2O solution at 25° C. in the range between 3 mPa.s and 50 mPa.s. Preferably, the cellulose derivative is a hydroxypropyl methylcellulose selected from HPMC E5, HPMC E6, HPMC E15, HPMC E50 and mixtures thereof.

[0318] 84. A pharmaceutical formulation for use according to any one of statements 70 to 83, wherein the pharmaceutical formulation comprises a methacrylic acid copolymer; preferably, wherein the compound of formula (I) and the methacrylic acid copolymer are present in the solid dosage form in the following ratio: 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 1:4.5w / w, preferably 3:1w / w to 1:4w / w, preferably 2.5:1w / w to 1:3.5w / w, preferably 2:1w / w to 1:3w / w, preferably 2.5:1w / w to 1:2.5w / w, preferably 2:1w / w to 1:2w / w, preferably 1.5:1w / w to 1:1.5w / w, or a ratio comprised within any two ratios mentioned herein, or a range or sub-range of ratios within any two ratios mentioned herein.

[0319] 85. A pharmaceutical formulation for use according to any one of statements 70 to 84, wherein the pharmaceutical formulation comprises a copolymer 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.

[0320] 86. A pharmaceutical formulation for use according to any one of statements 70 to 85, wherein the pharmaceutical formulation comprises at most 50% by weight, preferably at most 40% by weight, preferably at most 30% by weight, preferably at most 25% by weight, preferably at most 20% by weight, of a compound of formula (I) relative to the total weight of the formulation or any specific amount or range contained therein.

[0321] 87. A pharmaceutical formulation for use according to any one of statements 70 to 86, wherein the pharmaceutical formulation comprises from 0.1% to 50% by weight of a compound of formula (I) relative to the total weight of the formulation, preferably from 1% to 40% by weight, more preferably from 2.5% to 30% by weight, most preferably from 5% to 25% by weight, relative to the total weight of the formulation, or any specific amount or range of compounds of formula (I) contained therein.

[0322] 88. A pharmaceutical formulation for use according to any one of statements 70 to 87, wherein the pharmaceutical formulation further comprises one or more pharmaceutically acceptable excipients, the pharmaceutically acceptable excipients being preferably selected from the group consisting of disintegrants, binders, diluents, lubricants, stabilizers, wetting agents, glidants, osmotic agents, colorants, plasticizers, coating agents, fillers, surfactants, and mixtures thereof.

[0323] 89. A pharmaceutical formulation for use according to any one of statements 70 to 88, wherein the pharmaceutical formulation further comprises one or more pharmaceutically acceptable excipients; preferably wherein the formulation comprises at most 95% by weight, at most 90% by weight, at most 80% by weight of the one or more pharmaceutically acceptable excipients relative to the total weight of the formulation, preferably at most 70% by weight, preferably at most 60% by weight of the one or more pharmaceutically acceptable excipients relative to the total weight of the formulation.

[0324] 90. A pharmaceutical formulation for use according to any one of statements 70 to 89, wherein the pharmaceutical formulation further comprises one or more diluents; preferably wherein the formulation comprises up to 95% by weight, preferably up to 80% by weight, preferably up to 75% by weight of the diluent relative to the total weight of the formulation; and / or wherein the formulation comprises at least 5% by weight, preferably at least 10% by weight, preferably at least 15% by weight of the filler relative to the total weight of the formulation.

[0325] 91. A pharmaceutical formulation for use according to any one of statements 70 to 90, wherein the pharmaceutical formulation further comprises one or more disintegrants; preferably wherein the formulation comprises at most 30% by weight, preferably at most 20% by weight, preferably at most 15% by weight, preferably at most 10% by weight of said disintegrant relative to the total weight of the formulation; and /

[0326] Or wherein the formulation comprises at least 1 wt. %, preferably at least 2.5 wt. %, preferably at least 5 wt. %, preferably at least 8 wt. % of the disintegrant relative to the total weight of the formulation.

[0327] 92. A pharmaceutical formulation for use according to any one of statements 70 to 91, wherein the pharmaceutical formulation further comprises one or more binders; preferably wherein the formulation comprises at most 50% by weight, preferably at most 45% by weight, preferably at most 40% by weight, more preferably at most 35% by weight of the binder relative to the total weight of the formulation; and

[0328] And / or wherein the formulation comprises at least 5 wt.-%, preferably at least 10 wt.-%, preferably at least 15 wt.-%, more preferably at least 20 wt.-%, most preferably 25 wt.-% of said binder relative to the total weight of the formulation.

[0329] 93. A pharmaceutical formulation for use according to any one of statements 70 to 92, wherein the pharmaceutical formulation further comprises one or more lubricants; preferably wherein the formulation comprises at most 5.5 wt.-%, preferably at most 3.5 wt.-%, preferably at most 2 wt.-% of the lubricant relative to the total weight of the formulation; and / or wherein the formulation comprises at least 0.5 wt.-%, preferably at least 1 wt.-%, preferably at least 1.5 wt.-% of the lubricant relative to the total weight of the formulation.

[0330] 94. A pharmaceutical formulation for use according to any one of statements 70 to 93, wherein the pharmaceutical formulation further comprises one or more wetting agents; preferably wherein the formulation comprises at most 5.5 wt.-%, preferably at most 3.5 wt.-%, preferably at most 2 wt.-% of the wetting agent relative to the total weight of the formulation; and / or wherein the formulation comprises at least 0.5 wt.-%, preferably at least 1 wt.-%, preferably at least 1.5 wt.-% of the wetting agent relative to the total weight of the formulation.

[0331] 95. A pharmaceutical formulation for use according to any one of statements 70 to 94, wherein the pharmaceutical formulation further comprises one or more glidants; preferably wherein the formulation comprises at most 10 wt.-%, preferably at most 8 wt.-%, preferably at most 5 wt.-% of the glidant relative to the total weight of the formulation; and / or wherein the formulation comprises at least 0.1 wt.-%, preferably at least 1 wt.-%, preferably at least 2 wt.-% of the glidant relative to the total weight of the formulation.

[0332] 96. A pharmaceutical formulation for use according to any one of statements 70 to 95, wherein the pharmaceutical formulation comprises a plurality of particles forming an intragranular phase of the formulation, and one or more pharmaceutically acceptable excipients forming an extragranular phase of the formulation.

[0333] 97. A pharmaceutical formulation for use according to any one of statements 70 to 96, wherein the pharmaceutical formulation comprises at least 15% by weight of the intragranular phase, based on the weight of the pharmaceutical formulation;

[0334] Preferably at least 20 wt.-%, preferably at least 28 wt.-%, preferably at least 34 wt.-% of the intragranular phase, based on the total weight of the pharmaceutical formulation.

[0335] 98. A pharmaceutical formulation for use according to any one of statements 70 to 97, wherein the pharmaceutical formulation comprises up to 99% by weight of the intragranular phase, based on the weight of the pharmaceutical formulation;

[0336] Based on the total weight of the pharmaceutical formulation, 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 of the intragranular phase.

[0337] 99. A pharmaceutical formulation for use according to any one of statements 70 to 98, wherein the pharmaceutical formulation comprises an intragranular phase comprising 1% to 70% by weight of the compound of formula (I) based on the weight of the pharmaceutical formulation; preferably 2% to 60% by weight, preferably 3% to 55% by weight, preferably 4% to 50% by weight, preferably 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 total weight of the pharmaceutical formulation.

[0338] 100. A pharmaceutical formulation for use according to any one of statements 70 to 99, wherein the pharmaceutical formulation comprises an intragranular phase comprising 5 to 60 wt.-%, preferably 8 to 50 wt.-%, preferably 15 to 45 wt.-% of a methacrylic acid copolymer, a cellulose derivative or a mixture thereof, based on the total weight of the pharmaceutical formulation. Preferably, the cellulose derivative is hydroxypropyl methylcellulose.

[0339] 101. A pharmaceutical formulation for use according to any one of statements 70 to 100, wherein the pharmaceutical formulation comprises an intragranular phase comprising 5 to 60 wt.-%, preferably 10 to 60 wt.-%, preferably 10 to 50 wt.-%, preferably 15 to 50 wt.-% of filler, based on the total weight of the pharmaceutical formulation.

[0340] 102. A pharmaceutical formulation for use according to any one of statements 70 to 101, wherein the pharmaceutical formulation comprises an intragranular phase comprising 1 wt% to 10 wt%, preferably 1 wt% to 9 wt%, preferably 1.7 wt% to 8 wt% of disintegrant, based on the total weight of the pharmaceutical formulation.

[0341] 103. A pharmaceutical formulation for use according to any one of statements 70 to 102, wherein the pharmaceutical formulation comprises an intragranular phase comprising 0.1 wt.% to 5 wt.%, preferably 0.2 wt.% to 4.7 wt.%, preferably 0.5 wt.% to 4.5 wt.% of a glidant, based on the total weight of the pharmaceutical formulation.

[0342] 104. A pharmaceutical formulation for use according to any one of statements 70 to 103, wherein the pharmaceutical formulation comprises an intragranular phase comprising 0.1 wt.% to 5 wt.%, preferably 0.2 wt.% to 4.7 wt.%, preferably 0.5 wt.% to 4.5 wt.% of a surfactant, based on the total weight of the pharmaceutical formulation.

[0343] 105. A pharmaceutical formulation for use according to any one of statements 70 to 104, wherein the pharmaceutical formulation comprises an intragranular phase comprising 0.1 wt.% to 3 wt.%, preferably 0.2 wt.% to 2.7 wt.%, preferably 0.5 wt.% to 2.5 wt.% of a lubricant, based on the total weight of the pharmaceutical formulation.

[0344] 106. A pharmaceutical formulation for use according to any one of statements 70 to 105, wherein the pharmaceutical formulation comprises an intragranular phase comprising:

[0345] (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 a compound of formula (I), based on the weight of the pharmaceutical preparation;

[0346] (ii) 5 to 60 wt%, preferably 8 to 50 wt%, preferably 15 to 45 wt% of methacrylic acid copolymer or hydroxypropyl methylcellulose, based on the weight of the pharmaceutical formulation; and

[0347] Optionally (iii) 5 to 60 wt%, preferably 10 to 60 wt%, preferably 10 to 50 wt%, preferably 15 to 50 wt%, based on the weight of the pharmaceutical formulation, of a filler;

[0348] Optionally (iv) 1 to 10 wt %, preferably 1 to 9 wt %, preferably 1.7 to 8 wt % of a disintegrant, based on the weight of the pharmaceutical formulation;

[0349] Optionally (v) 0.1 wt% to 5 wt%, preferably 0.2 wt% to 4.7 wt%, preferably 0.5 wt% to 4.5 wt% of a glidant, based on the weight of the pharmaceutical formulation;

[0350] Optionally (vi) 0.1 wt% to 5 wt%, preferably 0.2 wt% to 4.7 wt%, preferably 0.5 wt% to 4.5 wt% of a surfactant, based on the weight of the pharmaceutical formulation; and

[0351] Optionally (vii) 0.1 wt% to 30 wt%, preferably 0.2 wt% to 2.7 wt%, preferably 0.5 wt% to 2.5 wt% of a lubricant, based on the weight of the pharmaceutical formulation.

[0352] 107. A pharmaceutical formulation for use according to any one of statements 70 to 106, wherein the pharmaceutical formulation comprises at least 5% by weight of an extragranular phase, based on the weight of the pharmaceutical formulation;

[0353] Based on the total weight of the pharmaceutical formulation, preferably at least 7 wt.-%, preferably at least 10 wt.-%, preferably at least 15 wt.-%, preferably at least 20 wt.-%, preferably at least 28 wt.-%, preferably at least 34 wt.-% of the extragranular phase.

[0354] 108. A pharmaceutical formulation for use according to any one of statements 70 to 107, wherein the pharmaceutical formulation comprises up to 74% by weight of the extragranular phase, based on the weight of the pharmaceutical formulation;

[0355] Preferably at most 73 wt.-%, preferably at most 67 wt.-%, preferably at most 63 wt.-%, preferably at most 53 wt.-%, preferably at most 40 wt.-% of the extragranular phase, based on the total weight of the pharmaceutical formulation.

[0356] 109. A pharmaceutical formulation for use according to any one of statements 70 to 108, wherein the pharmaceutical formulation comprises an extragranular phase comprising 0.1 wt% to 5 wt% of disintegrant, based on the weight of the pharmaceutical formulation; preferably 0.2 wt% to 4.7 wt%, preferably 0.5 wt% to 3.5 wt% of disintegrant, based on the total weight of the pharmaceutical formulation.

[0357] 110. A pharmaceutical formulation for use according to any one of statements 70 to 109, wherein the pharmaceutical formulation comprises an extragranular phase comprising 0.1 wt% to 3 wt% lubricant, based on the weight of the pharmaceutical formulation; preferably 0.2 wt% to 2.7 wt%, preferably 0.5 wt% to 2.5 wt% lubricant, based on the total weight of the pharmaceutical formulation.

[0358] 111. A pharmaceutical formulation for use according to any one of statements 70 to 110, wherein the pharmaceutical formulation comprises an extragranular phase comprising 0.1 wt% to 55 wt% of filler, based on the weight of the pharmaceutical formulation; 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% of filler, based on the total weight of the pharmaceutical formulation.

[0359] 112. A pharmaceutical formulation for use according to any one of statements 70 to 111, wherein the pharmaceutical formulation comprises an extragranular phase comprising:

[0360] (a) 0.1 wt % to 5 wt % of a disintegrant based on the weight of the pharmaceutical formulation;

[0361] Preferably 0.2 wt% to 4.7 wt%, preferably 0.5 wt% to 3.5 wt%, more preferably 1 wt% to 3 wt% of a disintegrant, based on the total weight of the pharmaceutical formulation;

[0362] (b) 0.1 wt % to 3 wt % of a lubricant, based on the weight of the pharmaceutical formulation;

[0363] Preferably 0.2 wt% to 2.7 wt%, preferably 0.5 wt% to 2.5 wt% of a lubricant, based on the total weight of the pharmaceutical formulation; and

[0364] (c) 1 wt% to 15 wt% filler based on the weight of the pharmaceutical formulation; preferably 1.3 wt% to 12 wt%, preferably 2.5 wt% to 8 wt%, more preferably 3 wt% to 5 wt% filler based on the total weight of the pharmaceutical formulation.

[0365] 113. A pharmaceutical preparation for use according to any one of statements 70 to 112, wherein the pharmaceutical preparation is a tablet.

[0366] 114. A pharmaceutical preparation for use according to any one of statements 70 to 113, wherein the pharmaceutical preparation, preferably a tablet, comprises at least 0.1 mg of a 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

[0367] 8mg, preferably contains at least 9mg, preferably contains at least, preferably contains at least

[0368] 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).

[0369] 115. A pharmaceutical preparation for use according to any one of statements 70 to 114, wherein the pharmaceutical preparation, preferably a tablet, comprises 0.5 mg to 1500 mg of a compound of formula (I), preferably 1 mg to 1400 mg of a compound of formula (I), preferably 2 mg to 1300 mg of a compound of formula (I), preferably 3 mg to 1200 mg of a compound of formula (I), preferably 40 mg to 1250 mg of a compound of formula (I), preferably 5 mg to 1000 mg of a compound of formula (I), preferably 6 mg to 1000 mg of a compound of formula (I), preferably 7 mg to 1300 mg of a compound of formula (I), preferably 8 mg to 1200 mg of a compound of formula (I), preferably 9 mg to 1000 mg of a compound of formula (I), preferably 10 mg to 950 mg of a compound of formula (I). mg of the compound of formula (I), preferably 15 mg to 900 mg of the compound of formula (I), preferably 20 mg to 800 mg of the compound of formula (I), preferably 25 mg to 700 mg of the compound of formula (I), preferably 30 mg to 600 mg of the compound of formula (I), preferably 35 mg to 500 mg of the compound of formula (I), preferably 37 mg to 400 mg of the compound of formula (I), preferably 38 mg to 300 mg of the compound of formula (I), preferably 40 mg to 250 mg of the compound of formula (I), preferably 10 mg to 200 mg of the compound of formula (I), preferably 10 mg to 100 mg of the compound of formula (I), preferably 10 mg to 50 mg of the compound of formula (I), or any specific amount or range of the compound of formula (I) contained therein.

[0370] 116. A pharmaceutical preparation for use according to any one of statements 70 to 115, wherein oral administration of the pharmaceutical preparation results in a maximum concentration (C 20 ) 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 subsumed therein.

[0371] 117. A pharmaceutical formulation for use according to any one of statements 70 to 116, wherein oral administration of the pharmaceutical formulation to a human in a fed state results in a maximum concentration (C 20 ) of the compound of formula (I) in the plasma of a 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 at least

[0372] 50 μg / L to 5000 μg / L, preferably 70 μg / L to 4800 μg / L, preferably

[0373] 80 μg / L to 4700 μg / L, preferably 90 μg / L to 4600 μg / L, preferably

[0374] 100 μg / L to 4300 μg / L, preferably 130 μg / L to 4000 μg / L, or any specific amount or range subsumed therein.

[0375] 118. A pharmaceutical formulation for use according to any one of statements 70 to 117, wherein the pharmaceutical formulation is orally administered to the human at least once a day, such as at least twice a day, at least three times a day, such as at least four times a day.

[0376] 119. A pharmaceutical formulation for use according to any one of statements 70 to 118, wherein said pharmaceutical formulation is administered orally to said human being once a day or twice a day.

[0377] 120. A pharmaceutical formulation for use according to any one of statements 70 to 119, wherein the amount of compound contained in the formulation and administered over a day or 24 hours (daily dose) is administered to the subject, preferably a human subject, in a single oral dosage form, or in two, three or four oral dosage forms. For example, where the oral dosage form is a tablet, the daily dose can be administered to the subject in the form of one, two, three or four tablets.

[0378] 121. A pharmaceutical formulation for use according to any one of statements 70 to 120, wherein the compound of formula (I) is:

[0379]

[0380] or a stereoisomeric form, a pharmaceutically acceptable salt, a solvate or a polymorph thereof. 122. A pharmaceutical preparation for use according to any one of statements 70 to 121, wherein the pharmaceutical preparation is administered according to a dosing regimen comprising:

[0381] 1) at least one loading phase during which at least one dose (A) of a compound of formula (I) is administered at least once a day over a period of at least one day; and

[0382] 2) at least one maintenance period starting from the last day of administration of dose (A) or the day after the last day of the loading period, during which at least one dose (B) of a 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 over a period of at least one day;

[0383] wherein the dose (A) is higher or lower than the dose (B). Preferably, the dose (A)

[0384] Higher than dose (B).

[0385] 123. A pharmaceutical preparation for use according to any one of statements 70 to 122, wherein the pharmaceutical preparation is administered according to a dosing regimen comprising:

[0386] 1) at least one loading phase during which at least one dose (A) of a compound of formula (I) is administered at least once a day within a period of 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 3 days

[0387] 1 day, or any specific amount or range subsumed therein; and

[0388] 2) at least one maintenance period starting from the day after the last day of administration of dose (A) or the last day of the loading period, during which at least one dose (B) of a 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 within the following period: at least one day to at most 12 months, preferably to at most 9 months, preferably to at most 6 months, preferably to at most 3 months, preferably to at most 1.5 months, preferably to at most 40 days, preferably to at most 39 days, preferably to at most 38 days, preferably to at most 37 days, preferably to at most 36 days, preferably to at most 35 days, preferably to at most 30 days, preferably to at most 28 days, preferably to at most 21 days, preferably to at most 14 days,

[0389] Preferably to at most 7 days, preferably to at most 5 days, or any specific amount or range subsumed therein;

[0390] wherein the dose (A) is higher or lower than the dose (B). Preferably, the dose (A)

[0391] Higher than dose (B).

[0392] 124. A pharmaceutical preparation for use according to any one of statements 70 to 123, wherein the pharmaceutical preparation is administered according to a dosing regimen comprising:

[0393] 1) at least one loading phase during which at least one dose (A) of a compound of formula (I) is administered at least once a day within the following time periods: up to 20 days,

[0394] 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days,

[0395] 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 subsumed therein; and

[0396] 2) at least one maintenance period starting from the last day of administration of dose (A) or the day after the last day of the loading period, during which at least one dose (B) 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 within the following time period:

[0397] Compound: at least one day to up to 12 months, 9 months, 6 months, 3 months,

[0398] 1.5 months, 40 days, 39 days, 38 days, 37 days, 36 days, 35 days, 30 days,

[0399] 28 days, 21 days, 14 days, 7 days, 5 days, or any specific amount or range subsumed therein;

[0400] wherein the dose (A) is higher or lower than the dose (B). Preferably, the dose (A)

[0401] Higher than dose (B).

[0402] 125. A pharmaceutical preparation for use according to any one of statements 70 to 124, wherein the pharmaceutical preparation is administered according to a dosing regimen comprising:

[0403] 1) at least one loading phase during which at least one dose (A) of a compound of formula (I) is administered at least once a day, preferably twice a day, preferably at least three times a day, preferably at least four times a day, within a period of at least 1 day to at most 20 days, preferably at least 2 days to at most 19 days, preferably at least 3 days to at most 18 days, preferably at least 4 days to at most 17 days, preferably at least 5 days to at most 16 days, preferably at least 6 days to at most 15 days, preferably at least 7 days to at most 14 days, preferably at least 8 days to at most 13 days, preferably at least 9 days to at most 12 days, preferably at least 10 days to at most 11 days, or any specific amount or range subsumed therein; and

[0404] 2) at least one maintenance period starting from the day after the last day of administration of dose (A) or the last day of the loading period, during which at least one dose (B) of a 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 at least three times a day, preferably at least four times a day within the following time period: at least 1 day to at most 12 months, preferably at least 2 days to at most 6 months, preferably at least 3 days to at most 3 months, preferably at least 1 day to at most 30 days,

[0405] Preferably at least 5 days to at most 28 days, preferably at least 10 days to at most 26 days, or any specific amount or range subsumed therein;

[0406] wherein the dose (A) is higher or lower than the dose (B). Preferably, the dose (A)

[0407] Higher than dose (B).

[0408] 126. A pharmaceutical preparation for use according to any one of statements 70 to 125, wherein the formula (I)

[0409] The dose (A) of the compound is in the range of 50 mg to 1200 mg, preferably in the range of 100 mg to 1100 mg, preferably in the range of 150 mg to 900 mg, preferably in the range of 50 mg to 800 mg, preferably in the range of 60 mg to 700 mg, preferably in the range of 70 mg to 650 mg, preferably in the range of 80 mg to 600 mg, preferably in the range of 90 mg to 550 mg, preferably in the range of 100 mg to 500 mg, or any specific amount or range subsumed therein.

[0410] 127. A pharmaceutical preparation for use according to any one of statements 70 to 126, wherein the formula (I)

[0411] The dosage of the compound (A) is in the range of 5 mg to 1500 mg, preferably in the range of 10 mg to

[0412] 1400mg, preferably in the range of 20mg to 1300mg, preferably in the range of

[0413] Preferably, the range of the present invention is 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 subsumed therein.

[0414] 128. A pharmaceutical formulation for use according to any one of statements 70 to 127, wherein the dose (A) of the compound of formula (I) is administered at least once a day, preferably at least twice a day.

[0415] 129. A pharmaceutical formulation for use according to any one of statements 70 to 128, wherein the dose (B) of the compound of formula (I) is in the range of 5 mg to 1500 mg, preferably in the range of 25 mg to 1200 mg, preferably in the range of 50 mg to 1100 mg, preferably in the range of 100 mg to 1000 mg, preferably in the range of 150 mg to 900 mg, preferably in the range of 5 mg to 500 mg, preferably in the range of 5 mg to 450 mg, preferably in the range of 5 mg to 400 mg, preferably in the range of 5 mg to 350 mg, preferably in the range of 10 mg to 300 mg, preferably in the range of 15 mg to 250 mg, preferably in the range of 20 mg to 230 mg, preferably in the range of 30 mg to 250 mg, preferably in the range of 35 mg to 200 mg, preferably in the range of 50 mg to 450 mg, or any specific amount or range subsumed therein.

[0416] 130. A pharmaceutical preparation for use according to any one of statements 70 to 129, wherein the formula (I)

[0417] The dose (B) of the compound 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.

[0418] 131. A pharmaceutical formulation for use according to any one of statements 70 to 130, wherein a dose (B) of a 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 at least three times a day, preferably at least four times a day within the following period: at least 1 day to at most 12 months, at least 2 days to at most 6 months, preferably at least 3 days to at most 3 months, preferably at least 1 day to at most 30 days, preferably at least 5 days to at most 28 days, preferably at least 10 days to at most 26 days, or any specific amount or range subsumed therein.

[0419] 132. A pharmaceutical formulation for use according to any one of statements 70 to 131, wherein dose (A) of a 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 within the following period of at least 1 day to at most 20 days, preferably at least 2 days to at most 19 days, preferably at least 3 days to at most 18 days, preferably at least 4 days to at most 17 days, preferably at least 5 days to at most 16 days, preferably at least 6 days to at most 15 days, preferably at least 7 days to at most 14 days, preferably at least 8 days to at most 13 days, preferably at least 9 days to at most 12 days, preferably at least 10 days to at most 11 days, or any specific amount or range subsumed therein.

[0420] 133. A pharmaceutical formulation for use according to any one of statements 70 to 132, wherein dose (A) of a 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 within the following period: at least 1 day to at most 20 days, preferably at least 2 days to at most 19 days, preferably at least 3 days to at most 18 days, preferably at least 4 days to at most 17 days, preferably at least 5 days to at most 16 days, preferably at least 6 days to at most 15 days, preferably at least 7 days to at most 14 days, preferably at least 8 days to at most 13 days, preferably at least 9 days to at most 12 days, preferably at least 10 days to at most 11 days, or any specific amount or range subsumed therein;

[0421] And wherein the dose (A) of the compound of formula (I) is in the range of 50 mg to 1200 mg, preferably in the range of 100 mg to 1100 mg, preferably in the range of 150 mg to 900 mg, preferably in the range of 50 mg to 800 mg, preferably in the range of 60 mg to 700 mg, preferably in the range of 70 mg to 650 mg, preferably in the range of 80 mg to 600 mg, preferably in the range of 90 mg to 550 mg, preferably in the range of 100 mg to 500 mg, or any specific amount or range subsumed therein.

[0422] 134. A pharmaceutical formulation for use according to any one of statements 70 to 133, wherein dose (A) of a 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 within the following period: at least 1 day to at most 20 days, preferably at least 2 days to at most 19 days, preferably at least 3 days to at most 18 days, preferably at least 4 days to at most 17 days, preferably at least 5 days to at most 16 days, preferably at least 6 days to at most 15 days, preferably at least 7 days to at most 14 days, preferably at least 8 days to at most 13 days, preferably at least 9 days to at most 12 days, preferably at least 10 days to at most 11 days, or any specific amount or range subsumed therein;

[0423] and wherein the dose (A) of the compound of formula (I) is in the range of 5 mg to 1500 mg, preferably in the range of 10 mg to 1400 mg, preferably in the range of 20 mg to 1300 mg, preferably in the range of 25 mg to 1200 mg, preferably in the range of 30 mg to

[0424] 1100mg range, preferably 35mg to 1000mg range, preferably

[0425] In the range of 15 mg to 1450 mg, preferably in the range of 15 mg to 1100 mg, preferably in the range of 25 mg to 1000 mg, preferably in the range of 10 mg to 900 mg, preferably in the range of 15 mg to 900 mg, preferably in the range of 20 mg to 900 mg, preferably in the range of 30 mg to 900 mg, preferably in the range of 35 mg to 800 mg, preferably in the range of 50 mg to 800 mg, or any specific amount or range subsumed therein.

[0426] 135. A pharmaceutical formulation for use according to any one of statements 70 to 134, wherein a dose (B) of a 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 at least three times a day, preferably at least four times a day within the following period: at least 1 day to at most 12 months, at least 2 days to at most 6 months, preferably at least 3 days to at most 3 months, preferably at least 1 day to at most 30 days, preferably at least 5 days to at most 28 days, preferably at least 10 days to at most 26 days, or any specific amount or range subsumed therein;

[0427] and wherein the dose (B) of the compound of formula (I) is in the range of 5 mg to 1500 mg, preferably in the range of 25 mg to 1200 mg, preferably in the range of 50 mg to 1100 mg, preferably in the range of 100 mg to 1000 mg, preferably in the range of 150 mg to 900 mg, preferably in the range of 5 mg to 500 mg, preferably in the range of 5 mg to 450 mg, preferably in the range of 5 mg to 400 mg, preferably in the range of 5 mg to 350 mg, preferably in the range of 10 mg to 300 mg, preferably in the range of 15 mg to 250 mg, preferably in the range of 20 mg to 230 mg, preferably in the range of 30 mg to 250 mg, preferably in the range of 35 mg to 200 mg, preferably in the range of 50 mg to 450 mg, or any specific amount or range subsumed therein.

[0428] 136. A method of treating or preventing dengue virus infection, comprising administering to a human subject in need thereof (at risk of or already infected with dengue virus) a therapeutically effective amount of a compound of formula (I) for use according to any one of statements 1 to 69

[0429] A compound, or an effective amount of a pharmaceutical formulation for use according to any one of statements 70 to 135, wherein the compound of formula (I) or the pharmaceutical formulation is administered to the human subject in a fed state or a fasted state, and wherein formula (I) corresponds to

[0430]

[0431] Its stereoisomeric form, pharmaceutically acceptable salt, solvate or polymorph; the compound is selected from the following group, wherein:

[0432] R1 is H, R2 is F, and R3 is H or CH3,

[0433] R1 is H, CH3 or F, R2 is OCH3, and R3 is H,

[0434] R1 is H, R2 is OCH3, and R3 is CH3,

[0435] R1 is CH3, R2 is F, and R3 is H,

[0436] R1 is CF3 or OCF3, R2 is H, and R3 is H,

[0437] R1 is OCF3, R2 is OCH3, and R3 is H,

[0438] R1 is OCF3, R2 is H, and R3 is CH3.

[0439] 137. A compound for use according to any one of statements 1 to 69, wherein oral administration of the oral dosage form results in a maximum concentration (C 20 ) of the compound of formula (I) in the plasma of a subject, preferably a human subject. max ) is at most 15,000 μg / L, preferably at most 12,000 μg / L, preferably at most 11,000 μg / L, preferably at most

[0440] 10,000 μg / L, preferably at most 9500 μg / L, preferably at most 9000 μg / L, preferably at most 8500 μg / L, preferably 25 μg / L to 15,000 μg / L, preferably 50 μg / L to 12,000 μg / L, preferably 60 μg / L to 10,000 μg / L, preferably 70 μg / L to 9500 μg / L, preferably 80 μg / L to 8500 μg / L, preferably 90 μg / L to 8000 μg / L, preferably 100 μg / L to 8000 μg / L, or any specific amount or range subsumed therein.

[0441] 138. A compound for use according to any one of statements 1 to 69 or 137, wherein the oral dosage form is administered according to a dosing regimen comprising:

[0442] 1) at least one loading phase during which at least one dose (A) of a compound of formula (I) is administered at least once, preferably twice a day, preferably three times a day, preferably four times a day within a period of 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 subsumed therein; and

[0443] 2) at least one maintenance period starting from the last day of administration of dose (A) or the day after the last day of the loading period, during which at least one dose (B) 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 within the following time period:

[0444] Compound: at least one day, preferably at least one day to at most 12 months, preferably at most 9 months, preferably at most 6 months, preferably at most 3 months, preferably at most 1.5 months, preferably at most 40 days, preferably at most 39 days, preferably at most 38 days, preferably at most 37 days, preferably at most 36 days, preferably at most 35 days, preferably at most 30 days, preferably at most 28 days, preferably at most 21 days, preferably at most 14 days, preferably at most 7 days, preferably at most 5 days, or any specific amount or range subsumed therein;

[0445] The dose (A) is higher or lower than the dose (B); preferably, the dose (A) is higher than the dose (B).

[0446] 139. A compound for use according to any one of statements 1 to 69 or 137 to 138, wherein the dose (A) of the compound of formula (I) is in the range of 55 mg to 1200 mg, preferably in the range of 50 mg to 1100 mg, preferably in the range of 50 mg to 1000 mg, preferably in the range of 55 mg to 1100 mg, preferably in the range of 55 mg to 1000 mg, preferably in the range of 55 mg to 900 mg, preferably in the range of 60 mg to 1200 mg, preferably in the range of 60 mg to 1100 mg, preferably in the range of 60 mg to 1000 mg, preferably in the range of 60 mg to 800 mg, preferably in the range of 60 mg to 750 mg, preferably in the range of 70 mg to 700 mg, preferably in the range of 75 mg to 600 mg, preferably in the range of 85 mg to 550 mg, preferably in the range of 50 mg to 500 mg, or any specific amount or range subsumed therein.

[0447] 140. A compound for use according to any one of statements 1 to 69 or 137 to 139, wherein 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, preferably at least four times a day.

[0448] 141. A compound for use according to any one of statements 1 to 69 or 137 to 140, wherein 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, preferably at least four times a day over a period of at least 1 day, preferably at least 1 day to at most 20 days, preferably at least 2 days to at most 19 days, preferably at least 3 days to at most 18 days, preferably at least 4 days to at most 17 days, preferably at least 5 days to at most 16 days, preferably at least 6 days to at most 15 days, preferably at least 7 days to at most 14 days, preferably at least 8 days to at most 13 days, preferably at least 9 days to at most 12 days, preferably at least 10 days to at most 11 days, or any specific amount or range subsumed therein.

[0449] 142. A compound for use according to any one of statements 1 to 69 or 137 to 141, wherein the dose (B) of the compound of formula (I) is in the range of 5 mg to 1450 mg, preferably in the range of 50 mg to 1500 mg, preferably in the range of 10 mg to 1300 mg, preferably in the range of 10 mg to 1200 mg, preferably in the range of 20 mg to 1100 mg, preferably in the range of 25 mg to 1000 mg, preferably in the range of 25 mg to 900 mg, preferably in the range of 15 mg to Preferably, the range of the present invention is 25 to 300 mg, preferably in the range of 10 to 250 mg, preferably in the range of 10 to 230 mg, preferably in the range of 25 to 250 mg, preferably in the range of 5 to 200 mg, preferably in the range of 10 to 450 mg, or any specific amount or range subsumed therein.

[0450] 143. A compound for use according to any one of statements 1 to 69 or 137 to 142, wherein

[0451] 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 once a day within the following period: at least one day, preferably at least one day to up to 12 months, preferably up to 9 months, preferably up to 6 months, preferably up to 3 months, preferably up to 1.5 months, preferably up to 40 days, preferably up to 39 days, preferably up to 38 days,

[0452] Preferably at most 37 days, preferably at most 36 days, preferably at most 35 days, preferably at most 30 days, preferably at most 28 days, preferably at most 21 days, preferably at most 14 days, preferably at most 7 days, preferably at most 5 days, or any specific amount or range subsumed therein.

[0453] 144. A compound for use according to any one of statements 1 to 69 or 137 to 143, wherein

[0454] The oral dosage form is administered according to the following dosing regimen, which comprises:

[0455] 1) at least one loading phase during which at least one dose (A) of a compound of formula (I) is administered at least once a day over a period of at least one day; and

[0456] 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 formula (I) is administered at least once a day over a period of at least one day.

[0457] Compounds;

[0458] wherein the dose (A) is higher or lower than the dose (B), preferably, the dose (A)

[0459] higher than the dose (B);

[0460] wherein the oral dosage form is a solid dosage form comprising a cellulose derivative having a viscosity in a 2 wt% H2O solution at 25°C ranging between 3 mPa.s and 5000 mPa.s and selected from the group consisting of HPMC E5, HPMC E6, HPMC E15, HPMC E50,

[0461] HPMC K4M HPMC-AS, and any combination thereof.

[0462] 145. A compound for use according to any one of statements 1 to 69 or 137 to 144, wherein

[0463] The oral dosage form is administered according to the following dosing regimen, which comprises:

[0464] 1) at least one loading phase during which at least one dose (A) of a compound of formula (I) is administered at least once, preferably twice a day, preferably three times a day, preferably four times a day within a period of 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 subsumed therein; and

[0465] 2) at least one maintenance period starting from the last day of administration of dose (A) or the day after the last day of the loading period, during which at least one dose (B) 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 within the following time period:

[0466] Compound: at least one day, preferably at least one day to at most 12 months, preferably at most 9 months, preferably at most 6 months, preferably at most 3 months, preferably at most 1.5 months, preferably at most 40 days, preferably at most 39 days,

[0467] Preferably at most 38 days, preferably at most 37 days, preferably at most 36 days, preferably at most 35 days, preferably at most 30 days, preferably at most 28 days, preferably at most 21 days, preferably at most 14 days, preferably at most 7 days, preferably at most 5 days, or any specific amount or range subsumed therein;

[0468] wherein the dose (A) is higher or lower than the dose (B). Preferably, the dose (A)

[0469] higher than the dose (B);

[0470] wherein the oral dosage form is a solid dosage form comprising a cellulose derivative having a viscosity in a 2 wt% H2O solution at 25°C ranging between 3 mPa.s and 5000 mPa.s and selected from the group consisting of HPMC E5, HPMC E6, HPMC E15, HPMC E50,

[0471] HPMC K4M HPMC-AS, and any combination thereof.

[0472] 146. A compound for use according to any one of statements 1 to 69 or 137 to 145, wherein

[0473] The oral dosage form is administered according to the following dosing regimen, which comprises:

[0474] 1) at least one loading phase during which at least one dose (A) of a compound of formula (I) is administered at least once a day, twice a day, three times a day or four times a day over a period of at least 1 day to at most 20 days, preferably at least 2 days to at most 19 days, preferably at least 3 days to at most 18 days, preferably at least 4 days to at most 17 days, preferably at least 5 days to at most 16 days, preferably at least 6 days to at most 15 days, preferably at least 7 days to at most 14 days, preferably at least 8 days to at most 13 days, preferably at least 9 days to at most 12 days, preferably at least 10 days to at most 11 days, or any specific amount or range subsumed therein; and

[0475] 2) at least one maintenance period starting from the last day of administration of dose (A) or the day after the last day of the loading period, during which at least one dose (B) of a compound of formula (I) is administered at least once every two weeks, at least once a week, at least twice a week, at least once a day, twice a day, three times a day, or four times a day within the following time periods:

[0476] At least 1 day to at most 12 months, at least 2 days to at most 6 months, at least 3 days to at most 3 months, at least 1 day to at most 30 days, preferably at least 5 days to at most 28 days, preferably at least 10 days to at most 26 days, or any specific amount or range subsumed therein;

[0477] wherein the dose (A) is higher or lower than the dose (B). Preferably, the dose (A)

[0478] higher than the dose (B);

[0479] Wherein the oral dosage form is a solid dosage form comprising a cellulose derivative having a viscosity in a 2 wt % H2O solution at 25°C ranging between 3 mPa.s and 5000 mPa.s and selected from the group comprising HPMC E5, HPMC E6, HPMC E15, HPMC E50, HPMC K4M HPMC-AS, and any combination thereof.

[0480] 147. A pharmaceutical formulation for use according to any one of statements 70 to 135, wherein oral administration of the oral dosage form results in a maximum concentration (C 20 ) of the compound of formula (I) in the plasma of a subject, preferably a human subject. max) is at most 15,000 μg / L, preferably at most 12,000 μg / L, preferably at most 11,000 μg / L, preferably at most 10,000 μg / L, preferably at most 9500 μg / L, preferably at most 9000 μg / L, preferably at most 8500 μg / L, preferably 25 μg / L to 15,000 μg / L, preferably 50 μg / L to 12,000 μg / L, preferably 60 μg / L to 10,000 μg / L, preferably 70 μg / L to 9500 μg / L, preferably 80 μg / L to 8500 μg / L, preferably 90 μg / L to 8000 μg / L, preferably 100 μg / L to 8000 μg / L, or any specific amount or range subsumed therein.

[0481] 148. A pharmaceutical preparation for use according to any one of statements 70 to 135 or 147, wherein

[0482] The oral dosage form is administered according to the following dosing regimen, which comprises:

[0483] 1) at least one loading phase during which at least one dose (A) of a compound of formula (I) is administered at least once, preferably twice a day, preferably three times a day, preferably four times a day within a period of 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 subsumed therein; and

[0484] 2) at least one maintenance period starting from the last day of administration of dose (A) or the day after the last day of the loading period, during which at least one dose (B) of a 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 within the following time period: at least one day, preferably at least one day to up to 12 months, preferably up to 9 months, preferably up to 6 months, preferably up to 3 months, preferably up to 1.5 months, preferably up to 40 days, preferably up to 39 days,

[0485] Preferably at most 38 days, preferably at most 37 days, preferably at most 36 days, preferably at most 35 days, preferably at most 30 days, preferably at most 28 days, preferably at most 21 days, preferably at most 14 days, preferably at most 7 days, preferably at most 5 days, or any specific amount or range subsumed therein;

[0486] wherein the dose (A) is higher or lower than the dose (B). Preferably, the dose (A) is higher than the dose (B).

[0487] 149. A pharmaceutical formulation for use according to any one of statements 70 to 135 or 147 to 148, wherein the dose (A) of the compound of formula (I) is in the range of 55 mg to 1200 mg, preferably in the range of 50 mg to 1100 mg, preferably in the range of 50 mg to 1000 mg, preferably in the range of 55 mg to 1100 mg, preferably in the range of 55 mg to 1000 mg, preferably in the range of 55 mg to 900 mg, preferably in the range of 60 mg to 1200 mg, preferably in the range of 60 mg to 1100 mg, preferably in the range of 60 mg to 1000 mg, preferably in the range of 60 mg to 800 mg, preferably in the range of 60 mg to 750 mg, preferably in the range of 70 mg to 700 mg, preferably in the range of 75 mg to 600 mg, preferably in the range of 85 mg to 550 mg, preferably in the range of 50 mg to 500 mg, or any specific amount or range subsumed therein.

[0488] 150. A pharmaceutical formulation for use according to any one of statements 70 to 135 or 147 to 150, wherein 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, preferably at least four times a day.

[0489] 151. A pharmaceutical formulation for use according to any of statements 70 to 135 or 147 to 150, wherein 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, preferably at least four times a day over a period of at least 1 day, preferably at least 1 day to at most 20 days, preferably at least 2 days to at most 19 days, preferably at least 3 days to at most 18 days, preferably at least 4 days to at most 17 days, preferably at least 5 days to at most 16 days, preferably at least 6 days to at most 15 days, preferably at least 7 days to at most 14 days, preferably at least 8 days to at most 13 days, preferably at least 9 days to at most 12 days, preferably at least 10 days to at most 11 days, or any specific amount or range subsumed therein.

[0490] 152. A pharmaceutical preparation for use according to any one of statements 70 to 135 or 147 to 151, wherein the dose (B) of the compound of formula (I) is in the range of 5 mg to 1450 mg, preferably in the range of 50 mg to 1500 mg, preferably in the range of 10 mg to 1300 mg, preferably in the range of 10 mg to 1200 mg, preferably in the range of 20 mg to 1100 mg, preferably in the range of 25 mg to 1000 mg, preferably in the range of 25 mg to 900 mg, preferably in the range of 15 mg to 1000 mg. g to 500 mg, preferably in the range of 15 mg to 450 mg, preferably in the range of 15 mg to 400 mg, preferably in the range of 15 mg to 350 mg, preferably in the range of 5 mg to 300 mg, preferably in the range of 10 mg to 250 mg, preferably in the range of 10 mg to 230 mg, preferably in the range of 25 mg to 250 mg, preferably in the range of 5 mg to 200 mg, preferably in the range of 10 mg to 450 mg, or any specific amount or range subsumed therein.

[0491] 153. A pharmaceutical formulation for use according to any one of statements 70 to 135 or 147 to 152, 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 once a day within the period of at least one day, preferably at least one day to at most 12 months, preferably at most 9 months, preferably at most 6 months, preferably at most 3 months, preferably at most 1.5 months, preferably at most 40 days, preferably at most 39 days, preferably at most 38 days, preferably at most 37 days, preferably at most 36 days, preferably at most 35 days,

[0492] Preferably at most 30 days, preferably at most 28 days, preferably at most 21 days, preferably at most 14 days, preferably at most 7 days, preferably at most 5 days, or any specific amount or range subsumed therein.

[0493] 154. A pharmaceutical preparation for use according to any one of statements 70 to 135 or 147 to 153, wherein the oral dosage form is administered according to a dosing regimen comprising:

[0494] 1) at least one loading phase during which at least one dose (A) of a compound of formula (I) is administered at least once a day over a period of at least one day; and

[0495] 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 formula (I) is administered at least once a day over a period of at least one day.

[0496] Compounds;

[0497] wherein the dose (A) is higher or lower than the dose (B), preferably, the dose (A)

[0498] higher than the dose (B);

[0499] wherein the oral dosage form is a solid dosage form comprising a cellulose derivative having a viscosity in a 2 wt% H2O solution at 25°C ranging between 3 mPa.s and 5000 mPa.s and selected from the group consisting of HPMC E5, HPMC E6, HPMC E15, HPMC E50,

[0500] HPMC K4M HPMC-AS, and any combination thereof.

[0501] 155. A pharmaceutical preparation for use according to any one of statements 70 to 135 or 147 to 154, wherein the oral dosage form is administered according to a dosing regimen comprising:

[0502] 1) at least one loading phase during which at least one dose (A) of a compound of formula (I) is administered at least once, preferably twice a day, preferably three times a day, preferably four times a day within a period of 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 subsumed therein; and

[0503] 2) at least one maintenance period starting from the last day of administration of dose (A) or the day after the last day of the loading period, during which at least one dose (B) 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 within the following time period:

[0504] Compound: at least one day, preferably at least one day to at most 12 months, preferably at most 9 months, preferably at most 6 months, preferably at most 3 months, preferably at most 1.5 months, preferably at most 40 days, preferably at most 39 days,

[0505] Preferably at most 38 days, preferably at most 37 days, preferably at most 36 days, preferably at most 35 days, preferably at most 30 days, preferably at most 28 days, preferably at most 21 days, preferably at most 14 days, preferably at most 7 days, preferably at most 5 days, or any specific amount or range subsumed therein;

[0506] wherein the dose (A) is higher or lower than the dose (B). Preferably, the dose (A)

[0507] higher than the dose (B);

[0508] wherein the oral dosage form is a solid dosage form comprising a cellulose derivative having a viscosity in a 2 wt% H2O solution at 25°C ranging between 3 mPa.s and 5000 mPa.s and selected from the group consisting of HPMC E5, HPMC E6, HPMC E15, HPMC E50,

[0509] HPMC K4M HPMC-AS, and any combination thereof.

[0510] 156. A pharmaceutical preparation for use according to any one of statements 70 to 135 or 147 to 155, wherein the oral dosage form is administered according to a dosing regimen comprising:

[0511] 1) at least one loading phase during which at least one dose (A) of a compound of formula (I) is administered at least once a day, twice a day, three times a day or four times a day over a period of at least 1 day to at most 20 days, preferably at least 2 days to at most 19 days, preferably at least 3 days to at most 18 days, preferably at least 4 days to at most 17 days, preferably at least 5 days to at most 16 days, preferably at least 6 days to at most 15 days, preferably at least 7 days to at most 14 days,

[0512] Preferably at least 8 days to at most 13 days, preferably at least 9 days to at most 12 days,

[0513] Preferably at least 10 days and at most 11 days, or any specific amount or range subsumed therein; and

[0514] 2) at least one maintenance period starting from the last day of administration of dose (A) or the day after the last day of the loading period, during which at least one dose (B) of a compound of formula (I) is administered at least once every two weeks, at least once a week, at least twice a week, at least once a day, twice a day, three times a day, or four times a day within the following time periods:

[0515] At least 1 day to at most 12 months, at least 2 days to at most 6 months, at least 3 days to at most 3 months, at least 1 day to at most 30 days, preferably at least 5 days to at most 28 days, preferably at least 10 days to at most 26 days, or any specific amount or range subsumed therein;

[0516] wherein the dose (A) is higher or lower than the dose (B). Preferably, the dose (A) is higher than the dose (B);

[0517] wherein the oral dosage form is a solid dosage form comprising a cellulose derivative having a viscosity in a 2 wt% H2O solution at 25°C ranging between 3 mPa.s and 5000 mPa.s and selected from the group consisting of HPMC E5, HPMC E6, HPMC E15, HPMC E50,

[0518] HPMC K4M HPMC-AS, and any combination thereof.

[0519] The present invention provides a compound of formula (I) for use in preventing and / or treating dengue virus infection, wherein the compound is administered to humans in a fed or fasting state in an oral dosage form, and wherein formula (I) corresponds to

[0520]

[0521] Its stereoisomeric form, pharmaceutically acceptable salt, solvate or polymorph; the compound is selected from the following group, wherein:

[0522] R1 is H, R2 is F, and R3 is H or CH3,

[0523] R1 is H, CH3 or F, R2 is OCH3, and R3 is H,

[0524] R1 is H, R2 is OCH3, and R3 is CH3,

[0525] R1 is CH3, R2 is F, and R3 is H,

[0526] R1 is CF3 or OCF3, R2 is H, and R3 is H,

[0527] R1 is OCF3, R2 is OCH3, and R3 is H,

[0528] R1 is OCF3, R2 is H, and R3 is CH3.

[0529] In some embodiments, the oral dosage form is a solid dosage form formulated with a pharmaceutical formulation comprising a cellulose derivative such as hydroxypropylmethylcellulose (HPMC), or a methacrylic acid copolymer, or a combination thereof.

[0530] The present invention also provides a compound of formula (I) for use in preventing and / or treating dengue virus infection, wherein the compound is administered to humans in a fed or fasting state in an oral dosage form, and wherein formula (I) corresponds to

[0531]

[0532] Its stereoisomeric form, pharmaceutically acceptable salt, solvate or polymorph; the compound is selected from the following group, wherein:

[0533] R1 is H, R2 is F, and R3 is H or CH3,

[0534] R1 is H, CH3 or F, R2 is OCH3, and R3 is H,

[0535] R1 is H, R2 is OCH3, and R3 is CH3,

[0536] R1 is CH3, R2 is F, and R3 is H,

[0537] R1 is CF3 or OCF3, R2 is H, and R3 is H,

[0538] R1 is OCF3, R2 is OCH3, and R3 is H,

[0539] R1 is OCF3, R2 is H, and R3 is CH3;

[0540] The oral dosage form is administered according to the following dosage regimen, which comprises:

[0541] 1) at least one loading phase during which at least one dose (A) of a compound of formula (I) is administered at least once, preferably twice a day, preferably three times a day, preferably four times a day within a period of 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 subsumed therein; and

[0542] 2) at least one maintenance period starting from the last day of administration of dose (A) or the day after the last day of the loading period, during which at least one dose (B) of a 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 within the following time period: at least one day, preferably at least one day to up to 12 months, preferably up to 9 months, preferably up to 6 months, preferably up to 3 months, preferably up to 1.5 months, preferably up to 40 days, preferably up to 39 days, preferably up to 38 days, preferably up to 37 days, preferably up to 36 days, preferably up to 35 days, preferably up to 30 days, preferably up to 28 days, preferably up to 21 days, preferably up to 14 days, preferably up to 7 days, preferably up to 5 days, or any specific amount or range subsumed therein;

[0543] The dose (A) is higher or lower than the dose (B); preferably, the dose (A) is higher than the dose (B).

[0544] In some embodiments, the human subject in the fed state has consumed a standard normal fat meal, a high fat high calorie meal, a low fat low calorie meal, or a low fat high calorie meal.

[0545] In some embodiments, the compound of formula (I) is applied to an individual who is at risk of being infected by dengue virus. The individual may be living in a dengue-endemic area, or may be traveling to a dengue-endemic area. The compound of formula (I) can also be applied to an individual who has been infected by dengue virus. In some embodiments, a human subject is infected by dengue virus or has the risk of being infected by dengue virus.

[0546] In some embodiments, up to 30% of subjects, particularly human subjects, in the fasting state or in the fed state experience adverse events associated with the administration of a compound of formula (I), particularly compound (a); preferably 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%, preferably up to 13% of subjects in the fasting state or in the fed state experience adverse events associated with the administration of a compound of formula (I), particularly compound (a).

[0547] In some embodiments, up to 30% of subjects, especially human subjects, in the fasting state or the fed state, experience adverse events associated with the treatment-emergent administration of a compound of formula (I), especially compound (a), wherein the adverse events associated with the treatment-emergent administration are grade 2 or lower; preferably 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 the fasting state or the fed state experience adverse events associated with the treatment-emergent administration of a compound of formula (I), especially compound (a), wherein the adverse events associated with the treatment-emergent administration are grade 2 or lower.

[0548] In some embodiments, up to 30% of subjects, particularly human subjects, in the fasting state or the fed state experience adverse events associated with the treatment-emergent administration of a compound of formula (I), particularly compound (a); preferably 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%, preferably up to 13% of subjects in the fed state experience adverse events associated with the treatment-emergent administration of a compound of formula (I), particularly compound (a).

[0549] In some embodiments, up to 30% of subjects, particularly human subjects, in the fasting state or the fed state experience adverse events associated with the treatment-emergent administration of a compound of formula (I), particularly compound (a), wherein the adverse events associated with the treatment-emergent administration are grade 2 or lower; preferably 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 the fed state experience adverse events associated with the treatment-emergent administration of a compound of formula (I), particularly compound (a), wherein the adverse events associated with the treatment-emergent administration are grade 2 or lower. In some embodiments, up to 30% of subjects, particularly human subjects, in the fasting state or the fed state experience adverse events associated with the treatment-emergent administration of a compound of formula (I), particularly compound (a); preferably 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%, preferably up to 13% of subjects in the fasting state experience adverse events associated with the treatment-emergent administration of a compound of formula (I), particularly compound (a).

[0550] In some embodiments, up to 30% of subjects, particularly human subjects, in the fasting state or the fed state, experience adverse events associated with the treatment-emergent administration of a compound of formula (I), particularly compound (a), wherein the adverse events associated with the treatment-emergent administration are grade 2 or lower; preferably 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 the fasting state experience adverse events associated with the treatment-emergent administration of a compound of formula (I), particularly compound (a), wherein the adverse events associated with the treatment-emergent administration are grade 2 or lower.

[0551] The present invention also provides a compound of formula (I) for use in preventing and / or treating dengue virus infection, wherein the compound is administered to humans in a fed or fasting state in an oral dosage form, and wherein formula (I) corresponds to

[0552]

[0553] Its stereoisomeric form, pharmaceutically acceptable salt, solvate or polymorph; the compound is selected from the following group, wherein:

[0554] R1 is H, R2 is F, and R3 is H or CH3,

[0555] R1 is H, CH3 or F, R2 is OCH3, and R3 is H,

[0556] R1 is H, R2 is OCH3, and R3 is CH3,

[0557] R1 is CH3, R2 is F, and R3 is H,

[0558] R1 is CF3 or OCF3, R2 is H, and R3 is H,

[0559] R1 is OCF3, R2 is OCH3, and R3 is H,

[0560] R1 is OCF3, R2 is H, and R3 is CH3;

[0561] The oral dosage form is administered according to the following dosage regimen, which comprises:

[0562] 1) at least one loading phase during which at least one dose (A) of a compound of formula (I) is administered at least once, preferably twice a day, preferably three times a day, preferably four times a day within a period of 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 subsumed therein; and

[0563] 2) at least one maintenance period starting from the last day of administration of dose (A) or the day after the last day of the loading period, during which at least one dose (B) of a 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 within the following time period: at least one day, preferably at least one day to up to 12 months, preferably up to 9 months, preferably up to 6 months, preferably up to 3 months, preferably up to 1.5 months, preferably up to 40 days, preferably up to 39 days, preferably up to 38 days, preferably up to 37 days, preferably up to 36 days, preferably up to 35 days, preferably up to 30 days, preferably up to 28 days, preferably up to 21 days, preferably up to 14 days, preferably up to 7 days, preferably up to 5 days, or any specific amount or range subsumed therein;

[0564] wherein the dose (A) is higher or lower than the dose (B); preferably, the dose (A) is higher than the dose (B);

[0565] wherein the oral dosage form is a solid dosage form comprising a cellulose derivative having a viscosity in a 2 wt% H2O solution at 25°C ranging between 3 mPa.s and 5000 mPa.s and selected from the group comprising: HPMC E5,

[0566] HPMC E6, HPMC E15, HPMC E50, HPMC K4M HPMC-AS, and any combination thereof.

[0567] The present invention also provides a compound of formula (I) for use in preventing and / or treating dengue virus infection, wherein the compound is administered to humans in a fed or fasting state in an oral dosage form, and wherein formula (I) corresponds to

[0568]

[0569] Its stereoisomeric form, pharmaceutically acceptable salt, solvate or polymorph; the compound is selected from the following group, wherein:

[0570] R1 is H, R2 is F, and R3 is H or CH3,

[0571] R1 is H, CH3 or F, R2 is OCH3, and R3 is H,

[0572] R1 is H, R2 is OCH3, and R3 is CH3,

[0573] R1 is CH3, R2 is F, and R3 is H,

[0574] R1 is CF3 or OCF3, R2 is H, and R3 is H,

[0575] R1 is OCF3, R2 is OCH3, and R3 is H,

[0576] R1 is OCF3, R2 is H, and R3 is CH3;

[0577] Wherein the oral dosage form is a solid dosage form comprising a cellulose derivative having a viscosity in a 2 wt % H2O solution at 25°C ranging between 3 mPa.s and 5000 mPa.s and selected from the group comprising HPMC E5, HPMC E6, HPMC E15, HPMC E50, HPMC K4M HPMC-AS, and any combination thereof.

[0578] The present invention also includes a pharmaceutical preparation for preventing and / or treating dengue virus infection, the preparation comprising

[0579] 11) a) a compound of formula (I) as described herein; and

[0580] b1) methacrylic acid copolymer, or

[0581] b2) cellulose derivatives, such as hydroxypropyl methylcellulose (HPMC);

[0582] The pharmaceutical preparation is administered in an oral dosage form to a human being in a fed state or a fasted state, wherein the human being is at risk of being infected by the dengue virus or has been infected by the dengue virus.

[0583] In some embodiments, oral dosage forms and / or pharmaceutical formulations according to the present invention comprise a compound of formula (I) as described herein and hydroxypropylmethylcellulose.

[0584] In some embodiments, the pharmaceutical preparation and / or oral dosage form according to the present invention comprising the compound of formula (I) according to the present invention is used to prevent and / or treat dengue virus infection. In some embodiments, the pharmaceutical preparation and / or oral dosage form is applied according to the following dosage regimen, which includes: 1) at least one loading phase, during which at least one dose (A) of the compound of formula (I) is applied at least once a day in a period of at least one day; and 2) at least one maintenance phase starting from the second day after the last day of the last day of the application of the dose (A) or the last day of the loading phase, during which at least one dose (B) of the compound of formula (I) is applied at least once every two weeks in a period of at least one day, preferably at least once a week, preferably at least twice a week, preferably at least once a day; wherein the dose (A) is higher or lower than the dose (B). Preferably, the dose (A) is higher than the dose (B).

[0585] In some embodiments, either dose (A) or dose (B) may vary throughout the days of the loading or maintenance phase, such as increasing and / or decreasing during the days of the loading or maintenance phase. For example, either dose (A) or dose (B) may be increased on the first day, preferably on the first 2 days, preferably on the first 3 days, preferably on the first 4 days, preferably on the first 5 days, preferably on the first 6 days, preferably on the first 7 days, preferably on the first 8 days, preferably on the first 9 days, preferably on the first 10 days, preferably on the first 11 days, preferably on the first 12 days, preferably on the first 13 days, preferably on the first 14 days, preferably on the first 15 days, preferably on the first 16 days, preferably on the first 17 days, preferably on the first 18 days, preferably on the first 19 days, preferably on the first 20 days, preferably on the first 21 days, preferably on the first 22 days, preferably on the first 23 days, preferably on the first 24 days, preferably on the first 25 days, preferably on the first 26 days, preferably on the first 27 days, preferably on the first 28 days, preferably on the first 29 days, preferably on the first 30 days, preferably on the first 31 days, preferably on the first 32 days, preferably on the first 33 days, preferably on the first 34 days, preferably on the first 35 days, preferably on the first 36 days, preferably on the first 37 days, preferably on the first 38 days, preferably on the first 39 days, preferably on the first 40 days 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 remain unchanged, followed by administration of lower and / or higher doses (e.g., biweekly doses, weekly doses, twice weekly doses, daily doses) on the remaining days of the same period. For example, either the dose (A) or the dose (B) can be maintained unchanged for the first 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, or more days, followed by administration of a lower and / or higher dose (e.g., biweekly dose, weekly dose, twice weekly dose, daily dose) on the remaining days of the same period.The remaining days in 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 days. The remaining days in each period may 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 formulation 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 every 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, the present invention relates to a method of administering the drug to the patient for at least 12 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 or more, and then 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 or every 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 formulation and / or oral dosage form can also be administered daily for 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, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 or more days, and thereafter 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 at least 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.

[0586] In some embodiments, the pharmaceutical formulation according to the present invention comprises a crystallization rate inhibitor. The term "crystallization rate inhibitor" refers to an excipient, such as a polymer excipient, added to the formulation in order to inhibit crystallization of the API when the formulation is administered to a subject. The crystallization rate inhibitor can be used to improve the bioavailability of the API, wherein the bioavailability of the crystalline form is significantly lower than that of the amorphous / dissolved state. The crystallization rate inhibitor can be referred to as a crystallization inhibitor or a stabilizer.

[0587] In one embodiment, the crystallization rate inhibitor is selected from polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone-vinyl acetate copolymer (PVPVA), poly (meth) acrylate polymers (e.g., methacrylic acid-methyl methacrylate copolymers), cyclodextrin or cyclodextrin derivatives (e.g., (2-hydroxypropyl)-β-cyclodextrin (HPBCD)), hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers, poly (vinyl alcohol), poloxamers (e.g., poloxamer 188, 338 or 407), and any combination thereof.

[0588] 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, polyvinyl pyrrolidone (PVP) and polyvinyl pyrrolidone-vinyl acetate copolymer (PVPVA), and combinations thereof. In another embodiment, the crystallization rate inhibitor is selected from hydroxypropyl methylcellulose (HPMC) and polyvinyl pyrrolidone-vinyl acetate copolymer (PVPVA). PVPVA can be a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate (PVPVA64) in a mass ratio of 6:4.

[0589] Names and abbreviations for polyvinylpyrrolidone-vinyl acetate copolymers include, but are not limited to, PVPVA, PVP-Vac-copolymer, and poly(1-vinylpyrrolidone-co-vinyl acetate).

[0590] The names and abbreviations 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, copolyvidone, copovidum, and copovidone. An example of commercially available PVPVA64 is VA64, VA64 Fine, Luviskol and Plasdone

[0591] Names and abbreviations for 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 K-12.

[0592] Hydroxypropyl methylcellulose (also known as hydroxypropyl methylcellulose (HPMC)) is a dehydrated glucose in which some of the hydroxyl groups are substituted with methyl groups to form methyl ether moieties, and other hydroxyl groups are substituted with hydroxypropyl groups or methoxypropyl groups to form hydroxypropyl ether or methoxypropyl ether moieties.

[0593] Hydroxypropyl methylcellulose polymer (HPMC) is available in different viscosity grades from several sources, such as under the trade names Available from Dow Chemical Co. and under the trade name Available from Shin Etsu. Non-limiting examples of low viscosity polymers include Methocel Methocel Methocel Methocel Methocel and Methocel The viscosities of their 2% aqueous solutions at 25°C are approximately 5 mPas, 6 mPas, 15 mPas, 50 mPas, 100 mPas and 50 mPas, respectively. Non-limiting examples of medium viscosity HPMC are Methocel and Methocel K4M, whose 2% aqueous solution has a viscosity of 4,000 mPas at 25°C. Non-limiting examples of high viscosity HPMC are Methocel and Methocel The viscosity of its 2% aqueous solution at 25°C is 15,000 mPas and 100,000 mPas.

[0594] In some embodiments, the viscosity of the hydroxypropyl methylcellulose is in the range of between 3 mPa.s and 5000 mPa.s (in a 2% H2O solution at 25°C), and may be selected from the group consisting of HPMC E5, HPMC E6, HPMC E15, HPMC E50, HPMC K4M, HPMC K15M, HPMC-AS, and mixtures thereof. In some embodiments, the viscosity of the hydroxypropyl methylcellulose is in the range of between 3 mPa.s and 500 mPa.s (in a 2% H2O solution at 25°C), and may be selected from the group consisting of HPMC E5, HPMC E6, HPMC E15, HPMC E50, and mixtures thereof. In some embodiments, the viscosity of the hydroxypropyl methylcellulose ranges between 3 and 50 mPa.s (in 2% H2O solution at 25°C), and may be selected from the group consisting of HPMC E5, HPMC E6, HPMC E15, HPMC E50, and mixtures thereof.

[0595] As used herein, the term "methacrylic acid copolymer" preferably refers to copolymers of acrylic acid and / or methacrylic acid / esters, such as those sold under the trade name Those compounds that are sold. It is commercially available from, for example, Evonik Healthcare & Nutrition GmbH, Essen, Germany.

[0596] Different types of methacrylic acid copolymers can be used and they include poly(methacrylic acid-co-methyl methacrylate) 1:1 (such as L-100, L12.5); poly(methacrylic acid-co-methyl methacrylate) 1:2 (such as S-100, S12,5, FS30D); poly(methacrylic acid-co-ethyl acrylate) 1:1 (such as L30D55, L100-55); poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride) 1:2:0.1 (such as RS30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) 1:2:0.2 (such as RL30D); poly(ethyl acrylate-co-methyl methacrylate) 2:1 (such as NM 30D or Eudragit NE 30D); a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate in a ratio of 2:1:1 ( E-100) and combinations thereof.

[0597] 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.

[0598] 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 (eg 1:1).

[0599] In some embodiments, the methacrylic acid copolymer is poly(methacrylic acid-co-methyl methacrylate) 1:1 ( L100, CAS number: 25086-15-1).

[0600] In some embodiments, the oral dosage form and / or pharmaceutical formulation according to the present invention comprises: a) a compound of formula (I) as defined above, preferably

[0601] or a stereoisomeric form, a pharmaceutically acceptable salt, a solvate or a polymorph thereof; and

[0602] b1) methacrylic acid copolymer, or

[0603] b2) Cellulose derivatives, such as hydroxypropylmethylcellulose (HPMC).

[0604] The oral dosage form and / or pharmaceutical preparation of the present invention may contain up to 50% by weight of the compound of formula (I) relative to the total weight of the preparation, 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) relative to the total weight of the preparation. The pharmaceutical preparation may contain at least 0.1% by weight of the compound of formula (I) relative to the total weight of the preparation, 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, preferably at least 20% by weight of the compound of formula (I) relative to the total weight of the preparation. The pharmaceutical preparation may contain 0.1% to 45% by weight of the compound of formula (I) relative to the total weight of the preparation, preferably 0.5% to 40% by weight, preferably 1% to 40% by weight, preferably 5% to 35% by weight, preferably 10% to 35% by weight of the compound of formula (I) relative to the total weight of the preparation.

[0605] The oral dosage forms and / or pharmaceutical preparations of the present invention may contain 0.1 mg to 3000 mg of the compound of formula (I), preferably 1 mg to 2000 mg of the compound of formula (I), preferably 5 mg to 1500 mg of the compound of formula (I), preferably 5 mg to 1000 mg of the compound of formula (I), preferably 10 mg to 1100 mg of the compound of formula (I), preferably 15 mg to 950 mg of the compound of formula (I), preferably 20 mg to 900 mg of the compound of formula (I), or any specific amount or range contained therein.

[0606] The oral dosage form and / or pharmaceutical preparation of the present invention may comprise:

[0607] 20 mg to 6000 mg of methacrylic acid copolymer, preferably 30 mg to 4000 mg of methacrylic acid copolymer, preferably 40 mg to 2000 mg of methacrylic acid copolymer, preferably 50 mg to 1500 mg of methacrylic acid copolymer, preferably 60 mg to 1000 mg of methacrylic acid copolymer, preferably 70 mg to 1000 mg of methacrylic acid copolymer, preferably 80 mg to 600 mg of methacrylic acid copolymer, or any specific amount or range subsumed therein; or

[0608] 20 mg to 6000 mg of hydroxypropyl methylcellulose, preferably 30 mg to 4000 mg of hydroxypropyl methylcellulose, preferably 40 mg to 2000 mg of hydroxypropyl methylcellulose, preferably 50 mg to 1500 mg of hydroxypropyl methylcellulose, preferably 60 mg to 1000 mg of hydroxypropyl methylcellulose, preferably 70 mg to 1000 mg of hydroxypropyl methylcellulose, preferably 80 mg to 600 mg of hydroxypropyl methylcellulose, or any specific amount or range subsumed therein.

[0609] The oral dosage form and / or pharmaceutical formulation of the present invention may further comprise one or more diluents; wherein the formulation comprises 20 mg to 7500 mg of filler, 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 of filler, or any specific amount or range contained therein.

[0610] The oral dosage form and / or pharmaceutical formulation of the present invention may further comprise one or more surfactants; wherein the formulation comprises 0.5 mg to 300 mg of a 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 of a surfactant, or any specific amount or range contained therein.

[0611] The oral dosage form and / or pharmaceutical formulation of the present invention may further comprise one or more disintegrants; wherein the formulation 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 of disintegrant, or any specific amount or range contained therein.

[0612] The oral dosage form and / or pharmaceutical formulation of the present invention may further comprise one or more glidants; wherein the formulation comprises 1 mg to 400 mg of glidant, 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 of glidant, or any specific amount or range contained therein.

[0613] The oral dosage form and / or pharmaceutical formulation of the present invention may further comprise one or more lubricants; wherein the formulation comprises 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 of lubricant, or any specific amount or range contained therein.

[0614] The oral dosage form and / or pharmaceutical preparation of the present invention may comprise:

[0615] Up to 60% by weight, preferably up to 50% by weight, preferably up to 45% by weight, preferably up to 40% by weight, preferably up to 35% by weight of methacrylic acid copolymer relative to the total weight of the formulation; or

[0616] At most 60% by weight, preferably at most 50% by weight, preferably at most 45% by weight, preferably at most 40% by weight, preferably at most 35% by weight of hydroxypropylmethylcellulose relative to the total weight of the formulation.

[0617] The oral dosage form and / or pharmaceutical preparation of the present invention may comprise:

[0618] 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 relative to the total weight of the formulation; or

[0619] At least 0.2 wt. %, preferably at least 1 wt. %, preferably at least 5 wt. %, preferably at least 10 wt. %, preferably at least 20 wt. % of hydroxypropyl methylcellulose relative to the total weight of the formulation.

[0620] The oral dosage form and / or pharmaceutical preparation according to the present invention may comprise:

[0621] 0.2% to 60% by weight, preferably 1% to 50% by weight, preferably 5% to 40% by weight, of a methacrylic acid copolymer relative to the total weight of the formulation; or

[0622] 0.2% to 60% by weight, preferably 1% to 50% by weight, preferably 5% to 40% by weight of hydroxypropylmethylcellulose relative to the total weight of the formulation.

[0623] In some embodiments, the compound of formula (I) and the methacrylic acid copolymer are present in the oral dosage form and / or pharmaceutical formulation of the present invention in the following ratios: 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 a ratio comprised within any two ratios mentioned herein, or a ratio range or sub-range within any two ratios mentioned herein.

[0624] In some embodiments, the compound of formula (I) and hydroxypropyl methylcellulose are present in the oral dosage form and / or pharmaceutical formulation of the present invention in the following ratios: 4:1 w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 3.8:1 w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 3.5:1 w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 3.3:1 w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 3:1 w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 2.8:1 w / w of the compound of formula (I): hydroxypropyl methylcellulose. propyl methylcellulose, preferably 2.5:1 w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 2.3:1 w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 2:1 w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 1.8:1 w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 1.5:1 w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 1:5 w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 1:4.8 w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 1:4.5w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 1:4.3w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 1:4w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 1:3.8w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 1:3.5w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 1:3.3w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 1:3w / w of the compound of formula (I): hydroxypropyl methylcellulose, preferably 1:2.8w / w of Compound of formula (I): hydroxypropyl methylcellulose, preferably 1:2.5 w / w compound of formula (I): hydroxypropyl methylcellulose, preferably 1:2.3 w / w compound of formula (I): hydroxypropyl methylcellulose, preferably 1:2 w / w compound of formula (I): hydroxypropyl methylcellulose, preferably 1:1.5 w / w compound of formula (I): hydroxypropyl methylcellulose, preferably 1:1.2 w / w compound of formula (I): hydroxypropyl methylcellulose, or a ratio comprised within any two ratios mentioned herein, or a range or sub-range of ratios within any two ratios mentioned herein.

[0625] As described in more detail herein, oral dosage forms and / or pharmaceutical preparations of the present invention may also include one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, but are not limited to, disintegrants, binders, diluents, lubricants, stabilizers, permeants, colorants, plasticizers, coating agents, fillers, surfactants, etc. Other suitable pharmaceutical excipients and their properties can be found in texts such as Handbook of Pharmaceutical Excipients, compiled by RC Rowe, PJ Sheskey and PJ Weller, the sixth edition (published by the Pharmaceutical Press of the Royal Pharmaceutical Society of Great Britain, a Division of Royal Pharmaceutical Society of Great Britain).

[0626] Fillers (or fillers) that can be used in the present invention include microcrystalline cellulose (e.g., PH 102, PH 101, Ceolus UF, Ceolus KG or Ceolus PH), silicified microcrystalline cellulose, lactose, sorbitol, cellulose, calcium phosphate, starch (e.g., partially or completely pregelatinized corn starch), sugar or lactose (e.g., mannitol, sucrose, etc.), or any combination thereof. Non-limiting examples of microcrystalline cellulose include commercially available series, such as microcrystalline cellulose with a particle size of 100 μm (e.g., PH 102). Microcrystalline cellulose also includes commercially available UF, KG or PH grade Ceolus. Other non-limiting examples of diluents include silicified microcrystalline cellulose, such as commercially available Series (for example, SMCC 50 and SMCC HD90). Lactose suitable for the present invention includes lactose monohydrate. The amount of diluent can be 5% to 95% by weight, preferably 20% to 80% by weight, preferably 25% to 50% by weight, preferably 30% to 48% by weight, preferably 30% to 52% by weight, preferably 35% to 52% by weight, preferably 40% to 50% by weight relative to the total weight of the pharmaceutical preparation. For example, the diluent in the pharmaceutical formulation may include microcrystalline cellulose, silicified microcrystalline cellulose, and partially or completely pregelatinized corn starch, with a combined (or total) concentration of 5% to 95% by weight, preferably 20% to 80% by weight, preferably 25% to 50% by weight, preferably 30% to 48% by weight, preferably 30% to 52% by weight, preferably 35% to 52% by weight, preferably 30% to 45% by weight, preferably 32.5% to 45% by weight, based on the weight of the pharmaceutical formulation.

[0627] Disintegrants enhance the dispersion of drug formulations. Non-limiting examples of disintegrants useful in the present invention include cross-linked carboxymethyl cellulose (e.g., cross-linked carboxymethyl cellulose sodium), crospovidone, metal starch glycolate (e.g., sodium starch glycolate), and any combination thereof. Other examples of disintegrants include cross-linked carboxymethyl cellulose sodium (e.g., ) and sodium starch glycolate. The pharmaceutical formulation of the present invention may include one or more disintegrants in 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, based on the weight of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation includes 2% to 8% by weight (e.g., 2.5% to 7.5% by weight), preferably 3% to 6% by weight, and more preferably 4% to 5% by weight of a disintegrant (e.g., crospovidone) based on the weight of the pharmaceutical formulation.

[0628] Binders may include agents used in preparing particles of an active pharmaceutical ingredient by mixing a binder with a filler and an active pharmaceutical ingredient. Non-limiting examples of binders that can be used in the present invention include polyvinyl pyrrolidone, sugars, modified celluloses (e.g., hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and hydroxyethyl cellulose (HEC)), and any combination thereof. Other examples of binders include polyvinyl pyrrolidone (PVP). Examples of HPC include low viscosity polymers HPC-SL. PVP can be characterized by its "K value," which is a useful measure of the viscosity of a polymer composition. PVP is available under the trade name K12, K17, K25, K30, K60 and K90 is commercially available (e.g., Tokyo Chemical Industry Co., Ltd.). Specific examples of PVP include soluble spray-dried PVP. Another example includes PVP with an average molecular weight of 3,000 to 4,000, such as PVP with an average molecular weight of 4,000. K12. PVP can be used in a wet or dry state. The pharmaceutical preparation of the present invention may include one or more binders, and its combined (or total) concentration is 0.1% to 50% by weight of the pharmaceutical preparation; preferably 0.5% to 43% by weight, preferably 2% to 45% by weight, preferably 5% to 40% by weight, preferably 10% to 35% by weight, preferably 15% to 30% by weight, preferably 20% to 25% by weight. In some embodiments, the pharmaceutical preparation includes 0.5% to 2% by weight (e.g., 1.5% to 2% by weight or 1.75% to 2.25% by weight) of a binder (e.g., hydroxypropyl methylcellulose) by weight of the pharmaceutical preparation.

[0629] Lubricants are used to improve the compression and ejection of pharmaceutical preparations from, for example, a molding machine. Non-limiting examples of lubricants that can be used for 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 includes sodium stearyl fumarate. In another example, the lubricant includes magnesium stearate. The pharmaceutical preparation of the present invention may include one or more lubricants, and its combined (or total) concentration is 0.10% to 10% by weight, preferably 0.5% to 6% by weight, preferably 0.8% to 3.5% by weight, preferably 1% to 3% by weight, preferably 1.50% to 5.5% by weight, preferably 2% to 4% by weight, or preferably 0.25% to 5.25% by weight by weight of the weight of the pharmaceutical preparation. In some embodiments, the pharmaceutical formulation comprises 0.5 wt % to 5.5 wt %, preferably 1 wt % to 2.5 wt % of a lubricant (eg, magnesium stearate).

[0630] One or more wetting agents may be employed in the oral dosage forms and / or pharmaceutical formulations of the present invention. Wetting agents suitable for use in the present invention generally enhance the solubility of the pharmaceutical formulation. 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™)), sorbitan fatty acid esters (e.g., ), sodium dodecylbenzene sulfonate (SDBS), dioctyl sodium sulfosuccinate (docusate), dioxycholic acid sodium salt (DOSS), sorbitan monostearate, sorbitan tristearate, sodium N-lauroyl sarcosinate, sodium oleate, sodium myristate, sodium stearate, sodium palmitate, gelucire 44 / 14 44 / 14, ethylenediaminetetraacetic acid (EDTA), vitamin E d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), lecithin, 15MW 677-692, sodium glutamate monohydrate, Labrasol, PEG 8 caprylic / capric glycerides, transcutol, diethylene glycol monoethyl ether, solutol HS-15, Polyethylene glycol / hydroxystearate, taurocholic acid, copolymers of polyoxypropylene and polyoxyethylene (e.g., poloxamers, are also known and can be used. Commercially available, such as L61, F68, F108 and F127), saturated polyglycolic acid glyceride And any combination thereof. Other examples include sodium lauryl sulfate, which is an anionic surfactant; and copolymers of polyoxypropylene and polyoxyethylene, which are nonionic surfactants. Examples of copolymers of polyoxypropylene and polyoxyethylene include poloxamers, such as poloxamers (e.g., poloxamer 188) having a polyoxypropylene molecular weight of 1,800 g / mol and 80% polyoxyethylene content. The pharmaceutical formulation of the present invention may include one or more wetting agents, the combined (or total) concentration of which is 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 includes 0.25% to 5.00% by weight (e.g., 0.35% to 4.50% by weight) of a wetting agent (e.g., sodium lauryl sulfate).

[0631] Glidants enhance the flow characteristics of the formulation during processing into the final drug product form. Non-limiting examples of glidants that can be used in the present invention include silicon dioxide (e.g., colloidal fumed silica, colloidal anhydrous silica) and / or talc. Specific examples of glidants include colloidal fumed silica (e.g., 200). The pharmaceutical formulation of the present invention may include one or more glidants, and the combined (or total) concentration thereof is 0.10 wt % to 10 wt %, preferably 1 wt % to 8 wt %, preferably 2 wt % to 7.5 wt %, preferably 3 wt % to 5 wt % by weight of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation includes a glidant in an amount of 0.10 wt % to 5 wt % (e.g., 0.75 wt % to 3.25 wt %) by weight of the pharmaceutical formulation. In other embodiments, the pharmaceutical formulation includes fumed silica in an amount of 0.10 wt % to 2 wt % (e.g., 0.75 wt % to 1.5 wt %) by weight of the pharmaceutical formulation.

[0632] In some embodiments, the oral dosage form according to the present invention is a solid dosage form formulated as a pharmaceutical preparation; preferably, the solid dosage form is a tablet. The tablet dosage form of the present invention may also have a coating. Suitable coatings are film-forming polymers, such as those from the following group: cellulose derivatives (such as HPC (hydroxypropyl cellulose), HPMC (hydroxypropoxymethyl cellulose), MC (methyl cellulose), HPMCAS (hydroxypropoxymethyl cellulose acetate succinate), dextrin, starch, natural gums (such as gum arabic, xanthan gum), alginates, polyvinyl alcohol, polymethacrylates and derivatives thereof, such as (It can be applied to tablets in the form of a solution or suspension by various conventional pharmaceutical methods, such as film coating.) The coating is usually applied as a solution / suspension and may contain, in addition to any film-forming polymer present, one or more adjuvants such as hydrophilizing agents, plasticizers, surfactants, dyes and white pigments (such as titanium dioxide).

[0633] In some embodiments, the oral dosage form according to the present invention is formulated as a pharmaceutical preparation comprising a plurality of particles forming an intragranular phase of the preparation and one or more pharmaceutically acceptable excipients forming an extragranular phase of the preparation. Preferably, the oral dosage form is a tablet comprising an intragranular phase and an extragranular phase.

[0634] As used herein, the term "intragranular phase" refers to those components of a formulation with the granules. As used herein, the term "extragranular phase" refers to those components of a formulation that are outside of the granules.

[0635] In some embodiments, the intragranular phase of the pharmaceutical preparation according to the present invention comprises an active pharmaceutical ingredient, and one or a combination of methacrylic acid copolymers or cellulose derivatives (such as methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose (NaCMC) or hydroxypropylmethylcellulose (HPMC). In some embodiments, the intragranular phase of the pharmaceutical preparation according to the present invention comprises an active pharmaceutical ingredient, one or a combination of methacrylic acid copolymers or hydroxypropylmethylcellulose (HPMC), and one or more pharmaceutically acceptable excipients selected from disintegrants, binders, diluents, lubricants, stabilizers, wetting agents, glidants, osmotic agents, colorants, plasticizers, coating agents, fillers and surfactants.

[0636] In some embodiments, the pharmaceutical formulation comprises 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 40 wt%, preferably at least 45 wt%, preferably at least 50 wt%, preferably at least 55 wt%, preferably at least 60 wt%, preferably at least 65 wt% of the intragranular phase, based on the total weight of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises at most 99 wt%, preferably at most 95 wt%, preferably at most 93 wt%, preferably at most 90 wt%, preferably at most 85 wt%, preferably at most 80 wt%, preferably at most 75 wt%, preferably at most 74 wt%, preferably at most 73 wt%, preferably at most 70 wt%, preferably at most 67 wt%, preferably at most 63 wt%, preferably at most 60 wt%, preferably at most 53 wt% of the intragranular phase, based on the total weight of the pharmaceutical formulation.

[0637] In some embodiments, the pharmaceutical formulation comprises an intragranular phase comprising, based on the total weight of the pharmaceutical formulation, preferably 1 wt% to 70 wt%, preferably 2 wt% to 69 wt%, preferably 3 wt% to 68 wt%, preferably 4 wt% to 67 wt%, preferably 5 wt% to 66 wt%, preferably 6 wt% to 65 wt%, preferably 10 wt% to 64 wt%, preferably 15 wt% to 60 wt%, preferably 20 wt% to 55 wt%, preferably 25 wt% to 50 wt%, preferably 30 wt% to 45 wt%, preferably 35 wt% to 40 wt% of the API.

[0638] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an intragranular phase comprising 5 wt % to 60 wt %, preferably 7 wt % to 55 wt %, preferably 8 wt % to 50 wt %, preferably 17 wt % to 45 wt %, preferably 15 wt % to 45 wt % of methacrylic acid copolymer or hydroxypropyl methylcellulose or a combination thereof, based on the total weight of the pharmaceutical formulation.

[0639] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an intragranular phase comprising 5 wt % to 60 wt %, preferably 10 wt % to 60 wt %, preferably 12 wt % to 60 wt %, preferably 15 wt % to 50 wt %, preferably 18 wt % to 45 wt % of a filler based on the total weight of the pharmaceutical formulation.

[0640] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an intragranular phase comprising 1 wt % to 10 wt %, preferably 1 wt % to 9 wt %, preferably 1.7 wt % to 8 wt %, preferably 1.6 wt % to 7.5 wt %, preferably 2 wt % to 5 wt % of a disintegrant, based on the total weight of the pharmaceutical formulation.

[0641] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an intragranular phase comprising 0.1 wt % to 5 wt %, preferably 0.2 wt % to 4.7 wt %, preferably 0.5 wt % to 4.5 wt %, preferably 0.8 wt % to 4 wt %, preferably 1 wt % to 3.5 wt % of a glidant based on the total weight of the pharmaceutical formulation.

[0642] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an intragranular phase comprising 0.1 wt % to 5 wt %, preferably 0.2 wt % to 4.7 wt %, preferably 0.5 wt % to 4.5 wt %, preferably 0.6 wt % to 4.5 wt %, preferably 0.8 wt % to 4.0 wt %, preferably 1 wt % to 3.5 wt % of a surfactant, based on the total weight of the pharmaceutical formulation.

[0643] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an intragranular phase comprising 0.1 wt % to 3 wt %, preferably 0.2 wt % to 2.7 wt %, preferably 0.5 wt % to 2.5 wt %, preferably 0.7 wt % to 2 wt % of a lubricant, based on the total weight of the pharmaceutical formulation.

[0644] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising at least 5 wt%, preferably at least 7 wt%, preferably at least 10 wt%, preferably at least 15 wt%, preferably 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% of the extragranular phase based on the total weight of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises 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 63 wt%, preferably up to 65 wt%, preferably up to 60 wt%, preferably up to 55 wt%, preferably up to 53 wt%, preferably up to 40 wt% of the extragranular phase based on the total weight of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises at least 15 wt% to at most 75 wt%, preferably at least 25 wt% to at most 70 wt%, preferably at least 30 wt% to at most 65 wt%, preferably at least 35 wt% to at most 60 wt%, preferably at least 35 wt% to at most 70 wt% of the extragranular phase, based on the total weight of the pharmaceutical formulation.

[0645] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising 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% of the intragranular phase based on the total weight of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises 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% of the intragranular phase based on the total weight of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises at least 15 wt% to at most 75 wt%, preferably at least 25 wt% to at most 70 wt%, preferably at least 30 wt% to at most 65 wt%, preferably at least 35 wt% to at most 60 wt%, preferably at least 35 wt% to at most 70 wt% of the intragranular phase, based on the total weight of the pharmaceutical formulation.

[0646] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an intragranular phase comprising:

[0647] (i) 5 to 45 wt%, preferably 10 wt%, based on the total weight of the pharmaceutical preparation

[0648] to 40 wt%, preferably 15 wt% to 35 wt% API;

[0649] (ii) 5 to 60 wt%, preferably 10 to 50 wt%, preferably 15 to 55 wt% of methacrylic acid copolymer or hydroxypropyl methylcellulose or a combination thereof, based on the total weight of the pharmaceutical formulation;

[0650] (iii) 5 to 60 wt %, preferably 10 to 50 wt %, preferably 15 to 40 wt % of a filler (e.g., mannitol, microcrystalline cellulose), based on the total weight of the pharmaceutical formulation;

[0651] (iv) 1 to 10 wt %, preferably 1.5 to 9 wt %, preferably 1.5 to 8 wt % of a disintegrant (e.g., croscarmellose sodium), based on the total weight of the pharmaceutical formulation;

[0652] (v) 0.1 to 5 wt %, preferably 0.2 to 4.5 wt %, preferably 0.5 to 4 wt % of a glidant (e.g., colloidal fumed silicon dioxide), based on the total weight of the pharmaceutical formulation;

[0653] (vi) 0.1 wt% to 5 wt%, preferably 0.2 wt% to 4.5 wt%, preferably 0.5 wt% to 4 wt% of a surfactant (e.g., sodium lauryl sulfate), based on the total weight of the pharmaceutical formulation; and

[0654] (vii) 0.1 wt% to 3 wt%, preferably 0.2 wt% to 2.5 wt%, preferably 0.5 wt% to 2 wt% of a lubricant (eg, magnesium stearate), based on the total weight of the pharmaceutical formulation.

[0655] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an extra-granular phase comprising 0.1 wt % to 5.0 wt %, preferably 0.2 wt % to 4.7 wt %, preferably 0.5 wt % to 4.5 wt %, preferably 1 wt % to 3.5 wt %, preferably 1.5 wt % to 3 wt % of a disintegrant, based on the total weight of the pharmaceutical formulation.

[0656] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an extra-granular phase comprising 0.1 wt % to 3 wt %, preferably 0.2 wt % to 2.7 wt %, preferably 0.5 wt % to 2.5 wt %, preferably 0.8 wt % to 2 wt % of a lubricant, based on the total weight of the pharmaceutical formulation.

[0657] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an extra-granular phase comprising 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% of filler, based on the total weight of the pharmaceutical formulation.

[0658] In some embodiments, the oral dosage form is formulated in a pharmaceutical formulation comprising an extragranular phase comprising:

[0659] (a) 0.1 wt% to 5.0 wt%, preferably 0.2 wt%, based on the total weight of the pharmaceutical preparation

[0660] to 4.5 wt%, preferably 0.5 wt% to 3 wt% of a disintegrant (e.g., croscarmellose sodium);

[0661] (b) 0.1 to 3 wt%, preferably 0.2 wt%, based on the total weight of the pharmaceutical preparation

[0662] to 2.5 wt %, preferably 0.5 wt % to 2 wt % of a lubricant (e.g., magnesium stearate); and

[0663] (c) 1 to 15 wt%, preferably 1.5 wt%, based on the total weight of the pharmaceutical preparation

[0664] To 10 wt%, preferably 2 wt% to 8 wt% of filler (eg, hydroxypropyl methylcellulose).

[0665] In some embodiments, the oral dosage form of the present invention is formulated in a pharmaceutical formulation comprising an intragranular phase and an extragranular phase; wherein the formulation comprises 50 mg to 17000 mg of the intragranular phase, 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 of the intragranular phase, or any specific amount or range contained therein.

[0666] In some embodiments, the oral dosage form of the present invention is formulated in a pharmaceutical formulation comprising an intragranular phase and an extragranular phase; wherein the formulation comprises 4 mg to 1500 mg of the extragranular phase, 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 of the extragranular phase, or any specific amount or range contained therein.

[0667] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an intragranular phase comprising 1 mg to 2000 mg, preferably 5 mg to 1500 mg, preferably 5 mg to 1000 mg, preferably 10 mg to 500 mg, preferably in the range of 15 mg to 400 mg, preferably 20 mg to 350 mg of a compound of formula (I), or any specific amount or range subsumed therein.

[0668] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an intragranular phase 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 copolymer or hydroxypropyl methylcellulose or a combination thereof, or any specific amount or range contained therein.

[0669] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an intragranular phase comprising 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 diluent / filler, or any specific amount or range contained therein.

[0670] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an intragranular phase comprising 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 of a surfactant, or any specific amount or range contained therein.

[0671] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an intragranular phase comprising 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 of a disintegrant, or any specific amount or range contained therein.

[0672] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an intragranular phase comprising 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 of a glidant, or any specific amount or range contained therein.

[0673] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an intragranular phase comprising 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 of a lubricant, or any specific amount or range contained therein.

[0674] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an intragranular phase comprising:

[0675] (i) 1 mg to 2000 mg; preferably 5 mg to 1500 mg, preferably 5 mg to 1000 mg;

[0676] Preferably 10 mg to 500 mg, preferably in the range of 15 mg to 400 mg, preferably 20 mg to 350 mg of API;

[0677] (ii) 20 mg to 6000 mg; preferably 30 mg to 4000 mg; preferably 40 mg to 2000 mg, preferably 70 mg to 1000 mg of methacrylic acid copolymer or hydroxypropyl methylcellulose or a combination thereof;

[0678] (iii) in some embodiments, a filler / filler (e.g., mannitol, microcrystalline cellulose) comprising 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 formula (I) according to the present invention;

[0679] (iv) in some embodiments, a disintegrant (e.g., croscarmellose sodium) containing 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 of formula (I) according to the present invention;

[0680] (v) in some embodiments, comprising 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 of a glidant (e.g., colloidal fumed silicon dioxide) according to formula (I) of the present invention;

[0681] (vi) In some embodiments, a surfactant (e.g., sodium lauryl sulfate) of formula (I) according to the present invention is contained in an amount of 0.5 to 300 mg, preferably 0.6 to 250 mg, preferably 0.8 to 200 mg, preferably 1 to 150 mg, preferably 1.2 to 100 mg, preferably 1.5 to 80 mg, preferably 2 to 30 mg; and

[0682] (vii) in some embodiments, comprising 0.3 mg to 90 mg of formula (I) according to the present invention;

[0683] 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 of a lubricant (eg magnesium stearate).

[0684] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an extra-granular phase comprising 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 of a disintegrant.

[0685] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an extra-granular phase comprising 3.5 mg to 1100 mg, preferably in the range of 5 mg to 500 mg, preferably in the range of 10 mg to 250 mg, preferably 15 mg to 100 mg, preferably 25 mg to 90 mg of a diluent / filler.

[0686] In some embodiments, the oral dosage form is formulated with a pharmaceutical formulation comprising an extra-granular phase comprising 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 of a lubricant.

[0687] In some embodiments, the oral dosage form is formulated in a pharmaceutical formulation comprising an extragranular phase comprising:

[0688] (a) 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 of a disintegrant (e.g., croscarmellose sodium);

[0689] (b) 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 of a lubricant (e.g., magnesium stearate); and

[0690] (c) 3.5 mg to 1100 mg, preferably in the range of 5 mg to 500 mg, preferably in the range of 10 mg to 250 mg, preferably 15 mg to 100 mg, preferably 25 mg to 90 mg of a diluent / filler (e.g. hydroxypropyl methylcellulose).

[0691] Those skilled in the art will readily recognize that appropriate pharmaceutically acceptable excipients are selected such that they are compatible with the other excipients and do not bind to or cause degradation of the active drug ingredient (ie, the compound of formula (I)).

[0692] It will be appreciated that any of the above descriptions relating to pharmaceutical formulation components may apply to any other aspects and embodiments of the invention.

[0693] The present invention provides a compound of formula (I) as described herein for use in preventing and / or treating dengue virus infection, wherein the compound is contained in a pharmaceutical formulation administered in a fed state or a fasted state. Preferably, the compound is administered to humans who are at risk of being infected by dengue virus or have been infected by dengue virus.

[0694] In some embodiments, the compound of Formula (I) is in an amorphous form or in solution (ie, a molecular dispersion) in the pharmaceutical formulation.

[0695] In additional embodiments of the present invention, the compound of formula (I) is selected from the group consisting of:

[0696]

[0697]

[0698] or a stereoisomeric form, a pharmaceutically acceptable salt, a solvate or a polymorph thereof.

[0699] The present invention also includes compounds of formula (I), or enantiomers, diastereomers or pharmaceutically acceptable salt forms thereof.

[0700] The present invention also includes compounds of formula (I) in an amorphous state or in a dissolved state (ie, molecularly dispersed), or in the form of an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof.

[0701] In particular, the starting material in the process for preparing a pharmaceutical formulation as described herein is a compound of formula (I), or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt form thereof; and the final pharmaceutical formulation or solid dosage form as defined herein also comprises a compound of formula (I), or an enantiomer, diastereomer or pharmaceutically acceptable salt form thereof, in amorphous form or in solution.

[0702] In a preferred embodiment, the compound of formula (I) is Compound (a), or a stereoisomeric form, a pharmaceutically acceptable salt, a solvate or a polymorph thereof.

[0703] The compound of formula (I) may be compound (a) or a solvate or a pharmaceutically acceptable salt thereof. The compound of formula (I) may be compound (a) or a pharmaceutically acceptable salt thereof. The compound of formula (I) may be compound (a) in a solvated form, for example as a monohydrate. The compound of formula (I) may be compound (a) solvated with an organic solvent and water, for example a solvate and a 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 anhydrous form. Preferably, the compound of formula (I) is compound (a) in amorphous form. Preferably, the compound of formula (I) is compound (a) in amorphous form or dissolved state or a pharmaceutically acceptable salt thereof. Preferably, the compound of formula (I) is compound (a) in amorphous form or dissolved state. Preferably, the compound of formula (I) is the (S)-enantiomer of compound (a) in amorphous form. Preferably, the compound of formula (I) is the (S)-enantiomer of compound (a) in anhydrous form.

[0704] In some embodiments, the compound of formula (I) is: Enantiomer 9A, wherein

[0705] 1H NMR(400MHz,DMSO-d6)δppm 3.09(s,3H)3.73(s,3H)3.99(s,3H)6.26(d,J=7.9Hz,1H)6.55-6.62(m,2H)6.91(t,J=1.5Hz,1H)6.98(dd,J=8.4,2.0Hz,1H)7.07(d,J=7.9H z,1H)7.13(d,J=2.0Hz,1H)7.21(dd,J=8.8,1.8Hz,1H)7.36(d,J=8.4Hz,1H)7.59(d,J=8.8Hz,1H)8.07(d,J=0.9Hz,1H)8.55(s,1H)12.29(br s,1H).

[0706] In some embodiments, the compound of formula (I) is: Enantiomer 9B, wherein

[0707] 1 H NMR(400MHz,DMSO-d6)δppm 3.09(s,3H)3.73(s,3H)3.99(s,3H)6.26(d,J=7.9Hz,1H)6.56-6.62(m,2H)6.92(t,J=2.0Hz,1H)6.98(dd,J=8.1,2.0Hz,1H)7.07(d,J=7.9H z,1H)7.13(d,J=2.0Hz,1H)7.22(dd,J=8.8,1.8Hz,1H)7.36(d,J=8.4Hz,1H)7.59(d,J=8.8Hz,1H)8.07(d,J=0.9Hz,1H)8.55(s,1H)12.30(br s,1H).

[0708] The compound of formula (I) can be synthesized according to the method disclosed in WO 2016 / 180696, which is incorporated herein by reference in its entirety.

[0709] The compounds of formula (I) used in the present invention can be synthesized according to the general synthetic methods described below and described in the schemes and examples thereafter. Since the schemes are illustrative, the present invention should not be construed as being limited by the chemical reactions and conditions in the schemes and examples. Compounds similar to the target compounds of these examples can be obtained by similar paths. The disclosed compounds can be used as medicines as described herein. The different raw materials used in the schemes and examples are commercially available or can be prepared by methods well known to those skilled in the art.

[0710] The synthesis of compounds 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 acyl chloride III with a substituted indole of general formula IV can be carried out using a Lewis acid reagent such as Et2AlCl or TiCl4 in a suitable solvent such as CH2Cl2 or 1,2-dichloroethane, and under suitable reaction conditions generally (but not exclusively) involving cooling, to provide 3-acylated indoles of general formula V. The introduction of the aniline moiety at the alpha position of the carbonyl moiety of the compound of formula V can be accomplished by a reaction sequence involving, for example, bromination of V with a reagent such as phenyltrimethylammonium tribromide in a suitable solvent such as THF (tetrahydrofuran) to give a compound of formula VI, and subsequent reaction of the compound of formula VI with 3-methoxy-5-(methylsulfonyl)aniline (VII) in a suitable solvent such as CH3CN and typically using a base such as TEA or DIPEA to give a racemic mixture of the compound of formula I. Chiral separation of the compounds of formula I can be performed, for example, by chiral chromatography to give enantiomers A and B of formula (I).

[0711]

[0712] In some cases, the synthesis of intermediates of general formula V via the Friedel-Crafts synthesis method benefits from the presence of a protecting group (PG) at the indole-N during the Friedel-Crafts reaction step, as outlined in Scheme 2. To this end, substituted indoles of general formula IV can be first converted to N-protected intermediates of general formula VIII, such as N-tosylated intermediates of general formula VIII (PG=Ts), using reagents such as tosyl chloride in the presence of a base such as sodium hydride. The Friedel-Crafts reaction of substituted indoles of general formula IV with acyl chlorides III can be carried out using Lewis acid reagents such as Et2AlCl or TiCl4 in a suitable solvent such as CH2Cl2 or 1,2-dichloroethane, and under suitable reaction conditions, typically (but not exclusively) including cooling, to give 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 accomplished with reagents such as LiOH (for PG = Ts) in a solvent mixture such as THF / water and at a suitable reaction temperature to afford 3-acylated indoles of general formula V.

[0713]

[0714] As an alternative, intermediates of general formula V can also be prepared as outlined in Scheme 3: N-Boc-protected substituted indole-3-carboxaldehydes of general formula X can be converted to the corresponding Strecker-type intermediates of general formula XI by reaction with morpholine in the presence of reagents such as sodium cyanide and sodium bisulfite, and in a mixture of a suitable solvent such as water and a water-miscible organic solvent such as dioxane. Alkylation of compounds of general formula XI with 4-chloro-2-methoxy-benzyl chloride can be carried out in the presence of a base such as potassium hexamethyldisilazane, and in a suitable solvent such as DMF to provide compounds of general formula XII. Compounds of general formula XII are subjected to suitable aqueous acidic hydrolysis conditions, for example by treatment with aqueous hydrochloric acid at elevated temperature, to provide intermediates of general formula V.

[0715]

[0716] In one embodiment, the compound of formula (I) is compound (a), or a stereoisomeric form, pharmaceutically acceptable salt, solvate or polymorph thereof.

[0717] The present invention also provides a compound of formula (I) as described herein, wherein the compound is contained in a pharmaceutical formulation for administration as a solid dosage form as described herein.

[0718] The dosage form may be an oral dosage form (e.g., a capsule for oral administration). Alternatively, the dosage form may be an enteral dosage form. Alternatively, the solid dosage form may be a tablet.

[0719] A solid dosage form (e.g., tablet) as described herein may contain 0.1 mg to 3000 mg of a compound of formula (I), preferably 1 mg to 2000 mg of a compound of formula (I), preferably 5 mg to 1500 mg of a compound of formula (I), preferably 5 mg to 1000 mg of a compound of formula (I), preferably 10 mg to 1100 mg of a compound of formula (I), preferably 15 mg to 950 mg of a compound of formula (I), preferably 20 mg to 900 mg of a compound of formula (I), or any specific amount or range subsumed therein.

[0720] A solid dosage form (eg, tablet) as described herein may contain 0.5 mg to 2000 mg of a compound of Formula (I), or any specific amount or range subsumed therein.

[0721] In some embodiments, the solid dosage form may contain 0.5 mg to 1800 mg, preferably 1 mg to 1600 mg, preferably 2 mg to 1500 mg, preferably 3 mg to 1450 mg, preferably 3 mg to 1300 mg, preferably 4 mg to 1200 mg, preferably 5 mg to 1100 mg, preferably 6 mg to 1000 mg, preferably 6 mg to 900 mg, preferably 7 mg to 800 mg, preferably 8 mg to 700 mg, preferably 9 mg to 600 mg, preferably 10 mg to 500 mg, preferably 11 mg to 400 mg, preferably 12 mg to 300 mg, preferably 13 mg to 200 mg, preferably 14 mg to 100 mg, preferably 15 mg to 50 mg, or any specific amount or range contained therein; preferably, the compound of formula (I) is compound (a) shown below:

[0722]

[0723] Preferably, the compound of formula (I) is the (+)-enantiomer of compound (a), preferably the (S)-enantiomer of compound (a).

[0724] The solid dosage form may comprise at least 2 mg of compound (a), 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).

[0725] In one embodiment, the solid dosage form is a tablet comprising

[0726] a) a compound of formula (I); and

[0727] b1) methacrylic acid copolymer, or

[0728] b2) Cellulose derivatives, such as hydroxypropylmethylcellulose (HPMC).

[0729] In one embodiment, the solid dosage form is a tablet comprising

[0730] a) a compound of formula (I); and

[0731] b1) methacrylic acid copolymer, or

[0732] b2) Cellulose derivatives, such as hydroxypropylmethylcellulose (HPMC).

[0733] c) one or more pharmaceutically acceptable excipients selected from the group consisting of disintegrants, binders, diluents, lubricants, stabilizers, wetting agents, glidants, osmotic agents, colorants, plasticizers, coating agents, fillers and surfactants.

[0734] In a particular embodiment, the solid dosage form is a tablet comprising the pharmaceutical formulation of the invention.

[0735] In one embodiment, the solid dosage form comprises a pharmaceutical formulation, wherein the formulation comprises 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, the compound of formula (I) is

[0736]

[0737] or a pharmaceutically acceptable salt thereof.

[0738] For oral administration, solid dosage forms are provided, in particular, 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 of a compound of formula (I); in particular 15 mg to 2500 mg of a compound of formula (I).

[0739] It will be appreciated that any of the above descriptions relating to solid dosage forms may apply to any other aspects and embodiments of the invention.

[0740] Advantageously, compounds of formula (I) may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, four or five times daily.

[0741] In some embodiments, the compound of Formula (I) is administered in the fed state or in the fasted state.

[0742] It should be understood that any of the above descriptions relating to oral dosage forms may apply to any other aspects and embodiments of the invention.

[0743] The present invention also provides a method for preparing the pharmaceutical preparation as described herein, the method comprising the following steps:

[0744] a) dissolving the compound of formula (I) in a solvent to form a solution;

[0745] b) adding methacrylic acid copolymer or hydroxypropyl methylcellulose or a combination thereof to the cellulose of step a)

[0746] mixing the solutions formed in the step of: ...

[0747] c) spray drying the mixture to obtain a solid dispersion;

[0748] d) optionally blending the solid dispersion with at least one pharmaceutically acceptable excipient;

[0749] To provide a pharmaceutical formulation as described herein.

[0750] As used herein, the term "solid dispersion" means a dispersion of an API (ie, a compound of formula (I)) in a solid matrix, wherein the matrix comprises small molecules, polymers, or a combination thereof.

[0751] The pharmaceutical preparation according to the present invention comprises a solid dispersion, wherein the matrix is ​​a polymer, and the polymer is selected from 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) or a combination thereof. Preferably, the cellulose derivative is HPMC.

[0752] The present invention also provides a method for preparing the solid dosage form described herein, the method comprising the following steps:

[0753] a) dissolving the compound of formula (I) in a solvent to form a solution;

[0754] b) methacrylic acid copolymers or cellulose derivatives such as methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose

[0755] (HPC), carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (NaCMC)

[0756] or hydroxypropyl methylcellulose or a combination thereof with the solution formed in step a) to obtain a mixture, and optionally further stirring the mixture;

[0757] c) spray drying the mixture to obtain a solid dispersion;

[0758] d) optionally blending the solid dispersion with one or more pharmaceutically acceptable excipients;

[0759] For example, the pharmaceutically acceptable excipient may be selected from the group consisting of fillers, surfactants, disintegrants, glidants, lubricants and mixtures thereof;

[0760] e) compressing the blend into tablets;

[0761] To provide a solid dosage form as described herein.

[0762] In some embodiments, the method of preparing a solid dosage form described herein comprises the following steps:

[0763] a) dissolving the compound of formula (I) in a solvent to form a solution;

[0764] b) adding methacrylic acid copolymer or hydroxypropyl methylcellulose or a combination thereof to the cellulose of step a)

[0765] mixing the solution formed in the step of: mixing with water to obtain a mixture, and optionally further stirring the mixture;

[0766] c) spray drying the mixture to obtain a solid dispersion;

[0767] d) blending the solid dispersion with at least one filler, at least one surfactant, at least one disintegrant, at least one glidant, and at least one lubricant;

[0768] e) granulating the blend;

[0769] f) blending the mixture obtained in step e) with at least one disintegrant, a filler and at least one lubricant;

[0770] g) compressing the blend into tablets;

[0771] To provide a solid dosage form as described herein.

[0772] In some embodiments, hot melt extrusion may be used to obtain a solid dispersion. In some embodiments, the step of granulating the blend is performed using a roller compactor or by weight compaction.

[0773] Another aspect of the present invention provides a packaged pharmaceutical preparation for preventing and / or treating dengue virus infection, wherein the pharmaceutical preparation is administered in an oral dosage form to a human subject in a fed state or a fasted state, preferably in a fed state, and wherein the pharmaceutical preparation is any preparation described herein (e.g., tablet) sealed in a blister film, wherein the blister film includes a preparation retaining layer configured to retain one or more pharmaceutical preparations (e.g., tablets) and a sealing layer configured to cover the retaining layer to seal the pharmaceutical preparation within the retaining layer, wherein the sealing layer includes aluminum foil and a desiccant material. As used herein, the term "drying material" refers to any hygroscopic substance that can be used as a desiccant. Examples of drying materials include, but are not limited to, silicon dioxide (e.g., silica gel), activated carbon, calcium sulfate, calcium chloride, and zeolite materials.

[0774] In some embodiments, the retention layer comprises one or more chambers, wherein each chamber is configured to accommodate one or more pharmaceutical formulations (such as any pharmaceutical formulation described herein (e.g., one or more tablets)), and each chamber is sealed by a sealing layer. In some embodiments, the retention layer comprises a transparent or opaque material (e.g., a transparent or opaque polyethylene material). In some embodiments, the sealing layer completely overlaps the retention layer and any chambers disposed in the retention layer.

[0775] Examples of commercially available blister films that can be used in the present invention include Dessiflex Plus and Dessiflex Ultra 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 to 4, 2 to 10, or 1 to 10) tablets sealed in a blister film, wherein the blister film comprises a card. Packaging with the blister film of the present invention wherein the sealing layer comprises a dry material improves the stability and shelf life of the pharmaceutical formulation of the present invention compared to packaging the pharmaceutical formulation in a blister film having a sealing layer without a dry material (e.g., Aclar 400 blister film).

[0776] Another aspect of the present invention provides a kit for preventing and / or treating dengue virus infection, wherein the kit is administered in an oral dosage form to a human subject in a fed state or a fasted state, preferably in a fed state, and comprises a packaged pharmaceutical formulation (such as any packaged pharmaceutical formulation described herein), and instructions for administering the packaged pharmaceutical formulation.

[0777] It should be understood that any of the above discussions involving solid dosage forms, formulations, and methods of making the same can be applied to any embodiment of the prophylactic and / or therapeutic methods described herein.

[0778] The present invention also encompasses a method for treating, ameliorating and / or preventing a disease, syndrome, condition affected by inhibition of dengue virus replication, most preferably in a human subject.

[0779] The method comprises administering to a subject a therapeutically effective amount of a compound of formula (I) as described herein, such as compound (a), or a pharmaceutical preparation and / or solid dosage form comprising the compound of formula (I), according to any dosing regimen described herein. The subject is at risk of being infected by dengue virus or has been infected by dengue virus.

[0780] One embodiment of the present invention relates to a method of preventing dengue virus infection in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation and / or solid dosage form comprising a compound of formula (I) as described herein, such as compound (a), according to any dosing regimen described herein, wherein the subject is in a fed state.

[0781] One embodiment of the present invention relates to a method of treating a dengue virus infection in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation and / or solid dosage form comprising a compound of formula (I) as described herein, such as compound (a), according to any dosing regimen described herein, wherein the subject is in a fed state.

[0782] The present invention also encompasses a method of producing multiple plasma levels of a compound of formula (I) as described herein, particularly compound (a), which are sufficient to treat or prevent dengue virus infection, preferably in a human subject. The method comprises administering a therapeutically effective amount of a compound of formula (I) as described herein, particularly compound (a), or a pharmaceutical preparation and / or solid dosage form comprising the compound of formula (I), particularly compound (a), to a subject, preferably a human subject, according to any dosing regimen described herein. The subject is at risk of being infected by dengue virus or has been infected by dengue virus.

[0783] Preferably, in the methods and uses described herein, the amount of a compound of formula (I), particularly compound (a), administered to a subject, preferably a human subject, is safe or effective in producing a plasma level of the compound of formula (I...

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 in an oral dosage form to a human being in a fed or fasting state, and wherein the compound of formula (I) corresponds to Its stereoisomeric form, pharmaceutically acceptable salt, solvate or polymorph; the compound is selected from the following group, wherein: R1 is H, R2 is F, and R3 is H or CH3, R1 is H, CH3 or F, R2 is OCH3, and R3 is H, R1 is H, R2 is OCH3, and R3 is CH3, R1 is CH3, R2 is F, and R3 is H, R1 is CF3 or OCF3, R2 is H, and R3 is H, R1 is OCF3, R2 is OCH3, and R3 is H, R1 is OCF3, R2 is H, and R3 is CH3.

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

3. The compound for use according to claim 2, wherein the human is in a fed state prior to or while administering the oral dosage form.

4. The compound for use according to any one of claims 1 to 3, wherein the human has eaten at most 3 hours before the time of administration of the oral dosage form.

5. The compound for use according to any one of claims 1 to 4, 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 any one of claims 1 to 5, wherein the oral dosage form is a solid dosage form.

7. The compound for use according to any one of claims 1 to 6, wherein the oral dosage form is administered according to the following dosing regimen comprising: 1) at least one loading phase, during which at least one dose (A) of a compound of formula (I) is administered at least once a day over a period of at least one day; as well as 2) at least one maintenance period starting from the last day of administration of dose (A) or the day after the last day of the loading period, during which at least one dose (B) of a compound of formula (I) is administered at least once a day over a period of at least one day; The dose (A) is higher or lower than the dose (B), preferably, the dose (A) is higher than the dose (B).

8. The compound for use according to any one of claims 1 to 7, wherein the oral dosage form is a solid dosage form comprising a cellulose derivative having a viscosity in a 2 wt% H2O solution at 25°C ranging between 3 mPa.s and 5000 mPa.s and selected from the group comprising HPMC E5, HPMC E6, HPMC E15, HPMC E50, HPMC K4M HPMC-AS, and any combination thereof.

9. The compound for use according to any one of claims 1 to 8, wherein the oral dosage form is formulated as a pharmaceutical preparation comprising 0.5 mg to 1500 mg of the compound of formula (I); preferably, the preparation comprises 1 mg to 1000 mg of the compound of formula (I); preferably, the preparation comprises 2 mg to 900 mg of the compound of formula (I).

10. The compound for use according to any one of claims 1 to 9, wherein the compound of formula (I) is: or a stereoisomeric form, a pharmaceutically acceptable salt, a solvate or a polymorph thereof.

11. A pharmaceutical preparation for preventing and / or treating dengue virus infection, comprising a) a compound of formula (I); and b1) methacrylic acid copolymer, or b2) Hydroxypropyl methylcellulose (HPMC); wherein the pharmaceutical preparation is administered in oral dosage form to humans in a fed or fasted state; and wherein formula (I) corresponds to Its stereoisomeric form, pharmaceutically acceptable salt, solvate or polymorph; the compound is selected from the following group, wherein: R1 is H, R2 is F, and R3 is H or CH3, R1 is H, CH3 or F, R2 is OCH3, and R3 is H, R1 is H, R2 is OCH3, and R3 is CH3, R1 is CH3, R2 is F, and R3 is H, R1 is CF3 or OCF3, R2 is H, and R3 is H, R1 is OCF3, R2 is OCH3, and R3 is H, R1 is OCF3, R2 is H, and R3 is CH3.

12. The pharmaceutical preparation for use according to claim 11, wherein the pharmaceutical preparation is administered to humans in a fed state in an oral dosage form.

13. The pharmaceutical formulation for use according to any one of claims 11 or 12, wherein the human is in a fed state before or during administration of the oral dosage form.

14. The pharmaceutical formulation for use according to any one of claims 11 to 13, wherein the human is in a fed state and has eaten at most 3 hours before the time of administration of the oral dosage form.

15. A pharmaceutical preparation for use according to any one of claims 11 to 14, wherein the oral dosage form is administered according to the following dosing regimen comprising: 1) at least one loading phase, during which at least one dose (A) of a compound of formula (I) is administered at least once a day over a period of at least one day; as well as 2) at least one maintenance period starting from the last day of administration of dose (A) or the day after the last day of the loading period, during which at least one dose (B) of a compound of formula (I) is administered at least once a day over a period of at least one day; The dose (A) is higher or lower than the dose (B), preferably, the dose (A) is higher than the dose (B).

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