Combination of mosnodenvir and close analogs with NITD-688 for use in the treatment and prevention of dengue disease

Abstract

The present invention relates to the use of a combination comprising Compound A selected from a compound of formula (I) or (I'): (I) (I') wherein R1, R2, R3, R1', R2', R3',and R4' have the same meaning as that defined in the claims and the description, or a stereo-isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof and Compound B or a stereo- isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof. The present invention also relates to compositions, in particular pharmaceuticals, comprising such combination, and to uses and methods of treatment of such combinations and compositions in the prevention and / or treatment of dengue viral infections.

Description

[0001]TREATMENT AND PREVENTION OF DENGUE DISEASE WITH DRUG COMBINATION FIELD OF THE INVENTION The present invention relates to a compound combination. The present invention also provides pharmaceutical compositions comprising such compounds, the use of the compounds, and methods for the prevention and / or treatment of dengue viral infections. BACKGROUND Dengue is caused by any of the 4 antigenically distinct DENV serotypes (DENV-1, - 2, -3, and -4), which belong to the genus Orthoflavivirus in the family of the Flaviviridae. The dengue viruses (DENVs) are human pathogens which are transmitted through the bite of an infected female mosquito of the genus Aedes. Dengue is endemic in more than 125 countries, and has also again become endemic in the United States (US) territories of Puerto Rico, American Samoa, and the Virgin Islands. About half of the global population is currently at risk of becoming infected with DENV. According to the World Health Organization (WHO), dengue is among the top 10 threats to global health in 2019. Currently, there is no dengue-specific treatment available and thus, clinical treatment is principally supportive in nature. During recent years, drugs developed for prophylactic use are getting more attention as potential alternatives to prevent dengue. Prophylaxis could be beneficial for travellers to dengue-endemic regions (e.g., aid workers, tourists, business and military travellers, and expatriates), as well as for vulnerable populations living in endemic regions. By preventing viremia and / or by reducing viral load, dengue-associated morbidity and mortality could be reduced remarkably or even prevented. In addition, an efficacious and safe dengue antiviral compound could still have its use as a therapeutic agent as well. WO 2016 / 180696 and WO2017 / 167951 disclose compounds for the prevention and / or treatment of dengue viral infections. WO2019 / 244047 discloses compounds for the treatment of viral infections caused by dengue virus. WO2021 / 094563 discloses the use of substituted indole derivatives and substituted indoline derivatives in the manufacture of a medicament for the treatment or the prevention of dengue disease in an individual at risk of being infected by Dengue virus. There is, however, a great unmet medical need for medicaments allowing the treatment or the prevention of dengue disease (also called dengue) in animals, more in particular in humans. SUMMARY OF THE INVENTION In a first aspect, the present invention provides for a combination comprising Compound A and Compound B, wherein, - Compound A is a compound of formula (I) (I) wherein: R1is H, R2is F and R3is H or CH3, R1is H, CH3or F, R2is OCH3and R3is H, R1is H, R2is OCH3and R3is CH3, R1is CH3, R2is F and R3is H, R1is CF3or OCF3, R2is H and R3is H, R1is OCF3, R2is OCH3and R3is H, R1is OCF3, R2is H and R3is CH3; or a stereo-isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof; or Compound A is a compound of formula (I’) (I’) wherein: R1’is chloro or fluoro, R2’ is hydrogen, R3’ is trifluoromethyl, and R4’is hydrogen; or R1’ is chloro or fluoro, R2’ is hydrogen, R3’ is trifluoromethoxy, and R4’is hydrogen; or R1’ is chloro, R2’ is hydrogen, R3’ is trifluoromethyl, and R4’is methoxy; or R1’ is chloro, R2’ is methoxy, R3’ is trifluoromethyl, and R4’is hydrogen; or R1’ is chloro, R2’ is methoxy, R3’ is trifluoromethyl, and R4’is methoxy; or R1’ is chloro, R2’ is methoxy, R3’ is trifluoromethoxy, and R4’is hydrogen; or R1’ is chloro, R2’ is fluoro, R3’ is trifluoromethyl, and R4’is hydrogen; or R1’ is chloro, R2’ is fluoro, R3’ is trifluoromethoxy, and R4’is hydrogen; or R1’ is chloro, R2’ is fluoro, R3’ is trifluoromethyl, and R4’is methoxy; or R1’ is chloro, R2’ is hydrogen, R3’ is trifluoromethoxy, and R4’is methoxy; or a stereo-isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof; and - Compound B is: a stereo-isomeric form, a pharmaceutically In a second aspect, the present invention provides a pharmaceutical composition said composition comprising the compound combination disclosed in the first aspect and at least one pharmaceutically acceptable excipient. In a third aspect, the present invention provides for a combination according to the first aspect or a pharmaceutical composition according to the second aspect, for use as a medicament. In a further aspect, the present invention provides for a combination according to the first aspect or a pharmaceutical composition according to the second aspect, for use in the treatment of dengue viral infections. In another aspect, the present invention provides for a combination according to the first aspect or a pharmaceutical composition according to the second aspect, for use in the prevention of dengue viral infections in an individual at risk of being infected by Dengue virus. In another aspect, the present invention provides for a combination according to the first aspect or a pharmaceutical composition according to the second aspect, for use in the prevention of dengue viral infections in an individual that has been exposed to Dengue virus. In a further aspect, the present invention provides for a kit comprising the combination according to the first aspect or a pharmaceutical composition according to the second aspect, optionally along with at least one pharmaceutically acceptable excipient and instruction manual. It has now been surprisingly found that the combination of a compound of formula (I) or (I’) (hereinafter referred to as (hereinafter referred to as Compound B) is the treatment and / or prevention of Dengue viral BRIEF DESCRIPTION OF THE FIGURES Figure 1: Shows a table of the results for the effect sizes and their confidence intervals using the Highest Single Agent (HSA) model for all the concentrations of Compound A (mosnodenvir) and Compound B (NITD-688) tested, according to Example 1. The shading indicates the concentrations at which synergy between the two compounds occurs. Figure 2: Shows a table of the results for the effect sizes and their confidence intervals using the Bliss Independence model for all the concentrations of Compound A (mosnodenvir) and Compound B (NITD-688) tested, according to Example 1. The shading indicates the concentrations at which synergy between the two compounds occurs. Figure 3: Shows a table of the results for the effect sizes and their confidence intervals using the Generalized Loewe model for all the concentrations of Compound A (mosnodenvir) and Compound B (NITD-688) tested, according to Example 1. The shading indicates the concentrations at which synergy between the two compounds occurs. Figure 4: Shows a table of the results for the effect sizes and their confidence intervals using the Alternative Loewe model for all the concentrations of Compound A (mosnodenvir) and Compound B (NITD-688) tested, according to Example 1. The shading indicates the concentrations at which synergy between the two compounds occurs. Figure 5: Shows a table of the results for the effect sizes and their confidence intervals using the Highest Single Agent (HSA) model for all the concentrations of Compound A and Compound B (NITD-688) tested, according to Example 2. The shading indicates the concentrations at which synergy between the two compounds occurs. Figure 6: Shows a table of the results for the effect sizes and their confidence intervals using the Bliss Independence model for all the concentrations of Compound A and Compound B (NITD-688) tested, according to Example 2. The shading indicates the concentrations at which synergy between the two compounds occurs. Figure 7: Shows a table of the results for the effect sizes and their confidence intervals using the Generalized Loewe model for all the concentrations of Compound A and Compound B (NITD-688) tested, according to Example 2. The shading indicates the concentrations at which synergy between the two compounds occurs. Figure 8: Shows a table of the results for the effect sizes and their confidence intervals using the Alternative Loewe model for all the concentrations of Compound A and Compound B (NITD-688) tested, according to Example 2. The shading indicates the concentrations at which synergy between the two compounds occurs. DETAILED DESCRIPTION OF THE INVENTION The disclosure may be more fully appreciated by reference to the following description, including the following glossary of terms and the concluding examples. It is to be appreciated that certain features of the disclosed pharmaceutical formulations and methods which are, for clarity, described herein in the context of separate aspects, may also be provided in combination in a single aspect. Conversely, various features of the disclosed pharmaceutical formulations and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any sub-combination. Some of the quantitative expressions given herein are not qualified with the term "about. " It is understood that whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and / or measurement conditions for such given value. The terms "about" or "approximately" as used herein, when referring to a numerical value or range, allow for a degree of variability 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 a stated value or of a stated limit of a range. Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", mean "including but not limited to", and are not intended to (and do not) exclude other components. The recitation of numerical ranges by endpoints includes all integer numbers and, where appropriate, fractions subsumed within that range (e.g.1 to 5 can include 1, 2, 3, 4 when referring to, for example, a number of elements, and can also include 1.5, 2, 2.75 and 3.80, when referring to, for example, measurements). The recitation of end points also includes the end point values themselves (e.g. from 1.0 to 5.0 includes both 1.0 and 5.0). Any numerical range recited herein is intended to include all sub-ranges subsumed therein. All references cited in the present specification are hereby incorporated by reference in their entirety. In particular, the teachings of all references herein specifically referred to are incorporated by reference. Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. As used herein, the term "dengue viral replication inhibitor" refers to an agent that inhibits or reduces at least one condition, symptom, disorder, and / or disease caused by a Dengue virus. The present invention provides for the prevention, also called prophylactic treatment, of dengue disease. The terms prophylactic and prophylaxis as used herein, refer to Post- Exposure Prophylaxis (PEP), and Pre-Exposure Prophylaxis (PrEP). PEP refers to treatment initiated after exposure to the Dengue virus and preferably before reaching peak viral load. PrEP refers to treatment initiated before exposure to the Dengue virus. The invention further relates to the treatment of dengue disease. Treatment is used herein to refer to treatment initiated after exposure to the Dengue virus and preferably after reaching peak viral load and / or symptoms manifestations. Preferred embodiments of the present invention are set herein below. Each statement and embodiment of the invention so defined may be combined with any other statement and / or embodiment unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features or statement indicated as being preferred or advantageous. Hereto, the present invention is in particular captured by any one or any combination of one or more of the below numbered aspects and embodiments, with any other statement and / or embodiment. In a first aspect, the present invention provides for a combination comprising Compound A and Compound B, wherein - Compound A is a compound of formula (I) (I) wherein: R1is H, R2is F and R3is H or CH3, R1is H, CH3or F, R2is OCH3and R3is H, R1is H, R2is OCH3and R3is CH3, R1is CH3, R2is F and R3is H, R1is CF3or OCF3, R2is H and R3is H, R1is OCF3, R2is OCH3and R3is H, R1is OCF3, R2is H and R3is CH3; or a stereo-isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof; or Compound A is a compound of formula (I’) (I’) wherein: R1’is chloro or fluoro, R2’ is hydrogen, R3’ is trifluoromethyl, and R4’is hydrogen; or R1’ is chloro or fluoro, R2’ is hydrogen, R3’ is trifluoromethoxy, and R4’is hydrogen; or R1’ is chloro, R2’ is hydrogen, R3’ is trifluoromethyl, and R4’is methoxy; or R1’ is chloro, R2’ is methoxy, R3’ is trifluoromethyl, and R4’is hydrogen; or R1’ is chloro, R2’ is methoxy, R3’ is trifluoromethyl, and R4’is methoxy; or R1’ is chloro, R2’ is methoxy, R3’ is trifluoromethoxy, and R4’is hydrogen; or R1’ is chloro, R2’ is fluoro, R3’ is trifluoromethyl, and R4’is hydrogen; or R1’ is chloro, R2’ is fluoro, R3’ is trifluoromethoxy, and R4’is hydrogen; or R1’ is chloro, R2’ is fluoro, R3’ is trifluoromethyl, and R4’is methoxy; or R1’ is chloro, R2’ is hydrogen, R3’ is trifluoromethoxy, and R4’is methoxy; or a stereo-isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof; and - Compound B is: or a stereo-isomeric form, a pharmaceutically thereof. As used herein, the term "solvate" means a solvent addition form that contains either a stoichiometric or non-stoichiometric amounts of one or more solvent(s). Some compounds have a tendency to non-covalently bind to a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. In certain embodiments, the solvate formed may be a combination of an organic solvent solvate and a hydrate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrate. In the hydrates, the water molecules are attached through secondary valencies by intermolecular forces, in particular hydrogen bridges. Solid hydrates contain water as so-called crystal water in stoichiometric ratios, where the water molecules do not have to be equivalent with respect to their binding state. Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Equally suitable are the hydrates of salts of the compounds used herein. Included within the scope of the present invention are anhydrous forms of Compound A. Included within the scope of the present invention are anhydrous forms of Compound B. When a compound is crystallized from a solution or slurry, it can be crystallized in a different arrangement lattice of spaces (this property is called "polymorphism") to form crystals with different crystalline forms, each of which is known as "polymorphs". “Polymorph”, as used herein, refers to a crystal form of Compound A and / or Compound B, where the molecules are localized in the three-dimensional lattice sites. Different polymorphs of the Compound A and / or Compound B may be different from each other in one or more physical properties, such as solubility and dissolution rate, true specific gravity, crystal form, accumulation mode, flowability and / or solid state stability, etc. Included within the scope of the present invention are amorphous forms of the Compound A. Included within the scope of the present invention are amorphous forms of the Compound B. Pharmaceutically acceptable salts of Compound A and Compound B include the acid addition and base addition salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Suitable base addition salts are formed from bases which form non-toxic salts. Suitable pharmaceutically acceptable salts of Compound A and / or Compound B include acid addition salts that can, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as, hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the Compound A and / or Compound B carry 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, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, valerate, and combinations of one or more thereof. Representative acids and bases that may be used in the preparation of 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-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L- glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L- malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L- pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)- ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine, tromethamine, zinc hydroxide, and combinations of one or more thereof. Compound A and / or Compound B may be administered as crystalline or amorphous products. They may be administered alone or in combination with one or more other drugs. In some embodiments, Compound A and / or Compound B are administered as a formulation in association with one or more pharmaceutically acceptable excipients. In some embodiments, Compound A and Compound B are formulated in separate formulation and may be indicated for administration in combination. In some embodiments, Compound A and Compound B are formulated in separate formulation and may be indicated for simultaneous administration or sequential administration. In some embodiments Compound A is a compound comprising, consisting of, and / or consisting essentially of the (+)-enantiomer wherein said compound is substantially free from the (-)-enantiomer. In the present context, 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 (-)- enantiomer calculated as%(( mass( ^)-enantiomer ) ^)- enantiomer^^100 (mass(^)-enantiomer)^( mass( ^)-enantiomer ) . In some embodiments Compound A is a compound comprising, consisting of, and consisting essentially of the (-)-enantiomer wherein said compound is substantially free from the (+)-enantiomer. In the present context, substantially free from 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 (+)- enantiomer calculated as%(( mass( ^)-enantiomer ) ^) - enantiomer^^100 (mass(^)-enantiomer)^( mass( ^)-enantiomer ) . In some embodiments, Compound A is a compound of formula (I) as described herein. In some embodiments Compound A is selected from the group: In some embodiments Compound A is Compound 1, having the following chemical ,and may also be referred to as 2-(4-chloro-2-3yl)-2-((3-methoxy-5- wherein1H NMR (500 MHz, DMSO-d6) ^ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 4.00 (s, 3 H) 6.24 (d, J=7.9 Hz, 1 H) 6.58 (s, 2 H) 6.91 (s, 1 H) 6.97 (dd, J=8.7, 1.9 Hz, 1 H) 7.02 - 7.09 (m, 2 H) 7.12 (d, J=1.9 Hz, 1 H) 7.27 (dd, J=9.5, 1.9 Hz, 1 H) 7.35 (d, J=8.5 Hz, 1 H) 8.14 (dd, J=8.7, 5.5 Hz, 1 H) 8.44 (s, 1 H) 12.10 (br. s., 1 H); and / or LC / MS (method LC-C): Rt3.08 min, MH+517. The High Performance Liquid Chromatography (HPLC) measurement may be performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors may be included (see table of methods below). Flow from the column may be brought to the Mass Spectrometer (MS) which may be configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time…) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition may be performed with appropriate software. In the embodiments herein, compounds are described by their retention times (Rt) and ions as determined by the methods described herein. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+(protonated molecule) and / or [M-H]- (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4]+, [M+HCOO]-, etc…). For molecules with multiple isotopic patterns (Br, Cl), the reported value is the one obtained for the lowest isotope mass. Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” Mass Selective Detector, “RT” room temperature, “BEH” bridged ethylsiloxane / silica hybrid, “DAD” Diode Array Detector, ”HSS” High Strength silica. LC / MS Method codes (Flow expressed in mL / min; column temperature (T) in °C; Run time in minutes) referred throughout this document correspond to: Flow Run Method Instrument Column Mobile phase time code Gradient ------- Col T (min) A: 10mM Waters: Waters: CH3COONH4 in F 0.8 Acquity®BEH C rom 95% A to LC-A 18 95% H2O + 5% mL / min UPLC®-DAD- (1.7µm, 5% A in 1.3 min, 2 CH3CN ------- SQD 2.1x50mm) held for 0.7 min 55°C B: CH3CN rs: W A: 10mM Wate aters: From 100% A to HSS T3 CH3COONH45 0.7 LC-B Acquity®% A in 2.10 min, m LC -DAD- (1. in 95% H2O + L / min UP®8µm, to 0% A in 0.90 3.5 5% CH3CN ------- SQD 2.1x100mm min, ) t 55°C B: CH3CN o 5% A in 0.5 min 84.2% A for 0.49 Waters: Waters: A: 95% min, to 10.5% A in Acquity®BEH C18 CH3COONH42.18 min, held for 0.343 LC-C UPLC®- (1.7µm, 7mM / 5% 1.94 min, back to mL / min D-Quattro 2.1x100mm 84.2% A in 0.73 ---- 6.2 DA CH3CN, --- MicroTM) 40°C B: CH3CN min, held for 0.73 min Waters: ® A: 10mM Acquity Waters: CH3COONH4 0.5 UPLC®- BEH From 50% A to LC-D C18 (adjusted at pH mL / min DAD- (1.7µm, 10% A in 3.5 min, 5 10) 2.1x50mm) he ------- Acquity®TQ ld for 1.5 min 40°C detector B: CH3CN 84.2% A for 0.49 Waters: Waters: A: 95% min, to 10.5% A in Acquity® BEH C18 CH3COONH4 2.18 min, held for 0.343 LC-AA UPLC® - (1.7µm, 7mM / 5% 1.94 min, back to mL / min ----- 6.2 DAD-Quattro 2.1x100mm CH3CN, B: 84.2% A in 0.73 -- MicroTM ) CH3CN min, held for 0.73 40°C min. Waters 84.2% A / 15.8% B Waters: BEH® A: to 10.5% A in Acquity® CH3COONH4 2.18 min, held for 0.343 LC-BB H-Class - C18 7mM 95% / 1.96 min, back to mL / min DAD and 1.7µm, CH3CN 5%, B: 84.2% A / 15.8% B -- 6.1 ( ----- SQD2TM 2.1x100mm CH3CN in 0.73 min, held 40°C ) for 0.49 min. Waters: Acquity® Waters: A: 0.1% 50% 0.5 UPLC® A to 10% A LC-CC - HSS C18 HCOOH mL / min DAD- (1.8µm, in 3.5 min, held 5 Acquity® TQ 2.1x50mm) 3CN fo ------- B: CH r 1.5 min. 40°C detector A: 10mM Waters: Waters: CH3COONH4 in fr 0.8 Acquity® BEH C1 om 95% A to 5% LC-DD 8 95% H2O + 5% A i mL / min UPLC® - (1.7µm, n 1.3 min, held 2 CH3CN for 0.7 min ------- DAD-SQD 2.1x50mm) . 55°C B: CH3CN In some embodiments Compound 1 is Enantiomer 1A, wherein1H NMR (500 MHz, DMSO-d6) ^ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 4.00 (s, 3 H) 6.24 (d, J=7.9 Hz, 1 H) 6.59 (s, 2 H) 6.91 (s, 1 H) 6.97 (dd, J=8.8, 2.2 Hz, 1 H) 7.02 - 7.10 (m, 2 H) 7.12 (d, J=2.2 Hz, 1 H) 7.27 (dd, J=9.6, 2.2 Hz, 1 H) 7.35 (d, J=8.2 Hz, 1 H) 8.14 (dd, J=8.8, 5.7 Hz, 1 H) 8.44 (s, 1 H) 12.10 (br. s., 1 H); and / or LC / MS (method LC-C): Rt3.09 min, MH+517; [α]D20: +130.3° (c 0.277, DMF); Chiral SFC (method SFC-D): Rt3.41 min, MH+517, chiral purity 100%. The Analytical Supercritical fluid chromatography (SFC) measurement referred to herein, may be performed using an system composed by a binary pump for delivering carbon dioxide (CO2) and modifier, an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell standing up to 400 bars. The SFC system may be further configured with a Mass Spectrometer (MS) the flow from the column may be brought to the (MS). It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time…) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition may be performed with appropriate software. Analytical SFC-MS Methods (Flow expressed in mL / min; column temperature (T) in °C; Run time in minutes, Backpressure (BPR) in bars) referred throughout this document correspond to: lumn mob Flow Run time Method code co ile phase gradient --------- ------------ Col T BPR WHELK-O1 (S,S) 5 µm 3 7 SFC-A A: CO250% B hold 7 ------ gis B: MeOH - ------- 250 x 4.6 mm Re min, 35 100 Daicel Chiralpak® IC-H 3 SFC-B x 4.6 A: CO 40% B hold 7 7 column (5 μm, 150 2 B: MeOH m ------- ------- mm) in, 35 100 WHELK-O1 (S,S) 5 µm 3 9 SFC-C A: CO2 60% B hold 9 B: MeOH min, ------- ------- 250 x 4.6 mm Regis 35 100 Daicel Chiralpak® IA-H 7 A: CO 3 SFC-D column (5 μm, 250 x 4.6250% B hold 7 B: MeOH min, ------- -------- mm) 35 100 A:CO2Daicel Chiralpak® AS3 B: EtOH 10%-50% B in 2.5 9.5 SFC-E column (3.0 μm, 150 x +0. 6 min, hold ------- ------- 4.6 mm) 2% iPrNH2 3.5 min 40 110 +3% H2O Daicel Chiralpak® AD-H A: CO2SFC-F column (5.0 μm, 150 x 3 3 7 B: iPrOH 0% B hold 7 ------- ------- 4.6 mm) min +0.3% iPrNH2 35 100 A:CO2 Daicel Chiralcel® OD-3 B: iPrOH n (3 μm, 100 x 4.6 40% B h 3.5 3 SFC-AA colum old 3 mi ------- ------- mm) (+0.3% n 35 105 iPrNH2) Daicel Chiralcel® OD-H A:CO2 40% B hold 7 3 7 SFC-BB column (5 μm, 150 x 4.6 B: MeOH ------- ------- mm) min 35 100 Daicel Chiralcel® OD-H A:CO2 40% B ho 3 7 SFC-CC column (5 μm, 150 x 4.6 ld 7 B: i ------- ------- mm) PrOH min 35 100 hod code column mobi Flow Run time Met le phase gradient --------- ------------ Col T BPR A:CO2 Daicel Chiralpak® AD-H B: iPrOH 3 7 SFC-DD column (5 μm, 150 x 4.6 50% B hold 7 mm) 3% m ------- ------- (+0. in 35 100 iPrNH2) Daicel Chiralcel® OD-H A 3 7 SFC-EE column (5 μm, 150 x 4.6 :CO2 30% B hold 7 ------- ------- mm) B: EtOH min 35 100 Daicel Chiralcel® OD-H 50 x 4.6 A:CO2 30% B ho 3 7 SFC-FF column (5 μm, 1 ld 7 ------- ------- mm) B: iPrOH min 35 100 A:CO2 Daicel Chiralcel® OD-H B: iPrOH 30% B hold 7 3 7 SFC-GG column (3 μm, 150 x 4.6 mi ------- ------- mm) (+0.3% n 35 100 iPrNH2) A:CO2 Daicel Chiralpak® IC B: iPrOH 50 x 4.6 30% B hol 3 7 SFC-HH column (5 μm, 1 d 7 ------- ------- mm) (+0.3% min 35 100 iPrNH2) A:CO2 Daicel Chiralpak® AD-3 B: iPrOH 5 3.5 3 SFC-II column (3 μm, 100 x 4.6 0% B hold 3 ------- ------- mm) (+0.3% min 35 103 iPrNH2) A:CO2 B: EtOH Daicel Chiralpak® AS3 10%-50% B in 2.5 9.5 SFC-JJ column (3.0 μm, 150 x (+0.2% 6 min, hold ------- ------- 4.6 mm) iPrNH2 3.5 min 40 110 +3% H2O) Optical rotations referred to herein, may be measured on a Perkin-Elmer 341 polarimeter with a sodium lamp and reported as follows: [α]º (λ, c g / 100ml, solvent, TºC). [α]^T= (100α) / (l x c) : where l is the path length in dm and c is the concentration in g / 100 ml for a sample at a temperature T (°C) and a wavelength λ (in nm). If the wavelength of light used is 589 nm (the sodium D line), then the symbol D might be used instead. The sign of the rotation (+ or -) should always be given. When using this equation the concentration and solvent are always provided in parentheses after the rotation. The rotation is reported using degrees and no units of concentration are given (it is assumed to be g / 100 ml). In some embodiments Compound 1 is Enantiomer 1B, wherein1H NMR (400 MHz, DMSO-d6) ^ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 4.00 (s, 3 H) 6.24 (d, J=7.6 Hz, 1 H) 6.53 - 6.65 (m, 2 H) 6.91 (s, 1 H) 6.97 (dd, J=8.6, 2.0 Hz, 1 H) 7.01 - 7.09 (m, 2 H) 7.12 (d, J=2.0 Hz, 1 H) 7.27 (dd, J=9.6, 2.0 Hz, 1 H) 7.35 (d, J=8.1 Hz, 1 H) 8.14 (dd, J=8.6, 5.6 Hz, 1 H) 8.43 (s, 1 H) 12.09 (br. s., 1 H); and / or LC / MS (method LC-C): Rt3.09 min, MH+517; [α]D20: -135.3° (c 0.283, DMF); Chiral SFC (method SFC-D): Rt4.89 min, MH+517, chiral purity 99.35%. In some embodiments Compound A is Compound 2 having the following chemical structure: may also be referred to as 2-(4-chloro-2- 3yl)-2-((3-methoxy-5- (methylsulfonyl)phenyl)amino)ethanone, wherein1H NMR (300 MHz, DMSO-d6) ^ ppm 2.38 (d, J=1.5 Hz, 3 H) 3.10 (s, 3 H) 3.73 (s, 3 H) 4.01 (s, 3 H) 6.27 (d, J=7.9 Hz, 1 H) 6.55 – 6.63 (m, 2 H) 6.93 (m, 1 H) 6.94 – 7.09 (m, 3 H) 7.13 (d, J=1.9 Hz, 1 H) 7.35 (d, J=8.3 Hz, 1 H) 7.97 (dd, J=8.7, 5.3 Hz, 1 H) 8.45 (s, 1H) 12.23 (br. s, 1 H); and / or LC / MS (method LC-D): Rt1.68 min, MH+531. In some embodiments Compound 2 is Enantiomer 2A, wherein1H NMR (500 MHz, DMSO-d6) ^ ppm 2.37 - 2.39 (m, 3 H) 3.09 (s, 3 H) 3.72 (s, 3 H) 4.01 (s, 3 H) 6.26 (d, J=7.9 Hz, 1 H) 6.54 - 6.63 (m, 2 H) 6.92 (s, 1 H) 6.97 (dd, J=8.4, 1.9 Hz, 1 H) 7.02 (dd, J=9.9, 9.0 Hz, 1 H) 7.07 (d, J=7.9 Hz, 1 H) 7.13 (d, J=1.9 Hz, 1 H) 7.35 (d, J=8.4 Hz, 1 H) 7.96 (dd, J=8.5, 5.4 Hz, 1 H) 8.45 (s, 1 H) 12.24 (br. s., 1 H); and / or LC / MS (method LC-C): Rt3.20 min, MH+531 [α]D20: +104.5° (c 0.2545, DMF) Chiral SFC (method SFC-A): Rt4.22 min, MH+531, chiral purity 100%. In some embodiments Compound 2 is Enantiomer 2B, wherein1H NMR (500 MHz, DMSO-d6) ^ ppm 2.36 - 2.41 (m, 3 H) 3.09 (s, 3 H) 3.72 (s, 3 H) 4.01 (s, 3 H) 6.26 (d, J=7.9 Hz, 1 H) 6.57 - 6.64 (m, 2 H) 6.92 (s, 1 H) 6.97 (dd, J=8.2, 1.9 Hz, 1 H) 6.99 - 7.04 (m, 1 H) 7.07 (d, J=7.9 Hz, 1 H) 7.13 (d, J=1.9 Hz, 1 H) 7.35 (d, J=8.2 Hz, 1 H) 7.96 (dd, J=8.7, 5.2 Hz, 1 H) 8.45 (s, 1 H) 12.24 (br. s., 1 H); and / or LC / MS (method LC-C): Rt3.20 min, MH+531 [α]D20: -104.1° (c 0.2536, DMF) Chiral SFC (method SFC-A): Rt 5.12 min, MH+531, chiral purity 99.53%. In some embodiments Compound A is Compound 3 having the following chemical structure: , and may also be referred to as 2-(4-chloro- 2- 3yl)-2-((3-methoxy-5- (methylsulfonyl)phenyl)amino)ethanone, wherein1H NMR (400 MHz, DMSO-d6) δ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 3.77 (s, 3 H) 4.01 (s, 3 H) 6.21 (d, J=7.9 Hz, 1 H) 6.54 - 6.64 (m, 2 H) 6.83 (dd, J=8.7, 2.3 Hz, 1 H) 6.91 (t, J=1.4 Hz, 1 H) 6.94 - 6.99 (m, 2 H) 7.04 (d, J=7.7 Hz, 1 H) 7.12 (d, J=2.0 Hz, 1 H) 7.35 (d, J=8.1 Hz, 1 H) 8.02 (d, J=8.8 Hz, 1 H) 8.30 (s, 1 H) 11.84 (s, 1 H); and / or LC / MS (method LC-A): Rt1.20 min, MH+529. In some embodiments Compound 3 is Enantiomer 3A, wherein1H NMR (360 MHz, DMSO-d6) δ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 3.77 (s, 3 H) 4.01 (s, 3 H) 6.22 (d, J=8.1 Hz, 1 H) 6.55 - 6.61 (m, 2 H) 6.84 (dd, J=8.8, 2.2 Hz, 1 H) 6.91 (t, J=1.8 Hz, 1 H) 6.94 - 7.00 (m, 2 H) 7.07 (d, J=7.0 Hz, 1 H) 7.13 (d, J=1.8 Hz, 1 H) 7.35 (d, J=8.4 Hz, 1 H) 8.02 (d, J=8.8 Hz, 1 H) 8.32 (d, J=2.9 Hz, 1 H) 11.87 (d, J=2.6 Hz, 1 H); and / or LC / MS (method LC-A): Rt1.08 min, MH+529; [α]D20: +134.9° (c 0.545, DMF); Chiral SFC (method SFC-E): Rt4.31 min, MH+529, chiral purity 100%. In some embodiments Compound 3 is Enantiomer 3B, wherein1H NMR (360 MHz, DMSO-d6) δ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 3.77 (s, 3 H) 4.01 (s, 3 H) 6.21 (d, J=8.1 Hz, 1 H) 6.54 - 6.62 (m, 2 H) 6.83 (dd, J=8.6, 2.4 Hz, 1 H) 6.91 (t, J=1.5 Hz, 1 H) 6.94 - 6.99 (m, 2 H) 7.07 (d, J=7.0 Hz, 1 H) 7.13 (d, J=1.8 Hz, 1 H) 7.35 (d, J=8.1 Hz, 1 H) 8.02 (d, J=8.8 Hz, 1 H) 8.32 (d, J=2.9 Hz, 1 H) 11.87 (br d, J=2.2 Hz, 1 H); and / or LC / MS (method LC-A): Rt1.08 min, MH+529; [α]D20: -116.7° (c 0.51, DMF); Chiral SFC (method SFC-E): Rt4.63 min, MH+529, chiral purity 94.7%. In some embodiments Compound A is Compound 4 having the following chemical structure: may also be referred to as 2-(4-chloro- 2- phenyl)amino)-1-(6-methoxy-5-methyl- 1H-indole- -1H NMR (500 MHz, DMSO-d6) δ ppm 2.21 (s, 3 H) 3.09 (s, 3 H) 3.72 (s, 3 H) 3.79 (s, 3 H) 4.01 (s, 3 H) 6.20 (d, J=7.9 Hz, 1 H) 6.58 (s, 2 H) 6.88 - 6.93 (m, 2 H) 6.96 (dd, J=8.5, 1.9 Hz, 1 H) 7.02 (d, J=7.9 Hz, 1 H) 7.12 (d, J=1.9 Hz, 1 H) 7.34 (d, J=8.5 Hz, 1 H) 7.89 (s, 1 H) 8.24 (s, 1 H) 11.78 (br. s., 1 H); and / or LC / MS (method LC-C): Rt3.16 min, MH+543. In some embodiments Compound 4 is Enantiomer 4A, wherein1H NMR (500 MHz, DMSO-d6) ^ ppm 2.21 (s, 3 H) 3.09 (s, 3 H) 3.72 (s, 3 H) 3.79 (s, 3 H) 4.01 (s, 3 H) 6.20 (d, J=7.6 Hz, 1 H) 6.58 (d, J=1.6 Hz, 2 H) 6.87 - 6.93 (m, 2 H) 6.96 (dd, J=8.2, 1.9 Hz, 1 H) 7.02 (d, J=7.6 Hz, 1 H) 7.12 (d, J=1.9 Hz, 1 H) 7.34 (d, J=8.2 Hz, 1 H) 7.89 (s, 1 H) 8.25 (s, 1 H) 11.78 (br. s., 1 H); and / or LC / MS (method LC-C): Rt3.15 min, MH+543; [α]D20: +141.8° (c 0.3936, DMF); Chiral SFC (method SFC-C): Rt4.95 min, MH+543, chiral purity 100%. In some embodiments Compound 4 is Enantiomer 4B, wherein1H NMR (500 MHz, DMSO-d6) ^ ppm 2.21 (s, 3 H) 3.09 (s, 3 H) 3.72 (s, 3 H) 3.79 (s, 3 H) 4.01 (s, 3 H) 6.20 (d, J=7.9 Hz, 1 H) 6.58 (s, 2 H) 6.88 - 6.93 (m, 2 H) 6.96 (dd, J=8.2, 1.9 Hz, 1 H) 7.02 (d, J=7.9 Hz, 1 H) 7.12 (d, J=1.9 Hz, 1 H) 7.34 (d, J=8.2 Hz, 1 H) 7.90 (s, 1 H) 8.25 (s, 1 H) 11.79 (br. s., 1 H); and / or LC / MS (method LC-C): Rt3.15 min, MH+543; [α]D20: -142.2° (c 0.3909, DMF); Chiral SFC (method SFC-C): Rt6.84 min, MH+543, chiral purity 100%. In some embodiments Compound A is Compound 5 having the following chemical , and may also be referred to as 2-(4-chloro- 2- indol-3-yl)-2-((3-methoxy-5- (methylsulfonyl)phenyl)amino)ethanone, wherein1H NMR (500 MHz, DMSO-d6) ^ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 3.85 (s, 3 H) 4.00 (s, 3 H) 6.21 (d, J=7.9 Hz, 1 H) 6.58 (d, J=1.3 Hz, 2 H) 6.90 (s, 1 H) 6.97 (dd, J=8.2, 1.9 Hz, 1 H) 7.06 (d, J=7.9 Hz, 1 H) 7.10 - 7.18 (m, 2 H) 7.34 (d, J=8.2 Hz, 1 H) 7.82 (d, J=12.0 Hz, 1 H) 8.35 (s, 1 H) 11.98 (br. s., 1 H); and / or LC / MS (method LC-C): Rt3.01 min, MH+547. In some embodiments Compound 5 is Enantiomer 5A, wherein1H NMR (500 MHz, DMSO-d6) ^ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 3.85 (s, 3 H) 4.00 (s, 3 H) 6.21 (d, J=7.9 Hz, 1 H) 6.58 (d, J=1.3 Hz, 2 H) 6.90 (s, 1 H) 6.97 (dd, J=8.2, 2.0 Hz, 1 H) 7.07 (d, J=7.9 Hz, 1 H) 7.11 - 7.17 (m, 2 H) 7.34 (d, J=8.2 Hz, 1 H) 7.82 (d, J=11.7 Hz, 1 H) 8.35 (s, 1 H) 11.98 (br. s., 1 H); and / or LC / MS (method LC-C): Rt3.00 min, MH+547; [α]D20: +136.4° (c 0.28, DMF); Chiral SFC (method SFC-B): Rt3.43 min, MH+547, chiral purity 100%. In some embodiments Compound 5 is Enantiomer 5B, wherein1H NMR (500 MHz, DMSO-d6) ^ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 3.85 (s, 3 H) 4.00 (s, 3 H) 6.21 (d, J=7.9 Hz, 1 H) 6.58 (d, J=1.3 Hz, 2 H) 6.90 (s, 1 H) 6.97 (dd, J=8.2, 2.0 Hz, 1 H) 7.07 (d, J=7.9 Hz, 1 H) 7.11 - 7.19 (m, 2 H) 7.34 (d, J=8.2 Hz, 1 H) 7.82 (d, J=11.7 Hz, 1 H) 8.35 (s, 1 H) 11.95 (br. s., 1 H); and / or LC / MS (method LC-C): Rt3.00 min, MH+547; [α]D20: -126.3° (c 0.2755, DMF); Chiral SFC (method SFC-B): Rt4.80 min, MH+547, chiral purity 98.06%. In some embodiments Compound A is Compound 6 having the following chemicalstructure: may also be referred to as 2-(4-chloro-2- phenyl)amino)-1-(6-methoxy-7-methyl- 1H-indole- In some embodiments Compound 6 is Enantiomer 6A, wherein1H NMR (360 MHz, DMSO-d6) δ ppm 2.29 (s, 3 H) 3.10 (s, 3 H) 3.72 (s, 3 H) 3.80 (s, 3 H) 4.02 (s, 3 H) 6.24 (d, J=7.7 Hz, 1 H) 6.56 - 6.59 (m, 1 H) 6.59 - 6.62 (m, 1 H) 6.92 (t, J=1.6 Hz, 1 H) 6.93 - 6.99 (m, 2 H) 7.06 (d, J=7.7 Hz, 1 H) 7.13 (d, J=1.8 Hz, 1 H) 7.35 (d, J=8.4 Hz, 1 H) 7.94 (d, J=8.4 Hz, 1 H) 8.35 (s, 1 H) 11.91 (br s, 1 H); and / or LC / MS (method LC-A): Rt1.18 min, MH+543; [α]D20: +122.9° (c 0.48, DMF); Chiral SFC (method SFC-E): Rt4.15 min MH+543, chiral purity 100%. In some embodiments Compound 6 is Enantiomer 6B, wherein1H NMR (360 MHz, DMSO-d6) δ ppm 2.29 (s, 3 H) 3.10 (s, 3 H) 3.72 (s, 3 H) 3.80 (s, 3 H) 4.02 (s, 3 H) 6.24 (d, J=7.7 Hz, 1 H) 6.57 - 6.59 (m, 1 H) 6.59 - 6.62 (m, 1 H) 6.92 (t, J=1.8 Hz, 1 H) 6.93 - 7.00 (m, 2 H) 7.06 (d, J=7.7 Hz, 1 H) 7.13 (d, J=1.8 Hz, 1 H) 7.35 (d, J=8.1 Hz, 1 H) 7.94 (d, J=8.8 Hz, 1 H) 8.35 (d, J=2.2 Hz, 1 H) 11.91 (br s, 1 H); and / or LC / MS (method LC-A): Rt1.22 min, MH+543; [α]D20: -120.6° (c 0.2755, DMF); Chiral SFC (method SFC-E): Rt4.50 min, MH+543, chiral purity 99.35%. In some embodiments Compound A is Compound 7 having the following chemical structure: Cl , and may also be referred to as 2-(4-chloro-2- methyl-1H-indol-3-yl)-2-((3-methoxy-5- ethanone, wherein1H NMR (400 MHz, DMSO-d6) δ ppm 2.30 (d, J=0.9 Hz, 3 H) 3.09 (s, 3 H) 3.72 (s, 3 H) 4.00 (s, 3 H) 6.22 (d, J=7.7 Hz, 1 H) 6.54 - 6.63 (m, 2 H) 6.92 (t, J=1.5 Hz, 1 H) 6.97 (dd, J=8.3, 1.9 Hz, 1 H) 7.01 (d, J=7.7 Hz, 1 H) 7.12 (d, J=1.8 Hz, 1 H) 7.22 (d, J=10.2 Hz, 1 H) 7.35 (d, J=8.4 Hz, 1 H) 8.02 (d, J=7.7 Hz, 1 H) 8.37 (s, 1 H) 11.97 (br s, 1 H); and / or LC / MS (method LC-A): Rt1.19 min, MH+531. In some embodiments Compound 7 is Enantiomer 7A, wherein1H NMR (400 MHz, DMSO-d6) δ ppm 2.30 (d, J=1.5 Hz, 3 H) 3.09 (s, 3 H) 3.72 (s, 3 H) 4.00 (s, 3 H) 6.22 (d, J=7.9 Hz, 1 H) 6.56 - 6.60 (m, 2 H) 6.91 (t, J=1.7 Hz, 1 H) 6.97 (dd, J=8.3, 2.1 Hz, 1 H) 7.01 (d, J=7.7 Hz, 1 H) 7.12 (d, J=2.0 Hz, 1 H) 7.22 (d, J=10.1 Hz, 1 H) 7.34 (d, J=8.1 Hz, 1 H) 8.02 (d, J=7.7 Hz, 1 H) 8.37 (s, 1 H) 11.96 (s, 1 H); and / or LC / MS (method LC-A): Rt1.15 min, MH+531; [α]D20: -163.2° (c 0.435, DMF); Chiral SFC (method SFC-E): Rt4.26 min, MH+531, chiral purity 100%. In some embodiments Compound 7 is Enantiomer 7B, wherein1H NMR (400 MHz, DMSO-d6) δ ppm 2.30 (d, J=1.5 Hz, 3 H) 3.09 (s, 3 H) 3.72 (s, 3 H) 4.00 (s, 3 H) 6.22 (d, J=7.7 Hz, 1 H) 6.57 - 6.61 (m, 2 H) 6.92 (t, J=1.8 Hz, 1 H) 6.97 (dd, J=8.1, 2.0 Hz, 1 H) 7.01 (d, J=7.7 Hz, 1 H) 7.12 (d, J=2.0 Hz, 1 H) 7.22 (d, J=10.0 Hz, 1 H) 7.35 (d, J=8.4 Hz, 1 H) 8.02 (d, J=7.9 Hz, 1 H) 8.37 (d, J=2.4 Hz, 1 H) 11.97 (s, 1 H); and / or LC / MS (method LC-A): Rt1.15 min, MH+531; [α]D20: +166.6° (c 0.5, DMF); Chiral SFC (method SFC-E): Rt3.78 min, MH+531, chiral purity 100%. In some embodiments Compound A is Compound 8 having the following chemical structure: , and may also be referred to as 2-(4-chloro-2- (methylsulfonyl)phenyl)amino)-1-(5-(trifluoromethyl)-1H- 1H NMR (500 MHz, DMSO-d6) δ ppm 3.10 (s, 3 H) 3.72 (s, 3 H) 3.99 (s, 3 H) 6.29 (d, J=7.9 Hz, 1 H) 6.56 - 6.62 (m, 2 H) 6.92 (s, 1 H) 6.98 (dd, J=8.4, 2.0 Hz, 1 H) 7.09 (d, J=7.9 Hz, 1 H) 7.13 (d, J=1.9 Hz, 1 H) 7.36 (d, J=8.5 Hz, 1 H) 7.54 (dd, J=8.5, 1.6 Hz, 1 H) 7.69 (d, J=8.5 Hz, 1 H) 8.48 (s, 1 H) 8.61 (s, 1 H) 12.45 (br s, 1 H); and / or LC / MS (method LC-C): Rt3.19 min, MH+567. In some embodiments Compound 8 is Enantiomer 8A, wherein1H NMR (400 MHz, DMSO-d6) δ ppm 3.09 (s, 3 H) 3.73 (s, 3 H) 3.99 (s, 3 H) 6.29 (d, J=7.6 Hz, 1 H) 6.60 (br s, 2 H) 6.92 (s, 1 H) 6.98 (dd, J=8.3, 1.8 Hz, 1 H) 7.07 (d, J=8.1 Hz, 1 H) 7.13 (d, J=1.5 Hz, 1 H) 7.36 (d, J=8.1 Hz, 1 H) 7.54 (d, J=8.1 Hz, 1 H) 7.69 (d, J=8.6 Hz, 1 H) 8.49 (s, 1 H) 8.60 (s, 1 H) 12.41 (br s, 1 H); and / or LC / MS (method LC-C): Rt3.25 min, MH+567; [α]D20: -119.2° (c 0.2727, DMF); Chiral SFC (method SFC-F): Rt2.64 min, MH+567, chiral purity 100%. In some embodiments Compound 8 is Enantiomer 8B, wherein1H NMR (400 MHz, DMSO-d6) δ ppm 3.09 (s, 3 H) 3.73 (s, 3 H) 3.99 (s, 3 H) 6.29 (d, J=8.1 Hz, 1 H) 6.60 (s, 2 H) 6.92 (s, 1 H) 6.98 (dd, J=8.6, 2.0 Hz, 1 H) 7.07 (d, J=8.1 Hz, 1 H) 7.13 (d, J=2.0 Hz, 1 H) 7.36 (d, J=8.6 Hz, 1 H) 7.54 (dd, J=8.6, 1.5 Hz, 1 H) 7.69 (d, J=8.6 Hz, 1 H) 8.49 (s, 1 H) 8.60 (s, 1 H) 12.40 (br s, 1 H); and / or LC / MS (method LC-C): Rt3.25 min, MH+567; [α]D20: +125.1° (c 0.2455, DMF); Chiral SFC (method SFC-F): Rt3.44 min, MH+567, chiral purity 100%. In some embodiments Compound A is Compound 10 having the following chemical structure: may also be referred to as 2-(4-chloro-2- phenyl)amino)-1-(6-methoxy-5- - In some embodiments Compound 10 is Enantiomer 10A, wherein1H NMR (360 MHz, DMSO-d6) δ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 3.87 (s, 3 H) 3.99 (s, 3 H) 6.22 (d, J=7.7 Hz, 1 H) 6.55 - 6.59 (m, 2 H) 6.88 - 6.91 (m, 1 H) 6.98 (dd, J=8.1, 1.8 Hz, 1 H) 7.08 (d, J=7.7 Hz, 1 H) 7.13 (d, J=2.2 Hz, 1 H) 7.21 (s, 1 H) 7.34 (d, J=8.1 Hz, 1 H) 8.02 (d, J=1.5 Hz, 1 H) 8.41 (s, 1 H) 12.05 (br s, 1 H) ; and / or LC / MS (method LC-A): Rt1.20 min, MH+613; [α]D20: +81.4° (c 0.29, DMF); Chiral SFC (method SFC-E): Rt3.44 min, MH+613, chiral purity 100%. In some embodiments Compound 10 is Enantiomer 10B, wherein1H NMR (360 MHz, DMSO-d6) δ ppm 3.09 (s, 3 H) 3.72 (s, 3 H) 3.87 (s, 3 H) 3.99 (s, 3 H) 6.22 (d, J=7.7 Hz, 1 H) 6.55 - 6.60 (m, 2 H) 6.90 (t, J=1.6 Hz, 1 H) 6.98 (dd, J=8.2, 2.0 Hz, 1 H) 7.08 (d, J=7.8 Hz, 1 H) 7.13 (d, J=2.2 Hz, 1 H) 7.21 (s, 1 H) 7.34 (d, J=8.4 Hz, 1 H) 8.01 (d, J=1.1 Hz, 1 H) 8.41 (s, 1 H) 12.08 (br s, 1 H); and / or LC / MS (method LC-A): Rt1.20 min, MH+613; [α]D20: -99.6° (c 0.261, DMF); Chiral SFC (method SFC-E): Rt3.69 min, MH+613, chiral purity 100%. In some embodiments Compound A is Compound 11 having the following chemical structure: ,and may also be referred to as 2-(4-chloro-2- (methylsulfonyl)phenyl)amino)-1-(7-methyl-5- - ethanone. In some embodiments Compound 11 is Enantiomer 11A, wherein1H NMR (600 MHz, DMSO-d6) δ ppm 2.50 (s, 3 H) 3.09 (s, 3 H) 3.72 (s, 3 H) 4.00 (s, 3 H) 6.28 (d, J=7.8 Hz, 1 H) 6.56 - 6.63 (m, 2 H) 6.92 (br s, 1 H) 6.97 (dd, J=8.4, 1.9 Hz, 1 H) 7.05 (br s, 1 H) 7.07 (d, J=7.9 Hz, 1 H) 7.13 (d, J=1.9 Hz, 1 H) 7.35 (d, J=8.4 Hz, 1 H) 7.90 (br s, 1 H) 8.53 (s, 1 H) 12.41 (br s, 1 H); and / or LC / MS (method LC-A): Rt1.26 min, MH+597; [α]D20: +81.3° (c 0.3455, DMF); Chiral SFC (method SFC-E): Rt2.96 min, MH+597, chiral purity 100%. In some embodiments Compound 11 is Enantiomer 11B, wherein1H NMR (600 MHz, DMSO-d6) δ ppm 2.51 (s, 3 H) 3.09 (s, 3 H) 3.72 (s, 3 H) 4.00 (s, 3 H) 6.28 (d, J=7.9 Hz, 1 H) 6.58 - 6.60 (m, 2 H) 6.92 (t, J=1.8 Hz, 1 H) 6.97 (dd, J=8.4, 1.9 Hz, 1 H) 7.05 (br s, 1 H) 7.06 (d, J=7.9 Hz, 1 H) 7.13 (d, J=2.1 Hz, 1 H) 7.35 (d, J=8.2 Hz, 1 H) 7.89 (br s, 1 H) 8.53 (s, 1 H) 12.37 (br s, 1 H); and / or LC / MS (method LC-A): Rt1.26 min, MH+597; [α]D20: -87.4° (c 0.342, DMF); Chiral SFC (method SFC-E): Rt3.44 min, MH+597, chiral purity 100%. In some embodiments Compound A is Compound 9, having the following chemical structure: , and may also be referred to as 2-(4-chloro-2- (methylsulfonyl)phenyl)amino)-1-(5-(trifluoromethoxy)- 1H NMR (400 MHz, DMSO-d6) δ ppm 3.09 (s, 3 H) 3.73 (s, 3 H) 3.99 (s, 3 H) 6.26 (d, J=7.9 Hz, 1 H) 6.57 - 6.62 (m, 2 H) 6.91 (t, J=1.9 Hz, 1 H) 6.98 (dd, J=8.4, 2.0 Hz, 1 H) 7.07 (d, J=7.9 Hz, 1 H) 7.13 (d, J=2.0 Hz, 1 H) 7.22 (dd, J=8.6, 2.2 Hz, 1 H) 7.36 (d, J=8.4 Hz, 1 H) 7.59 (d, J=8.8 Hz, 1 H) 8.06 (d, J=0.9 Hz, 1 H) 8.55 (s, 1 H) 12.28 (br s, 1 H); and / or LC / MS (method LC-A): Rt1.31 min, MH+583. In some embodiments Compound 9 is Enantiomer 9A, wherein1H NMR (400 MHz, DMSO-d6) δ ppm 3.09 (s, 3 H) 3.73 (s, 3 H) 3.99 (s, 3 H) 6.26 (d, J=7.9 Hz, 1 H) 6.55 – 6.62 (m, 2 H) 6.91 (t, J=1.5 Hz, 1 H) 6.98 (dd, J=8.4, 2.0 Hz, 1 H) 7.07 (d, J=7.9 Hz, 1 H) 7.13 (d, J=2.0 Hz, 1 H) 7.21 (dd, J=8.8, 1.8 Hz, 1 H) 7.36 (d, J=8.4 Hz, 1 H) 7.59 (d, J=8.8 Hz, 1 H) 8.07 (d, J=0.9 Hz, 1 H) 8.55 (s, 1 H) 12.29 (br s, 1 H); and / or LC / MS (method LC-A): Rt1.20 min, MH+583; [α]D20: +130.3° (c 0.555, DMF); Chiral SFC (method SFC-E): Rt3.10 min, MH+583, chiral purity 100%. In some embodiments Compound 9 is Enantiomer 9B, wherein1H NMR (400 MHz, DMSO-d6) δ ppm 3.09 (s, 3 H) 3.73 (s, 3 H) 3.99 (s, 3 H) 6.26 (d, J=7.9 Hz, 1 H) 6.56 – 6.62 (m, 2 H) 6.92 (t, J=2.0 Hz, 1 H) 6.98 (dd, J=8.1, 2.0 Hz, 1 H) 7.07 (d, J=7.9 Hz, 1 H) 7.13 (d, J=2.0 Hz, 1 H) 7.22 (dd, J=8.8, 1.8 Hz, 1 H) 7.36 (d, J=8.4 Hz, 1 H) 7.59 (d, J=8.8 Hz, 1 H) 8.07 (d, J=0.9 Hz, 1 H) 8.55 (s, 1 H) 12.30 (br s, 1 H); and / or LC / MS (method LC-A): Rt1.20 min, MH+583; [α]D20: -133.2° (c 0.5, DMF); Chiral SFC (method SFC-E): Rt3.50 min, MH+583, chiral purity 100%. In preferred embodiments, Compound A is represented by the following structure: . This compound is also referred herein as JNJ- JNJ-64281802 was described in WO2016 / 180696 as compound 9. WO2016 / 180696, which is incorporated herein by reference in its entirety, described a non-chiral synthesis method of JNJ-64281802. WO2023 / 274237, which is also incorporated herein by reference in its entirety, described an enantioselective process in which the enantiomers of JNJ-64281802 are separated by means of specific procedures. Cl O In some embodiments Compound A . Compound A may be in a solvated form, for embodiments Compound A is in anhydrous form. In some embodiments, Compound A is in amorphous form. In some embodiments, Compound A or a pharmaceutically acceptable salt form thereof is in amorphous form or dissolved state. In some embodiments Compound A is in amorphous form or dissolved state. In some embodiments Compound A is the (S)- enantiomer in amorphous form. In some embodiments Compound A is the (S)-enantiomer in anhydrous form. In some embodiments, Compound A is a compound of formula (I') as described herein. In some embodiments Compound A is selected from the group: herein. In some embodiments Compound A is selected from the group: F F OMe OMe OH OH OH OH . In some embodiments Compound A is Compound 1’ having the following chemical structure: F OMe , and may also be referred to as 4-(3-((1-(4- -indolin-1-yl)ethyl)amino)-5- 1H NMR (300 MHz, DMSO-d6) ^ ppm 1.80 - 1.94 (m, 2 H) 2.22 - 2.48 (m, 2 H) 3.09 - 3.27 (m, 2 H) 3.62 (s, 3 H) 3.85 (t, J=6.2 Hz, 2 H) 3.91 - 4.06 (m, 1 H) 4.48 - 4.61 (m, 1 H) 5.57 (d, J=8.7 Hz, 1 H) 5.76 (s, 1 H) 5.94 (s, 1 H) 5.96 (s, 1 H) 6.39 (d, J=8.3 Hz, 1 H) 7.21 (t, J=8.7 Hz, 2 H) 7.35 - 7.49 (m, 2 H) 7.58 (dd, J=8.1, 5.8 Hz, 2 H) 8.38 (s, 1 H) 12.1 (br. s., 1 H); and / or LC / MS (method LC-CC): Rt1.94 min, MH+547. In some embodiments Compound 1’ is Enantiomer 1’A: F OMe , wherein 1.87 (quin, J=6.8 Hz, 2 H) 2.33 (t, J=7.4 Hz, 2 H) 3.14 - 3.29 (m, 2 H) 3.62 (s, 3 H) 3.85 (t, J=6.5 Hz, 2 H) 4.00 (td, J=10.5, 7.3 Hz, 1 H) 4.54 (td, J=10.4, 6.3 Hz, 1 H) 5.56 (d, J=8.6 Hz, 1 H) 5.76 (t, J=2.0 Hz, 1 H) 5.95 (dt, J=9.1, 1.8 Hz, 2 H) 6.36 (d, J=8.8 Hz, 1 H) 7.20 (t, J=8.9 Hz, 2 H) 7.34 - 7.41 (m, 1 H) 7.42 - 7.49 (m, 1 H) 7.52 - 7.62 (m, 2 H) 8.38 (br s, 1 H) 12.10 (br s, 1 H); and / or LC / MS (method LC-DD): Rt0.99 min, MH+547; [α]D20: -49.0° (c 0.41, DMF); Chiral SFC (method SFC-JJ): Rt2.92 min, MH+547 chiral purity 100%. In some embodiments Compound 1’ is Enantiomer 1’B: F OMe , wherein 1.87 (quin, J=6.9 Hz, 2 H) 2.33 (t, J=7.3 Hz, 2 H) 3.12 - 3.29 (m, 2 H) 3.62 (s, 3 H) 3.85 (t, J=6.5 Hz, 2 H) 4.00 (td, J=10.4, 7.2 Hz, 1 H) 4.54 (td, J=10.4, 6.3 Hz, 1 H) 5.56 (d, J=8.8 Hz, 1 H) 5.76 (t, J=2.1 Hz, 1 H) 5.95 (dt, J=9.1, 2.0 Hz, 2 H) 6.36 (d, J=8.8 Hz, 1 H) 7.20 (t, J=8.2 Hz, 2 H) 7.35 - 7.41 (m, 1 H) 7.42 - 7.48 (m, 1 H) 7.53 - 7.62 (m, 2 H) 8.38 (br s, 1 H) 12.11 (br s, 1 H); and / or LC / MS (method LC-DD): Rt1.00 min, MH+547; [α]D20: +49.5° (c 0.525, DMF); Chiral SFC (method SFC-JJ): Rt2.81 min, MH+547, chiral purity 100%. In some embodiments Compound A is Compound 2’ having the following chemical structure: F OMe , and may also be referred to as 4-(3-((1-(4- -indolin-1-yl)ethyl)amino)-5- methoxyphenoxy)butanoic acid, wherein 1H NMR (500 MHz, DMSO-d6) δ ppm 1.87 (quin, J=6.9 Hz, 2 H) 2.34 (t, J=7.3 Hz, 2 H) 3.05 - 3.28 (m, 2 H) 3.62 (s, 3 H) 3.85 (t, J=6.5 Hz, 2 H) 4.01 (td, J=10.3, 7.4 Hz, 1 H) 4.53 (td, J=10.2, 6.6 Hz, 1 H) 5.56 (s, 1 H) 5.76 (s, 1 H) 5.96 (br d, J=10.4 Hz, 2 H) 7.01 (br d, J=7.9 Hz, 1 H) 7.21 (t, J=8.8 Hz, 2 H) 7.33 (d, J=8.2 Hz, 1 H) 7.57 (dd, J=8.5, 5.7 Hz, 2 H) 8.04 (s, 1 H); and / or LC / MS (method LC-AA): Rt 2.80 min, MH+563. In some embodiments Compound 2’ is Enantiomer 2’A: F OMe (quin, J=6.9 Hz, 2 H) 2.33 (t, J=7.3 Hz, 2 H) 3.05 - 2 H) 3.96 - 4.08 (m, 1 H) 4.46 - 4.60 (m, 1 H) 5.55 (d, J=8.8 Hz, 1 H) 5.75 (s, 1 H) 5.95 (br d, J=11.0 Hz, 2 H) 6.41 (br d, J=8.5 Hz, 1 H) 7.01 (br d, J=8.2 Hz, 1 H) 7.21 (t, J=8.8 Hz, 2 H) 7.33 (d, J=8.2 Hz, 1 H) 7.57 (dd, J=8.2, 5.7 Hz, 2 H) 8.04 (s, 1 H) 12.19 (br s, 1 H); and / or LC / MS (method LC-AA): Rt2.87 min, MH+563; [α]D20: -46.3° (c 0.27, DMF); Chiral SFC (method SFC-BB): Rt1.75 min, MH+563, chiral purity 100%. In some embodiments Compound 2’ is Enantiomer 2’B: F OMe (quin, J=6.9 Hz, 2 H) 2.32 (t, J=7.3 Hz, 2 H) 3.05 - 3.26 (m, 2 H) 3.61 (s, 3 H) 3.84 (t, J=6.5 Hz, 2 H) 4.01 (td, J=10.3, 7.4 Hz, 1 H) 4.53 (td, J=10.2, 6.0 Hz, 1 H) 5.55 (d, J=8.8 Hz, 1 H) 5.75 (s, 1 H) 5.95 (br d, J=12.0 Hz, 2 H) 6.41(d, J=8.8 Hz, 1 H) 7.01 (br d, J=7.9 Hz, 1 H) 7.20 (t, J=8.7 Hz, 2 H) 7.33 (d, J=8.2 Hz, 1 H) 7.57 (dd, J=8.5, 5.7 Hz, 2 H) 8.04 (s, 1 H) 11.49 - 12.49 (m, 1 H); and / or LC / MS (method LC-AA): Rt2.87 min, MH+563; [α]D20: +47.0° (c 0.27, DMF); Chiral SFC (method SFC-BB): Rt3.83 min, MH+563, chiral purity 100%. In some embodiments Compound A is Compound 3’ having the following chemical structure: Cl OMe , and may also be referred to as 4-(3-((1-(4- -indolin-1-yl)ethyl)amino)-5- wherein1H NMR (500 MHz, DMSO-d6) δ ppm 1.87 (quin, J=6.8 Hz, 2 H) 2.33 (t, J=7.3 Hz, 2 H) 3.18 - 3.27 (m, 2 H) 3.62 (s, 3 H) 3.85 (t, J=6.3 Hz, 2 H) 3.97 - 4.09 (m, 1 H) 4.46 - 4.59 (m, 1 H) 5.57 (d, J=8.6 Hz, 1 H) 5.76 (s, 1 H) 5.95 (br d, J=9.1 Hz, 2 H) 6.40 (br d, J=8.6 Hz, 1 H) 7.34 - 7.49 (m, 4 H) 7.55 (d, J=8.6 Hz, 2 H) 8.38 (s, 1 H) 11.90 - 12.25 (m, 1 H); and / or LC / MS (method LC-AA): Rt 2.88 min, MH+563. In some embodiments Compound 3’ is Enantiomer 3’A: Cl OMe , wherein ppm 1.87 (br t, J=6.6 Hz, 2 H) 2.34 (br t, J=7.1 Hz, 2 H) 3.15 - 3.31 (m, 2 H) 3.62 (s, 3 H) 3.85 (br t, J=6.1 Hz, 2 H) 3.97 - 4.09 (m, 1 H) 4.48 - 4.60 (m, 1 H) 5.59 (br d, J=8.5 Hz, 1 H) 5.77 (br s, 1 H) 5.95 (br d, J=11.3 Hz, 2 H) 6.44 (br d, J=8.5 Hz, 1 H) 7.36 - 7.50 (m, 4 H) 7.56 (br d, J=8.2 Hz, 2 H) 8.38 (s, 1 H) 12.17 (br s, 1 H); and / or LC / MS (method LC-AA): Rt2.93 min, MH+563; [α]D20: -42.4° (c 0.25, DMF); Chiral SFC (method SFC-CC): Rt2.12 min, MH+563, chiral purity 100%. In some embodiments Compound 3’ is Enantiomer 3’B: Cl , wherein 1H NMR (500 MHz, DMSO-d6) δ ppm 1.87 (quin, J=6.7 Hz, 2 H) 2.34 (br t, J=7.1 Hz, 2 H) 3.15 - 3.31 (m, 2 H) 3.62 (s, 3 H) 3.85 (br t, J=6.3 Hz, 2 H) 3.97 - 4.10 (m, 1 H) 4.49 - 4.61 (m, 1 H) 5.59 (br d, J=8.8 Hz, 1 H) 5.77 (s, 1 H) 5.95 (br d, J=11.3 Hz, 2 H) 6.44 (br d, J=8.5 Hz, 1 H) 7.36 - 7.49 (m, 4 H) 7.56 (br d, J=8.2 Hz, 2 H) 8.38 (s, 1 H) 12.17 (br s, 1 H); and / or LC / MS (method LC-AA): Rt2.93 min, MH+563; [α]D20: +50.7° (c 0.27, DMF); Chiral SFC (method SFC-CC): Rt4.87 min, MH+563, chiral purity 100%. In some embodiments Compound A is Compound 4’ having the following chemical structure: Cl OMe , and may also be referred to as 4-(3-((1-(4- -indolin-1-yl)ethyl)amino)-5- methoxyphenoxy)butanoic acid, wherein1H NMR (500 MHz, DMSO-d6) δ ppm 1.87 (quin, J=6.9 Hz, 2 H) 2.34 (t, J=7.3 Hz, 2 H) 3.07 - 3.28 (m, 2 H) 3.62 (s, 3 H) 3.85 (t, J=6.5 Hz, 2 H) 4.04 (td, J=10.5, 7.1 Hz, 1 H) 4.52 (td, J=10.3, 6.5 Hz, 1 H) 5.57 (s, 1 H) 5.76 (t, J=2.2 Hz, 1 H) 5.90 - 6.00 (m, 2 H) 7.01 (dd, J=8.2, 1.6 Hz, 1 H) 7.33 (d, J=8.2 Hz, 1 H) 7.41 - 7.48 (m, 2 H) 7.55 (d, J=8.5 Hz, 2 H) 8.03 (s, 1 H); and / or LC / MS (method LC-BB): Rt 2.70 min, MH+579. In some embodiments Compound 4’ is Enantiomer 4’A: Cl , wherein 1.87 (quin, J=6.7 Hz, 2 H) 2.34 (br t, J=7.3 Hz, 2 H) 3.08 - 3.27 (m, 2 H) 3.62 (s, 3 H) 3.85 (br t, J=6.3 Hz, 2 H) 3.99 - 4.11 (m, 1 H) 4.47 - 4.57 (m, 1 H) 5.57 (br s, 1 H) 5.76 (s, 1 H) 5.95 (br d, J=10.1 Hz, 2 H) 6.45 (br s, 1 H) 7.01 (br d, J=7.6 Hz, 1 H) 7.34 (br d, J=7.9 Hz, 1 H) 7.44 (br d, J=8.5 Hz, 2 H) 7.55 (br d, J=8.2 Hz, 2 H) 8.04 (br s, 1 H) 12.12 (br s, 1 H); and / or LC / MS (method LC-AA): Rt2.95 min, MH+579; [α]D20: -48.5° (c 0.27, DMF); Chiral SFC (method SFC-AA): Rt1.13 min, MH+579, chiral purity 100%. In some embodiments Compound 4’ is Enantiomer 4’B: Cl OMe (br t, J=6.8 Hz, 2 H) 2.34 (br t, J=7.3 Hz, 2 H) 3.09 - 3.27 (m, 2 H) 3.62 (s, 3 H) 3.85 (br t, J=6.1 Hz, 2 H) 3.99 - 4.10 (m, 1 H) 4.46 - 4.59 (m, 1 H) 5.57 (s, 1 H) 5.76 (br s, 1 H) 5.95 (br d, J=10.1 Hz, 2 H) 6.45 (br s, 1 H) 7.01 (br d, J=7.9 Hz, 1 H) 7.34 (br d, J=7.9 Hz, 1 H) 7.44 (br d, J=8.2 Hz, 2 H) 7.55 (br d, J=8.2 Hz, 2 H) 8.04 (br s, 1 H) 12.12 (br s, 1 H); and / or LC / MS (method LC-AA): Rt2.94 min, MH+579; [α]D20: +42.9° (c 0.28, DMF); Chiral SFC (method SFC-AA): Rt2.13 min, MH+579, chiral purity 100%. In some embodiments Compound A is Compound 5’ having the following chemical structure: Cl , and may also be referred to as 4-(3-((1-(4- indolin-1-yl)-2-oxoethyl)amino)-5- methoxyphenoxy)butanoic acid, wherein1H NMR (500 MHz, DMSO-d6) δ ppm 1.87 (quin, J=6.9 Hz, 2 H) 2.34 (t, J=7.3 Hz, 2 H) 3.14 - 3.35 (m, 2 H) 3.61 (s, 3 H) 3.80 - 3.89 (m, 5 H) 3.94 - 4.04 (m, 1 H) 4.51 (td, J=10.2, 6.3 Hz, 1 H) 5.55 (s, 1 H) 5.76 (s, 1 H) 5.95 (br d, J=11.7 Hz, 2 H) 7.23 (s, 1 H) 7.43 (d, J=8.2 Hz, 2 H) 7.55 (d, J=8.2 Hz, 2 H) 8.34 (s, 1 H); and / or LC / MS (method LC-AA): Rt 2.86 min, MH+593. In some embodiments Compound 5’ is Enantiomer 5’A: Cl OMe (quin, J=6.9 Hz, 2 H) 2.34 (t, J=7.3 Hz, 2 H) 3.12 - 3.31 (m, 2 H) 3.62 (s, 3 H) 3.81 - 3.89 (m, 5 H) 3.94 - 4.05 (m, 1 H) 4.45 - 4.56 (m, 1 H) 5.55 (br s, 1 H) 5.76 (s, 1 H) 5.95 (br d, J=11.0 Hz, 2 H) 6.40 (br s, 1 H) 7.23 (s, 1 H) 7.44 (d, J=8.2 Hz, 2 H) 7.56 (d, J=8.5 Hz, 2 H) 8.34 (s, 1 H) 12.14 (br s, 1 H); and / or LC / MS (method LC-AA): Rt2.85 min, MH+593; [α]D20: -43.2° (c 0.25, DMF); Chiral SFC (method SFC-DD): Rt2.16 min, MH+593, chiral purity 100%. In some embodiments Compound 5’ is Enantiomer 5’B: Cl OMe (quin, J=6.8 Hz, 2 H) 2.34 (t, J=7.3 Hz, 2 H) 3.13 - 3.33 (m, 2 H) 3.62 (s, 3 H) 3.79 - 3.88 (m, 5 H) 3.94 - 4.03 (m, 1 H) 4.51 (td, J=10.3, 6.1 Hz, 1 H) 5.54 (br s, 1 H) 5.75 (s, 1 H) 5.95 (br d, J=11.3 Hz, 2 H) 6.40 (br s, 1 H) 7.23 (s, 1 H) 7.43 (d, J=8.2 Hz, 2 H) 7.55 (d, J=8.5 Hz, 2 H) 8.34 (s, 1 H) 12.14 (br s, 1 H); and / or LC / MS (method LC-AA): Rt2.85 min, MH+593; [α]D20: +41.4° (c 0.28, DMF); Chiral SFC (method SFC-DD): Rt3.75 min, MH+593, chiral purity 99.37%. In some embodiments Compound A is Compound 6’ having the following chemical structure: Cl OMe may also be referred to as 4-(3-((1-(4-chloro-2- indolin-1-yl)ethyl)amino)-5- 1H NMR (400 MHz, DMSO-d6) δ ppm 1.87 (br t, J=6.6 Hz, 2 H) 2.33 (br t, J=7.3 Hz, 2 H) 3.18 - 3.32 (m, 2 H) 3.61 (s, 3 H) 3.80 - 3.87 (m, 2 H) 3.90 (s, 3 H) 3.96 - 4.07 (m, 1 H) 4.31 - 4.45 (m, 1 H) 5.61 (s, 1 H) 5.76 (s, 1 H) 5.87 (br d, J=7.6 Hz, 2 H) 7.02 (br d, J=8.1 Hz, 1 H) 7.14 (s, 1 H) 7.32 (d, J=8.1 Hz, 1 H) 7.35 - 7.41 (m, 1 H) 7.43 - 7.50 (m, 1 H) 8.37 (s, 1 H); and / or LC / MS (method LC-AA): Rt 2.90 min, MH+593. In some embodiments Compound 6’ is Enantiomer 6’A: Cl OMe , wherein ppm 1.87 (quin, J=6.9 Hz, 2 H) 2.33 (t, J=7.3 Hz, 2 H) 3.24 (br dd, J=18.6, 11.7 Hz, 2 H) 3.61 (s, 3 H) 3.80 - 3.87 (m, 2 H) 3.90 (s, 3 H) 3.97 - 4.06 (m, 1 H) 4.33 - 4.43 (m, 1 H) 5.61 (d, J=8.8 Hz, 1 H) 5.76 (s, 1 H) 5.87 (br d, J=10.4 Hz, 2 H) 6.43 (d, J=8.5 Hz, 1 H) 7.03 (dd, J=8.2, 1.9 Hz, 1 H) 7.15 (d, J=1.6 Hz, 1 H) 7.32 (d, J=8.2 Hz, 1 H) 7.39 (d, J=7.9 Hz, 1 H) 7.46 (d, J=7.9 Hz, 1 H) 8.37 (s, 1 H) 12.16 (br s, 1 H); and / or LC / MS (method LC-AA): Rt2.99 min, MH+593; [α]D20: -28.6° (c 0.29, DMF); Chiral SFC (method SFC-EE): Rt2.17 min, MH+593, chiral purity 100%. In some embodiments Compound 6’ is Enantiomer 6’B: Cl OMe , wherein ppm 1.87 (quin, J=6.9 Hz, 2 H) 2.33 (t, J=7.3 Hz, 2 H) 3.24 (br dd, J=18.8, 11.5 Hz, 2 H) 3.61 (s, 3 H) 3.83 (q, J=6.2 Hz, 2 H) 3.90 (s, 3 H) 3.96 - 4.08 (m, 1 H) 4.32 - 4.43 (m, 1 H) 5.61 (d, J=8.5 Hz, 1 H) 5.76 (s, 1 H) 5.87 (br d, J=10.1 Hz, 2 H) 6.43 (br d, J=8.5 Hz, 1 H) 7.03 (dd, J=8.2, 1.6 Hz, 1 H) 7.15 (d, J=1.6 Hz, 1 H) 7.32 (d, J=8.2 Hz, 1 H) 7.39 (d, J=7.6 Hz, 1 H) 7.46 (d, J=7.9 Hz, 1 H) 8.37 (s, 1 H) 12.16 (br s, 1 H); and / or LC / MS (method LC-AA): Rt3.00 min, MH+593; [α]D20: +32.1° (c 0.28, DMF); Chiral SFC (method SFC-EE): Rt4.04 min, MH+593, chiral purity 100%. In some embodiments Compound A is Compound 7’ having the following chemical structure: Cl OMe may also be referred to as 4-(3-((1-(4-chloro-2- indolin-1-yl)-2-oxoethyl)amino)-5- methoxyphenoxy)butanoic acid, wherein1H NMR (500 MHz, DMSO-d6) δ ppm 1.87 (quin, J=6.7 Hz, 2 H) 2.34 (t, J=7.3 Hz, 2 H) 3.17 - 3.30 (m, 2 H) 3.61 (s, 3 H) 3.79 - 3.87 (m, 5 H) 3.90 (s, 3 H) 3.93 - 4.02 (m, 1 H) 4.29 - 4.40 (m, 1 H) 5.59 (s, 1 H) 5.75 (s, 1 H) 5.87 (br d, J=10.7 Hz, 2 H) 7.02 (dd, J=8.2, 1.6 Hz, 1 H) 7.14 (d, J=1.3 Hz, 1 H) 7.24 (s, 1 H) 7.32 (d, J=8.5 Hz, 1 H) 8.32 (s, 1 H); and / or LC / MS (method LC-AA): Rt 2.89 min, MH+623. In some embodiments Compound 7’ is Enantiomer 7’A: Cl OMe , wherein ppm 1.87 (br t, J=6.8 Hz, 2 H) 2.34 (br t, J=7.1 Hz, 2 H) 3.18 - 3.28 (m, 2 H) 3.61 (s, 3 H) 3.79 - 3.87 (m, 5 H) 3.91 (s, 3 H) 3.94 - 4.05 (m, 1 H) 4.31 - 4.42 (m, 1 H) 5.59 (br d, J=8.2 Hz, 1 H) 5.76 (br s, 1 H) 5.87 (br d, J=10.4 Hz, 2 H) 6.40 (br d, J=8.5 Hz, 1 H) 7.02 (br d, J=7.9 Hz, 1 H) 7.14 (s, 1 H) 7.24 (s, 1 H) 7.33 (br d, J=8.2 Hz, 1 H) 8.33 (s, 1 H) 12.18 (br s, 1 H); and / or LC / MS (method LC-AA): Rt2.87 min, MH+623; [α]D20: -23.9° (c 0.28, DMF); Chiral SFC (method SFC-CC): Rt1.76 min, MH+623, chiral purity 100%. In some embodiments Compound 7’ is Enantiomer 7’B: Cl OMe , wherein ppm 1.87 (quin, J=6.5 Hz, 2 H) 2.34 (br t, J=7.1 Hz, 2 H) 3.18 - 3.28 (m, 2 H) 3.61 (s, 3 H) 3.80 - 3.87 (m, 5 H) 3.91 (s, 3 H) 3.94 - 4.02 (m, 1 H) 4.28 - 4.41 (m, 1 H) 5.59 (br d, J=8.2 Hz, 1 H) 5.75 (br s, 1 H) 5.87 (br d, J=10.4 Hz, 2 H) 6.40 (br d, J=8.5 Hz, 1 H) 7.02 (br d, J=7.9 Hz, 1 H) 7.14 (s, 1 H) 7.24 (s, 1 H) 7.33 (br d, J=8.2 Hz, 1 H) 8.33 (s, 1 H) 12.17 (br s, 1 H); LC / MS (method LC-AA): Rt2.87 min, MH+623; [α]D20: +28.5° (c 0.26, DMF); Chiral SFC (method SFC-CC): Rt3.52 min, MH+623, chiral purity 100%. In some embodiments Compound A is Compound 8’ having the following chemical structure: Cl OMe may also be referred to as 4-(3-((1-(4-chloro-2- indolin-1-yl)ethyl)amino)-5- 1H NMR (500 MHz, DMSO-d6) δ ppm 1.87 (quin, J=6.9 Hz, 2 H) 2.34 (br t, J=7.3 Hz, 2 H) 3.08 - 3.26 (m, 2 H) 3.61 (s, 3 H) 3.83 (q, J=6.5 Hz, 2 H) 3.90 (s, 3 H) 3.98 - 4.09 (m, 1 H) 4.31 - 4.42 (m, 1 H) 5.60 (s, 1 H) 5.76 (s, 1 H) 5.87 (br d, J=9.5 Hz, 2 H) 6.98 - 7.05 (m, 2 H) 7.14 (d, J=1.9 Hz, 1 H) 7.31 (d, J=8.2 Hz, 1 H) 7.34 (d, J=8.2 Hz, 1 H) 8.02 (s, 1 H); and / or LC / MS (method LC-AA): Rt 3.04 min, MH+609. In some embodiments Compound 8’ is Enantiomer 8’A: Cl OMe , wherein 1.87 (quin, J=6.9 Hz, 2 H) 2.33 (t, J=7.4 Hz, 2 H) 3.09 - 3.25 (m, 2 H) 3.61 (s, 3 H) 3.78 - 3.87 (m, 2 H) 3.90 (s, 3 H) 3.98 - 4.07 (m, 1 H) 4.32 - 4.42 (m, 1 H) 5.59 (d, J=8.5 Hz, 1 H) 5.76 (s, 1 H) 5.86 (s, 1 H) 5.88 (s, 1 H) 6.45 (d, J=8.8 Hz, 1 H) 6.97 - 7.06 (m, 2 H) 7.14 (d, J=1.3 Hz, 1 H) 7.31 (d, J=8.5 Hz, 1 H) 7.34 (d, J=8.2 Hz, 1 H) 8.02 (s, 1 H) 12.14 (br s, 1 H); and / or LC / MS (method LC-AA): Rt3.03 min, MH+609; [α]D20: -39.3° (c 0.28, DMF); Chiral SFC (method SFC-FF): Rt2.32 min, MH+609, chiral purity 100%. In some embodiments Compound 8’ is Enantiomer 8’B: Cl OMe , wherein 1.87 (quin, J=6.8 Hz, 2 H) 2.34 (t, J=7.3 Hz, 2 H) 3.09 - 3.25 (m, 2 H) 3.61 (s, 3 H) 3.79 - 3.88 (m, 2 H) 3.90 (s, 3 H) 4.02 (td, J=10.2, 6.9 Hz, 1 H) 4.33 - 4.41 (m, 1 H) 5.60 (s, 1 H) 5.76 (s, 1 H) 5.86 (s, 1 H) 5.88 (s, 1 H) 6.45 (br s, 1 H) 6.99 - 7.05 (m, 2 H) 7.14 (d, J=1.6 Hz, 1 H) 7.31 (d, J=8.5 Hz, 1 H) 7.34 (d, J=8.2 Hz, 1 H) 8.02 (s, 1 H) 12.12 (br s, 1 H); and / or LC / MS (method LC-AA): Rt3.03 min, MH+609; [α]D20: +34.5° (c 0.29, DMF); Chiral SFC (method SFC-FF): Rt3.51 min, MH+609, chiral purity 100%. In some embodiments Compound A is Compound 9’ having the following chemical structure: Cl OMe may also be referred to as 4-(3-((1-(4-chloro-2- indolin-1-yl)ethyl)amino)-5- methoxyphenoxy)butanoic acid, wherein1H NMR (500 MHz, DMSO-d6) δ ppm 1.87 (quin, J=6.9 Hz, 2 H) 2.34 (t, J=7.3 Hz, 2 H) 3.18 - 3.34 (m, 2 H) 3.63 (s, 3 H) 3.80 - 3.90 (m, 2 H) 4.02 - 4.14 (m, 1 H) 4.40 - 4.49 (m, 1 H) 5.72 (s, 1 H) 5.80 (s, 1 H) 5.94 (br d, J=10.1 Hz, 2 H) 7.33 (dd, J=8.5, 1.6 Hz, 1 H) 7.39 - 7.43 (m, 1 H) 7.43 - 7.50 (m, 3 H) 8.36 (s, 1 H); and / or LC / MS (method LC-AA): Rt 2.99 min, MH+581. In some embodiments Compound 9’ is Enantiomer 9’A: Cl OMe , wherein ppm 1.87 (quin, J=6.7 Hz, 2 H) 2.33 (br t, J=7.1 Hz, 2 H) 3.22 - 3.28 (m, 2 H) 3.62 (s, 3 H) 3.80 - 3.90 (m, 2 H) 4.03 - 4.13 (m, 1 H) 4.39 - 4.48 (m, 1 H) 5.72 (br d, J=8.8 Hz, 1 H) 5.80 (s, 1 H) 5.93 (br d, J=10.7 Hz, 2 H) 6.60 (br d, J=8.8 Hz, 1 H) 7.33 (br d, J=7.9 Hz, 1 H) 7.39 - 7.43 (m, 1 H) 7.43 - 7.51 (m, 3 H) 8.36 (s, 1 H) 12.19 (br s, 1 H); and / or LC / MS (method LC-AA): Rt2.98 min, MH+581; [α]D20: -30.0° (c 0.29, DMF); Chiral SFC (method SFC-GG): Rt1.97 min, MH+581, chiral purity 100%. In some embodiments Compound 9’ is Enantiomer 9’B: Cl OMe , wherein ppm 1.87 (quin, J=6.9 Hz, 2 H) 2.33 (t, J=7.3 Hz, 2 H) 3.21 - 3.28 (m, 2 H) 3.63 (s, 3 H) 3.80 - 3.91 (m, 2 H) 4.02 - 4.12 (m, 1 H) 4.40 - 4.49 (m, 1 H) 5.72 (d, J=9.1 Hz, 1 H) 5.80 (s, 1 H) 5.94 (br d, J=11.0 Hz, 2 H) 6.60 (br d, J=8.8 Hz, 1 H) 7.33 (dd, J=8.2, 1.6 Hz, 1 H) 7.38 - 7.43 (m, 1 H) 7.43 - 7.50 (m, 3 H) 8.36 (s, 1 H) 11.04 - 12.93 (m, 1 H); and / or LC / MS (method LC-AA): Rt 2.98 min, MH+581; [α]D20: +27.9° (c 0.28, DMF); Chiral SFC (method SFC-GG): Rt 3.19 min, MH+581, chiral purity 99.35%.. In some embodiments Compound A is Compound 10’ having the following chemical structure: Cl OMe may also be referred to as 4-(3-((1-(4-chloro-2- indolin-1-yl)ethyl)amino)-5- 1H NMR (500 MHz, DMSO-d6) δ ppm 1.87 (quin, J=6.8 Hz, 2 H) 2.33 (br t, J=7.3 Hz, 2 H) 3.09 - 3.24 (m, 2 H) 3.62 (s, 3 H) 3.81- 3.89 (m, 2 H) 4.05 - 4.13 (m, 1 H) 4.38 - 4.47 (m, 1 H) 5.70 (br d, J=9.1 Hz, 1 H) 5.79 (s, 1 H) 5.93 (br d, J=9.8 Hz, 2 H) 6.62 (br d, J=8.8 Hz, 1 H) 7.03 (br d, J=8.2 Hz, 1 H) 7.31- 7.37 (m, 2 H) 7.41 - 7.50 (m, 2 H) 8.02 (s, 1 H) 12.15 (br s, 1 H); and / or LC / MS (method LC-AA): Rt 3.07 min, MH+597. In some embodiments Compound 10’ is Enantiomer 10’A: Cl OMe , wherein 1.87 (quin, J=6.9 Hz, 2 H) 2.34 (t, J=7.3 Hz, 2 H) 3.12 - 3.22 (m, 2 H) 3.62 (s, 3 H) 3.79 - 3.90 (m, 2 H) 4.04 - 4.13 (m, 1 H) 4.38 - 4.48 (m, 1 H) 5.70 (d, J=8.8 Hz, 1 H) 5.79 (s, 1 H) 5.93 (br d, J=9.8 Hz, 2 H) 6.62 (d, J=8.8 Hz, 1 H) 7.03 (br d, J=9.5 Hz, 1 H) 7.30 - 7.38 (m, 2 H) 7.41 - 7.51 (m, 2 H) 8.02 (s, 1 H) 12.10 (br s, 1 H); and / or LC / MS (method LC-AA): Rt3.04 min, MH+597; [α]D20: +23.1° (c 0.26, DMF); Chiral SFC (method SFC-HH): Rt3.22 min, MH+597, chiral purity 100%. In some embodiments Compound 10’ is Enantiomer 10’B: Cl OMe , wherein ppm 1.87 (br t, J=6.8 Hz, 2 H) 2.34 (br t, J=7.3 Hz, 2 H) 3.12 - 3.25 (m, 2 H) 3.63 (s, 3 H) 3.80- 3.90 (m, 2 H) 4.05 - 4.14 (m, 1 H) 4.38 - 4.49 (m, 1 H) 5.71 (br d, J=9.1 Hz, 1 H) 5.80 (br s, 1 H) 5.94 (br d, J=9.5 Hz, 2 H) 6.62 (br d, J=8.8 Hz, 1 H) 7.03 (br d, J=7.9 Hz, 1 H) 7.30- 7.38 (m, 2 H) 7.41 - 7.52 (m, 2 H) 8.02 (br s, 1 H) 12.12 (br s, 1 H); and / or LC / MS (method LC-AA): Rt3.04 min, MH+597; [α]D20: -23.0° (c 0.3, DMF); Chiral SFC (method SFC-HH): Rt4.05 min, MH+597, chiral purity 100%. In some embodiments Compound A is Compound 11’ having the following chemical structure: Cl OMe may also be referred to as 4-(3-((1-(4-chloro-2- indolin-1-yl)-2-oxoethyl)amino)-5- methoxyphenoxy)butanoic acid, wherein1H NMR (500 MHz, DMSO-d6) δ ppm 1.87 (quin, J=6.8 Hz, 2 H) 2.34 (br t, J=7.4 Hz, 2 H) 3.18 - 3.31 (m, 2 H) 3.63 (s, 3 H) 3.85 (s, 5 H) 3.98 - 4.09 (m, 1 H) 4.37 - 4.48 (m, 1 H) 5.69 (s, 1 H) 5.79 (s, 1 H) 5.93 (br d, J=11.0 Hz, 2 H) 7.26 (s, 1 H) 7.32 (br d, J=8.5 Hz, 1 H) 7.44 - 7.52 (m, 2 H) 8.32 (s, 1 H); and / or LC / MS (method LC-AA): Rt 2.90 min, MH+611. In some embodiments Compound 11’ is Enantiomer 11’A: Cl OMe , wherein ppm 1.88 (quin, J=6.8 Hz, 2 H) 2.34 (t, J=7.3 Hz, 2 H) 3.18 - 3.29 (m, 2 H) 3.63 (s, 3 H) 3.86 (s, 5 H) 3.99 - 4.07 (m, 1 H) 4.38 - 4.47 (m, 1 H) 5.69 (br s, 1 H) 5.79 (s, 1 H) 5.93 (br d, J=10.7 Hz, 2 H) 6.55 (br s, 1 H) 7.25 (s, 1 H) 7.32 (dd, J=8.5, 1.3 Hz, 1 H) 7.43 - 7.51 (m, 2 H) 8.33 (s, 1 H) 12.13 (br s, 1 H); and / or LC / MS (method LC-AA): Rt2.90 min, MH+611; [α]D20: -23.9° (c 0.26, DMF); Chiral SFC (method SFC-CC): Rt1.70 min, MH+611, chiral purity 100%. In some embodiments Compound 11’ is Enantiomer 11’B: Cl OMe (quin, J=6.8 Hz, 2 H) 2.34 (br t, J=7.3 Hz, 2 H) 3.18 - 3.31 (m, 2 H) 3.63 (s, 3 H) 3.85 (s, 5 H) 3.99 - 4.07 (m, 1 H) 4.37 - 4.47 (m, 1 H) 5.69 (br s, 1 H) 5.79 (s, 1 H) 5.93 (br d, J=11.0 Hz, 2 H) 6.56 (br s, 1 H) 7.25 (s, 1 H) 7.32 (br d, J=8.2 Hz, 1 H) 7.43 - 7.50 (m, 2 H) 8.33 (s, 1 H) 12.13 (br s, 1 H); and / or LC / MS (method LC-AA): Rt2.89 min, MH+611; [α]D20: +24.0° (c 0.25, DMF); Chiral SFC (method SFC-CC): Rt2.96 min, MH+611, chiral purity 100%. In some embodiments Compound A is Compound 12’ having the following chemical structure: Cl OMe , and may also be referred to as 4-(3-((1-(4- indolin-1-yl)-2-oxoethyl)amino)-5- 1H NMR (500 MHz, DMSO-d6) δ ppm 1.86 (quin, J=6.9 Hz, 2 H) 2.33 (t, J=7.3 Hz, 2 H) 3.08 - 3.28 (m, 2 H) 3.61 (s, 3 H) 3.81 (s, 3 H) 3.84 (br t, J=6.5 Hz, 2 H) 3.97 - 4.06 (m, 1 H) 4.48 (td, J=10.4, 6.3 Hz, 1 H) 5.53 (s, 1 H) 5.75 (s, 1 H) 5.94 (br d, J=10.1 Hz, 2 H) 7.20 (s, 1 H) 7.43 (d, J=8.5 Hz, 2 H) 7.54 (d, J=8.5 Hz, 2 H) 8.06 (s, 1 H); and / or LC / MS (method LC-AA): Rt 2.89 min, MH+609. In some embodiments Compound 12’ is Enantiomer 12’A: Cl OMe , wherein 1.86 (quin, J=6.8 Hz, 2 H) 2.33 (t, J=7.3 Hz, 2 H) 3.09 - 3.26 (m, 2 H) 3.61 (s, 3 H) 3.81 (s, 3 H) 3.84 (br t, J=6.5 Hz, 2 H) 4.02 (td, J=10.3, 7.1 Hz, 1 H) 4.48 (td, J=10.4, 6.3 Hz, 1 H) 5.53 (d, J=8.5 Hz, 1 H) 5.75 (s, 1 H) 5.93 (s, 1 H) 5.95 (s, 1 H) 6.43 (d, J=8.8 Hz, 1 H) 7.20 (s, 1 H) 7.43 (d, J=8.2 Hz, 2 H) 7.55 (d, J=8.5 Hz, 2 H) 8.06 (s, 1 H) 12.12 (br s, 1 H); and / or LC / MS (method LC-AA): Rt2.92 min, MH+609; [α]D20: -44.2° (c 0.197, DMF); Chiral SFC (method SFC-II): Rt0.99 min, MH+609, chiral purity 100%. In some embodiments Compound 12’ is Enantiomer 12’B: Cl OMe (quin, J=6.9 Hz, 2 H) 2.33 (t, J=7.3 Hz, 2 H) 3.09 - (br t, J=6.5 Hz, 2 H) 3.98 - 4.06 (m, 1 H) 4.48 (td, J=10.5, 6.1 Hz, 1 H) 5.53 (d, J=8.8 Hz, 1 H) 5.75 (s, 1 H) 5.93 (s, 1 H) 5.95 (s, 1 H) 6.43 (d, J=8.8 Hz, 1 H) 7.20 (s, 1 H) 7.43 (d, J=8.5 Hz, 2 H) 7.54 (d, J=8.5 Hz, 2 H) 8.06 (s, 1 H) 12.16 (br s, 1 H); and / or LC / MS (method LC-AA): Rt2.91 min, MH+609; [α]D20: +40.7° (c 0.189, DMF); Chiral SFC (method SFC-II): Rt1.45 min, MH+609, chiral purity 98.53%. In preferred embodiments, Compound A is represented by the following structure: Cl OMe . This compound is also referred herein as JNJ-A07. as compound 4. WO2017 / 167951, which is incorporated herein by reference in its entirety, described a non-chiral synthesis method of JNJ-A07. Cl In some embodiments In some embodiments Compound A is in A is in amorphous form. In some embodiments, Compound A or a pharmaceutically acceptable salt form thereof is in amorphous form or dissolved state. In some embodiments Compound A is in amorphous form or dissolved state. In some embodiments Compound A is the (+)-enantiomer in amorphous form. In some embodiments Compound A is the (+)- enantiomer in anhydrous form. In some embodiments Compound A is the (+)-enantiomer in anhydrous form. Compound B is also referred herein as NITD-688. NITD-688 was described in WO2019 / 244047 as Example 71. WO2019 / 244047, which is incorporated herein by reference in its entirety, also describes synthesis method of NITD-688. In some embodiments, Compound B is represented by the following structure: , 7.78 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.33 (s, 2H), 3.96 (s, 2H), 3.49 (s, 2H), 2.46 (s, 2H), 2.24 (d, J = 6.8 Hz, 2H), 1.76 - 1.73 (m, 2H), 1.67 - 1.64 (m, 3H), 1.39 - 1.33 (m, 1H), 1.25 - 1.15 (m, 3H), 1.02 (s, 6H), 0.88 - 0.75 (m, 2H). Some embodiments disclosed herein relate to the combination of Compound A and Compound B as described herein and the use of this combination in the treatment of Dengue viral infections. Some embodiments disclosed herein relate to the combination of Compound A and Compound B as described herein and the use of this combination in the prevention of Dengue viral infections in an individual at risk of being infected by Dengue virus. Said individual is living in or traveling to a dengue endemic region. Some embodiments disclosed herein relate to the combination of Compound A and Compound B as described herein and the use of this combination in the prevention of Dengue viral infections in an individual that has been exposed to Dengue virus. Said individual is already infected by Dengue virus but the peak viral load in blood has not yet been reached. In some embodiments the viral load in the patient that has been exposed is of 1.0 log virus copies / mL of blood; preferably the viral load is of 1.5 log virus copies / mL; preferably the viral load is of 2.0 log virus copies / mL; preferably the viral load is of 2.5 log virus copies / mL; preferably the viral load is of 3.0 log virus copies / mL; preferably the viral load is of 3.5 log virus copies / mL; preferably the viral load is of 4.0 log virus copies / mL; preferably the viral load is of 4.5 log virus copies / mL; preferably the viral load is of 5.0 log virus copies / mL; preferably the viral load is of 5.5 log virus copies / mL; preferably the viral load is of 6.0 log virus copies / mL; preferably the viral load is of 6.5 log virus copies / mL; preferably the viral load is of 7.0 log virus copies / mL; preferably the viral load is of 7.5 log virus copies / mL; preferably the viral load is of 8.0 log virus copies / mL; preferably the viral load is of 8.5 log virus copies / mL. Still other embodiments relate to a method of treatment of Dengue viral infections in an individual in need thereof, comprising administering the combination of Compound A and Compound B as described herein in an effective amount to said individual. Some embodiments relate to a method of prevention of Dengue viral infections in an individual that has been exposed to Dengue virus (for example, said individual may be already infected by Dengue virus but the peak viral load in blood has not yet been reached) comprising administering the combination of Compound A and Compound B as described herein to said individual. Some embodiments relate to a method of prevention of Dengue viral infections in an individual at risk of being infected by Dengue virus, comprising administering the combination of Compound A and Compound B as described herein to said individual. For example, said individual may be living in or traveling to a dengue endemic region. As used herein, the terms "treat," "treating," "treatment," "therapeutic," and "therapy" do not necessarily mean total cure or abolition of the disease or condition. Any reduction of viral load or alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and / or therapy. The terms "therapeutically effective amount" and "effective amount" are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, a therapeutically effective amount of compound can be the amount needed to prevent, alleviate or ameliorate symptoms of disease, reduce viral load, or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes reduction of viral load, alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. Various indicators for determining the effectiveness of a method for the treatment and / or prophylaxis (PEP and / or PrEP) of a Dengue viral infection are known to those skilled in the art. Example of suitable indicators include, but are not limited to a reduction in viral load, a reduction of the viral load area under the curve compared to a placebo treated group, a reduction in viral replication, a reduction in time to seroconversion (virus undetectable in patient serum), a reduction of morbidity or mortality in clinical outcomes, and / or other indicator of disease response (such as a reduction in signs and symptoms of the disease). In some embodiments, when referring to the treatment and / or post-exposure treatment (PEP) of an individual, the first administration of the combination of Compound A and Compound B as described herein may occur at most 15 days after being infected by Dengue virus, preferably at most 14 days, preferably at most 13 days, preferably at most 12 days, preferably at most 11 days, preferably at most 10 days, preferably at most 8 days, preferably at most 6 days, preferably at most 5 days, preferably at most 4 days, preferably at most 72 hours, preferably at most 48 hours, preferably at most 36 hours, preferably at most 24 hours, preferably at most 12 hours after being infected by Dengue virus. In some embodiments, treatment and / or post-exposure treatment of an individual with a combination of Compound A and Compound B as described herein, can reduce the viral load compared to the viral load of an individual treated with a placebo, for example dengue viral load in blood is lowered to a level of at most 10 log10copies / mL, at most 9.5 log10copies / mL, at most 9 log10copies / mL, at most 8.5 log10copies / mL, at most 8 log10copies / mL, at most 7.5 log10copies / mL, at most 7 log10copies / mL, at most 6.5 log10copies / mL, at most 6 log10copies / mL, at most 5.5 log10copies / mL, at most 5 log10copies / mL, at most 4.5 log10copies / mL, at most 4 log10copies / mL, at most 3.5 log10copies / mL, at most 3 log10 copies / mL, at most 2.5 log10 copies / mL, at most 2 log10 copies / mL, at most 1.5 log10copies / mL, at most 1 log10copies / mL, at most 0.5 log10copies / mL, at most 0 copies / mL. In some embodiments, treatment and / or post-exposure treatment of an individual with a combination of Compound A and Compound B as described herein, can reduce the viral load area under the curve of the treated individual, compared to the viral load area under the curve of a placebo treated individual. In some embodiments, treatment and / or post-exposure treatment of an individual with a combination of Compound A and Compound B as described herein, can result in at least a 1-fold reduction in the replication of Dengue virus relative to levels in a placebo treated individual preferably at least 5-fold reduction, preferably at least 10-fold, preferably at least 100-fold reduction, preferably at least 1000-fold reduction, preferably at least 5000-fold reduction, preferably at least 10000-fold reduction, preferably at least 20000-fold reduction, preferably at least 25000-fold reduction, preferably at least 50000-fold reduction, preferably at least 75000-fold reduction. In some embodiments, treatment and / or post-exposure treatment of an individual with a combination of Compound A and Compound B as described herein can result in a reduction in the number of copies / mL of Dengue virus (i.e. viral load) relative a placebo treated individual in the range of from 5- to 1000000-fold, preferably from 100- to 900000- fold, preferably from 1000- to 800000-fold, preferably from 1000- to 600000-fold; preferably from 10000- to 600000-fold. In some embodiments, a combination of Compound A and Compound B as described herein can result in a reduction of Dengue virus copies / mL in the range of from 0.01 log to 6 log, preferably in the range of from 0.1 log to 5.5 log, preferably from 0.5 log to 5.5 log, preferably from 1.0 log to 5 log reduction of Dengue virus copies / mL compared to the reduction of Dengue virus reduction achieved by the use of one anti-Dengue virus agent (e.g., Compound A alone or Compound B alone) administered as monotherapy, or may achieve the same reduction in a shorter period of time. In some embodiments, post-exposure treatment of an individual with a combination of Compound A and Compound B as described herein, can reduce the viral load compared to the viral load of an individual being administered a placebo, for example dengue viral load in blood is lowered to a level of at most 0 copies / mL, at most 0.5 log10copies / mL, at most 1 log10copies / mL, at most 1.5 log10copies / mL, at most 2 log10copies / mL, at most 2.5 log10copies / mL, at most 3 log10copies / mL, at most 3.5 log10copies / mL, at most 4 log10copies / mL, at most 4.5 log10copies / mL, at most 5 log10copies / mL, at most 5.5 log10copies / mL, at most 6 log10copies / mL, at most 6.5 log10copies / mL, at most 7 log10copies / mL, at most 7.5 log10copies / mL, at most 8 log10copies / mL, at most 8.5 log10copies / mL, at most 9 log10copies / mL, at most 9.5 log10copies / mL, at most 10 log10copies / mL. In some embodiments a combination of Compound A and Compound B as described herein may be administered to an individual at risk of being infected by Dengue virus. In some embodiments, for individuals at risk of being infected by Dengue virus, the first administration of the combination of Compound A and Compound B is occurring at least 5 minutes prior to infection; preferably at least 30 minutes, preferably at least 1 hour, preferably at least 2 hours, preferably at least 3 hours, preferably at least 4 hours, preferably at least 5 hours, preferably at least 6 hours, preferably at least 7 hours, preferably at least 8 hours, preferably at least 9 hours, preferably at least 10 hours, preferably at least 11 hours, preferably at least 12 hours, preferably at least 24 hours, preferably at least 36 hours, preferably at least 48 hours, preferably at least 72 hours, preferably at least one week, preferably at least two weeks, preferably at least three weeks, preferably at least one month, preferably at least two months, preferably at least three months, preferably at least four months prior to infection (so for example prior to entering into an endemic geographical area for travellers or prior to dengue season for individuals living in endemic regions). In some embodiments, pre-exposure prevention in an individual with administration of a combination of Compound A and Compound B as described herein, can reduce the dengue viral load (upon exposure to dengue virus) compared to the dengue viral load of an individual being administered a placebo (upon exposure to dengue virus), for example dengue viral load in blood is lower by a level of at most 0 copies / mL, at most 0.5 log10copies / mL, at most 1 log10copies / mL, at most 1.5 log10copies / mL, at most 2 log10copies / mL, at most 2.5 log10copies / mL, at most 3 log10copies / mL, at most 3.5 log10copies / mL, at most 4 log10copies / mL, at most 4.5 log10copies / mL, at most 5 log10copies / mL, at most 5.5 log10copies / mL, at most 6 log10copies / mL, at most 6.5 log10copies / mL, at most 7 log10copies / mL, at most 7.5 log10copies / mL, at most 8 log10copies / mL, at most 8.5 log10copies / mL, at most 9 log10copies / mL, at most 9.5 log10copies / mL, at most 10 log10copies / mL. In some embodiments, pre-exposure prevention in an individual with administration of a combination of Compound A and Compound B as described herein, can reduce the dengue viral load area under the curve of the treated individual (upon exposure to dengue virus), compared to the viral load area under the curve of a placebo treated individual (upon exposure to dengue virus). In some embodiments, pre-exposure prevention in an individual with a administration of a combination of Compound A and Compound B as described herein, can result in at least a 1-fold greater reduction in the replication of Dengue virus relative to the viral load reduction observed in an individual being administered a placebo, as determined several hours after receiving the initial dosage of the combination (for example, 60 hours after receiving the initial dosage of the combination), preferably at least 5-fold greater reduction, preferably at least 10-fold greater reduction, preferably at least 100-fold greater reduction, preferably at least 1000-fold greater reduction, preferably at least 5000-fold greater reduction, preferably at least 10000-fold greater reduction, preferably at least 20000-fold greater reduction, preferably at least 25000-fold greater reduction, preferably at least 50000-fold greater reduction, preferably at least 75000-fold greater reduction in the replication of Dengue virus relative to viral load reduction levels observed in a subject administered a placebo, as determined several hours after receiving the placebo (for example, 60 hours after receiving the initial dosage of the combination). In some embodiments, pre-exposure prevention in an individual with administration of a combination of Compound A and Compound B as described herein can result in a reduction in the number of copies / mL of Dengue virus (i.e. viral load) relative to the number of copies / mL in an individual being administered a placebo, for example, the reduction may be in the range of from 5- to 1000000-fold, preferably from 100- to 900000-fold, preferably from 1000- to 800000-fold, preferably from 1000- to 600000-fold; preferably from 10000- to 600000-fold. In some embodiments, a combination of Compound A and Compound B as described herein can result in a reduction of Dengue virus copies / mL in the range of from 0.01 log to 6 log, preferably in the range of from 0.1 log to 5.5 log, preferably from 0.5 log to 5.5 log, preferably from 1.0 log to 5 log more reduction of Dengue virus copies / mL compared to the reduction of Dengue virus reduction achieved by the use of one anti- Dengue virus agent (e.g., Compound A alone or Compound B alone) administered as monotherapy, or may achieve the same reduction in a shorter period of time. In some embodiments, treatment and / or prophylaxis (PEP and / or PrEP) of an individual with a combination of Compound A and Compound B as described herein, can decrease the percentage of subjects that experience complications from Dengue viral infection compared to the percentage of subjects that experience complication being treated with one anti-Dengue virus agent (e.g., Compound A alone or Compound B alone). A potential advantage of utilizing a combination of Compound A and of Compound B as described herein, may be a reduction in the required amount(s) of Compound A, and / or of Compound B, that is effective in the treatment and / or prophylaxis (PEP and / or PrEP) Dengue viral infection, as compared to the amount required to achieve same therapeutic result when each of Compound B and / or Compound A are used individually. For example, the amount of Compound A and / or of Compound B can be less compared to the amount of the aforementioned compounds needed to achieve the same viral load reduction when administered as a monotherapy. Another potential advantage of utilizing a combination described herein is that the use of two or more compounds having different mechanism of actions can create a higher barrier to the development of resistant viral strains compared to the barrier when a compound is administered as monotherapy. Additional advantages of utilizing a combination described herein may include little to no cross resistance between the compounds of the combination; different routes for elimination of the compounds of the combination; avoidance that the toxicity of one compound is worsened due to addition of the other compound; avoidance of reaching a level of toxicity that cannot be tolerated; little to no overlapping toxicities between the compounds of the combination; and / or little to no pharmacokinetic interactions between the compounds of the combination. In some embodiments the amount of Compound A and the amount of Compound B in the combinations according to the present invention is such that a synergistic antiviral effect (e.g., antiviral activity) against Dengue virus is obtained. As used herein, the term “synergistic” refers to when two or more drugs are applied in combination, at a given amount, the resulting response (e.g., effect, result, or antiviral activity) is greater (e.g., better) as compared to what is expected from the combination (under specific null models) based on what is observed from the individual drugs in the monotherapies. In other words, the compounds work together. If the resulting response of the two or more drugs in combination is equal compared to what is expected from the combination (under specific null models) based on what is observed from the individual drugs in the monotherapies, the combination is said to be additive or zero-interactive. If the resulting response of the two or more drugs in combination is less as compared to what is expected from the combination (under specific null models) based on what is observed from the individual drugs in the monotherapies, the combination is said to be “antagonistic.” In other words, the compounds work against each other. The combination according to anyone of claims 1 to 5, wherein the ratio by weight of Compound A to Compound B is from 1:3000 to 1:2800; preferably the ratio by weight of Compound A to Compound B is from 1:2800 to 1:2600; preferably from 1:2600 to 1:2400; preferably from 1:2400 to 1:2200; preferably from 1:2300 to 1:2100; preferably from 1:2150 to 1:2100; preferably from 1:1800 to 1:1600; preferably from 1:1600 to 1:1400; preferably from 1:1400 to 1:1200; preferably from 1:1200 to 1:1100. In some embodiments, the ratio by weight of Compound A to Compound B is from 1:100 to 1:5000, from 1:300 to 1:4000, from 1:500 to 1:3000, from 1:800 to 1:2500, from 1:900 to 1:1100, from 1:500 to 1:1500, from 1:1500 to 1:2500, or from 1:1800 to 1:2200. Other embodiments relate to a pharmaceutical composition comprising the combination of Compound A and Compound B as described herein and at least one pharmaceutically acceptable excipient. In certain embodiments, Compound A and Compound B may be formulated in separate pharmaceutical compositions. In certain embodiments, Compound A and Compound B may be formulated together in a single pharmaceutical composition. The present invention also encompasses the use of said pharmaceutical composition(s) in the prevention (PEP or PrEP) or treatment of Dengue viral infections. In certain embodiments, when Compound A and Compound B are formulated in separate pharmaceutical compositions, the invention also encompasses using said pharmaceutical composition(s) in the prevention (PEP or PrEP) or treatment of Dengue viral infections by sequentially or concurrently administering the pharmaceutical compositions to an individual in need thereof. As used herein, an "excipient" is an inactive ingredient in a pharmaceutical formulation. Examples of excipients include diluents or fillers, wetting agents (e.g., surfactants), binders, glidants, lubricants, disintegrants, and the like. The choice of excipient depends largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. In some embodiments the pharmaceutical composition according to the invention further comprises one or more pharmaceutically acceptable excipients, preferably selected from the group comprising disintegrants, binders, diluents or fillers, lubricants, stabilizers, wetting agents (e.g., surfactants), glidants, osmotic agents, colorants, plasticizers, coatings and mixtures thereof. As used herein, a "disintegrant agent" or "disintegrant" is an excipient that hydrates a pharmaceutical composition and aids in tablet dispersion. Examples of disintegrant agents include croscarmellose sodium, crospovidone (i.e., cross-linked polyvinyl N-pyrrolidone), sodium starch glycolate, or any combination thereof. As used herein, a "diluent" or "filler" is an excipient that adds bulkiness to a pharmaceutical composition. Examples of diluents include lactose, sorbitol, celluloses, calcium phosphates, starches, sugars (e.g., mannitol, sucrose, or the like) or any combination thereof. As used herein, a "wetting agent" or a "surfactant" is an excipient that imparts pharmaceutical compositions with enhanced solubility and / or wettability. Examples of wetting agents include sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polyoxyethylene 20 sorbitan mono-oleate (i.e. polysorbate 20) (e.g., Tween™ or Tween 20), Soluplus®, or any combination thereof. As used herein, a "binder" is an excipient that imparts a pharmaceutical composition with enhanced cohesion or tensile strength (e.g., hardness). Examples of binders include dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose, and modified cellulose (e.g., hydroxymethyl cellulose). As used herein, a "glidant" is an excipient that imparts pharmaceutical composition with enhanced flow properties. Examples of glidants include colloidal silica and / or talc. As used herein, a "colorant" is an excipient that imparts a pharmaceutical composition with a desired colour. Examples of colorants include commercially available pigments such as FD&C Blue #1 Aluminium Lake, FD&C Blue #2, other FD&C Blue colours, titanium dioxide, iron oxide, and / or combinations thereof. Other colorants include commercially available pigments such as FD&C Green #3. As used herein, a "lubricant" is an excipient that is added to pharmaceutical composition that are pressed into tablets. The lubricant aids in compaction of granules into tablets and ejection of a tablet of a pharmaceutical composition from a die press. Examples of lubricants include magnesium stearate, stearic acid (stearin), hydrogenated oil, sodium stearyl fumarate, or any combination thereof. Pharmaceutical compositions may be prepared as dosage forms to be administered orally, parenterally (including subcutaneously, intramuscularly, and intravenously), rectally, buccally, or nasally. Suitable compositions for oral administration include powders, granulates, aggregates, tablets, semi-solid formulations, compressed or coated pills, dragees, sachets, hard or gelatine capsules, syrups and suspensions. Suitable compositions for parenteral administration include aqueous or non-aqueous solutions or emulsions, while for rectal administration suitable compositions for administration include suppositories with a hydrophilic or hydrophobic vehicle. For nasal delivery there can be used suitable aerosol delivery systems. For example, in preparing the compositions for oral administration, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid compositions such as suspensions, syrups, elixirs, emulsions and solutions; or solid excipients such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of solid compositions. For parenteral compositions, the excipient will usually comprise sterile water, at least in large part, though other ingredients, such as solubilizers, emulsifiers or further auxiliaries may be added thereto. Injectable solutions may be prepared in which the excipient comprises saline solution, glucose solution or a mixture of both. Injectable suspensions may also be prepared in which case appropriate liquid excipients, suspending agents and the like may be employed. Also included are solid form preparations intended to be converted, shortly before use, to liquid form preparations such as powders for reconstitution. The pharmaceutical compositions may be conveniently presented in unit dosage form for ease of administration and uniformity of dosage. Examples include tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof. It is especially advantageous to formulate the aforementioned pharmaceutical composition in unit dosage form for ease of administration and / or uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical excipient. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof. The dosages may be presented as one, two, three, four or more sub-doses administered at appropriate intervals throughout the day. In certain embodiments, the dosages may be administered at time intervals that are less frequent than once daily, such as once weekly, or twice weekly. The dosage used preferably corresponds or is calculated based on a daily amount of Compound A and Compound B mentioned above, or a sub- dose thereof, such as 1 / 2, 1 / 3, or 1 / 4 thereof. A dosage form may contain the Compound A and Compound B, in an amount equal to the ranges, quantities or ratios by weight mentioned in the previous paragraphs, either in separate compositions or in a combined composition. In some embodiments, the dosing regimens may be ones that are described in WO2023 / 218285, which is incorporated herein by reference in its entirety. In the instance where Compound A and Compound B are to be administered once daily, this can be accomplished by administering a combined fixed dose combination containing Compound A and Compound B. Dosage forms that can be administered are described hereinafter. In some embodiments the pharmaceutical composition is administered in an oral dosage form. In some embodiments, the pharmaceutical composition is administered in a solid oral form. In some embodiments, the pharmaceutical composition is administered in a semi-solid oral form. In some embodiments the pharmaceutical composition is that described in WO2022 / 095912 and / or WO2022 / 095913, each of which are incorporated herein by reference in their entirety. Active ingredients may be formulated in pharmaceutical compositions either separately or as a combined pharmaceutical composition. In the latter instance, there is provided a pharmaceutical composition comprising a therapeutically effective amount of Compound A, or a stereo-isomeric form, a pharmaceutically acceptable salt, solvate, or polymorph thereof; a therapeutically effective amount of Compound B, or a stereo-isomeric form, a pharmaceutically acceptable salt, solvate, or polymorph thereof; and a pharmaceutically acceptable excipient. In a further aspect, this invention relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable excipient with a therapeutically effective amount of the Compound A, or a stereo-isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof, and a therapeutically effective amount of the Compound B, or a stereo-isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof. It being understood that, due to the observed synergism, the therapeutically effective amount of each of Compound A and Compound B in the combined pharmaceutical composition (or in separate pharmaceutical compositions which are indicated for administration of the Compounds in combination) is lower than the therapeutically effective amount of each of Compound A and Compound B if they were indicated for administration as a monotherapy. The combinations provided herein may also be formulated as separate pharmaceutical compositions indicated combined use or administration, e.g., for simultaneous or sequential use in Dengue viral infections therapy. In such a case, Compound A is formulated in a pharmaceutical composition containing other pharmaceutically acceptable excipients, and the Compound B is formulated separately in a pharmaceutical composition containing other pharmaceutically acceptable excipients. These separate pharmaceutical compositions can be part of a kit for simultaneous or sequential use. The individual components of the combination of the present invention can be administered simultaneously or separately at different times during the course of therapy or concurrently in divided or single combination forms. Therefore, Compound A and Compound B, individually or combined, may be formulated into various pharmaceutical compositions suitable for administration purposes. In these, a therapeutically effective amount of each of the particular Compounds A and / or B is combined with a pharmaceutically acceptable excipient, which excipient may take a wide variety of forms depending on the form of preparation desired for administration. In some embodiments the combination of Compound A and of Compound B as described herein, be additionally used in combination with one or more other drugs or agents, such as other antiviral agents or vaccines. GENERAL SYNTHETIC METHODS Representative compounds for use in the present invention can be synthesized in accordance with the general synthetic methods described below and illustrated in the schemes and examples that follow. Since the schemes are an illustration, the invention should not be construed as being limited by the chemical reactions and conditions described in the schemes and examples. Compounds from a similar chemical space as the compounds of these examples can be made according to similar routes. The disclosed compounds are useful as pharmaceutical agents as described herein. The various starting materials used in the schemes and examples are commercially available or may be prepared by methods well within the skill of persons versed in the art. Compounds of Formula I. The synthesis of compounds of general Formula (I) as described herein, where R1, R2and R3are as disclosed herein, can be performed 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 with a chlorination reagent like for example thionyl chloride. The Friedel-Crafts reaction of the acid chloride III with a substituted indole of general formula IV can be performed using a Lewis acid reagent like for example Et2AlCl or TiCl4in a suitable solvent like for example CH2Cl2or 1,2-dichloroethane, and under suitable reaction conditions that typically (but not exclusively) involve cooling, to provide the 3- acylated indole of general formula V. The introduction of an aniline moiety in alpha position to the carbonyl moiety of the compounds of general formula V can be accomplished by a reaction sequence that involves for example bromination of V with a reagent like for example phenyltrimethylammonium tribromide in a suitable solvent like for example THF (tetrahydrofuran), to provide the compounds of general formula VI, and subsequent reaction of the compounds of general formula VI with 3-methoxy-5-(methyl-sulfonyl)aniline (VII) in a suitable solvent like for example CH3CN, and typically using a base like for example triethylamine (TEA) or N,N-Diisopropylethylamine (DIPEA), to provide the compounds of general formula I as racemic mixtures. Chiral separation of the compounds of general formula I can be performed by for example chiral chromatography to provide the Enantiomers A and B of general Formula I. Scheme 1 In some cases, the synthesis of the intermediate of general formula V via the Friedel- Crafts synthesis approach, 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, the substituted indole of general formula IV can be converted first to an N-protected intermediate of general formula VIII, such as for example an N-Tosylated intermediate of general formula VIII (PG = Ts), using a reagent like for example tosyl chloride, in the presence of a base like for example sodium hydride. The Friedel-Crafts reaction of the substituted indole of general formula IV with acid chloride III can be performed using a Lewis acid reagent like for example Et2AlCl or TiCl4in a suitable solvent like for example CH2Cl2or 1,2-dichloroethane, and under suitable reaction conditions that typically (but not exclusively) involve cooling, to provide the 3-acylated N-protected indole of general formula IX. Removal of the indole-N protecting group PG of the intermediate of general formula IX can be accomplished with a reagent like for example LiOH (for PG = Ts) in a solvent mixture like for example THF / water an at a suitable reaction temperature, to provide the 3-acylated indole of general formula V. As an alternative approach, the intermediate of general formula V can also be prepared as outlined in Scheme 3: The N-Boc-protected substituted indole-3-carbaldehyde of general formula X can be converted to the corresponding Strecker-type of intermediate of general formula XI by reaction with morpholine in the presence of reagents like for example sodium cyanide and sodium bisulfite and in a suitable solvent like for example a mixture of water and a water-mixable organic solvent like for example dioxane. Alkylation of the compound of general formula XI with 4-chloro-2-methoxy-benzylchloride can be accomplished in the presence of a base like for example potassium hexamethyldisilazane and in a suitable solvent like for example dimethylformamide (DMF) to provide the compound of general formula XII. Submission of the compound of general formula XII to a suitable aqueous acidic hydrolytic condition like for example by treatment with an aqueous hydrochloric acid solution at elevated temperature, provides the intermediate of general formula V. Compounds of Formula I’. The synthesis of compounds of general Formula (I’) as described herein, where R1’, R2’, R3’and R4’are as disclosed herein, can be performed as outlined in Scheme 4. Reaction of the carboxylic acid XIII with an indoline of general formula XIV can be performed in the presence of for instance hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU) and diisopropylethylamine in a suitable solvent like for example DMF, to provide indoline- ethanone of general formula XV. The introduction of an aniline moiety in alpha position to the carbonyl moiety of XV can be accomplished by a reaction sequence that involves for example bromination of compound XV with a reagent like for example N-bromosuccinimide in the presence of LiHMDS and in a suitable solvent like for example THF (tetrahydrofuran), to provide intermediate XVI, and subsequent reaction of this compound with tert-butyl 4-(3- amino-5-methoxyphenoxy)butanoate XVII in a suitable solvent such as for example CH3CN, and typically using a base like for example N,N-diisopropylethylamine (DIPEA), followed by removal of the protecting group by for instance acid hydrolysis, to provide the compounds of general formula I’ as racemic mixtures. Chiral separation of the compounds of general Formula I’ can be performed by for example chiral chromatography to provide the Enantiomers A and B of general Formula I’. R N R R Br Scheme 4 Compound B. The synthesis of Compound B (also known as N-[3-cyano-5-(cyclohexylmethyl)-6,6- dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl]-2-(4-sulfamoylphenyl)acetamide) can for example be performed as outlined in Scheme 5. Mixing 2-amino-5-(cyclohexylmethyl)- 6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carbonitrile Core-1-c_A (prepared for instance as described in pages 51-56 of WO2019 / 244047) with 2-(4-sulfamoylphenyl)acetic acid Core-1 c_C in the presence of DIPEA and T3P, in a suitable solvent such as DMF. This mixture may be kept at 65 °C (for example one hour under stirring) to obtain N-[3-cyano-5- (cyclohexylmethyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl]-2-(4- sulfamoylphenyl)acetamide. All possible combinations of the above-indicated embodiments are considered to be embraced within the scope of this invention. Reference is now made to the following examples, which illustrate the invention in a non-limiting fashion. EXAMPLES Test compounds Compound JNJ-64281802 was synthesized as described in WO2016 / 180696, under Example 9. Compound JNJ-A07 was synthesized as described in WO2017 / 167951, under Example 4. Compound NITD-688 was synthesized as described in WO2019 / 244047. Antiviral assay The antiviral activity of Compound A and / or Compound B or a combination of both against DENV-2 / 16681 was determined using recombinant virus (DENV-2 / 16681 / eGFP) with eGFP read out. In parallel, cytotoxicity of Compound A and Compound B or a combination of both was measured using ATPLite™ (PerkinElmer), which is based on the bioluminescent measurement of adenosine triphosphate (ATP) in metabolically active cells. Three different controls were used: (i) medium control wells containing only assay medium, (ii) cell control wells containing cells in assay medium, and (iii) virus control wells containing virus and cells in assay medium. In brief, 2,500 Vero cells were seeded per well in assay medium in 384-well blackview plates (Costar) containing a combination of diluted test compounds and the cells were incubated for an additional 30 minutes at room temperature. Next, the plates were incubated during 24 hours at 37°C and 5% CO2. After the incubation step, the cells were infected with DENV-2 / 16681 / eGFP (multiplicity of infection [MOI] = 0.5 CCID50 / cell). After 3 days of incubation at 37 °C and 5% CO2, the viral replication was quantified by measuring eGFP expression in the cells with a laser microscope. A relative EC50value was calculated with the commercial Genedata Screener software. Here, the EC50value was calculated as the concentration corresponding to the midpoint between the estimates of the lower and upper plateaus of the fitted dose-response curve. In the same way, the EC90value was calculated. In parallel, cytotoxic effects of Compound A and / or Compound B or a combination of both were evaluated using an ATPlite™ cell viability luminescence assay. To measure ATP levels, ATPlite™ was added to the wells according to the supplier’s instructions once the eGFP read-out was performed, and the resulting luminescence was measured using a ViewLux apparatus (PerkinElmer). This measure is directly related to the number of viable cells. A relative CC50value was calculated with the commercial Genedata Screener software. Here, the CC50value was calculated as the concentration corresponding to the midpoint between the estimates of the lower and upper plateaus of the fitted dose-response curve. In the same way, the CC90value was calculated. Normalization Prior to the analysis the following normalization was applied to account for the between-plate variability where CC = Cell = where CC = Cell Controls and MC = Medium Controls. Methodology The observed combination data was evaluated using the BIGL R package. The monotherapy data was modelled using 4-parameter logistic (4PL) regression, assuming a common baseline for both monotherapy curves and individual estimates for the remaining 3 parameters. Additionally, the lower asymptote was constraint to ≥ 0. The 4PL models were subsequently used to model the effect of the combinations under the HSA, Bliss, Generalized Loewe, and Alternative Loewe null models. Differences in mean observed combination effects and mean modelled combination effects were calculated, together with a bootstrapped confidence interval (using 5000 iterations). A linear model was fitted on the original dataset, modelling the variance of each off-axis point as a function of its mean effect. The FWER was controlled at the 5% alpha level. Marginal monotherapy curves First, a monotherapy model was described by the following equation. where y is the response (or , of the compound, ℎ is the Hill’s coefficient and b and m are respectively baseline and maximum response for that compound. Lastly, EC50 stands for the dose level of the compound needed to attain the midpoint effect, i.e. Note that m>b if and increasing with the dose of the compound. If the response is decreasing, then m<b. This monotherapy equation was estimated for both A and B compounds with the constraint that b, the baseline level, was shared across compounds. This baseline level was denoted by b in the parameter vector. Additionally, m1 and m2 in the parameter vector stand for estimates of maximal responses m1 and m2, respectively, whereas h1 and h2 are Hill’s coefficients (slope) of the monotherapy curve for each compound. Lastly, e1 and e2 were log-transformed inflection points, i.e. e1 = log(EC501) and e2 =log(EC502). More information on the null models and the methodology applied, can be found in Van der Borght, Koen, et al. “BIGL: Biochemically Intuitive Generalized Loewe null model for prediction of the modelled combined effect compatible with partial agonism and antagonism.” Scientific reports 7.1 (2017): 1-9 and Thas, Olivier, et al. “Statistical detection of synergy: New methods and a comparative study.” Pharmaceutical Statistics 21.2 (2022): 345-360. The methodology described herein below was adapted from the Van der Borght, et al. Null models of no synergy Occupancy Define the occupancy level occup, i.e. the fractional (enzymatic) effect or observed effect relative to maximal effect, for both compounds A and B at given dose levels as Alternatively, the to express dose in terms of occupancy so that Although the occupancy was considered here in the marginal case, it is equally well- defined when compounds are combined and is understood as the fraction of enzyme bound to any compound. It can thus be used to re-express classical Loewe additivity equations. Classical Loewe model In the classical Loewe model where both marginal models share upper (m) and lower (b) asymptotes, occupancy was defined as the solution to this additivity equation for eachdose combination (d1,d2), namely Once occupancy is computed, in the classical Loewe model the response at dose combination (d1,d2) can be calculated to be Generalized Loewe model extends the classical Loewe model by allowing compounds to have different upper asymptotes so that when adjusted, the above response is written instead as In Highest Single Agent A null model based on the Highest Single Agent (HSA) model does not attempt to model interaction effects at all and the modelled effect of a combination is either the minimum (if marginal curves are decreasing) or the maximum (if marginal curves are increasing) of both monotherapy curves. Bliss independence model Bliss independence implies that two agents do not cooperate, i.e. act independently of each other. Additionally, the assumption is that a decreasing monotherapy curves express the fractions of unaffected control populations, while increasing curves express the fractions of affected control populations. Bliss independence model was formulated for the fractional responses f (“fraction affected”), where the modelled response f12at dose combination (d1,d2) is defined as: with In the classical share baseline and maximum response. To allow the compounds to have different maximal responses, the fractional responses are rescaled to the maximum range (i.e. absolute difference between baseline and maximal response). Then the modelled response is defined as: where mmax This both compounds with decreasing and increasing monotherapy profiles. However using one compound with a decreasing profile and another with an increasing profile in combination is not supported. Alternative Loewe Generalization An alternative generalization of Loewe Additivity for the case of different asymptotes can be defined as a combination of Loewe and HSA approaches as follows: In a classical Loewe equation, predicted response y at a given dose combination (d1,d2) can be found by solving the equation: where i = 1,2 is the dose of the i-th compound that gives defined only if y is between b and mi. For the case of different asymptotes, say when y>m1(increasing curve) or y<m1(decreasing curve), it was set , so that the y is determined from the equation d2= D2(y), replicating what was done in the HSA approach. Calculation procedure In order to evaluate any of the null models described above, the fitSurface function will use the monotherapy parameter estimates from the previous step. The idea is if there are synergistic or antagonistic effects, then administration of both compounds will lead to important deviations from what combined monotherapy data would suggest according to the null model. Routines within fitSurface function do essentially the following. 1. Find occupancy for each combination of doses by solving the additivity equation of the classical Loewe model. This step does not require knowledge of the baseline or maximal response for either of the compounds. Occupancy solution is also reported in the HSA model case although occupancy plays no role in such a model. 2. Compute the modelled response based on the above described response equations and the previously computed occupancy rate for each dose combination. 3. If desired, the function will then calculate the selected statistic to evaluate the deviation of the modelled response from the desired null model. Synergy evaluation assuming equal variances for on- and off-axis points Synergy was evaluated for all off-axis dose combinations, i.e. dose combinations that were not used in the monotherapy curve estimation. Synergy evaluation depends on the underlying null model and any of the above models, i.e. generalized or classical Loewe or Highest Single Agent, can be used for this purpose. Here is provided a brief summary of both statistical tests. Technical derivations and further details are available in the article cited hereinabove. To define test statistics, the following notations were used. o Let yij be the observed effect for replicate j of dose combination i, so that y11,y12,y13,y21,...,yknkis a set of observed effects. k different dose combinations and nkreplicates for each combination are assumed. The number of different off-axis dose combinations was denoted as n1. o p1,...,pkare the modelled responses for the k off-axis dose combinations. o σ2is the variance of the replicate observations, assumed to be constant over all dose combinations, and estimated by taking MSE of the null model. o df0is the number of degrees of freedom from the marginal model estimation. A vector R =(r1,...,rk) was constructed which represents mean deviation from the modelled effect. In particular, With the help of of R can be estimated under the null hypothesis of no synergy so that Var(R) = σ2(D+Cp) where D is a diagonal matrix with in the i-th position and Cpis the covariance matrix obtained from bootstrap. The m eanR test will evaluate whether the null model globally fits well the observeddata. It is derived using a lack-of-fit sum of squares technique. In particular, the test statistic is given by Assuming that residuals from model are normally distributed, it can be shown that this statistic follows an distribution under the null. If these assumptions are not satisfied, the null distribution can be approximated by bootstrapping. maxR The m axR test evaluates whether the null model locally fits the observed data. Inparticular, it provides a test score for each off-axis combination. Based on the sign of this score, it can be determined whether synergy or antagonism is more likely and a formal test can be constructed. Under the null hypothesis of no lack-of-fit and normally distributed effects, where . More particularly, the test statistic for the k-th off-axis dose (d1,d2) is computed as where indicates the k-th coordinate. This test statistic was then compared either to the null based on normal approximation or a bootstrapped approximation. Synergy in case of variance heterogeneity In the methodology described above one important assumption is made regarding the variance of the on- and off-axis dose combinations. It is considered to be equal across all points. This assumption is also mentioned in the original article and its technical supplement. In reality it is often seen that the variance of the monotherapies is not equal to the variance of the off-axis combinations. The assumption of equal variances is thus not alwaysvalid. That is why the m eanR and m axR test-statistics can also estimate the variances foron-axis (monotherapies) and off-axis dose-combinations separately. Two extra methodsare described below: the unequal method (Separated variance) and the m odel method(Modelled variance). For both methods replicates are required and no variance-stabilizing transformations are required. The latter is often necessary when assuming equal variances. Adapted meanR The adapted m eanR test uses two separate variance estimates for (a) themonotherapies (= ) and (b) the dose combinations (= Σ1, a diagonal matrix). Thenotation for both as m odel will be the same, but the estimation of Σ1 will bedifferent. The variance of the monotherapies was estimated as σ2above by taking the MSE of the null model. The test statistic is by: 1. unequal is estimated by taking the variance in each dose combination and then taking the mean of all these variances, thus . The downside of this method is that the variance for all combinations is to be equal. In reality the variance often depends on the mean effect. This is taken into account in the m odel method.2. m odel method: In this method the diagonal elements of Σ1 are no longer estimatedas single number but rather as a vector of variances. Each off-axis point has now its own variance. A linear model is fitted on the original dataset, modelling the variance of each off-axis point as a function of its mean effect. The estimated model parameters are then used to model the variance for the corresponding mean effect measured for that dose combination. These modelled variances are placed in the diagonal of Σ1. Modelling the variance with a linear model may require a transformation, to achieve a better fit and to avoid negative variances being modelled. A log-transformation often makes a good impression.Adapted m axRThe same approach was taken for the adapted m axR test statistic. Instead of usingone estimated variance for both on- and off-axis points, two separate estimates were used.The estimates for Σ1 are different depending on the method used (unequal or m odel). Themethodology of estimating the variance was the same as was described in the“Adapted m eanR” section above.The m axR test becomes where . axis dose combination as where indicates the k-th coordinate. under unequal variances In case of the unequal variance assumption, the bootstrap proceeds as before, withthe off-axis residuals being pooled and resampled. With the m odel assumption, theresampling is more complicated, as the residuals are no longer exchangeable. One option is to rescale the observed residuals according to the mean-variance model (i.e. dividing them by their standard deviations), resample from this pool of standardized residuals, and then scale back to the true variance (by multiplying by the standard deviation). Yet this approach has proven to be unstable as it leads to extreme observations. An alternative (the default) is to generate zero-mean normal data with the modelled variances (see the rescaleResids argument in fitSurface()). Effect size for off-axis points Confidence intervals for two types of effect sizes were developed. The first is a pointwise effect size, which is defined at every off axis point as the difference between the true mean response and the modelled response under additivity. It is estimated as with j = 1,...,ni, for every off-axis point i = 1,...,n1, whereby a all off-axis points of 95% was striven to be achieved. Confidence interval Let denote the true effect size on off axis point i, and call Eiits estimate based on the on the asymptotic normality of the estimator, an approximate (asymptotic) interval would be formed as the set: with the estimated error Ei, 1 − α / 2 quantile of the standard normal distribution. We know, however, from the meanR and maxR tests that the asymptotic distributions provide poor approximations. Therefore, we use the bootstrap here too to build the confidence intervals. For every bootstrap instance, bootstrap observations are sampled for on- as well as off axis points. For the on-axis points, a parametric bootstrap based on the estimated monotherapy curves is used, as for the calculation of the meanR and maxR statistics. Based on these on-axis bootstrap samples, new monotherapy curves are fitted with resulting residual variances bootstrap variance , and corresponding response surfaces with modelled are derived. For the off-axis points, with ni replicates at a given point, are the pointwise residuals j = 1,...,ni. Here is the observed outcome and , the average outcome at point i, an estimator of the true response. Note that these residuals are different from the residuals used to construct the test statistics; for the departure with respect to the mean outcome at that off-axis point is used. These residuals are resampled with replacement from the observed residuals, possibly using rescaling as explained below. The resampled residuals are then added to the estimated effect sizes to obtain bootstrapped observations , with b = 1,...,B denoting the bootstrap instance. option of using the wild bootstrap is also available. In this method, a new response variable is calculated by multiplying the sampled residuals Ri with yet another random variable so that the bootstrapped observations are given by Where are with mean zero and variance 1, and can be sampled from a normal, gamma, rademacher or two-point distributions. This leads to the bootstrap effect sizes and test statistics from the bootstrap. distribution of Call the threshold such that Finally, we find for every interval as the collection: Standard error As an estimate of the standard error used With equal to , depending on which variance model is used. This estimators of the meanR and maxR statistics By using only the diagonal elements of , we ignore the covariance between test statistics. The studentised-range concept is also central to Tukey’s method for multiple testing) was used for controlling the wise error rate (FWER) as default. Other available options are false coverage rate (FCR) and directional false coverage rate (dFCR). For the covariance matrix Cpthe one estimated for the observed data was used. This matrix turns out to be quite stable over the bootstrap runs; moreover the calculation of the matrix for each bootstrap sample would imply a time-consuming nested bootstrap procedure. On the other hand, was re-estimated with each bootstrap sample. Also was re- estimated bootstrapped data. Single effect measure To calculate a single measure for the strength of the synergy for a single experiment, e.g. in order to be able to rank compound combinations according to their synergistic effect. The average of the pointwise off-axis effect sizes is calculated. This is estimated as . It may be considered as a measure of the response surfaces, similar to the “integrated synergy” of . Confidence interval The construction of the bootstrap confidence interval for the single effect size follows the general procedure for bootstrap-t confidence intervals. Let F denote the estimated covariance matrix of the raw residuals as before. Using Equation in the main text and the fact that the standard error of bootstrapped data for on- and off-axis points for bootstrap and the corresponding mean residual and standard error and are calculated. Then define the statistic Noting that relies on the bootstrap covariance matrix Fb. Making the quantiles of distribution such that Finally, the On resampling residuals Depending on the mean-variance structure in the data, residuals are resampled differently. The same strategies are used for resampling 1) residuals with respect to the modelled response surface under the null hypothesis for the meanR and maxR statistics as for 2) residuals with respect to the average at the off-axis point under the alternative hypothesis for constructing the confidence intervals. In the description below, is used as generic notation for either or .In case of constant variability within the off-axis points, the residuals can simply be pooled and resampled with replacement. When a linear mean-variance structure is assumed, one option is to rescale the pointwise residuals first , then pool and resample them, and then scale them back to according to their new position i. Yet in practice this leads to destabilizes the fitting procedure. A second option is to use random draws from a zero-mean normal distribution with the modelled variance to generate new . This latter option was found to be more stable 1. Synergy JNJ-64281802 and NITD-688 Using the antiviral test described hereinabove, Compound A (i.e. JNJ-64281802) and Compound B (i.e. NITD-688) were tested individually as monotherapy to determine their individual EC50: EC50of 64281802 = 4.6089084^{-5} μM EC50of NITD-688 = 0.0855433 μM These values were used to determine the compound concentrations ranges used in the synergy test (see Table 1). Table 1. Compound A Compound B (µM) (µM) 0.000000 0.000000 0.000005 0.009766 0.000010 0.019531 0.000020 0.039062 0.000039 0.078125 0.000078 0.156250 0.000156 0.312500 0.000312 0.625000 0.000625 1.250000 0.001250 2.500000 The data obtained from the antiviral tests were analysed using four different models: Highest Single Agent (HSA), Bliss Independence, Generalized Loewe and Alternative Loewe. Results for effect sizes using the HSA model are shown on Table 2 and Figure 1. A call is given for each dose combination of the compounds. Here Syn indicates points found to be synergistic, Ant points found to be antagonistic. Table 2. Compound A_Compound B estimate lower upper call (µM) 1e-05_0.078125 0.169 0.019 0.320 Syn 2e-05_0.039062 0.281 0.128 0.434 Syn 2e-05_0.078125 0.325 0.193 0.457 Syn 3.9e-05_0.019531 0.232 0.081 0.382 Syn 3.9e-05_0.039062 0.356 0.219 0.492 Syn 3.9e-05_0.078125 0.459 0.350 0.568 Syn 3.9e-05_0.15625 0.118 0.007 0.229 Syn 7.8e-05_0.039062 0.117 0.004 0.230 Syn 7.8e-05_0.078125 0.121 0.008 0.233 Syn Results for effect sizes using the Bliss Independence model are shown in Table 2 and Figure 3. A call is given for each dose combination of the compounds. Here Syn indicates points found to be synergistic, Ant points found to be antagonistic. Table 3. Compound A_Compound B estimate lower upper call (µM) 1e-05_0.078125 0.164 0.018 0.310 Syn 2e-05_0.039062 0.218 0.054 0.382 Syn 2e-05_0.078125 0.284 0.154 0.415 Syn 3.9e-05_0.019531 0.223 0.078 0.368 Syn 3.9e-05_0.039062 0.301 0.165 0.438 Syn 3.9e-05_0.078125 0.263 0.160 0.366 Syn Results for effect sizes using the Generalized Loewe model are shown in Table 4 and Figure 3. A call is given for each dose combination of the compounds. Here Syn indicates points found to be synergistic, Ant points found to be antagonistic. Table 4. Compound A_Compound B estimate lower upper call (µM) 3.9e-05_0.078125 0.104 0.018 0.19 Syn Results for effect sizes using the Alternative Loewe are shown in Table 5 and Figure 5. A call is given for each dose combination of the compounds. Here Syn indicates points found to be synergistic, Ant points found to be antagonistic. Table 5. Compound A_Compound B estimate lower upper call (µM) 3.9e-05_0.078125 0.105 0.02 0.19 Syn Toxicity was below 30% throughout all experiments. Synergy between Compound A and Compound B was observed at a concentration of 3.9e- 05 µM Compound A and 0.078125 µM Compound B according to the four different models: Highest Single Agent (HSA), Bliss Independence, Generalized Loewe and Alternative Loewe. Some models found additional concentration combinations of Compound A and Compound B to be synergistic too. Example 2. Synergy between JNJ-A07 and NITD-688 Using the antiviral test described hereinabove, Compound A (i.e. JNJ- A07) and Compound B (i.e. NITD-688) were tested individually as monotherapy to determine their individual EC50: EC50of JNJ-A07 = 1.5815215^{-4} μM. EC50of NITD-688 = 0.1343758 μM. These values were used to determine the compound concentrations ranges used in the synergy test (see Table 6). Table 6. Compound A Compound B (µM) (µM) 0.000000 0.000000 0.000010 0.009766 0.000020 0.019531 0.000039 0.039062 0.000078 0.078125 0.000156 0.156250 0.000312 0.312500 0.000625 0.625000 0.001250 1.250000 0.002500 2.500000 The data obtained from the antiviral tests were analysed using four different models: Highest Single Agent (HSA), Bliss Independence, Generalized Loewe and Alternative Loewe. Results for effect sizes using the HSA model are shown on Table 7 and Figure 5. A call is given for each dose combination of the compounds. Here Syn indicates points found to be synergistic, Ant points found to be antagonistic. Table 7. Compound B_Compound A estimate lower upper call (µM) 0.019531_0.000156 0.226 0.073 0.380 Syn 0.019531_7.8e-05 0.155 0.005 0.304 Syn 0.039062_0.000156 0.368 0.215 0.521 Syn 0.039062_3.9e-05 0.166 0.021 0.312 Syn 0.039062_7.8e-05 0.356 0.206 0.506 Syn 0.078125_0.000156 0.476 0.323 0.630 Syn 0.078125_1e-05 0.153 0.000 0.306 Syn 0.078125_3.9e-05 0.326 0.173 0.479 Syn 0.078125_7.8e-05 0.597 0.444 0.750 Syn 0.15625_0.000156 0.428 0.273 0.583 Syn 0.15625_2e-05 0.162 0.007 0.317 Syn 0.15625_3.9e-05 0.286 0.131 0.441 Syn 0.15625_7.8e-05 0.404 0.249 0.559 Syn Results for effect sizes using the Bliss Independence model are shown in Table 8 and Figure 6. A call is given for each dose combination of the compounds. Here Syn indicates points found to be synergistic, Ant points found to be antagonistic. Table 8. Compound B_Compound A estimate lower upper call (µM) 0.019531_0.000156 0.225 0.071 0.379 Syn 0.019531_7.8e-05 0.153 0.002 0.303 Syn 0.039062_0.000156 0.359 0.205 0.512 Syn 0.039062_3.9e-05 0.158 0.012 0.304 Syn 0.039062_7.8e-05 0.339 0.188 0.490 Syn 0.078125_0.000156 0.408 0.253 0.563 Syn 0.078125_3.9e-05 0.318 0.164 0.472 Syn 0.078125_7.8e-05 0.526 0.368 0.684 Syn 0.15625_0.000156 0.218 0.068 0.368 Syn 0.15625_2e-05 0.162 0.007 0.316 Syn 0.15625_3.9e-05 0.282 0.127 0.437 Syn 0.15625_7.8e-05 0.368 0.213 0.523 Syn Results for effect sizes using the Generalized Loewe model are shown in Table 9 and Figure 7. A call is given for each dose combination of the compounds. Here Syn indicates points found to be synergistic, Ant points found to be antagonistic. Table 9. Compound B_Compound A estimate lower upper call (µM) 0.039062_0.000156 0.178 0.029 0.326 Syn 0.039062_7.8e-05 0.150 0.004 0.297 Syn 0.078125_0.000156 0.168 0.021 0.315 Syn 0.078125_7.8e-05 0.212 0.066 0.358 Syn 0.15625_7.8e-05 0.161 0.014 0.308 Syn Results for effect sizes using the Alternative Loewe are shown in Table 10 and Figure 8. A call is given for each dose combination of the compounds. Here Syn indicates points found to be synergistic, Ant points found to be antagonistic. Table 10. Compound B_Compound A estimate lower upper call (µM) 0.039062_0.000156 0.178 0.029 0.326 Syn 0.039062_7.8e-05 0.150 0.003 0.297 Syn 0.078125_0.000156 0.168 0.020 0.315 Syn 0.078125_7.8e-05 0.212 0.066 0.358 Syn 0.15625_7.8e-05 0.161 0.014 0.308 Syn Toxicity was below 30% throughout all experiments. Synergy between Compound A and Compound B was observed according to the four different models (Highest Single Agent (HSA), Bliss Independence, Generalized Loewe and Alternative Loewe) at the concentrations: indicated in Table 11. Table 11 Compound B_Compound A estimate lower upper call (µM) 0.039062_0.000156 0.178 0.029 0.326 Syn 0.039062_7.8-e-05 0.150 0.004 0.297 Syn 0.078125_0.000156 0.168 0.021 0.315 Syn 0.078125_7.8e-05 0.212 0.066 0.258 Syn

Claims

CLAIMS 1. A combination comprising Compound A and Compound B, wherein - Compound A is a compound of formula (I) (I) wherein:R1is H, R2is F and R3is H or CH3, R1is H, CH3or F, R2is OCH3and R3is H, R1is H, R2is OCH3and R3is CH3, R1is CH3, R2is F and R3is H, R1is CF3or OCF3, R2is H and R3is H, R1is OCF3, R2is OCH3and R3is H, R1is OCF3, R2is H and R3is CH3; or a stereo-isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof; or Compound A is a compound of formula (I’) (I’) wherein:R1’is chloro or fluoro, R2’ is hydrogen, R3’ is trifluoromethyl, and R4’is hydrogen; or R1’ is chloro or fluoro, R2’ is hydrogen, R3’ is trifluoromethoxy, and R4’is hydrogen; orR1’ is chloro, R2’ is hydrogen, R3’ is trifluoromethyl, and R4’is methoxy; or R1’ is chloro, R2’ is methoxy, R3’ is trifluoromethyl, and R4’is hydrogen; or R1’ is chloro, R2’ is methoxy, R3’ is trifluoromethyl, and R4’is methoxy; or R1’ is chloro, R2’ is methoxy, R3’ is trifluoromethoxy, and R4’is hydrogen; or R1’ is chloro, R2’ is fluoro, R3’ is trifluoromethyl, and R4’is hydrogen; or R1’ is chloro, R2’ is fluoro, R3’ is trifluoromethoxy, and R4’is hydrogen; or R1’ is chloro, R2’ is fluoro, R3’ is trifluoromethyl, and R4’is methoxy; or R1’ is chloro, R2’ is hydrogen, R3’ is trifluoromethoxy, and R4’is methoxy; or a stereo-isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof; and - Compound B is: a stereo-isomeric form, a pharmaceutically2. The combination according to claim 1, wherein Compound A is a compound of formula (I); preferably Compound A is a compound of formula (I) having formula: O .

3. The combination according to claim 1, wherein Compound A is a compound of formula (I’); preferably Compound A is a compound of formula (I’) having formula: Cl OMe .

4. the amount ofranges mg mg Compound B ranges from 10 to 2500mg.

5. The combination according to anyone of claims 1 to 4, wherein the ratio by weight of Compound A to Compound B is 1:500 to 1:5000.

6. A pharmaceutical composition comprising the combination according to any one of claims 1 to 5 and at least one pharmaceutically acceptable excipient.

7. A combination according to any one of claims 1 to 5, or a pharmaceutical composition according to claim 6 for use as a medicament.

8. A combination according to any one of claims 1 to 5, or a pharmaceutical composition according to claim 6 for use in the treatment of dengue viral infections.

9. A combination according to any one of claims 1 to 5, or a pharmaceutical composition according to claim 6 for use in the prevention of dengue viral infections in an individual at risk of being infected by Dengue virus.

10. A combination according to any one of claims 1 to 5, or a pharmaceutical composition according to claim 6 for use in the prevention of dengue viral infections in an individual that has been exposed to Dengue virus.

11. The combination for use according to any one of claims 8-10, wherein the amount of Compound A and the amount of Compound B is such that a synergistic antiviral effect against Dengue virus or dengue viral infection is obtained.

12. A kit comprising the combination according to any one of claims 1 to 5, optionally along with at least one pharmaceutically acceptable excipient and instruction manual.

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