2-(4-chloro-2 methoxyphenyl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)amino)-1-(5-(trifluoro¬methoxy)-1h-indol-3-YL)ethanone and pharmaceutical compositions comprising the same

Abstract

The present invention relates to processes with an improved enantiomeric excess of the desired enantiomer of the dengue viral replication inhibitor 2-(4-chloro-2-methoxyphenyl)-2- ((3-methoxy-5-(methylsulfonyl)phenyl)amino)-1-(5-(trifluoro-methoxy)-1H-indol-3-yl)ethan-1-5 one, to polymorphic forms and solvates of (S)-2-(4-chloro-2 methoxyphenyl)-2-((3-methoxy-5- (methylsulfonyl)phenyl)amino)-1-(5-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-one (Compound A), to pharmaceutical compositions comprising said forms, to processes for preparing said forms, and the use of these forms.

Description

2-(4-CHLORO-2-METHOXYPHENYL)-2-((3-METHOXY-5- (METHYLSULFONYL)PHENYL) (5-(TRIFLUOROMETHOXY)-1H-INDOL-3- YL)ETHAN-1-ONE AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME FIELD

[0001] The present invention relates to processes with an improved enantiomeric excess of the desired enantiomer of the dengue viral replication inhibitor 2-(4-chloro- 2-methoxyphenyl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)amino)-1-(5-(trifluoromethoxy)- 1H-indol-3-yl)ethan1-one, to polymorphic forms or solvates of said inhibitor, to pharmaceutical compositions of said forms or solvates, to processes for preparing said forms or solvates, and the use of these forms or solvates. BACKGROUND

[0002] Flaviviruses, which are transmitted by mosquitoes or ticks, cause life-threatening infections in humans, such as encephalitis and hemorrhagic fever. According to the World Health Organization (WHO), 2.5 billion people of which 1 billion children are at risk of dengue virus (DENV) infection (WHO, 2002). To prevent and / or control the disease associated with dengue viral infection, the only available methods at present are mosquito eradication strategies to control the vector. While efforts have been made to develop dengue vaccines, there is still considerable room for improvement. Intervention with a small-molecule dengue viral replication inhibitor presents an important therapeutic opportunity, but no such compound is approved today.

[0003] The dengue viral replication inhibitor 2-(4-chloro-2 methoxyphenyl)-2-((3-methoxy- 5-(methylsulfonyl)phenyl)amino)-1-(5-(trifluoro¬methoxy)-1H-indol-3-yl)ethan-1-one is a chiral indole represented by the following structure:

[0004] This inhibitorcompound 9.

[0005] WO-2016 / 180696, which is incorporated herein by reference in its entirety, described a non-chiral synthesis method of 2-(4-chloro-2 methoxyphenyl)-2-((3-methoxy-5- (methylsulfonyl)phenyl)amino)-1-(5-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-one. WO- 2023 / 274237, which is also incorporated herein by reference in its entirety, described an enantioselective process in which the desired enantiomer of 2-(4-chloro-2 methoxyphenyl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)amino)-1-(5-(trifluoromethoxy)-1H-indol-3-yl)ethan-1- one was separated by means of specific There remains a need for additional procedures that would upgrade the enantiomeric excess of the desired enantiomer. SUMMARY OF THE INVENTION

[0006] To at least partially overcome the problems stated above, the present invention provides processes, compounds, products, and uses as defined in the appended claims.

[0007] A first aspect of the invention is the provision of a process for the preparation of (S)-2-(4-chloro-2 methoxyphenyl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)amino)-1-(5- (trifluoromethoxy)-1H-indol-3-yl)ethan-1-one (also referred herein as compound A, or JNJ- 64281802 or JNJ-1802 or mosnodenvir) represented by the following structure: A comprising the stepsa) separating racemic material from a mixture of racemic material and enantiopure compound A to produce an enantiomerically enriched filtrate, wherein said mixture is in solvent A; b) crystallizing the enantiomerically enriched filtrate to produce enantiopure compound A.

[0008] A second aspect of the invention is the provision of compound A of formula A or acompound A is in amorphous free form characterized by an X-ray powder diffraction pattern as depicted in Figure 19, or in a crystalline form characterized by an X-ray powder diffraction pattern obtained using copper K-α1 X-rays at a wavelength of 1.541 Angstroms, which: comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 10.08, 19.35, 23.73, 24.09, 24.99, 29.57, and 30.72, degrees two theta ± 0.2 degrees two theta; orcomprises one, two, three, or more peaks at diffraction angles selected from the group comprising 7.0, 8.4, 12.2, 16.9, 20.6, and 28.5 degrees two theta ± 0.2 degrees two theta; or comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 9.6, 12.5, 13.3, 13.9, 22.7, 30.2, and 31.5 degrees two theta ± 0.2 degrees two theta; or comprises one, two, or three peaks at diffraction angles selected from the group comprising 10.4, 13.1, and 26.2 degrees two theta ± 0.2 degrees two theta.

[0009] A third aspect of the invention is the provision of a pharmaceutical composition comprising the compound A prepared by the process of the first aspect or the compound A according to the second aspect and one or more pharmaceutically acceptable excipients.

[0010] A fourth aspect of the invention is the provision of a method of treating dengue viral infection in a subject in need thereof comprising administering the compound A prepared by the process of the first aspect or the compound A according to the second aspect or the pharmaceutical composition according to the third aspect to a subject who is infected with a dengue viral infection.

[0011] A fifth aspect of the invention is the provision of the compound A prepared by the process of the first aspect or the compound A according to the second aspect or the pharmaceutical composition according to the third aspect for use in the treatment of dengue viral infection.

[0012] A sixth aspect of the invention is the provision of a method of preventing dengue viral infection in a subject in need thereof comprising administering the compound A prepared by the process of the first aspect or the compound A according to the second aspect or the pharmaceutical composition according to the third aspect to a subject who is at a risk of being infected with a dengue viral infection.

[0013] A seventh aspect of the invention encompasses the compound A prepared by the process of the first aspect or the compound A according to the second aspect or the pharmaceutical composition according to the third aspect for use in the prophylaxis of a dengue viral infection, for example Post Exposure Prophylaxis and Pre Exposure Prophylaxis. BRIEF DESCRIPTION OF THE FIGURES

[0014] Figure 1 represents a graph plotting the X-ray powder diffraction (XRPD) pattern of Form 30 of Compound A (Pattern B).

[0015] Figure 2 represents a graph plotting the IR spectrum of Form 30 of Compound A.

[0016] Figure 3 represents a graph plotting the DSC thermogram of Form 30 of Compound A.

[0017] Figure 4 represents a graph plotting the TGA data of Form 30 of Compound A.

[0018] Figure 5 represents a graph plotting the 1H-NMR spectrum of Form 30 of Compound A.

[0019] Figure 6 represents a graph plotting the XRPD pattern of Form 1 of Compound A (Pattern A).

[0020] Figure 7 represents a graph plotting the DSC thermogram of Form 1 of Compound A.

[0021] Figure 8 represents a graph plotting the IR spectrum of Form 1 of Compound A.

[0022] Figure 9 represents a graph plotting the TGA data of Form 1 of Compound A.

[0023] Figure 10 represents a graph plotting the1H-NMR spectrum of Form 1 of Compound A.

[0024] Figure 11 represents a graph plotting the XRPD pattern of the acetone solvate of Compound A (Pattern C).

[0025] Figure 12 represents a graph plotting the DSC thermogram of the acetone solvate of Compound A.

[0026] Figure 13 represents a graph plotting the TGA thermogram of the acetone solvate of Compound A.

[0027] Figure 14 represents a graph plotting the1H-NMR spectrum of the acetone solvate of Compound A.

[0028] Figure 15 represents a graph plotting the XRPD pattern for the isopropyl alcohol (IPA) solvate of Compound A (Form 2) (Pattern D).

[0029] Figure 16 represents a graph plotting the DSC thermogram for the IPA solvate of Compound A (Form 2).

[0030] Figure 17 represents a graph plotting the TGA thermogram for the IPA solvate of Compound A (Form 2).

[0031] Figure 18 represents a graph plotting the1H-NMR spectrum for the IPA solvate of Compound A (Form 2).

[0032] Figure 19 represents a graph plotting the XRPD pattern for the amorphous free from of Compound A obtained from 1,4-dioxane.

[0033] Figure 20 represents a graph plotting the DSC thermogram for the amorphous free from of Compound A obtained from 1,4-dioxane.

[0034] Figure 21 represents a graph plotting the TGA thermogram for the amorphous free from of Compound A obtained from 1,4-dioxane.

[0035] Figure 22 represents a graph plotting the1H-NMR data for the amorphous free from of Compound A obtained from 1,4-dioxane. DESCRIPTION OF THE INVENTION

[0036] 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 beappreciated that certain features of the disclosed processes, compounds, pharmaceutical products, methods, and uses which are, described herein in the context of separate aspects, may also be provided in combination in a single aspect. Conversely, various features of the disclosed processes, compounds, pharmaceutical products, methods, and uses that are, for brevity, described in the context of a single aspect, may also be provided separately or in any sub-combination.

[0037] 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.

[0038] As used herein, the singular forms "a", "an", and "the" include both singular and plural referents unless the context clearly dictates otherwise. By way of example, "a compound" means one compound or more than one compound.

[0039] 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, 5 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.

[0040] 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 in their entirety.

[0041] In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects 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 indicated as being preferred or advantageous.

[0042] 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.

[0043] Pure stereoisomeric forms of the compounds as mentioned herein are defined as isomers substantially free of other or diastereomeric forms of the same basic molecular structure of said compounds. In particular, the term “stereoisomerically pure” concerns compounds having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e.100% of one isomer and none of the other), more in particular, compounds having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms “enantiopure or enantiomerically pure” and “diastereomerically pure” should be understood in a similar way, but then having regard to the enantiomeric excess, respectively the diastereomeric excess of the mixture in question.

[0044] As used herein and unless otherwise stated, the term “solvate” includes any combination which may be formed by Compound A with a suitable inorganic solvent (e.g., hydrates) or organic solvent. Preferred statements (features) and embodiments of the compounds, processes, methods, compositions, and uses of this 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 features or statements 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 statements and embodiments, with any other aspect and / or embodiment. 1. The present invention encompasses a process for the preparation of (S)-2-(4-chloro-2 methoxyphenyl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)amino)-1-(5-(trifluoromethoxy)- 1H-indol-3-yl)ethan-1-one (Compound A): A comprising the stepsa) separating racemic material from a mixture of racemic material and enantiopure Compound A to produce an enantiomerically enriched filtrate, wherein said mixture is in solvent A; b) crystallizing the enantiomerically enriched filtrate to produce enantiopure compound A.2. In some embodiments of the process of statement 1, step a) further comprises: a1) precipitating the racemic produce a solid racemic material via one or both of: i) solvent switch the mixture from solvent A to solvent B ii) addition of an anti-solvent; and a2) removing the solid racemic material via filtration. 3. In some embodiments of the process of statement 2, solvent B is a solvent in which a solubility ratio of a solubility of the enantiopure Compound A in solvent B at 25°C (Solubilityenantiopure) to a solubility of the racemic material in solvent B at 25 °C (Solubilityracemic) is at least 4: ௌ^^௨^^^^௧௬^^ೌ^^^^^ೠ^^ௌ^^௨^^^^௧௬^ೌ^^^^^ ^ 4.4. of the process of any one of statements 2-3, solvent B is selectedmethyl ethyl ketone (MEK), dimethyl sulfoxide (DMSO), 1,4- dioxane, dimethylacetamide (DMAc), THF, and cyclohexanone. 5. In some embodiments of the process of any one of statements 2-4, solvent B is selected from the group comprising MEK, THF, and 1,4-dioxane. 6. In some embodiments of the process of any one of statements 2-5, solvent B is MEK or THF. 7. In some embodiments of the process of any one of statements 2-6, solvent B is MEK. 8. In some embodiments of the process of any one of statements 2-6, solvent B is THF. 9. In some embodiments of the process of any one of statements 2-8, step a1) comprises precipitating the racemic material to produce a solid racemic material via addition of an anti-solvent. 10. In some embodiments of the process of any one of statements 2-8, step a1) comprises precipitating the racemic material to produce a solid racemic material via a solvent switch, and the solvent switch comprises: I) concentrating the mixture in solvent A at a temperature of between 20-50 °C; II) adding solvent B; and III) optionally, repeating steps I) to II) one, two, three, four, five or six times until solvent A is removed to <18.0 wt% based on the total weight of the solvent mixture, as determined by headspace gas chromatography as described in the Example section. 11. In some embodiments of the process of statement 10, the step of concentrating the mixture in solvent A is carried out at a temperature between 21-47 °C; preferably at a temperature of between 22-45 ºC. 12. In some embodiments of the process of any one of statements 10-11, step II) comprises adding 1.5V (V=volume) to 15.0V of solvent B, wherein V is referenced on the content ofcompound A in the mixture; preferably adding from 2.0 to 14.0 V of solvent B; preferably adding from 2.5 to 13.0 V of solvent B; adding from 3.0 to 13.5 V of solvent B. In some embodiments of the process of any one of statements 10-12, steps I) and II) are repeated one, two, three, four, five or six times until solvent A is removed to <17.0 wt% based on the total weight of the solvent mixture; preferably solvent A is removed to <16.0 wt%; preferably solvent A is removed to <10.0 wt%; preferably solvent A is removed to <5.0 wt% based on the total weight of the solvent mixture, as determined by headspace gas chromatography as described in the Example section. In some embodiments of the process of any one of statements 10-13, the solvent switch further comprises: IV) concentrating the mixture in solvent B to 0.5V - 8.0V, wherein V is referenced on the content of compound A in the mixture. In some embodiments of the process of any one of statements 10-14, the solvent switch further comprises: IV) concentrating the mixture in solvent B to 0.8V – 7.5V, wherein V is referenced on the content of compound A in the mixture; preferably solvent B is concentrated to 1.0V – 7.0V; preferably solvent B is concentrated to 1.5V – 6.7V. In some embodiments of the process of any one of the preceding statements, step b) comprises crystallization of the enantiomerically enriched filtrate with an anti-solvent to produce enantiopure compound A. In some embodiments of the process of any one of the preceding statements, step b) comprises adding seeds of enantiopure compound A. In some embodiments of the process of any one of statements 16-17, the anti-solvent is selected from the group comprising n-heptane, methanol, water, cyclopentanone, dichloromethane, n-hexane, ethyl acetate, isopropyl alcohol, propyl, polyethylene glycol 400 and a mixture thereof, preferably from the group comprising n-heptane, methanol, water, and a mixture thereof. In some embodiments of the process of statement 18, the anti-solvent is n-heptane. In some embodiments of the process of any one of statements 16-19, comprise adding 0.1-1.50 V of n-heptane; adding -1-8 wt% seeds of enantiopure compound A based on the amount of enantiopure compound A in the filtrate; and adding 8.0 – 30.0 V of n-heptane; wherein V is referenced on the content of compound A in the enantiomerically enriched filtrate. In some embodiments of the process of any one of statements 16-18, the anti-solvent is methanol. In some embodiments of the process of statement 21, comprise adding 1.0-6.0V of methanol; adding 1-8 wt% seeds of enantiopure compound A based on the amount ofenantiopure compound A in the filtrate; and adding 7.0-13.5 V of methanol; wherein V is referenced on the content of the enantiomerically enriched filtrate. 23. In some embodiments of the process of statement 21, comprise adding 4.0-15.0 V of methanol, wherein V is referenced on the content of compound A in the enantiomerically enriched filtrate. 24. In some embodiments of the process of any one of statements 16-18, the anti-solvent is water. 25. In some embodiments of the process of any one of statements 16-18, the anti-solvent is a mixture of methanol and water. 26. In some embodiments of the process of any one of statements 16-19, 21, 24, 25, the ratio by volume (V / V ratio) of solvent B to the anti-solvent ranges from 1:30 to 10:7; preferably from 1.5:28 to 8:6; preferably from 2:27 to 7:5; preferably from 2.5:26.5 to 7:5; preferably from 2.5:25.5 to 6:5; preferably from 1:1 to 1:6, preferably from 1:2 to 1:4. 27. In some embodiments of the process of statement 25, comprise adding 2.0-15.0 V methanol; adding 1-8 wt% seeds of enantiopure compound A based on the amount of enantiopure compound A in the filtrate; and adding more than 0 to 12.0 V water; wherein V is referenced on the content of compound A in the enantiomerically enriched filtrate. 28. In some embodiments of the process of statement 25, comprise adding 2.0-7.0 V methanol; adding 1-8 wt% seeds of enantiopure compound A based on the amount of enantiopure compound A in the filtrate; adding 0.15-5.0 V water; and adding 7.0-13.5 V methanol, wherein V is referenced on the content of compound A in the enantiomerically enriched filtrate. 29. In some embodiments of the process of statement 25, comprise adding 2.0-15.0 V methanol; adding 1-8 wt% seeds of enantiopure compound A based on the amount of enantiopure compound A in the filtrate; and adding 0.15-7.0 V water, wherein V is referenced on the content of compound A in the enantiomerically enriched filtrate. 30. In some embodiments of the process of statement 25, comprise adding 1-8 wt% seeds of enantiopure compound A based on the amount of enantiopure compound A in the filtrate; adding 4.0-15.0 V methanol; and adding 0.15-7.0 V water, wherein V (volume) is referenced on the content of compound A in the enantiomerically enriched filtrate. 31. In some embodiments of the process of statement 25, a MEK:MeOH:water ratio by volume ranging from 1:1:0.2 to 1:3:3, preferably from 1:1:1 to 1:1:2, preferably from 1:1:1 to 1:3:1, or preferably from 1:1:0.2 to 1:3:0.5 is used. 32. In some embodiments of the process of statement 9, said process further comprises: I. concentrating the mixture in solvent A at a temperature of between 20-50 °C; II. adding 0.01-5.0 V of the anti-solvent to precipitate the racemic material; III. filtering the precipitate off.33. In some embodiments of the process of statement 32, the anti-solvent is selected from the group comprising n-heptane, methanol, water, cyclopentanone, dichloromethane, n- hexane, ethyl acetate, isopropyl alcohol, propyl, polyethylene glycol 400 and a mixture thereof, preferably from the group comprising n-heptane, methanol, water, and a mixture thereof. 34. In some embodiments of the process of statement 32, the anti-solvent is n-heptane. 35. In some embodiments of the process of any one of statements 32-34, the step of concentrating the mixture in solvent A is carried out at a temperature between 21-47 °C; preferably at a temperature of between 22-45 ºC. 36. In some embodiments of the process of any one of statements 32-34, step b) comprises crystallization of the enantiomerically enriched filtrate with an anti-solvent to produce enantiopure compound A. 37. In some embodiments of the process of statement 36, the anti-solvent is selected from the group comprising n-heptane, methanol, water, cyclopentanone, dichloromethane, n- hexane, ethyl acetate, isopropyl alcohol, propyl, polyethylene glycol 400 and a mixture thereof. 38. In some embodiments of the process of statement 37, the anti-solvent is n-heptane. 39. In some embodiments of the process of statement 38, comprise adding 2.0 – 13.0 V of n- heptane; wherein V is referenced on the content of compound A in the enantiomerically enriched filtrate. 40. In some embodiments of the process of any one of statements 32-39, step b) comprises adding seeds of enantiopure compound A. 41. In some embodiments of the process of any one of the preceding statements, step b) comprises cooling the enantiomerically enriched filtrate to -5 to 5 °C. 42. In some embodiments of the process of any one of the preceding statements, the mixture of racemic material and enantiopure Compound A is treated with activated carbon prior to step a). 43. In some embodiments of the process of any one of the preceding statements, the enantiopure compound A has an enantiomeric excess greater than 99%. 44. In some embodiments of the process of any one of the preceding statements, the yield of enantiopure compound A is greater than 70%. 45. In some embodiments of the process of any one of the preceding statements, enantiopure compound A is a crystalline form of Compound A designated as Form 30, characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, or more peaks at diffraction angles selected from the group comprising 10.08, 19.35, 23.73, 24.09, 24.99, 29.57, and 30.72, degrees two theta ± 0.2 degrees two theta (°2θ ± 0.2° 2θ), with XRPD pattern obtained using copper K-α1 X-rays at a wavelength of 1.541 Angstroms.In some embodiments of the process of any one of the preceding statements, enantiopure compound A is a crystalline form of A designated as Form 30, characterized by an X-ray powder diffraction (XRPD) pattern comprising two, three or more peaks, preferably three or more peaks, preferably four or more peaks, preferably five or more peaks at diffraction angles selected from the group comprising 10.08, 19.35, 23.73, 24.09, 24.99, 29.57, and 30.72, degrees two theta ± 0.2 degrees two theta. In some embodiments of the process of any one of the preceding statements, enantiopure compound A is a crystalline form of Compound A designated as Form 30, characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three or more peaks at diffraction angles selected from the group comprising at 10.08, 23.73, 24.09, 24.99 degrees two theta ± 0.2 degrees two theta (°2θ ± 0.2° 2θ), preferably two, three or more peaks, preferably three or more peaks at 10.08, 23.73, 24.09, 24.99 degrees two theta ± 0.2 degrees two theta (°2θ ± 0.2° 2θ), wherein the XRPD is made using CuKαl radiation. In some embodiments of the process of any one of the preceding statements, enantiopure compound A is a crystalline form of Compound A designated as Form 30, characterized by an XRPD pattern comprising peaks at 7.57, 8.31, 8.89, 9.33, 9.52, 10.08, 10.58, 11.57, 12.04, 12.30, 12.50, 13.57, 14.13, 14.36, 14.74, 15.29, 15.90, 16.34, 16.67, 17.35, 17.57, 17.99, 18.11, 18.75, 19.14, 19.35, 19.58, 20.18, 20.25, 20.44, 20.98, 21.24, 21.58, 21.83, 22.06, 22.52, 23.21, 23.38, 23.73, 24.09, 24.325, 24.54, 24.69, 24.99, 25.60, 25.88, 26.94, 27.24, 27.83, 28.24, 28.97, 29.38, 29.57, 30.27, 30.72, 31.12, 32.16, 33.01, 33.88, and 34.58 degrees two theta ± 0.2 degrees two theta (°2θ ± 0.2° 2θ), wherein the XRPD is made using CuKal radiation. In some embodiments of the process of any one of the preceding statements, enantiopure compound A is in crystalline Form 30 characterized by an X-ray powder diffraction pattern as depicted in Figure 1. In some embodiments of the process of any one of the preceding statements, enantiopure compound A is in crystalline Form 30 characterized by an FTIR spectrum having peaks at 3400, 3292, 3111, 3027, 2943, 1650, 1599, 1582, 1497, 1486, 1456, 1435, 1332, 1281, 1249, 1237, 1222, 1173, 1155, 1120, 1091, 1054, 1026, 1003, 964, 945, 896, 881, 841826, 757, 737, 710, and 657 cm-1± 4 cm-1. In some embodiments of the process of any one of the preceding statements, enantiopure compound A is in crystalline Form 30 characterized by an IR spectrum as depicted in Figure 2. In some embodiments of the process of any one of the preceding statements, enantiopure compound A is in crystalline Form 30 characterized by a DSC thermogram as depicted in Figure 3.In some embodiments of the process of any one of the preceding statements, enantiopure compound A is in crystalline Form 30 by TGA thermogram as depicted in Figure 4. In some embodiments of the process of any one of the preceding statements, enantiopure compound A is in crystalline Form 30 characterized by1H-NMR spectrum as depicted in Figure 5. In some embodiments of the process of any one of the preceding statements, enantiopure compound A is in crystalline Form 30 characterized by an X-ray powder diffraction pattern comprising the peaks indicated below at degrees two theta ± 0.2 degrees two theta, when measured using Cu- Kα (1.541874 Å) radiation. The present invention also encompasses (S)-2-(4-chloro-2 methoxyphenyl)-2-((3- methoxy-5-(methylsulfonyl)phenyl)amino)-1-(5-(trifluoromethoxy)-1H-indol-3-yl)ethan-1- one (Compound A) of formula A or acompound A is in amorphous free form characterized by an X-ray powder diffraction pattern as depicted in Figure 19, or in a crystalline form characterized by an X-ray powder diffraction pattern obtained using copper K-α1 X-rays at a wavelength of 1.541 Angstroms, which: comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 10.08, 19.35, 23.73, 24.09, 24.99, 29.57, and 30.72, degrees two theta ± 0.2 degrees two theta; or comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 7.0, 8.4, 12.2, 16.9, 20.6, 24.8, and 28.5 degrees two theta ± 0.2 degrees two theta; or comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 9.6, 12.5, 13.3, 13.9, 22.7, 30.2, and 31.5 degrees two theta ± 0.2 degrees two theta; or comprises one, two, or three peaks at diffraction angles selected from the group comprising 10.4, 13.1, and 26.2 degrees two theta ± 0.2 degrees two theta. In some embodiments of the compound of statement 56, said compound is crystalline Form 30 of Compound A characterized by an XRPD pattern comprising two, three or more peaks, preferably three or more peaks, preferably four or more peaks, preferably five or morepeaks at 10.08, 19.35, 23.73, 24.09, 24.99, 29.57, 30.72, degrees two theta ± 0.2 degrees two theta. 58. In some embodiments of the compound of any one of statements 56 or 57, said compound is crystalline Form 30 of Compound A characterized by an XRPD pattern comprising one, two, three or more peaks at diffraction angles selected from the group comprising at 10.08, 23.73, 24.09, 24.99 degrees two theta ± 0.2 degrees two theta, preferably two, three or more peaks, preferably three or more peaks at 10.08, 23.73, 24.09, 24.99 degrees two theta ± 0.2 degrees two theta. 59. In some embodiments of the compound of any one of statements 56-58, said compound is crystalline Form 30 of Compound A characterized by an XRPD pattern comprising peaks at 7.57, 8.31, 8.89, 9.33, 9.52, 10.08, 10.58, 11.57, 12.04, 12.30, 12.50, 13.57, 14.13, 14.36, 14.74, 15.29, 15.90, 16.34, 16.67, 17.35, 17.57, 17.99, 18.11, 18.75, 19.14, 19.35, 19.58, 20.18, 20.25, 20.44, 20.98, 21.24, 21.58, 21.83, 22.06, 22.52, 23.21, 23.38, 23.73, 24.09, 24.325, 24.54, 24.69, 24.99, 25.60, 25.88, 26.94, 27.24, 27.83, 28.24, 28.97, 29.38, 29.57, 30.27, 30.72, 31.12, 32.16, 33.01, 33.88, and 34.58 degrees two theta ± 0.2 degrees two theta. 60. In some embodiments of the compound of any one of statements 56-59, said compound is crystalline Form 30 of Compound A characterized by an XRPD pattern comprising as depicted in Figure 1. 61. In some embodiments of the compound of any one of statements 56-60, said compound is crystalline Form 30 of Compound A characterized by an FTIR spectrum having peaks at 3400, 3292, 3111, 3027, 2943, 1650, 1599, 1582, 1497, 1486, 1456, 1435, 1332, 1281, 1249, 1237, 1222, 1173, 1155, 1120, 1091, 1054, 1026, 1003, 964, 945, 896, 881, 841826, 757, 737, 710, and 657 cm-1± 4 cm-1. 62. In some embodiments of the compound of any one of statements 56-60, said compound is crystalline Form 30 of Compound A characterized by an FTIR spectrum as depicted in Figure 2. 63. In some embodiments of the compound of any one of statements 56-60, said compound is crystalline Form 30 of Compound A characterized by a DSC thermogram as depicted in Figure 3. 64. In some embodiments of the compound of any one of statements 56-60, said compound is crystalline Form 30 of Compound A characterized by a TGA thermogram as depicted in Figure 4. 65. In some embodiments of the compound of any one of statements 56-60, said compound is crystalline Form 30 of Compound A characterized by a1H-NMR spectrum as depicted in Figure 5.66. In some embodiments of the compound of statement 56, wherein compound is crystalline Form 1 of Compound A characterized by an XRPD pattern comprising two, three or more peaks, preferably three or more peaks, preferably four or more peaks, preferably five or more peaks at 9.6, 12.5, 13.3, 13.9, 22.7, 30.2, and 31.5 degrees two theta ± 0.2 degrees two theta. 67. In some embodiments of the compound of any one of statements 56, 66, said compound is crystalline Form 1 of Compound A characterized by an XRPD pattern comprising peaks at 5.48, 9.63, 12.53, 13.29, 13.91, 15.94, 16.09, 16.66, 17.75, 17.96, 18.68, 18.78, 19.15, 19.70, 19.83, 20.22, 20.70, 21.03, 21.33, 21.48, 22.43, 22.51, 22.59, 22.69, 23.26, 24.30, 25.39, 25.54, 26.66, 26.76, 27.14, 27.26, 27.99, 28.63, 29.08, 30.07, 30.15, 31.22, 31.50, 32.23, 33.17, 33.60, 34.12, 34.65, 35.05, 36.21, 36.81, 37.79, 38.76, 39.11, 40.23, 41.30, 41.96, 42.11, 43.51, 45.22, 45.90, 46.49, 47.43, 47.80, 48.61, 49.27 degrees two theta ± 0.2 degrees two theta. 68. In some embodiments of the compound of any one of statements 56, 66, 67, said compound is crystalline Form 1 of Compound A characterized by an X-ray powder diffraction pattern A as depicted in Figure 6. 69. In some embodiments of the compound of any one of statements 56, 66- 68, said compound is crystalline Form 1 of Compound A characterized by a DSC thermogram as depicted in Figure 7. 70. In some embodiments of the compound of any one of statements 56, 66- 69, said compound is crystalline Form 1 of Compound A characterized by an FTIR spectrum as depicted in Figure 8. 71. In some embodiments of the compound of any one of statements 56, 66- 70, said compound is crystalline Form 1 of Compound A characterized by a TGA thermogram as depicted in Figure 9. 72. In some embodiments of the compound of any one of statements 56, 66- 71, said compound is crystalline Form 1 of Compound A characterized by a1H-NMR spectrum as depicted in Figure 10. 73. In some embodiments of the compound of statement 56, said compound is a crystalline acetone solvate of Compound A characterized by an XRPD pattern comprising two, or three peaks, preferably comprising three peaks at 10.4, 13.1, 26.2 degrees two theta ± 0.2 degrees two theta. 74. In some embodiments of the compound of any one of statements 56, 73, said compound is a crystalline acetone solvate of Compound A characterized by an XRPD pattern comprising peaks at 7.82, 8.15, 8.92, 10.37, 13.09, 14.33, 15.74, 16.23, 17.95, 19.56, 20.16, 20.72, 21.62, 21.99, 22.64, 26.20, 26.91, 30.04, 35.25, degrees two theta ± 0.2 degrees two theta.75. In some embodiments of the compound of any one of statements 56, 73, 74, said compound is a crystalline acetone of Compound A characterized by an X-ray powder diffraction pattern C as depicted in Figure 11. 76. In some embodiments of the compound of any one of statements 56, 73-75, said compound is a crystalline acetone solvate of Compound A characterized by a DSC thermogram as depicted in Figure 12. 77. In some embodiments of the compound of any one of statements 56, 73-76, said compound is a crystalline acetone solvate of Compound A characterized by a TGA thermogram as depicted in Figure 13. 78. In some embodiments of the compound of any one of statements 56, 73-77, said compound is a crystalline acetone solvate of Compound A characterized by a1H-NMR spectrum as depicted in Figure 14. 79. In some embodiments of the compound of statement 56, said compound is a crystalline form 2 of Compound A characterized by XRPD pattern comprising two, three or more peaks, preferably three or more peaks, preferably four or more peaks, preferably five or more peaks at 7.0, 8.4, 12.2, 16.9, 20.6, 24.8, and 28.5 degrees two theta ± 0.2 degrees two theta. 80. In some embodiments of the compound of any one of statements 56, 79, said compound is a form 2 of Compound A characterized by an XRPD pattern comprising peaks at 7.05, 7.24, 7.56, 8.42, 11.73, 12.19, 13.75, 14.28, 14.68, 15.11, 15.47, 15.89, 16.40, 16.89, 17.52, 18.41, 18.95, 20.59, 21.08, 21.62, 22.28, 22.75, 23.14, 24.76, 25.69, 27.68, 28.20, 28.52, 29.15, 31.88, 32.85, 34.11, 38.14, degrees two theta ± 0.2 degrees two theta. 81. In some embodiments of the compound of any one of statements 56, 79-80, said compound is a form 2 of Compound A characterized by an X-ray powder diffraction pattern D as depicted in Figure 15. 82. In some embodiments of the compound of any one of statements 56, 79-81, said compound is a form 2 of Compound A characterized by a DSC thermogram as depicted in Figure 16. 83. In some embodiments of the compound of any one of statements 56, 79-82, said compound is a form 2 of Compound A characterized by a TGA thermogram as depicted in Figure 17. 84. In some embodiments of the compound of any one of statements 56, 79-83, said compound is a form 2 of Compound A characterized by a1H-NMR spectrum as depicted in Figure 18. 85. In some embodiments of the compound of statement 56, said compound is an amorphous free form of compound A characterized by a DSC thermogram as depicted in Figure 20.86. In some embodiments of the compound of any one of statements 56, 85, said compound is an amorphous free form of by a TGA thermogram as depicted in Figure 21. 87. In some embodiments of the compound of any one of statements 56, 85-56, said compound is an amorphous free form of compound A characterized by a1H-NMR spectrum as depicted in Figure 22. 88. The invention also encompasses a pharmaceutical composition comprising the compound A of any one of statements 56-87 or the compound A prepared by the process of any one of statements 1-55 and one or more pharmaceutically acceptable excipients. 89. The invention also encompasses a method of treating dengue viral infection in a subject in need thereof comprising administering the compound A prepared by the process of any one of statements 1-55 or the compound A of any one of statements 56-87 or the pharmaceutical composition of statement 88 to a subject who is infected with a dengue viral infection. 90. The invention also encompasses a method of preventing dengue viral infection in a subject in need thereof comprising administering the compound A prepared by the process of any one of statements 1-55 or the compound A of any one of statements 56-87 or the pharmaceutical composition of statement 88 to a subject who is at a risk of being infected with a dengue viral infection. 91. The invention also encompasses a compound A prepared by the process of any one of statements 1-55 or the compound A of any one of statements 56-87 or the pharmaceutical composition of statement 88 for use in the treatment or prophylaxis of dengue viral infection in a subject. Polymorphic forms

[0045] Certain compounds can exist in or form different polymorphic forms. As known in the art, polymorphism is an ability of a compound to crystallize as more than one distinct crystalline or "polymorphic" species. A polymorph is one solid crystalline phase of a compound that has at least two different arrangements or polymorphic forms in the solid state. Polymorphic forms of any given compound are defined by the same chemical formula or composition that are distinct in their crystalline structures and typically have different physico- chemical properties. Generally, different polymorphs can be characterized by analytical methods such as X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC), melting point analysis, or other techniques known in the art.

[0046] For the purposes of this disclosure, the terms "crystalline form" and "polymorph" are synonymous. Characterizing information for crystalline forms is provided herein. It shouldbe understood that the determination of a particular form can be achieved using any portion of the characterizing information that one in the art would recognize as sufficient for establishing the presence of a particular form. For example, even a single distinguishing peak can be sufficient for one skilled in the art to appreciate that a particular form is present.

[0047] When a crystalline form is identified using one or more XRPD peaks given as angles 2θ (two theta), each of the 2θ values is understood to mean the given value ± 0.2 degrees, unless otherwise expressed.

[0048] The term “seeding” refers to the addition of crystalline material to a solution or mixture to initiate crystallization or recrystallisation. Seeding material can be obtained by spontaneous crystallization or from previous crystallizations. Preparation Process

[0049] A first aspect of the invention is the provision of a process for the preparation (also referred herein as isolation) of (S)-2-(4-chloro-2 methoxyphenyl)-2-((3-methoxy-5- (methylsulfonyl)phenyl)amino)-1-(5-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-one (compound A) A comprising the stepsa) separating racemic material from a mixture of racemic material and enantiopure compound A to produce an enantiomerically enriched filtrate, wherein said mixture is in solvent A; b) crystallizing the enantiomerically enriched filtrate to produce enantiopure compound A.

[0050] The mixture of racemic material and enantiopure compound A is the starting material for the process described herein. In certain embodiments, this mixture may be formed from pure materials. In certain embodiments, this mixture may be formed after performing certain synthesis steps to form compound A and may be referred to as crude solution. In certain embodiments, the crude solution mixture of racemic material and enantiopure compound A may be derived from any of the synthesis processes for synthesizing compound A, as described in WO-2016 / 180696 or in WO-2023 / 274237, which are incorporated herein by reference in their entirety. In a preferred embodiment, the crude solution mixture of racemic material and enantiopure compound A is derived from an enantioselective synthesis process described in WO-2023 / 274237.

[0051] In some embodiments, the step of separating racemic material from a mixture of racemic material and enantiopure produce an enantiomerically enriched filtrate (step a)) further comprises: a1) precipitating the racemic material to produce a solid racemic material via one or both of: i) a solvent switch the mixture from solvent A to solvent B (wherein solvent A and solvent B are different) ii) addition of an anti-solvent; and a2) removing the solid racemic material via filtration.

[0052] The inventors have surprisingly found that in order to reject the racemic material from the crude solution mixture of racemic material and enantiopure compound A, there has to be a solubility difference between the solubility of the enantiopure form of compound A and the racemic material in a given solvent. In other words, the solvent in which the racemic material may be separated from the mixture, is a solvent in which enantiopure compound A is more soluble than the racemic material. In certain embodiments, a solubility ratio of a solubility of the enantiopure compound A in solvent A at 25°C (Solubilityenantiopure) to a solubility of the racemic material in solvent A at 25 °C (Solubilityracemic) is at least 4:^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^^^^^^ ^^^ ൌௌ^^௨^^^^௧௬ ^^^^௩^^௧ ^^^^ೌ^^^^^ೠ^^ௌ^^௨^^^^௧௬ ^^^^௩^^௧ ^^^ೌ^^^^^ ^ 4.If the solubility ratio in solvent A is at least 4, step a1) may comprise addition of an anti-solvent only. In certain embodiments, a solubility ratio of a solubility of the enantiopure compound A in solvent B at 25°C (Solubilityenantiopure) to a solubility of the racemic material in solvent B at 25 °C (Solubilityracemic) is at least 4: ^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^ ^^^ ^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^^^^^^ ^^^ ൌ ^^^^௧^^^௨^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^ ^^^^ 4^^^^^^^If the switch fromsolvent A to solvent B having a solubility ratio of at least 4.

[0053] In some embodiments solvent B is selected from the group comprising dimethyl methyl ethyl ketone (MEK), sulfoxide (DMSO), 1,4-dioxane, dimethylacetamide (DMAc), tetrahydrofuran (THF), and cyclohexanone. Preferably, solvent B is selected from the group comprising MEK, THF, and 1,4-dioxane; preferably solvent B is MEK or THF.

[0054] In some embodiments the present invention provides a process for the preparation of Compound A comprising the steps of crystallizing Compound A with the addition of an anti- solvent. Preferably the anti-solvent is selected from the group comprising n-heptane, methanol, water, cyclopentanone, dichloromethane, n-hexane, ethyl acetate, isopropyl alcohol, propyl, polyethylene glycol 400 and a mixture thereof. More preferably the anti-solvent is selected from the group comprising n-heptane, methanol, water, and mixtures thereof. Preferably the anti- solvent is n-heptane. Crystallization may comprise cooling from elevated temperature.

[0055] In some embodiments of the present process, the ratio by volume (V / V ratio) of solvent B to anti-solvent is from 1:30 to the ratio by volume of solvent B to anti-solvent is from 1.5:28 to 8:6; preferably the ratio by volume of solvent B to anti-solvent is from 2:27 to 7:5; preferably the ratio by volume of solvent B to anti-solvent is from 2.5:26.5 to 7:5; preferably the ratio by volume of solvent B to anti-solvent is from 2.5:25.5 to 6:5. Preferably, the ratio by volume of solvent B to the anti-solvent ranges from 1:1 to 1:6, preferably from 1:2 to 1:4.

[0056] In some embodiments of the present process, the ratio by volume of solvent B to anti-solvent is from 1:30 to 10:7; preferably the ratio by volume of solvent B to anti-solvent is from 1.5:28 to 8:6; preferably the ratio by volume of solvent B to anti-solvent is from 2:27 to 7:5; preferably the ratio by volume of solvent B to anti-solvent is from 2.5:26.5 to 7:5; preferably the ratio by volume of solvent B to anti-solvent is from 2.5:25.5 to 6:5, preferably from 1:1 to 1:6, preferably from 1:2 to 1:4; and the yield of enantiopure compound A is greater than 50.0%; preferably the yield of enantiopure compound A is greater than 60.0%; preferably the yield of enantiopure Compound A is greater than 65.0%; preferably the yield of enantiopure Compound A is greater than 70.0%.

[0057] In some embodiments of the present process, the ratio by volume of solvent B to anti-solvent is from 1:30 to 10:7; preferably the ratio by volume of solvent B to anti-solvent is from 1.5:28 to 8:6; preferably the ratio by volume of solvent B to anti-solvent is from 2:27 to 7:5; preferably the ratio by volume of solvent B to anti-solvent is from 2.5:26.5 to 7:5; preferably the ratio by volume of solvent B to anti-solvent is from 2.5:25.5 to 6:5; preferably from 1:1 to 1:6, preferably from 1:2 to 1:4; and the chiral purity of enantiopure compound A is greater than 97.0%; preferably the chiral purity enantiopure Compound A is greater than 98.0%; preferably the chiral purity enantiopure Compound A is greater than 98.5%; preferably the chiral purity of enantiopure Compound A is greater than 99.0%.

[0058] In some embodiments of the present process, the mixture of racemic material and enantiopure Compound A is treated with activated carbon prior to step a).

[0059] In some embodiments of the present process, the enantiopure compound A has an enantiomeric excess greater than 97.0%; preferably an enantiomeric excess greater than 98.0%; preferably an enantiomeric excess greater than 99.0%; preferably an enantiomeric excess greater than 99.5%.

[0060] As used herein the term “enantiomeric excess” is used to indicate the degree to which a sample contains one enantiomer in greater amounts than the other. It may be calculated as: ee = (S-R) / (S+R) where S and R are the masses or concentrations of the S and R enantiomers.

[0061] In some embodiments of the present process, the yield of enantiopure compound A is greater than 50.0%; preferably the compound A is greater than 60.0%; preferably the yield of enantiopure compound A is greater than 65.0%; preferably the yield of enantiopure compound A is greater than 70.0%.

[0062] In some embodiments of the present process, the chiral purity of enantiopure compound A is greater than 97.0% by weight, preferably the chiral purity enantiopure compound A is greater than 98.0% by weight, preferably the chiral purity enantiopure compound A is greater than 98.5% by weight, preferably the yield of enantiopure compound A is greater than 99.0% by weight. Enantiopure Compound A – Form 30

[0063] The present invention also encompasses a crystalline form of Compound A designated as Form 30.

[0064] It has surprisingly been found that a certain crystalline form (Form 30) of compound A was very stable and greatly facilitates the purification of the desired enantiomer, allowing manufacture on an industrial scale under GMP conditions. Preferably Compound A in crystalline Form 30 is prepared as described in Example 34.

[0065] The enantiopure Compound A in crystalline Form 30 may be prepared by concentrating the mixture of racemic material and enantiopure Compound A in Solvent A, adding methyl ethyl ketone (MEK), concentrating the mixture at a temperature of between 20- 50 °C, repeating these two steps one, two, three, four, five or six times until Solvent A is removed to <18.0% by weight based on the total weight of the solvent mixture, as determined by headspace gas chromatography as described in the Example section. Then, the resulting suspension may be filtered off to remove the racemate. An anti-solvent may then be added to the filtrate, preferably wherein said anti-solvent is selected from the group comprising n- heptane, methanol, water, cyclopentanone, dichloromethane, n-hexane, ethyl acetate, isopropyl alcohol, propyl, polyethylene glycol 400 and a mixture thereof , more preferably selected from the group comprising n-heptane, methanol, water and mixtures thereof to crystallize enantiopure Form 30 of Compound A.

[0066] Alternatively, enantiopure Compound A in crystalline Form 30 may be prepared by concentrating the mixture of racemic material and enantiopure Compound A in solvent A at a temperature of between 20-50 °C, adding an anti-solvent (for example selected from the group comprising n-heptane, methanol, water, cyclopentanone, dichloromethane, n-hexane, ethyl acetate, isopropyl alcohol, propyl, polyethylene glycol 400 and a mixture thereof, preferably from the group comprising n-heptane, methanol, water, and a mixture thereof), filtering the suspension off to remove the racemate. The filtrate may then be charged with an anti-solvent preferably selected from the group comprising n-heptane, methanol, water, cyclopentanone,dichloromethane, n-hexane, ethyl acetate, isopropyl alcohol, propyl, polyethylene glycol 400 and a mixture thereof; more preferably from the group comprising n-heptane, methanol, water and mixtures thereof, to crystallize Compound A in Form 30.

[0067] In some embodiments enantiopure Compound A in crystalline Form 30 prepared according to the present process has a water content of less than 0.50 weight % by weight based on the total weight of Compound A in crystalline Form 30 as determined by Karl Fischer titration as described in the Example section; preferably a water content of less than 0.40 weight %; preferably a water content of less than 0.30 weight %; preferably a water content of less than 0.20 weight %; preferably a water content of less than 0.10 weight % as determined by Karl Fischer titration as described in the Example section.

[0068] In some embodiments enantiopure Compound A in crystalline Form 30 prepared according to the present process has a methyl ethyl ketone (MEK) content of less than 3500 ppm by weight based on the total weight of Compound A in crystalline Form 30 as determined by headspace gas chromatography as described in the Example section; preferably a MEK content of less than 3300 ppm; preferably a MEK content of less than 3000 ppm; preferably a MEK content of less than 2900 ppm; preferably a MEK content of less than 2800 ppm as determined by headspace gas chromatography as described in the Example section.

[0069] Preferably the crystalline Form 30 of Compound A can be characterized by an X- ray powder diffraction (XRPD) pattern comprising one, two, three, or more peaks at diffraction angles selected from the group comprising 10.08, 19.35, 23.73, 24.09, 24.99, 29.57, and 30.72, degrees two theta ± 0.2 degrees two theta (°2θ ± 0.2° 2θ), (wherein XRPD pattern is obtained using copper K-α1 X-rays at a wavelength of 1.541 Angstroms). In some embodiments, crystalline form 30 of Compound A can be characterized by XRPD pattern comprising two, three or more peaks, preferably three or more peaks, preferably four or more peaks, preferably five or more peaks at 10.08, 19.35, 23.73, 24.09, 24.99, 29.57, 30.72, degrees two theta ± 0.2 degrees two theta.

[0070] Preferably crystalline form 30 of Compound A can be characterized by an XRPD pattern comprising one, two, three or more peaks, preferably two, three or more peaks, preferably three or more peaks at 10.08, 23.73, 24.09, 24.99 degrees two theta ± 0.2 degrees two theta (°2θ ± 0.2° 2θ), wherein the XRPD is made using CuKαl radiation.

[0071] In some embodiments, crystalline form 30 of Compound A can be characterized by an XRPD pattern comprising peaks at 7.57, 8.31, 8.89, 9.33, 9.52, 10.08, 10.58, 11.57, 12.04, 12.30, 12.50, 13.57, 14.13, 14.36, 14.74, 15.29, 15.90, 16.34, 16.67, 17.35, 17.57, 17.99, 18.11, 18.75, 19.14, 19.35, 19.58, 20.18, 20.25, 20.44, 20.98, 21.24, 21.58, 21.83, 22.06, 22.52, 23.21, 23.38, 23.73, 24.09, 24.325, 24.54, 24.69, 24.99, 25.60, 25.88, 26.94, 27.24, 27.83, 28.24, 28.97, 29.38, 29.57, 30.27, 30.72, 31.12, 32.16, 33.01, 33.88, and 34.58 degrees two theta ± 0.2 degrees two theta (°2θ ± 0.2° 2θ), wherein the XRPD is made usingCuKal radiation.

[0072] In some embodiments, in crystalline Form 30 is characterized by an XRPD pattern substantially as depicted in Figure 1 (also referred herein as Pattern B).

[0073] In some embodiments, compound A in crystalline Form 30 is characterized by an FTIR spectrum having peaks at 3400, 3292, 3111, 3027, 2943, 1650, 1599, 1582, 1497, 1486, 1456, 1435, 1332, 1281, 1249, 1237, 1222, 1173, 1155, 1120, 1091, 1054, 1026, 1003, 964, 945, 896, 881, 841, 826, 757, 737, 710, 657 cm-1± 4 cm-1.

[0074] In some embodiments, compound A in crystalline Form 30 is characterized by an FTIR spectrum as depicted in Figure 2.

[0075] In some embodiments, compound A in crystalline Form 30 is characterized by a DSC thermogram as depicted in Figure 3.

[0076] In some embodiments, compound A in crystalline Form 30 is characterized by TGA thermogram as depicted in Figure 4.

[0077] In some embodiments, compound A in crystalline Form 30 is characterized by1H- NMR spectrum as depicted in Figure 5. Other Enantiopure Forms of Compound A

[0078] The present invention also encompasses an amorphous form of Compound A of compound A obtained from 1,4-dioxane.

[0079] In some embodiments the amorphous free form of compound A obtained from 1,4- dioxane can be prepared by dissolving Form 30 of compound A in 1,4-dioxane at 25 ºC, pre- freezing the resulting solution in an ethanol / dry ice mixture, and lyophilizing this mixture for 7 days. Preferably the amorphous free form of compound A is prepared as described in Example 34.

[0080] Additionally, or alternatively, the invention encompasses an enantiopure compound A in amorphous free form obtained from 1,4-dioxane characterized by an X-ray powder diffraction pattern as depicted in Figure 19.

[0081] Additionally, or alternatively, the invention encompasses an enantiopure compound A in amorphous free form obtained from 1,4-dioxane characterized by a DSC thermogram as depicted in Figure 20.

[0082] Additionally, or alternatively, the invention encompasses an enantiopure compound A in amorphous free form obtained from 1,4-dioxane characterized by TGA thermogram as depicted in Figure 21.

[0083] Additionally, or alternatively, the invention encompasses an enantiopure compound A in amorphous free form obtained from 1,4-dioxane characterized by1H-NMR spectrum as depicted in Figure 22.

[0084] The present invention also encompasses a crystalline form of Compound A designated as Form 2. This crystalline an isopropyl alcohol solvate of Compound A.

[0085] In some embodiments, crystalline Form 2 of compound A can be obtained by equilibrating the amorphous free form of Compound A obtained from 1,4-dioxane in isopropyl alcohol at 25 ºC for two weeks. Preferably crystalline Form 2 of compound A is prepared as described in Example 34.

[0086] Preferably the crystalline Form 2 of Compound A can be characterized by an X- ray powder diffraction (XRPD) pattern comprising one, two, three, or more peaks at diffraction angles selected from the group comprising 7.0, 8.4, 12.2, 16.9, 20.6, 24.8, and 28.5 degrees two theta ± 0.2 degrees two theta (°2θ ± 0.2° 2θ). In some embodiments, crystalline form 2 of Compound A can be characterized by XRPD pattern comprising two, three or more peaks, preferably three or more peaks, preferably four or more peaks, preferably five or more peaks at 7.0, 8.4, 12.2, 16.9, 20.6, 24.8, and 28.5 degrees two theta ± 0.2 degrees two theta.

[0087] In some embodiments, crystalline form 2 of Compound A can be characterized by an XRPD pattern comprising peaks at 7.05, 7.24, 7.56, 8.42, 11.73, 12.19, 13.75, 14.28, 14.68, 15.11, 15.47, 15.89, 16.40, 16.89, 17.52, 18.41, 18.95, 20.59, 21.08, 21.62, 22.28, 22.75, 23.14, 24.76, 25.69, 27.68, 28.20, 28.52, 29.15, 31.88, 32.85, 34.11, 38.14, degrees two theta ± 0.2 degrees two theta.

[0088] Additionally, or alternatively, the invention encompasses an enantiopure Compound A in crystalline Form 2 characterized by an X-ray powder diffraction pattern as depicted in Figure 15 (Pattern D).

[0089] Additionally, or alternatively, the invention encompasses an enantiopure compound A in crystalline Form 2 characterized by a DSC thermogram as depicted in Figure 16.

[0090] Additionally, or alternatively, the invention encompasses an enantiopure compound A in crystalline Form 2 characterized by TGA thermogram as depicted in Figure 17.

[0091] Additionally, or alternatively, the invention encompasses an enantiopure compound A in crystalline Form 2 characterized by1H-NMR as depicted in Figure 18.

[0092] The present invention also encompasses a crystalline form of Compound A designated as Form 1. In an embodiment said Form 1 is an anhydrate. Preferably crystalline Form 1 of compound A is prepared as described in Example 34.

[0093] Preferably the crystalline Form 1 of Compound A can be characterized by an X- ray powder diffraction (XRPD) pattern comprising one, two, three, or more peaks at diffraction angles selected from the group comprising 9.6, 12.5, 13.3, 13.9, 22.7, 30.2, and 31.5 degrees two theta ± 0.2 degrees two theta (°2θ ± 0.2° 2θ). In some embodiments, crystalline form 1 of Compound A can be characterized by XRPD pattern comprising two, three or more peaks,preferably three or more peaks, preferably four or more peaks, preferably five or more peaks at 9.6, 12.5, 13.3, 13.9, 22.7, 30.2, and two theta ± 0.2 degrees two theta.

[0094] In some embodiments, crystalline form 1 of Compound A can be characterized by an XRPD pattern comprising peaks at 5.48, 9.63, 12.53, 13.29, 13.91, 15.94, 16.09, 16.66, 17.75, 17.96, 18.68, 18.78, 19.15, 19.70, 19.83, 20.22, 20.70, 21.03, 21.33, 21.48, 22.43, 22.51, 22.59, 22.69, 23.26, 24.30, 25.39, 25.54, 26.66, 26.76, 27.14, 27.26, 27.99, 28.63, 29.08, 30.07, 30.15, 31.22, 31.50, 32.23, 33.17, 33.60, 34.12, 34.65, 35.05, 36.21, 36.81, 37.79, 38.76, 39.11, 40.23, 41.30, 41.96, 42.11, 43.51, 45.22, 45.90, 46.49, 47.43, 47.80, 48.61, 49.27 degrees two theta ± 0.2 degrees two theta.

[0095] Additionally, or alternatively, the invention encompasses an enantiopure Compound A in crystalline Form 1 characterized by an X-ray powder diffraction pattern as depicted in Figure 6 (Pattern A).

[0096] Additionally, or alternatively, the invention encompasses an enantiopure compound A in crystalline Form 1 characterized by a DSC thermogram as depicted in Figure 7.

[0097] In some embodiments, compound A in crystalline Form 1 is characterized by an FTIR spectrum having peaks at 3333, 3276, 3136, 3070, 3011, 2978, 2947, 2916, 1641, 1623, 1595, 1585, 1491, 1462, 1440, 1375, 1318, 1259, 1245, 1225, 1159, 1094, 1085, 1050, 1030, 989, 976, 961, 889, 871, 856, 846, 817, 807, 772, 762, 720 cm-1± 4 cm-1.

[0098] Additionally, or alternatively, the invention encompasses an enantiopure compound A in crystalline Form 1 characterized by an IR spectrum as depicted in Figure 8.

[0099] Additionally, or alternatively, the invention encompasses an enantiopure compound A in crystalline Form 1 characterized by TGA thermogram as depicted in Figure 9.

[0100] Additionally, or alternatively, the invention encompasses an enantiopure compound A in crystalline Form 1 characterized by1H-NMR as depicted in Figure 10.

[0101] The present invention also encompasses an acetone solvate in crystalline form of Compound A.

[0102] Preferably the crystalline acetone solvate of Compound A can be characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, or three peaks at diffraction angles selected from the group comprising 10.4, 13.1, and 26.2 degrees two theta ± 0.2 degrees two theta (°2θ ± 0.2° 2θ). In some embodiments, the acetone solvate of Compound A can be characterized by XRPD pattern comprising two, or three peaks, preferably comprising three peaks at 10.4, 13.1, 26.2 degrees two theta ± 0.2 degrees two theta.

[0103] In some embodiments, the acetone solvate of Compound A can be characterized by an XRPD pattern comprising peaks at 7.82, 8.15, 8.92, 10.37, 13.09, 14.33, 15.74, 16.23, 17.95, 19.56, 20.16, 20.72, 21.62, 21.99, 22.64, 26.20, 26.91, 30.04, 35.25, degrees two theta ± 0.2 degrees two theta.

[0104] Additionally, or alternatively, the invention encompasses an enantiopure acetone solvate of Compound A characterized by ray powder diffraction pattern as depicted in Figure 11 (Pattern C).

[0105] Additionally, or alternatively, the invention encompasses an enantiopure acetone solvate of compound A characterized by a DSC thermogram as depicted in Figure 12.

[0106] Additionally, or alternatively, the invention encompasses an enantiopure acetone solvate of compound A characterized by TGA thermogram as depicted in Figure 13.

[0107] Additionally, or alternatively, the invention encompasses an enantiopure acetone solvate of compound A characterized by1H-NMR as depicted in Figure 14. Pharmaceutical compositions

[0108] The present invention also encompasses a pharmaceutical composition comprising compound A as prepared by the process described herein, or compound A as described herein (including all embodiments thereof as described herein), and one or more pharmaceutically acceptable excipients. Compound A can be in an amorphous free form or Compound A can be in a crystalline form as described herein above (including all embodiments thereof as described herein), preferably characterized by an X-ray powder diffraction pattern as described herein above, for example Compound A can be in an amorphous free form characterized by an X-ray powder diffraction pattern as depicted in Figure 19, or in a crystalline Form 30 characterized by an X-ray powder diffraction pattern which comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 10.08, 19.35, 23.73, 24.09, 24.99, 29.57, and 30.72, degrees two theta ± 0.2 degrees two theta; or Compound A can be in a crystalline Form 2 characterized by an X-ray powder diffraction pattern which comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 7.0, 8.4, 12.2, 16.9, 20.6, 24.8, and 28.5 degrees two theta ± 0.2 degrees two theta; or Compound A can be in a crystalline Form 1 characterized by an X-ray powder diffraction pattern which comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 9.6, 12.5, 13.3, 13.9, 22.7, 30.2, and 31.5 degrees two theta ± 0.2 degrees two theta; or Compound A can be in a crystalline acetone solvate form characterized by an X- ray powder diffraction pattern which comprises one, two, or three peaks at diffraction angles selected from the group comprising 10.4, 13.1, and 26.2 degrees two theta ± 0.2 degrees two theta; for example Compound A can be characterized by an X-ray powder diffraction pattern selected from the group comprising pattern A, pattern B, pattern C, and pattern D.

[0109] The pharmaceutical composition may be provided in solid form or semi-solid form. Ingredients suitable for such pharmaceutical compositions are known and such a composition may be formulated by methods known in the art. In some embodiments the pharmaceutical composition according to the present invention may be prepared as disclosed inWO2022 / 095913 or as disclosed in WO2022 / 095912, both of which are herein incorporated by reference in their entirety.

[0110] Additionally, or alternatively, the pharmaceutical composition may be a solid form or semi-solid form comprising Compound A in an amorphous free form or Compound A in a crystalline form as described herein above (including all embodiments thereof as described herein), preferably characterized by an X-ray powder diffraction pattern as described herein above. For example, the pharmaceutical composition may be a solid form or semi-solid form comprising Compound A in an amorphous free form characterized by an X-ray powder diffraction pattern as depicted in Figure 19, or in a crystalline Form 30 characterized by an X- ray powder diffraction pattern which comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 10.08, 19.35, 23.73, 24.09, 24.99, 29.57, and 30.72, degrees two theta ± 0.2 degrees two theta; or in a crystalline Form 2 characterized by an X-ray powder diffraction pattern which comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 7.0, 8.4, 12.2, 16.9, 20.6, 24.8, and 28.5 degrees two theta ± 0.2 degrees two theta; or in a crystalline Form 1 characterized by an X- ray powder diffraction pattern which comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 9.6, 12.5, 13.3, 13.9, 22.7, 30.2, and 31.5 degrees two theta ± 0.2 degrees two theta; or in a crystalline acetone solvate form characterized by an X-ray powder diffraction pattern which comprises one, two, or three peaks at diffraction angles selected from the group comprising 10.4, 13.1, and 26.2 degrees two theta ± 0.2 degrees two theta; for example Compound A can be characterized by an X-ray powder diffraction pattern selected from the group comprising pattern A, pattern B, pattern C, and pattern D.

[0111] The pharmaceutical composition may comprise at most 50 wt% of Compound A relative to the total weight of the composition, for example at most 40 wt%, for example at most 35 wt%, for example at most 30 wt%, or for example at most 25 wt%. The pharmaceutical composition may comprise at least 0.1 wt% of Compound A relative to the total weight of the composition, for example at least 0.5 wt%, for example at least 1 wt%, for example at least 5 wt%, for example at least 10 wt%, for example at least 15 wt%, for example at least 17 wt%, or for example at least 20 wt%. The pharmaceutical composition may comprise from 0.1 wt% to 45 wt% of Compound A relative to the total weight of the composition, for example from 0.5 wt% to 40 wt%, for example from 1 wt% to 40 wt%, for example from 5 wt% to 35 wt%, or for example from 10 wt% to 35 wt%.

[0112] The amount of the amorphous free form or the crystalline form of Compound A as described herein (including all embodiments thereof as described herein) in the pharmaceutical composition can range from 0.1 mg to 3000 mg, for example from 1 mg to 2000 mg, for example from 5 mg to 1500 mg, for example from 5 mg to 1000 mg, for examplefrom 10 mg to 500 mg, for example from 15 mg to 400 mg, for example from 20 mg to 350 mg or any particular amount or range

[0113] The invention also provides a solid dosage form or a semi-solid dosage form comprising a pharmaceutical composition as described herein.

[0114] The dosage form may comprise a capsule encapsulating the pharmaceutical composition.

[0115] The dosage form may be an oral dosage form (e.g. a capsule for oral administration).

[0116] The solid dosage form may alternatively be a tablet.

[0117] In some embodiments, the pharmaceutical composition as described herein further comprises one or more pharmaceutically acceptable excipients selected from disintegrants, binders, diluents, lubricants, stabilizers, wetting agents, glidants, osmotic agents, colorants, plasticizers, and coatings.

[0118] As used herein, an "excipient" is an inactive ingredient in a pharmaceutical composition. Examples of excipients include diluents, wetting agents (e.g., surfactants), binders, glidants, lubricants, disintegrants, and the like.

[0119] 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.

[0120] 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.

[0121] 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 sulphate (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.

[0122] 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).

[0123] 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.

[0124] As used herein, a "colorant" is an excipient that imparts a pharmaceutical composition with a desired color. Examples of colorants include commercially available pigments such as FD&C Blue #1 Aluminum Lake, FD&C Blue #2, other FD&C Blue colors,titanium dioxide, iron oxide, and / or combinations thereof. Other colorants include commercially available pigments such as FD&C Green

[0125] 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.

[0126] In any of the above solid forms, Compound A can be in an amorphous free form or Compound A can be in a crystalline form as described herein above (including all embodiments thereof as described herein), preferably characterized by an X-ray powder diffraction pattern as described herein above. For example, Compound A can be in an amorphous free form characterized by an X-ray powder diffraction pattern as depicted in Figure 19, or can be in a crystalline Form 30 characterized by an X-ray powder diffraction pattern which comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 10.08, 19.35, 23.73, 24.09, 24.99, 29.57, and 30.72, degrees two theta ± 0.2 degrees two theta; or can be in a crystalline Form 2 characterized by an X-ray powder diffraction pattern which comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 7.0, 8.4, 12.2, 16.9, 20.6, 24.8, and 28.5 degrees two theta ± 0.2 degrees two theta; or can be in a crystalline Form 1 characterized by an X-ray powder diffraction pattern which comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 9.6, 12.5, 13.3, 13.9, 22.7, 30.2, and 31.5 degrees two theta ± 0.2 degrees two theta; or can be in a crystalline acetone solvate form characterized by an X-ray powder diffraction pattern which comprises one, two, or three peaks at diffraction angles selected from the group comprising 10.4, 13.1, and 26.2 degrees two theta ± 0.2 degrees two theta; for example Compound A can be characterized by an X-ray powder diffraction pattern selected from the group comprising pattern A, pattern B, pattern C, and pattern D.

[0127] As used herein, the term "treat", "treating", or "treatment" of any disease, condition, syndrome or disorder refers, in one embodiment, to ameliorating the disease, condition, syndrome or disorder (i.e. slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment, "treat", "treating", or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In a further embodiment, "treat", "treating", or "treatment" refers to modulating the disease, condition, syndrome or disorder either physically (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In yet another embodiment, "treat", "treating", or "treatment" refers to preventing or delaying the onset or development or progression of the disease, condition, syndrome or disorder.

[0128] As used herein, “preventing” a viral infection is an approach for eliminating or reducing the risk of developing a viral or delaying the onset of a viral infection, including biochemical, histological and / or behavioral symptoms of a viral infection. Prevention may be in the context of an individual at risk of developing the viral infection, such as where the “at risk” individual does not develop the viral infection over a period of time, such as during a viral season or during a period of exposure to the virus, which may be days to weeks to months. An individual “at risk” of developing a viral infection is an individual with one or more risk factors for developing the viral infection but who has not been diagnosed with and does not display symptoms consistent with a viral infection.

[0129] As used herein, a “therapeutically effective amount” or a “therapeutically effective dosage” of the amorphous free form or the crystalline form of Compound A as described herein (including all embodiments thereof as described herein) is an amount sufficient to produce a desired therapeutic outcome. A therapeutically effective amount or a therapeutically effective dosage can be administered in one or more administrations per day. A therapeutically effective amount or dosage may be considered in the context of administering one or more therapeutic agents (e.g., a compound, or pharmaceutically acceptable salt thereof), and a single agent may be considered to be given in a therapeutically effective amount if, in conjunction with one or more other agents, a desired therapeutic outcome is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0130] As used herein, a “prophylactically effective amount” or “prophylactically effective dosage” is an amount sufficient to effect the preventative result of eliminating or reducing the risk of developing a viral infection or delaying the onset of a viral infection, including biochemical, histological and / or behavioral symptoms of a viral infection. A prophylactically effective amount or a prophylactically effective dosage can be administered in one or more administrations per day and over a period of time in which such prevention is desired. Additionally, the present invention provides pharmaceutical compositions comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of an amorphous free form of Compound A or of a crystalline form of Compound A as described herein (including all embodiments thereof as described herein), preferably characterized by an X-ray powder diffraction pattern as described herein above. For example, Compound A can be in an amorphous free form characterized by an X-ray powder diffraction pattern as depicted in Figure 19, or can be in a crystalline Form 30 characterized by an X-ray powder diffraction pattern which comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 10.08, 19.35, 23.73, 24.09, 24.99, 29.57, and 30.72, degrees two theta ± 0.2 degrees two theta; or can be in a crystalline Form 2 characterized by an X-ray powder diffraction pattern which comprises one, two, three, or more peaks at diffraction anglesselected from the group comprising 7.0, 8.4, 12.2, 16.9, 20.6, 24.8, and 28.5 degrees two theta ± 0.2 degrees two theta; or can be in a Form 1 characterized by an X-ray powder diffraction pattern which comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 9.6, 12.5, 13.3, 13.9, 22.7, 30.2, and 31.5 degrees two theta ± 0.2 degrees two theta; or can be in a crystalline acetone solvate form characterized by an X-ray powder diffraction pattern which comprises one, two, or three peaks at diffraction angles selected from the group comprising 10.4, 13.1, and 26.2 degrees two theta ± 0.2 degrees two theta. For example Compound A can be characterized by an X-ray powder diffraction pattern selected from the group comprising pattern A, pattern B, pattern C, pattern D, and mixture thereof.

[0131] “Dosage” or “dose” may mean either a single administration of a composition or can mean several administrations of the same composition depending on context. For example, if the composition is given twice a day, a dose could be taken to mean two administrations of the same composition, in suitably measured amounts. Thus, the same "dose" may be given two or three times (or more if necessary) in the treatment regimen before progressing to the subsequent dose, which would be of a composition having a different given amount of medication. However, a unit dose means a single dose given a single time, i.e. in one administration.

[0132] "Patient" may be any human treated with a composition of this invention.

[0133] Advantageously, the amorphous free form or the crystalline form of Compound A as described herein (including all embodiments thereof as described herein) may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, four or five daily. The daily dose may be maintained unchanged throughout all days or some days of a treatment or prevention period. Said daily dose may change throughout the days of a treatment or prevention period such as it increases and / or decreases during the days of said treatment or prevention period. For instance, said daily dose may be unchanged for the first 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 days or more (or any single value or range comprised thereon) followed by a lower and / or a higher daily dose for the remaining days of the treatment or prevention period. Said remaining days of the treatment or prevention period can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 days or more (or any single value or range comprised thereon).

[0134] In certain embodiments, the amorphous free form or the crystalline form of Compound A as described herein (including all embodiments thereof as described herein) may be administered at one dose for a first duration (e.g., a loading phase) and at a second dosefor a second duration (e.g., maintenance phase). The loading phase may include administration of any of the dosages herein (e.g., from about 10 mg to about 1000 mg, from about 25 mg to about 800 mg, or from about 50 mg to about 400 mg). The first duration of administration in the loading phase may be for any of the time periods contemplated herein (e.g., from about 1 day to about 40 days, from about 3 days to about 20 days, or from about 5 days to about 10 days). The maintenance phase may include administration of any of the dosages described herein (e.g., from about 10 mg to about 1000 mg, from about 25 mg to about 800 mg, or from about 50 mg to about 400 mg). The second duration of administration in the maintenance phase may be for any of the periods contemplated herein (e.g., from about 1 day to about 60 days, from about 5 days to about 45 days, or from about 10 days to about 30 days).

[0135] Optimal dosages of the pharmaceutical composition to be administered may vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease, syndrome, condition or disorder. In addition, factors associated with the particular subject being treated, including subject gender, age, weight, diet and time of administration, may result in the need to adjust the dose to achieve an appropriate therapeutic level and desired therapeutic effect. The above dosages are thus exemplary of the average case. There can be individual instances wherein higher or lower dosage ranges are merited, and such are within the scope of this invention. EXAMPLES Abbreviations: DCM = dichloromethane. DMSO = dimethyl sulfoxide. MeOH = methanol. EtOH = ethanol. IPA = isopropyl alcohol. MTBE = methyl tert-butyl ether. 2-Me THF = 2-methyltetrahydrofuran. DMAc = dimethylacetamide. DMF = dimethylformamide. MEK = methyl ethyl ketone (butanone). MIBK = methyl isobutyl ketone. PEG 400 = Polyethylene glycol 400. ACN = acetonitrile. THF = tetrahydrofuran. RS = Residual solvent. ML = Mother liquor.LOQ = Limit of quantification. wt% = % by weight. V = Volume. Material and methodology

[0136] General. All reagents were commercially available and used without further purification unless otherwise stated. All reactions were performed under a nitrogen atmosphere unless otherwise stated. All reactions were monitored by HPLC method using Waters H-Class with UV detector or equivalent. All1H NMR and13C NMR spectra were recorded on a Bruker 400 or 500 MHz spectrometer using DMSO-d6 or CDCl3as the solvent. Methodology UHPLC method for the determination of Compound A purity - Identification, Assay and Related Substances Determination of Compound A by Ultra High Performance Liquid Chromatography (UHPLC) The concentrations of enantiopure Compound A and its impurities were determined by gradient Reversed-Phase UHPLC with UV Detection. 1. Mobile Phases Mobile Phase A:10 mM Ammonium acetate in water / acetonitrile (95 / 5, V / V) Mobile Phase B: Acetonitrile. Dilution Solvent: Water / acetonitrile (50 / 50, V / V). 2. Solutions Blank Solution: Dilution Solvent as Blank Solution. Reference Solutions 1 and 2 (at 100% Level) 50.00 mg of Compound A were dissolved in approximately 50mL acetonitrile and 50mL of water were added and mixed. The solution was equilibrated to ambient temperature, then diluted to volume with dilution solvent twice. Reference Solution 3 at Reporting Threshold Level (at 0.05% Level): Transferring, 2.0 mL of Reference Solution 1 into a 200-mL volumetric flask and diluting to volume with Dilution Solvent: Diluted Reference Solution 1. Transferring 5.0mL Diluted Reference Solution 1 into a 100-ml volumetric flask and dilute to volume with Dilution Solvent. Sample Solution: Weighing approximately 50.00 mg of Compound A into a 250-mL volumetric flask. Dissolving in approximately 50mL acetonitrile, then transferring 50mL water and mixing, Allowing the Solution to equilibrate to ambient temperature. Diluting to volume twice with Dilution Solvent. 3. PROCEDURE 3.1. UHPLC Conditions for Identification, Assay and Chromatographic Purity Column: Waters Acquity UPLC HSS T3, 150 mm length x 2.1 mm i.d.,1.8 µm particle sizeColumn Temperature: 45 °C Auto-Sampler Temperature: Ambient Flow Rate: 0.30 mL / min Detection: UV Wavelength: 235 nm Injection Volume: 2.0µL Data Collection Time: 31 minutes Analysis Run Time: 35 minutes Elution Mode: Gradient A linear gradient is programmed as demonstrated in Table A1. Table A1: Linear Gradient Program Time (min) A (%vol) B (%vol) 0 90 10 25 2831 5 95 32 90 10 35 90 10 Relative Standard Deviation (% RSD) for the Compound A areas of the 5 successive injections of Reference Solution 1 was ≤1.0%. 4. CALCULATIONS 4.1. Assay Compound A ^^^^^^^^^^^^^^^^^^^ %ൌ^^ ^^ ^^ ^^ ^^100 ^^^^^^^^^^^′ ^^^^^^Where:Vs= Volume of the = 250 ds= Dilution Factor Sample Solution = 1.0 Vr= Volume of the volumetric flask in which the reference material of Reference Solution 1 is weighed = 250 dr= Dilution Factor Reference Solution 1 = 1.0 Pr= purity factor (≤1.000), corresponds with the content Compound A Reference material, taking into account: total Solvents, total Water and achiral Process Impurities Fr’ = 1.000 = salt / base factor of Compound A Reference material rm= peak response (area) of Compound A in each individual injection of Sample Solution rr= mean peak response (area) of Compound A in the 5 successive injections for System Suitability of Reference Solution 1 qr= weight (in mg) Compound A Reference -material in Reference Solution 1 Qth= 1G = Fr; = 1.000 = salt / base factor of Compound A Sample material qs= weighed amount (in mg) of the Note: When scaling factor (S) is used, instead of volume stock solution and dilution factor, S can be determined as follows:^^ ൌ^^^^^^^^^ൌ 1^^^^^^^of Impurities^^^^^^ ^^ ^^ ^ ൌ^^ 1 ^^ %^^^^^^^^^^^^ ^^ ^^100 ^^^^^^^^^^^′ ^^^^^௧^^^^^^^ ^^^Where: Vs= Volume of the= 250 ds= Dilution Factor Sample Solution = 1.0 Vr= Volume of the volumetric flask in which the reference material of Reference Solution 1 is weighed = 250 dr= Dilution Factor Reference Solution 1 = 1.0 Pr= purity factor (≤1.000), corresponds with the content Compound A Reference material, taking into account: total Solvents, total Water and achiral Process Impurities Fr’ = 1.000 = salt / base factor of Compound A Reference material ri = peak response (area) of Impurity in each individual injection of Sample Solution rr= mean peak response (area) of Compound A in the 5 successive injections for System Suitability of Reference Solution 1 qr= weight (in mg) Compound A -material in Reference Solution 1 Qth= 1 RRF = 1.000 (for all impurities except Compound F, starting material of Step 6 of the below described synthesis 1) = 0.657 (for Compound F) G = Fr; = 1.000 = salt / base factor of Compound A Sample material qs= weighed amount (in mg) of the Sample Note: When scaling factor (S) is used, instead of volume stock solution and dilution factor, S can be determined as follows: ^^ ^^^^^^ ^^ 15. METHOD SUMMARYThe operating conditions for the UHPLC method are provided in Table A2 Table A2: Operating Conditions UHPLC MethodParameter ConditionsMobile phase Aqueous ammonium acetate / acetonitrile (or equivalent) Flow Rate 0.30 mL / min Detection UV at 235 nm Injection Volume 2.0µL Elution Mode Gradient elution UPLC method for determination on chiral purity - Chiral Purity Determination by HPLC INSTRUMENTS AND EQUIPMENT Agilent 1260 HPLC with UV detector Pure water generator Column: CHIRALPAK AS-3R, 150 x 4.6 mm, 3.0 µm PN: 20824 CHROMATOGRAPHIC CONDITIONS Instrument Agilent 1260 HPLC with UV detector Column CHIRALPAK AS-3R, 150 x 4.6 mm, 3.0 µm PN: 20824 Wavelength 235 nm Reference wavelength Off Column Temperature 30 ºC Flow Rate 0.8 mL / min Injector Volume 5 μL Needle Wash Solvent Methanol Seal Wash: Water / Methanol (90 / 10, V / V) Sampling Rate: 2 points / second Mobile Phase A 15 mM Ammonium trifluoroacetate and 0.1% trifluoroacetic acid in water Mobile Phase B Acetonitrile Gradient program Time (min) A% B%65 0.01 60 40 20.00 35 65 30.00 35 65 30.10 60 40 40.00 60 40 Run Time 40 min Data Acquisition Time 30 min CHIRAL PURITY Preparation of solutions Solutions Preparation of solutions Label as Diluent 1 Acetonitrile / Water (1 / 1,V / V) N / A Diluent 2 Acetonitrile Blank Diluent 2 BLK Resolution solution 50 mg of Compound A and 3 mg of Racemic, diluted to volume RS with diluent 1 Stock Reference Solution 50 mg of compound A diluted to volume with diluent 1 SSS-1 (1.0mg / mL) Standard Solution (for 3 mL of the Stock Reference Solution diluted to volume with STD enantiomer Assay diluent 1 Determination) (0.03 mg / mL )Sample Solution For IPC sample SPL 400 mg of sample diluted to volume with diluent 1 For wet cake sample . SPL 50mg of sample diluted to volume with diluent 1. For filtrate sample SPL 800 mg of sample diluted to volume with diluent 2 For mother liquor sample SPL 1200mg of sample diluted to volume with diluent 1 Chiral purity Sample chromatogram were compared with blank chromatogram, and the peaks integrated, calculate the chiral purity by weight percent (w / w %) as follows: %ൌ^^ௌ^^^^^^^ ^^ ^^ 1 ^^ ^^^^^^^^^^^ ^^ ^^100 ^^^^^^^^^^^′ ^^^^^௧^^^^^^^ ^^^where: Vs= Volume of the volumetric flask in which the sample is weighed = 50 ds= Dilution Factor Sample Solution = 1Vr= Volume of the volumetric flask in which the compound working standard of Standard Solution is weighed (Stock Reference Solution ) = 50 dr= Dilution Factor Standard Solution = 100 / 3Pc=weight percent (^ 100.0%), corresponding with the Certificate of AnalysisFr’ = 1.000= salt / base factor of the working standard ri= peak response (area) of Chiral Impurity enantiomer of Sample Solution rr= mean peak response (area) of the compound of Standard Solution qr= weight (in mg) C16022919-D working standard in Stock Reference Solution Qth= 1 RRF= 1.000 G = Fr = 1.000 = salt / base factor of the Sample qs= weighed amount (in mg) of the Sample When scaling factor (S) is used instead of volume stock solution and dilution factor, S can be determined as follows ^^^^^^ ^^ ൌ ^ ^^^^^^^ൌ 3 / 100^ ^Procedure of carbon treatment (before / after hydrogenation) 1. Charging 530 g 5.3X (5.04-5.57X) THF in a reactor. 2. Charging in said reactor 100g 1.0X (0.99-1.01X) of Compound (F) under N2protection.3. Decoloring organic layer in the reactor by CUNO (10wt% Nuchar, based on compound (F)) at 25 °C (20-30 °C) for 4 hours (2~8 . 4. Washing CUNO with 356g 3.6X (3.42-3.78X) THF. Example of a calculation of enantiomer yield in crystallization experiments Crude solution crude solution Assay (wt%) net amount C Content of Enantiomer amount amount (g) (g) hiral purity enantiomer (g) 76.92 9.10% 7.00 94.50% 89.00% 6.23 Process of racemate rejection Filtrate Filter cake Yield of Material loss Amount (g) assay (%) Chiral purity (%) Amount ( Chiral purity enantiomer (%) g) (%) （%) 39.84 15.80% 99.70% 89.39 1.04 52.70% 0.80 Product Mother liquor Amount (g) assay (wt%) Chiral purity (%) Isolation yield (%) Amount (%) Assay (wt%) ML loss (%)5.75 97.20% 100% 79.8 81.7 0.35% 4.09%Mother liquor: is the liquid phase collected after solid-liquid separation in the end of the crystallization process. PSD method - Laser diffraction method for the determination of the particle size of JNJ- 64281802-AAA drug substance The volume based particle size distribution of Compound A was determined by means of wet dispersion laser diffraction using a Malvern Mastersizer 3000 laser diffraction particle size analyzer in combination with a Hydro MV wet dispersion unit, according to the procedure shown in Table C. Dispersant: ISOIPAR G . Wetting agent: 0.1% w / v of Lecithin-ISOPAR G Rinsing Agent: ISOPAR G Dispersant for System Suitability Testing (SST): Water (Milli-Q®) + 2 drops of 5% Igepal CA- 630 Sampling: Weighing about 15 mg of the sample powder. Sample preparation: Adding dropwise the wetting agent (5 mL 0.1% w / v of Lecithin-ISOPAR G) to the sample powder vortexed about 2.5 min and sonicated for about 50 seconds (KQ- 50TDB high frequency ultrasonic cleaner, ultrasonic power was 40% (full power 50 W) or equivalent) whilst mixing it until paste or slurry was obtained. Table C: Procedure of the Laser Diffraction Test Method DS-TMD-25153 by Wet DispersionSample AdditionStirrer Speed 2000 rpm Obscuration 5-20% Ultrasonics No Data Acquisition Red Background measurement duration 10s Red Sample measurement duration 10s Blue Background measurement duration 10s Blue Sample measurement duration 10s Data Processing Optical Model Mie Particle R1 1.59 Particle Abs 0.01 Dispersant RJ ISOPAR G (R1:1.42) Calculation Model General Purpose Calculation Sensitivity Normal Particle shape Non-Spherical KF method for water determination- Coulometric Karl Fischer Test Method for the Determination of water in Compound A The water content was determined by means of a vaporized coulometric Karl Fischer determination in accordance with USP / Ph. Eur. Instruments: KF coulometer: 851 KF coulometer Metrohm. Oven sampler: 885 KF thermoprep Metrohm.Oven temperature 120°C. Generator electrode: Electrode with diaphragm Metrohm. Indicator electrode: Double Pt-wire electrode Metrohm REAGENTS AND SOLUTIONS (OR EQUIVALENT) Anode solution: Hydranal Coulomat AG oven (Fluka 34739) Cathode solution: Hydranal Coulomat CG (Fluka 34840) Water standard: Hydranal water standard 1.00 (Fluka 34828) PROCEDURE Sample: Weighing accurately about 100.00 mg of the sample into a vial and crimping the vial securely. 4.3. Conditions Oven Parameters: Carrier gas: Compressed Air or N2, Flow rate Setpoint: 60 mL / min, Read out value minimum 20 mL / min Oven. temperature 120°C Coulometer Parameters: Titration parameters Extr. Time: 60 s Drift correction: Auto Start conditions Pause: 60 sStart drift Maximum: 12 µg / min Time cond. OK: 10 s Stop parameters Rel. Drift: 5 µg / min Calculations: the water content was calculated as: %,^^ / ^^ ൌ ^µ^^ ^^^^^^^^^^^^ െ µ^^ ^^^^^^^^^^^^^^^ ^^ 10 where: µg sample = measuredµg blank = mean water content in the 3 blank vials (in µg) mg = Weight of the. sample in mg GCHS method for residual solvents - Determination of Residual Solvents in Compound A by GC Chromatography The residual solvents concentration were determined by Headspace Gas Chromatography with FID Detection. Agilent 789OB, equipped with FID Detector and 7697A Headspace auto-sampler was used Data Acquisition System: Waters Empower was used Dilution solvent: Purged 1,3-dimethyl-2-imidazolidinone (DMI) Sample Solution (100.00 mg compound A in 2.0 mL Dilution Solvent). CALCULATIONS Concentration was calculated as ppm, w / w according to an external calibration procedure using the average area of 6 successive injections of a Reference solution 1 containing known amounts of a selection of solvents of interest (multi solvents). Calculate the concentration in ppm, w / w of each Residual Solvent, by the following formula: ^^^^^^ ൌ^^^^^ ^^^^^,௧^^^^1 ^^^^^^ ^^ ^^^^^^^^ Where:Cref1= Concentration of the Residual Solvent in ppm, w / w of Reference Solution 1 ri= Peak response (area) of each Residual Solvent in the Sample Solution rr= Mean peak response (area) of each Residual Solvent in the 6 successive injections for System Suitability of Reference Solution 1 qs= Weight (in mg) of the sample material in the Sample Solution qs,theor= Nominal weight (in mg) = 100.00 M = Matrix factor = 1.000 The operating conditions for the GC method are provided in Table B1. Table B1: Operating Conditions GC MethodParameter ConditionsInlet Mode Split mode, Split ratio 30:1 Carrier gas Hydrogen, Helium or Nitrogen of appropriate quality Constant Flow: 1.2 mL / min DetectorFlame Ionization Detector (FID)Temperature 280°C An oven temperature gradient was programmed as demonstrated in Table B2. Table B2: Oven Temperature Gradient Program Temperature (°C) Rate (°C / min) Final Temperature (°C) Hold Time (min) Run Time (min) 45 0.0 45 0.2 0.2 45 2.0 50 0.0 2.7 50 35.02603.312.0GCHS method: Determination of THF residual content by Gas Chromatography Method Parameter Setting Equipment Agilent GC-HS with FID detector and headspace sampler (HS) Column: DB-624 (25 m x 0.2 mm, ID 1.12 µm) Carrier Gas N2FID Temperature: 260°C Makeup (N2) Flow 30 ml / min H2Flow 40 ml / min Air Flow 400 ml / min Control Mode Shimadzu: Linear Velocity; Agilent: Constant Flow Flow rate 1.2 ml / min Temperature Ramp 45°C (0.2 min) → 2°C / min → 50°C (0 min) → 35°C / min → 250°C (3.3 min) Injector Temperature 240°C Split Ratio 30:1 Run Time 11.7 min HS Parameters PE HS Agilent HS Oven temperature 110°C Needle temperature 150°C Transfer temperature 180°C Thermo time 30 min / Vial equilibration time / 30 min Pressurize time 0.5 min I Withdraw Time 0.2 min I Injection Time 0.03 min I Injection Duration Time / 2.5 min Vial shake / Frequency: 71 shakes / min Acceleration: 260 cm / s2High Pressure SamplingYes / Operating Mode Constant / Column Pressure 300 kPa / Injection / Vial Pressure300 kPa 17 psiLoop fill mode / Default HS Vial load volume 2.0 ml HS Vial Size 22 ml or 20 ml GC Cycle Time 36 min 36 min Diluent: 1,3-dimethyl-2-imidazolinone (DMI) The ppm or % w / w of each residual solvent was calculated, by the formula: ^^^^^^,௧^^^^1 ^^^^^^ ൌ^^^^ௌ்^^^^^^^^^^^ ^^ ^^^^^^^^ 1 ^^ where: CSTD= concentration ofsolution ri= peak area of each residual solvent in the sample solution rr= mean peak area of each residual solvent in the 3 or 6 injections for system suitability of standard solution Cs= actual concentration (mg / ml) of the sample solution Cs,theor= theoretical sample concentration (mg / ml) M = Matrix factor = 1 Differential Scanning Calorimetry (DSC) Differential Scanning TA DSC 250 instrument by TA Instruments was used. Material was heated from 30 °C to 300 °C at 10 °C / min ramp. The parameters are shown in Table C1. Table C1 Instrument TA DSC 250 Initial temperature 30 °C Heating rate Heating rate 10 °C / min Final temperature 300 °C Nitrogen flow 50 ml / min Synthesis 1 Synthesis of (S)-2-(4-chloro-2 methoxyphenyl)-2-((3-methoxy-5- (methylsulfonyl)phenyl)amino)-1-(5-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-one:

[0137] Step 1. Synthesis of 2-oxo-2-(5-(trifluoromethoxy)-1H-indol-3-yl) acetyl chloride

[0138] A solution of 20 g of-1H-indole (99.4 mmol) in 60 mL drymethyl tert-butyl ether (MTBE) was cooled to 0 ℃. Oxalyl chloride (10.4 mL, 119.3 mmol, 1.2 equiv.) was added dropwise over 5 the solution was warmed up to 20 ℃. After stirring for 1 hour, 20 mL heptane were added, and a yellow precipitate was formed. The mixture was stirred for another 10 minutes at 0 ℃ after which it was filtered on a glass filter (pore size 3). The filter cake was washed with 40 mL of heptane and dried under vacuum at 50 ℃ for 2 hours. The product was obtained as a yellow solid that was sensitive to moisture (26.3 g, 90.2 mmol, 91% yield).1H NMR (THF-d8, 400 MHz) δ ppm 11.77 (s, 1H), 8.48 (d, J = 3.4 Hz, 1H), 8.34 –8.06 (m, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.24 (ddd, J = 8.8, 2.4, 1.0 Hz, 1H).13C NMR (THF-d8, 101 MHz) δ 172.8, 169.1, 146.6, 140.2, 136.6, 128.1, 122.0 (q, J = 254.7 Hz, CF3), 119.1, 115.2, 114.5, 112.1.

[0139] Step 2. Synthesis of 1-morpholino-2-(5-(trifluoromethoxy)-1H-indol-3-yl) ethane- 1,2-dione O

[0140] A solution of 15.7 g 2.0 equiv.) in 100 mL dry THF wascooled to 0 ℃. A solution of 26.0 g oxo- -1H-indol-3-yl) acetyl chloride (89.1 mmol) in 100 mL THF was added dropwise over 1 hour while maintaining the temperature below 5 ℃. After the addition was complete, the reaction was stirred for another 30 minutes at 0 ℃ before 780 mL water was added dropwise over 30 minutes. The white precipitate that was filtered and washed with 130 mL sat. aq. NaHCO3and 100 mL of water. The product was dried under vacuum at 50 ℃ for 18 hours. The product was obtained as a white solid (28.2 g, 89.2 mmol, 92% yield).1H-NMR (DMSO, 400 MHz) δ ppm 12.57 (s, 1H), 8.36 (s, 1H), 8.01 (d, J = 2.3 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.28 (dd, J = 8.8, 2.4 Hz, 1H), 3.71 (t, J = 4.7 Hz, 2H), 3.62 (t, J = 4.7 Hz, 2H), 3.52 (t, J = 4.7 Hz, 2H), 3.36 (t, J = 4.8 Hz, 2H) .13C-NMR (DMSO, 101 MHz) δ ppm 186.0, 165.4, 144.3 (q, J = 2.2 Hz), 135.4, 125.3, 120.3 (q, J = 254.4 Hz, CF3) 116.5, 66.2, 65.9, 46.0, 41.1.

[0141] Step 3. Synthesis of 4-chloro-2-methoxyphenyl) magnesium bromide

[0142] To a suspension ofturnings (24 mmol, 1.2 equiv.) in 30 mL THF was added 0.07 mL of diisobutylaluminium hydride (DiBAL-H) (1.0M in THF, 2 mol%) at 20℃. The solution was warmed up to 40℃ and a solution of 4.4 g 4-chloro-2-methoxyphenylbromide in 7.2 mL THF (total volume of 10 mL) was added dropwise over 1 hour. The reaction was stirred for another 30 minutes at it was cooled down to 20℃. Titration with iodine determined a concentration of 0.44M.

[0143] Step 4. Synthesis of 1-(4-chloro-2-methoxyphenyl)-2-(5-(trifluoromethoxy)-1H- indol-3-yl)ethane-1,2-dione

[0144] A solution of 5 g -1H-indol-3-yl)ethane-1,2- dione (14.5 mmol) in 25 mL0 ℃. A 1M solution of lithium bis(trimethylsilyl) amide (LiHMDS) (15.9 mL, 1.1 equiv. ) was added dropwise over 15 minutes and the mixture was stirred for an additional 15 minutes at 0 ℃. A solution of (4-chloro-2- methoxyphenyl) magnesium bromide in THF (0.44M, 36.3 mL, 1.1 equiv.) was added dropwise over 30 minutes. The reaction was warmed up to 25 ℃ and stirred overnight before quenching with 50 mL 1M HCl. The phases were separated, and the aqueous layer was extracted with 25 mL MeTHF. Combined organic layers were dried on MgSO4, filtered, and concentrated in vacuo to 10-15 mL. The solution was warmed up and stirred 60 ℃ before adding 50 mL heptane. The mixture was stirred at 60 ℃ for 1 hour before slowly cooling down to 20 ℃. The solid was filtered off and the cake was washed with 20 mL heptane. The product was dried under vacuum at 50 ℃ for 18 hours. The product was obtained as a yellow solid (4.7 g, 11.8 mmol, 81%yield).1H-NMR (DMSO, 400 MHz) δ ppm 12.51 (s, 1H), 8.24 (d, J = 3.2 Hz, 1H), 8.03 (t, J = 1.9 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.65 (dd, J = 8.8, 0.5 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.29 (dd, J = 8.8, 1.6 Hz, 1H), 7.24 (dd, J = 8.3, 1.9 Hz, 1H), 3.61 (s, 3H) .13C-NMR (DMSO, 101 MHz) δ ppm 192.6, 187.5, 160.4, 144.1 (q, J = 2.3 Hz), 140.6, 138.3, 135.3, 131.9, 125.8, 122.7, 121.5, 121.0 (q, J = 255.6 Hz, CF3), 117.2, 114.1, 113.7, 112.9, 111.7, 56.8.

[0145] Step 5. Synthesis of 2-(4-chloro-2-methoxyphenyl)-2-((3-methoxy-5- (methylsulfonyl)phenyl)imino)-1-(5-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-one (Compound F)F

[0146] To a -1H-indol-3- yl)ethane-1,2-dione (100 mL) at 20-30 ℃ were added 3-methoxy-5-(methylsulfonyl) aniline (10.1 g, 50.3 mmol) and Zn (OTf)2(9.1 g, 25.1 mmol). The reaction mixture was heated to reflux with a Dean-Stark. After the mixture was stirred for 20 h, the reaction mixture was diluted with 2-Me-THF (200 mL) and quenched with Et3N (10.5 mL, 75.4 mmol) at 20 ℃. Then H2O (200 mL) was added and stirred for an hour. The mixture was filtered, and the filtrate was separated, and then the organic layer was washed with H2O (100 mL). The organic layer was concentrated to 20 mL under reduced pressure and chased with isopropyl alcohol (IPA) (100 mL). After the mixture was concentrated to 20 mL, another portion of IPA (120 mL) was added. The mixture was added H2O (60 mL) at 60 ℃ to precipitate out the solid. The mixture was cooled to 25 ℃ and stirred for 10 hours. The mixture was filtered. The cake was dried to give the final product (F) (25.1 g, 41.7 mmol, 83% yield) as an off-white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.26 (s, 2 H), 9.21 (s, 1 H), 8.35 (d, J = 1.8 Hz, 2 H), 8.27 (s, 1 H), 7.97 (br s, 1 H), 7.89 (d, J = 8.5 Hz, 1 H), 7.40 (br s, 1 H), 7.34 (d, J = 8.8 Hz, 2 H), 7.15 -7.22 (m, 2 H), 7.00 -7.12 (m, 5 H), 6.86 -6.94 (m, 5 H), 6.71 -6.83 (m, 4 H), 6.54 -6.63 (m, 2 H), 3.70 (s, 5 H), 3.61 -3.52 (m, 8 H), 3.41 (s, 3 H), 2.83 (s, 5 H), 2.70 (s, 3 H), 1.36 (br s, 1 H), 1.27 -1.01 (m, 5 H), 0.97 -0.69 (m, 3 H).

[0147] Step 6: Synthesis of (S)-2-(4-chloro-2 methoxyphenyl)-2-((3-methoxy-5- (methylsulfonyl)phenyl)amino)-1-(5-(trifluoro¬methoxy)-1H-indol-3-yl)ethan-1-one A

[0148] To a N2added 2-(4-chloro-2- methoxyphenyl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)imino)-1-(5-(trifluoromethoxy)-1H- indol-3-yl)ethanone (F) (20 g, 34.4 mmol), bis(norbornadiene)rhodium (I) tetrafluoroborate (38.6 mg, 103 μmol) and (S)-1-[(RP)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert- butylphosphine (57 mg, 103 μmol) in degassed THF (200 mL). The reaction mixture wasevacuated and backfilled with N2 and H2 three times respectively. The reaction mixture was heated to 50 ℃ under 3 bar H2pressure. stirring for 16 h, silica thiol (2.0 g, 10% wt.%) was added to the reaction mixture and it was stirred for another 16 h at 50 ℃. The reaction mixture was filtered through a pad of Celite. Unless otherwise specified, the THF filtrate as obtained after filtration to the Celite pad constituted the crude solution (or THF crude solution) for all rejection experiments. Then heptane (200 mL) was added to the filtrate dropwise at 40 ℃ and stirred for 16 h. The resulting suspension was filtered to remove solid impurities and the filtrate was concentrated under reduced pressure to give crude compound A (20 g) as an off-white solid. To a separate jacketed reactor was added crude compound A (10 g) and MeOH (63 mL). The mixture was heated to 64 ℃ and stirred for 0.5 hour to a clear solution. Then the solution was cooled to 45 ℃ linearly and seed of the product was added (2 wt.%). The mixture was aged for 3 h and H2O was added (21 mL) dropwise at 45 ℃. Then the mixture was cooled to 25 ℃ and stirred for another 8 h. The mixture was filtered. The cake was dried to give Compound A (7.6 g, 13 mmol, 76% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d 6) δ ppm 12.32 (br d, J = 2.6 Hz, 1 H), 8.56 (d, J = 3.3 Hz, 1 H), 8.08 (s, 1 H), 7.60 (d, J = 8.8 Hz, 1 H), 7.37 (d, J = 8.3 Hz, 1 H), 7.28 -7.18 (m, 1 H), 7.18 -7.06 (m, 2 H), 6.99 (dd, J = 8.3, 1.9 Hz, 1 H), 6.92 (s, 1 H), 6.68 -6.52 (m, 2 H), 6.27 (br d, J = 7.6 Hz, 1 H), 4.00 (s, 3 H), 3.73 (s, 3 H), 3.10 (s, 3 H). Example 1: Solubility of Form 30 of JNJ-64281802 and racemate at 25 °C in single solvents

[0149] Solubility of Form 30 and the racemate was measured by equilibrating slurries of the respective form in the respective solvent overnight, sampling the liquid by filtration and determining the equilibrium concentration by HPLC. The slurries for solubility measurements were prepared by addition of the respective solid form (form 30 or racemate) to a known amount of solvent (mixture) at the desired temperature in 2 mL vials equipped with magnetic stirrers. Solids were added until the material would not dissolve further. Table 1 summarizes the experimental solubility data of Form 30 and the racemate.

[0150] The solubility ratio was defined as: solubility ratio = solubility of Form 30 / solubility of racemate

[0151] The theoretical eutectic ee percentage was calculated as: Ee_eut = (4 * sol_30^2 - sol_rac^2) / (4*sol_30^2 + sol_rac^2) where sol_30 is solubility of form 30 and sol_rac is solubility of racemate. Table 1.Solubility of Form 30 of JNJ-64281802 and racemate at 25 °C in single solvents.Temperature: 25oC Theoretical Solvent system Form 30 Racemate Solubility Ratio (-) eutectic ee (%) Solubility (mg / mL) Solubility (mg / mL) Cyclopentanone 250-333 259 < 1 / DCM 7 13 < 1 / Chlorobenzene ~0 ~0 / / Dimethylbenzene ~0 ~0 / / Ethyl acetate 30 43 < 1 / N-butyl-2-Pyrrolidone 705 >333 ~ 2 ~89 DMSO 1235 >333 ~ 4 ~96.4 Toluene ~0 ~0 / / MeOH 2 1 ~ 2 ~88 EtOH 2 1 ~ 2 ~88 IPA 1 3 < 1 / MTBE 2 1 ~ 2 ~88 2-MeTHF 85 48 ~ 2 ~85 1,4-Dioxane 113 15 ~ 8 > 99 n-heptane ~0 1 < 1 / H2O ~0 ~0 / / DMAc 1252 >333 ~ 4 ~96.5 DMF 869 >333 ~ 3 ~93 MEK 126 16 ~ 8 > 99 MIBK 34 33 ~ 1 ~62 PEG400 >98 201 < 1 / Cyclohexanone >226 64 ~ 4 ~96.0 Acetone 172 131 ~ 1.5 ~75 ACN 28 25 ~ 1 ~ 67 THF 370 62 ~ 6 > 98

[0152] From the results in Table 1, it can be observed that Form 30 was 1.5-2.5 fold more soluble for most of the tested solvents than the racemate. A minimum solubility ratio of 4 was sought to achieve rejection of the racemate (eutectic enantiomeric excess >97%). Potential solvents with a solubility ratio higher or equal to 4 were DMSO, 1,4-Dioxane, DMAc, MEK, cyclohexanone, and THF.

[0153] In the below Examples 2-10 when a “crude solution” is used, said crude solution is obtained in Step 6 of the above described synthesis 1, after the filtration stage through the Celite pad and before the addition of heptane. The crude solution at this stage comprised a mixture of racemic material and enantiopure compound A in THF.

[0154] The racemate can be precipitated and removed as a solid by filtration after a solvent switch to MEK for example and optionally the addition of anti-solvent. Subsequently, the enantiomerically enriched filtrate can be crystallized using suitable anti-solvent (forexample selected from the group comprising n-heptane, methanol, water, cyclopentanone, dichloromethane, n-hexane, ethyl acetate, isopropyl alcohol, propyl, polyethylene glycol 400 and a mixture thereof n-heptane, methanol, water and / or methanol / water mixtures) as the non- solvated free Form 30 of Compound A.

[0155] In the below examples, when carbon treatment occurred, it occurred either before and / or after the hydrogenation step described in Step 6 of the described synthesis 1. For example, after dissolution of the starting material (compound F, 530 g) in THF (350 g) before hydrogenation, loose activated carbon (for example 10wt% Nuchar) was added and mixed in the reactor with the liquid at 25°C for 2 to 8 hours. It was filtered off, washed with THF, before the chiral hydrogenation step and the reaction step proceeded. Example 2: Racemate rejection and Form 30 crystallization in MEK / MeOH / Water MEK / MeOH / Water 1 / 6 / 0.5 – Crystallization of Form 30 from the Crude Reaction Mixture* The below general procedure was followed: 1. Providing 20 g (net amount) of THF crude solution (crude solution comprising Form 30 of Compound A + racemate in ~10 V of THF). 2. Concentrating crude solution to 3 V at 25°C. 3. Adding 3.4 V MEK to the concentrated solution of step 2. 4. Steps 2 and 3 were repeated several times (for example 3 times) to ensure that the residual amount of THF in the mixture was below 1% by weight of the mixture (the residual amount of THF was measured as described under the materials and methods section). 5. Stirring the mixture for 5-20 hr. 6. Filtering the racemate and isolating the filtrate. 7. Concentrating the filtrate to 2.1 V to create supersaturation for the crystallization to take place at 40 ºC. 8. Adjusting the temperature of the concentrated filtrate to 40 °C. 9. Adding seed of Form 30 to the concentrated filtrate (2 wt% seed of Form 30 based on the amount of Form 30 already present in the filtrate). 10. Adding MeOH followed by adding water thereby obtaining a MeOH:MEK:water (V:V:V) ratio of 1:6:0.5 11. Adjusting the temperature of the mixture of step 10to 0 °C 12. Stirring the mixture. 13. Isolating, washing and drying the resulting solids. * Volumes are referenced to net amounts of Form 30 of Compound A and racemate in the crude solutionExample 3 Racemate rejection and Form 30 crystallization in MEK / n-heptane

[0156] The crystallization yields were on the basis of input (both racemate and pure enantiomer) as y = (isolated mass) / (input mass R +input mass S) with “input” corresponding to the amounts originally used The below general procedure was followed: 1. Concentrating the THF solution containing the starting material at temperatures between 25 – 40 °C. ^ The starting material for Batch Nos. A-C described in Tables 2-4 were pure compound A as obtained at the end of synthesis 1 step 6. ^ The starting material for Batch Nos. D-E described in Tables 5-7 were crude solutions . 2. Adding MEK (3.4 V – 4.3 V). 3. Repeating steps 1-2 one to six times until the amount of THF was below < 3% by weight. 4. Concentrating to 4.6 – 6.3 V. 5. Filtering the suspension to remove racemate and collecting the filtrate and heating to 25 - 40 °C. 6. Adding anti-solvent n-heptane (0.4 – 0.95 V). 7. Add 2-5 wt% seeds of Form 30 of Compound A (wt% seed of Form 30 based on the amount of Form 30 present in the filtrate). 8. Adding n-heptane (11.16 – 24.15 V). 9. Isolating, washing and drying the resulting solids. Table 2. Racemate rejection procedures in MEK / n-heptane starting from pure materials. Batch Starting No material Procedure Result 1. Charging 88 wt% Form 30 and 12 wt% racemate into a reactor / 2. Charging 10 V THF, stirring at 25 °C to clear solution / 3. Concentrating to 3 V, then adding 4.3 V MEK / 4. Concentrating to 3 V, solid nucleation, then adding 4.3 V Cake: racemate 88 wt% Form 30 MEK Chiral purity: 51.9% A1 12 wt% 5. Repeating step 4 twice RS of THF: 1057 ppm racemate 6. Repeating step 4 twice RS of THF: 706 ppm Cake: racemate Chiral purity: 52.1% 7. Filtering the suspension Filtrate: Chiral purity: 99.5% Yield of enantiomer: 83%Batch Starting NomaterialProcedure Result1. Charging 88 wt% Form 30 and 12 wt% racemate into a reactor / 2. Charging 10 V THF, stirring at 25°C to clear solution / 3. Concentrating to 3 V, then adding 4.3 V MEK / 4. Concentrating to 3 V, solid nucleation, then adding 4.3 V 88 wt% Form 30: MEK / B1 12 wt% 5. Repeating step 4 twice RS of THF: 2995 ppm racemate: Cake: racemate Chiral purity: 52.8% 6. Filtering the suspension Filtrate: Chiral purity: 99.5% Yield of enantiomer: 86% 1. Charging 88 wt% Form 30 and 12 wt% racemate into a reactor. / 2. Charging 10 V THF, stirring at 25 °C to clear solution / 3. Concentrating to 3 V, then adding 3.4V MEK / 4. Concentrating to 3 V, solid nucleation, then adding 3.4 V Cake: racemate MEK Chiral Purity: 55.0% 88 wt% Form 30: RS of THF : 15.9% C1 12 wt% 5. Concentrating to 3 V, then adding 3.4 V MEK RS of THF: 4.4% racemate: 6. Concentrating to 3 V, then adding 3.4 V MEK RS of THF: 1.0% Cake: racemate Chiral purity: 51.4 % 7. Filtering the suspension Filtrate: Chiral purity: 99.4% Yield of enantiomer: 85% 8. Concentrating filtrate to 4.6 V / Table 3. Crystallization of Form 30 in MEK / n-heptane system starting from mixtures in Table 2. Initial point1See2 3Anti-solvent MEK / n-heptane ding & aging addition Cooling ratio (V / V) Filtrate source T (°C) MEK / n-heptane T ( MEK / n-heptane Ratio (V / V) °C) final ratio (V / V) Time (h) T (°C) Time (h) 6.0 / 12.1 Table 2, Batch A1, (1V / 2V) 6.0 V MEK 25 6.0 / 0.94 25 6.0 / 12.1 12 / 1stratio 6.3 / 12.6 8 6.3 / 25.1 Table 2, Batch B1,nd(1V / 4V)6.3 V MEK25 6.3 / 0.95 252 ratio 6.3 / 18.84 / 3rdratio 6.3 / 25.1 4 4.6 / 13.8 Table 2, Batch C1, (1V / 3V) 4.6 V MEK 40 4.6 / 0.4 40 4.6 / 13.8 12 25 2.5 Note: 1. Volume was based on input of Form 30 and racemate. 2. Seed loading 2 wt% based on Form 30 (wt% seed of Form 30 based on the amount of Form 30 present in the filtrate). 3. Aging for 4 hours.

[0157] Material loss was determined by weighing the mother liquor and measuring its assay in wt% of the product by HPLC.

[0158] The amount of solvents in the crystallized product were determined by Headspace gas Chromatography (GC-HS) Table 4. Results of crystallization experiment in MEK / n-heptane system yielding XRPD of Form 30. MEK / n-heptane Purity Chiral Isolati1ML loss (wt / wt%) Batch No ratio (V / V) (a%) Purity on yield 1:2 MEK / n- 1:3 MEK / n- 1:4 MEK / n- GC-HS (ppm) (a%) (%) heptane heptane heptane MEK: 1087 A2 6.0 / 12.1 (1V / 2V) 100 99.4 70 13 / / THF: <200 n-hep: <200 MEK: 2642 B2 6.3 / 25.1 (1V / 4V) 99.9 99.6 82 12 4 2 THF: <48 n-hep: <162 MEK: 1389 C2 4.6 / 13.8 (1V / 3V) 100 99.5 82 / 2 / THF: <200 n-hep: <200 Note: 1. Based on input amount (including Form 30 and racemate corrected for the added seeds). Table 5. Racemate rejection procedures in MEK / n-heptane starting from crude reaction solution. Batch Starting NomaterialProcedure Result1. Crude solution (11.0 V THF) was concentrated to 3 V, then adding 3.4 V MEK / Cake: racemate 2. Concentrating to 3 V, solid nucleation, Chiral Purity: 53.5% then adding 3.4 V MEK Filtrate: Chiral Purity: 97.3% RS of THF: 10.96%, Cake: racemate crude solution Chiral purity: 54.3% purity: 99.2%, D1 chiral purity: 3. Concentrating to 3 V, then adding 3.4 V MEK Filtrate: 92.5%, Chiral purity: 99.5% 85% Form 30 RS of THF: 2.98%, 4. Concentrating to 3 V, then adding 3.4V MEK RS of THF: 0.95% Cake: racemate Chiral purity: 53.2% 5. Filtering the suspension Filtrate: Chiral purity: 99.5% Yield of enantiomer: 82% 6. Concentrating filtrate to 4.6 vol RS of THF: 0.46% crude solution, 1. Crude solution (10.7 V THF) was concentrated to 3 V, then adding / E1 purity: 94.4%, 3.4 V MEK chiral purity: 2. Concentrating to 3 V, solid nucleation, then adding 3.4 V 92.6%,MEK / Batch Starting NomaterialProcedure Result85.2% Form 30 Cake: racemate Chiral purity: 52.7% 3. Concentrating to 3 V, then adding 3.4 V MEK Filtrate: Chiral purity: 99.0% RS of THF: 6859 ppm, 4. Concentrating to 3 V, then adding 3.4V MEK RS of THF: 2687 ppm Cake: racemate Chiral purity: 52.3% 5. Filtering the suspension Filtrate: Chiral purity: 99.2% Yield of enantiomer: 77% 6. Concentrating filtrate to 4.6 vol RS of THF: 114 ppm

[0159] Form 30 seed micronization was performed by Jet milling or manual grinding using pestle and mortar before being used in the crystallization experiments. Table 6. Crystallization of Form 30 in MEK / n-heptane system starting from mixtures in Table 5. MEK / n-heptane o (V / V) Initial po1 3rati int Seeding & aging Anti-solvent addition Cooling Filtrate MEK / n-heptane Seed Loading MEK / n-he rce T (° ptane Time T Time sou C) Ratio (V / V) (wt%)2final ratio (V / V) (h) (°C) (h) Table 5, 4.6 / 13.8 Batch D1, 40 4.6 / 0.4 2 4.6 / 13.8 12 25 2.5 4.6 vol MEK Table 5, 4.6 / 13.8 Batch E1, 40 4.6 / 0.4 5 (micronized see4.6 / 13.8 12 25 2.54.6 vol MEKd)Note: 1. Volume was based on input of Form 30 and racemate. 2. Seed loading based on Form 30 (wt% seed of Form 30 based on the amount of Form 30 present in the filtrate). 3. Aging for 4 hours.

[0160] ML loss corresponds to the percentage of material which did not crystalize. Table 7. Result of crystallization experiment in MEK / n-heptane system yielding XRPD of Form 30. Batch NoMEK / n-heptane ratioPurity Chiral Isolation ML loss (V / V) (a%) Purity (a%) yield (%)1(wt / wt%) GC-HS (ppm) MEK: 1789 D2 4.6 / 13.8 99.9 99.6 75 4 THF: <200 n-hep: 170 4.6 / 13 MEK: 2036 E2 .8 5wt% micronized seed 99.9 99.3 70 3 THF: <200 n-hep: 169 Note: 1. Based on input amount (including Form 30 and racemate corrected for the added seeds).Example 4: Racemate rejection and form 30 crystallization in MEK / methanol The below general procedure was 1. Concentrating the THF crude reaction solution at temperatures between 25 – 40 °C 2. Adding MEK (3.4 V) 3. Repeating steps 1-2 one to five times until the amount of THF was below to < 3% by weight 4. Concentrating to 4.6 V 4. Filtering the suspension to remove racemate and collecting the filtrate and heating to 40 °C 5. Adding anti-solvent MeOH (2.5 – 4.6 V) 7. Adding 2-5 wt% seeds of Form 30 (based on the amount of Form 30 present in the filtrate) 8. Adding MeOH (9.2 – 11.3 V) 9. Cooling to 0 °C 10. Isolating, washing and drying the resulting solids Table 8. Racemate rejection procedures in MEK / MeOH starting from crude reaction solution. Batch No Starting material Procedure Result 1. Crude solution (12 V THF) was concentrated to 3 V, then adding 3.4 V MEK / 2. Concentrating to 3 V, solid nucleation, then adding / crude solution, 3.4 V MEK F1 purity: 94.4%, 3. Repeating step 2 twice / chiral purity 92.6%, Filtrate: 85.2% Form 30 4. Filtering the suspension Chiral purity: 99.3% Yield of enantiomer: 79% 5. Concentrating filtrate to 4.6 V RS of THF: 0.05% 1. Crude solution (7 V THF) was concentrated to 3 V, then adding 3.4 V MEK / 2. Concentrating to 3 V, solid nucleation, then adding 3.4 V MEK / crude solution, 3. Repeating step 2 twice / purity: 99.1%, Cake: racemate chiral purity 94 Chiral purity: G1 .8%, 89.6% Form 30, 51.7%, 10% 3M-R55 treatment at F Material loss: dissolution step 4. Filtering the suspension ~0.1%; Filtrate: Chiral purity: 99.5% Yield of enantiomer: 88% 5. Concentrating filtrate to 4.6 V RS of THF: 0.62%Table 9. Crystallization procedure of Form 30 in MEK / MeOH system Initial point1& aging3Anti-solvent addition Cooling MEK / MeOH V) Filtrate source T (°C) MEK / MeO Time ratio (V / H Seed MEK / MeOH Time ratio (V / V) Loading (wt%)2final ratio (V / V) (h) T (°C) (h) 4.6 / 13.8 Table 8, Batch F1 5 (micr (1V / 3V) 4.6 vol MEK 40 4.6 V / 2.5 V onized seed) 4.6 / 13.8 12 0 6.7 4.6v / 13.8v Table 8, Batch G1 (1V / 3V) 4.6 vol MEK 40 4.6 V / 4.6 V 2% 4.6 / 13.8 12 0 6.7 Note: 1. Volume was based on input of Form 30 and racemate. 2. Seed loading based on Form 30 (wt% seed of Form 30 based on the amount of Form 30 present in the filtrate). 3. Aging for 4 hours. Particle size determination (PSD) was performed with laser diffraction as described in the Methodology section. Table 10. Result of crystallization experiment with MEK / MeOH system yielding XRPD of Form 30.Batch NoMEK / MeOHPurity Chiral Isolation ML loss GC-HS PSD (µm) ratio (V / V) (a%) purity (a%) yield1(%) (%) (ppm) Dv (10) Dv (50) Dv (90) 4.6 / 13 MEK: 253 F2 .8 (1V / 3V) 5% micronized seed100 100 43 36MeOH: 465 / THF: <200 4 MEK: 274 G2 .6 / 13.8 (1V / 3V) 2% normal seed100 100 46 39MeOH:<200 11.5 26.1 46.8 THF: <200 Note: 1. Based on input amount (including Form 30 and racemate corrected for the added seeds). Example 5: Racemate rejection and form 30 crystallization in MEK / methanol (MeOH) / water – first MeOH addition The below general procedure was followed: 1. Concentrating the THF crude reaction solution at temperatures between 25 – 40 °C 2. Adding MEK (3.4 V) 3. Repeating steps 1-2 one to five times until the amount of THF was below < 3% by weight 4. Concentrating to 4.6 V 5. Filtering the suspension to remove racemate and collecting the filtrate and heating to 40 °C 6. Adding anti-solvent MeOH (4.6 – 13.8 V) 7. Adding 2% seeds of form 30 of Compound A (wt% seed of Form 30 based on the amount of Form 30 present in the filtrate) 8. Adding water (0 – 9.2 V)9. Cooling to 0 – 25 °C 10. Isolating, washing and drying the solids Table 11. Racemate rejection procedures in MEK / MeOH / water (first MeOH addition) starting from crude reaction solution. Batch No Starting material Procedure Result 1. Crude solution (11.7 V THF) was concentrated to 3 V, then adding 3.4 V MEK / 2. Concentrating to 3 V, solid nucleation, then adding 3.4 V MEK / H1 3. Repeating step 2 two times / Filtrate: 4. Filtering the suspension Chiral purity: 99.5% Yield of enantiomer: 84% 5. Concentrate filtrate to 4.6 vol RS of THF: 0.3% 1. Crude solution (11.7 V THF) was concentrated to 3 V, then adding 3.4 V MEK / crude solution, 2. Concentrating to 3 V, solid nucleation, then adding 3.4 V MEK / I1 purity: 99.3%, chiral purity: 94.3% 3. Repeating step 2 twice / 88.6 wt% Form 30 Filtrate: 4. Filtering the suspension Chiral purity: 99.5% Yield of enantiomer: 82% 5. Concentrating filtrate to 4.6 vol RS of THF: 0.6% 1. Crude solution (11.7 V THF) was concentrated to 3 V, then adding 3.4 V MEK / 2. Concentrate to 3 V, solid nucleation, then adding 3.4 V MEK / J1 3. Repeating step 2 twice / Filtrate: 4. Filtering the suspension Chiral purity: 99.4% Yield of enantiomer: 83% 5. Concentrating filtrate to 4.6 vol RS of THF: <200ppm Table 12. Crystallization procedures of Form 30 in MEK / MeOH / water system (first MeOH addition) starting from crude solution. al point Seeding21stanti-ndIniti1solvent 2 anti-solvent & aging3addit Cooling MEK / MeOH / H2O ion addition target ratio (V / V / V) Filtrate MEK / MeOH MEK / MeOH / H2O MEK / MeOH / H2O source Solvent ratio Solvent ratio T (°C) Solvent ratio T = 40 °C (V / V) (V / V / V) – time (h) Time (h) (V / V / V) Time (h) 4.6 / 4.6 / 9.2 Table 11, Batch V / V / V) H1,44.6 / 4.6 / 9.225 °C (1 / 1 / 2.6 / 4.6 / 4.6 V MEK 12 hours 2.5 h 4.6 / 4.6 / 2.3 4.6 / 4.6 / 4.6 Table 11, Batch I1, 4.6 / 6 hours 25°C (1 / 1 / 1 V / V / V) 4.6 V MEK 4.6 4.6 / 4.6 / 4.6 2.5 h / 6 hours 4.6 / 13.8 / 4.6 Table 11, Batch MEK / MeOH 0°C 4.6 / 13.8 / 0.92 (1 / 3 / 1 V / V / V) J1, 4.6 / 4.6 4.6 / 13.8 6.7h 1 hoint Seeding21stanti-solvendInitial p1nt 2 anti-solvent & aging3additCoolingMEK / MeOH / H2Oionaddition target ratio (V / V / V) Filtrate MEK / MeOH MEK / MeOH / H2O MEK / MeOH / H2O source Solvent ratio Solvent ratio T (°C) So (V / V) (V / V / V) – time (h) T lvent ratio T = 40 °C ime (h) (V / V / V) Time (h) 4.6 V MEK 12 hours 4.6 / 13.8 / 2.3 1 h 4.6 / 13.8 / 4.6 1 h Note: 1. Volume was based on input of Form 30 and racemate. 2. Seed loading 2% based on Form 30 (wt% seed of Form 30 based on the amount of Form 30 present in the filtrate). 3. Aging for 4 hours. Table 13. Results of crystallization experiment with MEK / MeOH / water system (first MeOH addition). MEK / MeOH / H2O Puri ChiralML loss (wt / wt%)Batch No target ratio ty Purity Isolation GC-HS 1Actual(V / V / V) (a%) (a%) yield (%)(ppm)4.6 / 4.6 / 9.2 MEK: 1241 H22, 3(1 / 1 / 2 V / V / V) 100 100 79 1 MeOH: <200 THF: <200 4.6 / 4.6 / 4 MEK: 624 I22, 3.6 (1 / 1 / 1 V / V / V) 100 100 71 5 MeOH: 447 THF: <200 4.6 / 13.8 / 4.6 31 (1 / 3 / 0.2) (1 / 3 / 1 V / V / V, 15 (1 / 3 / 0.5) J2 add different / / 65 / amount 3 (1 / 3 / 1) of water) Note: 1. Based on input amount (including Form 30 and racemate corrected for the added seeds). 2. XRPD of Form 30. 3. KF 0.02 wt% water. Example 6: Racemate rejection and form 30 crystallization in MEK / methanol (MeOH) / water – first water addition The below general procedure was followed: 1. Concentrating the THF crude reaction solution at temperatures between 25 – 40 °C. The starting material for Batch described in Tables 14-16 were crude solutions. 2. Adding MEK (3.4 V). 3. Repeating steps 1-2 one to five times until the amount of THF was below < 3% by weight. 4. Concentrating to 4.6 V. 5. Filtering the suspension to remove racemate and collecting the filtrate and heating to 40 °C. 6. Adding anti-solvent MeOH (4.6 V for Batch in Tables 14-16 or 4.6-13.8 V for Batch in Tables 17-19).7. Adding 2% seeds of form 30 JNJ-64281802 (wt% seed of Form 30 based on the amount of Form 30 present in the filtrate). 8. Adding water (0.92 – 2.3 V for Batch in Tables 14-16 or 0.92 – 4.6 V for Batch in Tables 17-19). 9. Adding anti-solvent MeOH (9.2 V) for Batch Nos. K-O. 10. Cooling to 0 °C. 11. Isolating, washing and drying the resulting solids. Table 14. Racemate rejection procedures in MEK / MeOH / water (first water addition) starting from crude reaction solution. Batch No Starting material Procedure Result 1. Crude solution (11.7 V THF) was concentrated to 3 V, then adding 3.4 V MEK / 2. Concentrating to 3 V, solid nucleation, then adding 3.4 V MEK / K1 3. Repeating step 2 two times / Filtrate: 4. Filtering the suspension Chiral purity: 99.6% Yield of enantiomer: Crude D, 88% no carbon treatment, 5 Concentrating filtrate to 4.6 vol RS of THF: 0.14% purity: 99.3%, 1. Crude solution (11.7 V THF) was concentrated to 3 V, chiral purity: 94.3%, then adding 3.4 V MEK / 88.6 wt% Form 30 2. Concentrating to 3 V, solid nucleation, then adding 3.4 V MEK / 3. Repeating step 2 two times / L1 Filtrate: 4. Filtering the suspension Chiral purity: 99.5% Yield of enantiomer: 81.4% 5. Concentrate filtrate to 4.6 volRS of THF: THF:0.96% 1. Crude solution (10.0 V THF) was concentrated to 3 V, then adding 3.4 V MEK / Crude D, 2. Concentrating to 3 V, solid nucleation, then addin / no carbon treatment,g 3.4 V MEKM1 purity: 99.5%, 3. Repeating step 2 two times / chiral purity 94.4%, Filtrate: 88.8% Form 30 4. Filtering the suspension Chiral purity: 99.3% Yield of enantiomer: 88.8% 5. Concentrating filtrate to 4.6 V RS of THF: 0.74%Table 15. Crystallization procedures of Form 30 in MEK / MeOH / water system (first water addition) starting from crude reaction l point Seed2Initia1ing & ch No ag3Anti-solvent addition Cooling Bat ing Filtrate T MEK / MeOH Solvent rati Time T Time source (°C) Ratio (V / V) o (h) (°C) (h) 1stwater addition (MEK / MeOH / water 8 K2 Batch J1, 4.6 V / 4.6 V / 2.3 V) (aging for 4 h after water Table 11 40 4.6 / 4.6 Aging 4 0 6.7 addition) 4.6 V MEK 2ndMeOH addition (MEK / MeOH / water 6 4.6 V / 13.8 V / 2.3 V) 1stwater addition (MEK / MeOH / water 8 L2 Batch L1, 4.6 V / 4.6 V / 2.3 V) (aging for 9 h after water Table 14 40 4.6 / 4.6 Aging 9 0 6.7 addition) 4.6 V MEK 2ndMeOH addition (MEK / MeOH / water 6 4.6 V / 13.8 V / 2.3 V) 1stwater addition (MEK / MeOH / water 8 M2 Batch M1, 4.6 V / 4.6 V / 2.3 V) (aging for 24 h after water Table 14, 40 4.6 / 4.6 Aging 24 0 6.7 addition) 4.6 V MEK 2ndMeOH addition (MEK / MeOH / water 6 4.6 V / 13.8 V / 2.3 V) 1stwater addition (MEK / MeOH / water 5 M3 Batch 4.6 V / 4.6 V / 0.92 V) (aging for 9 h after water M1,Table 14, 40 4.6 / 4.6 Aging 9 reduce water amount) 4.6 V MEK 2nd0 6.7 addition, MeOH addition (MEK / MeOH / water 4.6 V / 13.8 V / 0.92 6 V) 1stwater addition (MEK / MeOH / water 4 4.6 V / 4.6 V / 0.92 V) Aging 10 M4 (aging for 10 hours, charge Batch M1, 2ndMeOH addition additional water after MeOH Table 14, 40 4.6 / 4.6 (MEK / MeOH / water MEK 4.6 V / 13 6 0 6.7 addition) 4.6 V .8 V / 0.92 V) 3rdwater addition (MEK / MeOH / water 4.6 V / 13.8 V / 1.84 4 V) Note: 1. Volume was based on input of Form 30 and racemate. 2. Seed loading 2% based on Form 30 (wt% seed of Form 30 based on the amount of Form 30 present in the filtrate). 3. Aging for 4 hours.The water content in weight % of the isolated solids was determined by Karl Fischer (KF) titration. Table 16. Results of crystallization experiment with MEK / MeOH / water system (first water addition) Batch No MEK / MeOH / water Purity ( Chiral Isolation ML loss KF GC-HS Ratio (V / V / V) a%) Purity (a%) yield (%)1(wt / wt%) (wt%) (ppm) 4.6 / 13.8 / 2.3 MEK: 607 K2 (1V / 3V / 0.5V) 100 100 77 8 0.03 MeOH: <200 (aging for 4 h after water addition) THF: <200 4.6 / 13.8 / 2.3 MEK: 588 L2 (1V / 3V / 0.5V) 100 100 75 7 0.07 MeOH: 728 (aging for 9 h after water addition) THF: <200 4.6 / 13.8 / 2.3 MEK: 618 M2 (1V / 3V / 0.5V) 99.9 100 71 6 0.02 MeOH: 508 (aging for 24 h after water addition) THF: <200 4.6 / 13.8 / 0.92 MEK: 376 M3 (1V / 3V / 0.2V) 100 100 62 19 0.07 MeOH: 691 THF: <200 MEK: 550 M4 4.6 / 13.8 / 1.84 (1V / 3V / 0.4V) 100 100 64 12 0.01 MeOH: <200 THF: <200 Note: 1. Based on input amount (including Form 30 and racemate corrected for the added seeds). Example 7: Racemate rejection and form 30 crystallization in MEK / methanol (MeOH)- 2.1 V MEK (concentrated process) The below general procedure was followed: 1. Concentrating the THF crude reaction solution at temperatures between 25 – 40 °C 2. Adding MEK (3.4 V) 3. Repeating steps 1-2 one to five times until the amount of THF was below < 3% by weight 4. Filtering the suspension to remove the racemate and collecting the filtrate 5. Concentrating the filtrate to 2.1 V and heating to 40 °C 6. Adding the anti-solvent MeOH (6.3 V - 12.6 V) and crystallizing Compound A as non- solvated form 30 7. Cooling to 0 °C 8. Isolating, washing and drying the resulting solids. Table 17. Racemate rejection procedures in MEK / MeOH – 2.1 V MEK Batch NoStarting material Procedure Resultcrude solution, 1. Crude solution (10 V THF) was concentrated to 3 V, then adding 3.4 V / purity: 99.5%, MEK W1 chiral purity 2. Concentrating to 3 V, solid nucleation, then adding 94.4%, 3.4 V MEK / 88.8% Form 30 3. Repeating step 2 two times / Batch NoStarting material Procedure ResultFiltrate: 4. Filtering the suspension Chiral purity: 98.8% Yield of enantiomer: 89% 5. Concentrating filtrate to 2.1 vol RS of THF: 0.05% 1. Crude solution (10 V THF) was concentrated to 3 V, then adding 3.4 V MEK / crude solution, 2. Concentrating to 3 V, solid nucleation, then adding 9.5%, 3. / purity: 9 4 V MEK X1 chiral purity 3. Repeating step 2 two times / 94.4%, Filtrate: 88.8% Form 30 4. Filtering the suspension Chiral purity: 99.3% Yield of enantiomer: 88% 6. Concentrating filtrate to 2.1 vol RS of THF: 0.74% 1. Crude solution (7 V THF) was concentrated to 3 V, then adding 3.4 V MEK / crude solution, 2. Concentrating to 3 V, solid nucleation, then adding 3.4 V MEK / purity: 99.1%, chiral purity 3. Repeating step 2 two times / Y1 94.8%, Cake: racemate 89.6% Form 30, Chiral purity: 52.2% 10% 3M-R55 4. Filtering the suspension material loss: ~0.4% treatment Filtrate: Chiral purity: 99.5% 6. Concentrating filtrate to 2.1 vol RS of THF: 0.17% 1. Crude solution (13.9 V THF) was concentrated to 3 V, then adding 3.4 V MEK / 2. Concentrating to 3 V, solid nucleation, then adding crude solution3.4 / purity: 97.3,V MEKchiral purity 3. Repeating step 2 two times / Z1 93.5%, Cake: racemate 87% Form 30 chiral purity: 54.2, 10% 3M-R55 4. Filtering the suspension material loss: ~1.2%; treatment Filtrate: Chiral purity: 99.3% Yield of enantiomer: 85% 5. Concentrating filtrate to 2.1 vol RS of THF: 0.61% 1. Crude solution (8.2 V THF) was concentrated to 3 V, then adding 3.4 V MEK / 2. Concentrating to 3 V, solid nucleation, then adding 3.4 V MEK / crude solution 3. Repeating step 2 two times / purity: 99.3%, Cake: racemate chiral purity chiral purity: 51.7%, material AZ1 94.8%, 4. Filterin loss: ~0.3%; 90% Form 30, g the suspension Filtrate: 10% 3M-R55 Chiral purity: 99.5% treatment Yield of enantiomer: 87% 5. Concentrating filtrate to 4.6 vol RS of THF: 1.14% 6. Adding 10% 3M-R55 and stirring for 3 h at 40 °C / 7. Filtering by pressure filter, then concentrated to 2.1 vol RS of THF: < 1.14%Table 18. Crystallization procedures of Form 30 MEK / MeOH – 2.1 V MEK Initial point1& aging4Anti-solvent addition Cooling Batch No Filtrate source Solvent Seed S T (°C) T = 40 °C Loading2(wt%) olvent ratio Time (h) Time (h) W1 Batch W1, Table 17, MEK / MEK / MeOH 0°C 1V / 6V, no carbon treatment 2.1 vol MEK 2.1V (nucleation)2.1 V / 12.6 V126.7 h 1 X1 MEK / MeOH 1V / 6V, Batch X1, Table 17, MEK 2.1 V / 6.3 V 6 0 °C 6.7 h MeOH addition with 2 steps, 2.1 vol MEK 2.1V 2%2MEK / MeOH no carbon treatment 2.1V / 12.6 V (0°C for 6h) Y1 1V / 6V, batch Y1, Table 17, MEK MEK / MeOH 2.1 vol MEK 2.1V 2% 2 12 0°C 10% 3M-R55 treatment .1 V / 12.6 V Z1 1V / 6V, Batch Z1, Table 17, MEK3MEK / MeOH 0 10% 3M-R55 treatment 2.1 vol MEK 2.1V 2% 2.1 V / 12.6 V 12 6.7 h AZ1 1V / 6V, Batch AZ1, Table 17, MEK 2 MEK / MeOH 0°C charcoal treatment 2.1 vol MEK % 12 double 2.1V 2.1 V / 12.6 V 6.7h Note: 1. Volume was based on input of Form 30 and racemate. 2. Seed loading based on Form 30 (wt% seed of Form 30 based on the amount of Form 30 present in the filtrate). 3. A little of solid nucleation before seed addition. 4. Aging for 4 hours. Table 19. Results of crystallization experiment with MEK / MeOH – 2.1 V MEK Batch Chiral ML Key point Purity (a%) p Isolation KF GC-HS No urity1loss (a%) yield (%) (%) (wt%) (ppm) MEK / MeOH 2.1 / MEK: 317 W2212.6 V / V,no carbon treatment 99.9 100 76 10 / MeOH: <200 THF: <200 MEK / MeOH 2.1 / 12.6 V / V 21 73 (5% l (1 / 3) MEK: 434 X22(MeOH addition with 2 steps, 100 100 oss on the / MeOH: arbon treatment) wal 661 no c l)8(1 / 6)THF: <200M MEK: 300 Y22EK / MeOH 2.1 / 12.6 V / V, 10% 3M-R55 treatment100 100 76 9 / MeOH: 778 THF: <200 MEK / MeOH 2.1 MEK: 330 Z22 / 12.6 V / V, 10% 3M-R55 treatment 99.92 100 73 11.6 0.02 MeOH:231 THF: <200 MEK / MeOH 2.1 / MEK: 406 AZ2212.6 V / V double charcoal treatment 100 100 75110 / MeOH:<200 THF: <200 Note: 1. ~5% material loss in polish filtration step. 2. XRPD Form 30Example 8: Racemate rejection and form 30 crystallization in MEK / methanol (MeOH) / water (H2O) – crude solution 3M-R55 carbon (Tables 20-22), by other types of carbon (Tables 23-25), or by Nuchar AquaGuard® carbon (Tables 26-28) The below general procedure was followed: 1. Concentrating the THF crude reaction solution at temperatures between 25 – 40 °C 2. Adding MEK (3.4 V) 3. Repeating steps 1-2 one to five times until the amount of THF was below < 3% by weight 4. Filtering the suspension to remove racemate and collecting the filtrate 5. Concentrating filtrate to 2.1 V and heating to 40 °C 6. Adding seeds of form 30 of Compound A (2 wt% of Form 30 based on the amount of Form 30 present in the filtrate) 7. Adding anti-solvent MeOH (12.6 V) and crystallizing Compound A as non-solvated form 30 8. Adding water 1.05 V and cooling to 0 °C 9. Isolating, washing and drying the resulting solids. Table 20. Racemate rejection procedures in MEK / MeOH / water - crude solution was treated with 3M-R55 carbon at the chiral hydrogenation step. Batch No Starting material Procedure Result 1. Crude solution (8.2 V THF) was concentrated to 3 V, then adding 3.4 V MEK / AA1 2. Concentrating to 3 V, solid nucleation, then adding 3.4 V MEK / Crude Solution, purity: 99.3%, 3. Repeating step 2 two times / chiral purity 94.8%, Cake: racemate 90% Form 30, chiral purity: 10% 3M-R55 51.7%, material loss: loose carbon 4. Filtering the sus ~0.3% BB1 pension treatment Filtrate: Chiral purity: 99.5% Yield of enantiomer: 87% 5. Concentrating filtrate to 2.1 vol RS of THF: <1.14% 1. Crude solution (13.9 V THF) was concentrated to 3 V, then adding 3.4 V MEK / 2. Concentrating to 3 V, solid nucleation, then adding 3.4 Crude Solution, V MEK / purity: 98.0, 3. Repeating step 2 two times / CC1 chiral purity 93.5%, Cake:racemate 87% Form 30, Chiral purity: 52.8%, 10% 3M-R55 carbon material loss: ~0.9% cartridge treatment 4. Filtering the suspension Filtrate: Chiral purity: 99.7% Yield of enantiomer: 85%Batch NoStarting material Procedure Result5. Concentrating filtrate to 2.1 vol RS of THF: 0.13% 1. Crude solution (13.9 V THF) was concentrated to 3 V, then adding 3.4 V MEK / 2. Concentrating to 3 V, solid nucleation, then adding 3.4 / Crude Solution, V MEK purity:97.3, 3. Repeating step 2 two times / chiral purity 93.5%, Cake:racemate DD1 87% Form 30, Chiral purity: 52.4%, 10% 3M-R55 material loss: 0.59% carbon cartridge 4. Filtering the suspension Filtrate: treatment Chiral purity: 99.3% Yield of enantiomer: 85% 5. Concentrating filtrate to 2.1 vol RS of THF: 0.85% 1. Crude solution (8.4 V THF) was concentrated to 3 V, then adding 3.4 V MEK / Crude Solution, 2. Concentrating to 3 V, solid nucleation, then adding 3.4 / purity:99.46, V MEK chiral purity: 92.7%, 3. Repeating step 2 two times / EE1 85.4% Form 30, Cake:racemate 10% pre-treated 3M- Chiral purity:52.7%, R55 4. Filterin material loss: ~1% carbon cartridge g the suspension Filtrate: with TEA treatment Chiral purity: 99.6% RS of THF: 1.8% 5. Concentrating filtrate to 2.1 vol / 1. Crude solution (13.9 V THF) was concentrated to 3 V, then adding 3.4 V MEK / 2. Aging for 18h at 25oC, no solid nucleation / 3. Adding 2.0% racemate as seed / 4. Aging for 3h, no solid nucleation / Crude Solution, 5. Concentrating to 3 V, solid nucleation, then adding 3.4 purity:97.3, V MEK / FF1 chiral purity 93.5%, 6. Repeating step 1 twice / 87% Form 30, Cake:racemate 10% 3M-R55 carbon Chiral purity: 52.8%, cartridge treatment material loss: 0.56% 7. Filter the suspension Filtrate: Chiral purity: 99.4% Yield of enantiomer: 85.7% 8. Concentrate filtrate to 2.1 vol / Table 21. Crystallization procedures of Form 30 in MEK / MeOH / water - crude solution was treated with 3M-R55 carbon at the chiral step. Initial Seeding & Batch No point1aging4Anti-solvent addition Cooling MEK / MeOH / water Filtrate Seed T (°C) ratio (V / V / V) source Ratio Loading Solvent ratio Time 0 °C (wt%) ( Time T= 42h) (h) 1stMeOH addition Batch AA1, (MEK / MeOH 10 2.1 V / 12.6 V) AA1 Table 20 MEK / 6 / 0.5 2.1 vol 2.1 V 2 A 0 °C 1 ging 4 nd6.7 h MEK 2 water addition n (MEK / MeOH / water 2 2.1 V / 12.6 V / 1.05 V) 1stMeOH addition CC1 (MEK / MeOH 10 1 / 6 / 0.5, Batch CC1, 2.1 l was treated with 10% Tabl V / 12.6 V) 0 °C (starting materia e 20 MEK3arbon cartridge with 328 g 2.1 vol 2 2 Aging 4 6. 3M-R55 c .1 Vnde) M 2 water addition 7 h scal EK (MEK / MeOH / water 2 2.1 V / 12.6 V / 1.05 V) 1stMeOH addition (MEK / MeOH 10 EE1 Batch EE1, 1 / 6 / 0.5, Table 20 MEK 2.1 V / 12.6 V) arting material was treated with3M- 2.1 vol 2.1 V 2 Agi 0 °C (st ng 4 6.7 h R55 carbon cartridge with TEA) MEK 2ndwater addition (MEK / MeOH / water 2 2.1 V / 12.6 V / 1.05 V) 1stMeOH addition DD1 Batch DD1 (MEK / MeOH 10 1 / 6 / 0.5 , 2.1 V / 12.6 V) (starting material was treated with 10% Table 20 MEK30 °C M-R55 carbon cartridge with 328 g 2.1 vo2 Aging 43 l2.1 Vnd6.7 hMEK 2 water addition scale, 100g scale) (MEK / MeOH / water 2 2.1 V / 12.6 V / 1.05 V) 1stMeOH addition (MEK / MeOH 10 BB1 Batch BB1, 2.1 V / 12.6 V) 1 / 6 / 1 Table 20 MEK 0 ° arting material was treated with 10% 2.1 vol 2.1 V 2 Agi C (st ng 4 n 6.7 h 3M-R55 loose carbon treatment) MEK 2dwater addition (MEK / MeOH / water 2 2.1 V / 12.6 V / 2.1 V) 1stMeOH addition FF1 (MEK / MeOH 10 1 / 6 / 1.0 Batch FF1, 2.1 V / 12.6 V) (starting material was treated with 10% Table 20 MEK30 °C 2.1 vol 2. 2 Aging 4 3M-R55 carbon cartridge with 328 g 1 V 2ndwater addition 6.7 h scale) MEK (MEK / MeOH / water 2 2.1 V / 12.6 V / 2.1 V)Initial Seeding & Batch Noaging4Anti-solvent addition CoolingMEK / MeOH / water Seed T (°C) ratio (V / V / V) source Ratio Loading Solvent ratio Time (h) Time T= 40 °C2(wt%) (h) Note: 1. Volume was based on input of Form 30 and racemate. 2. Seed loading based on Form 30 (wt% seed of Form 30 based on the amount of Form 30 present in the filtrate). 3. A little of solid nucleation before seed addition. 4. Aging for 4 hours. Table 22. Results of crystallization experiment with MEK / MeOH - crude solution was treated with 3M-R55 carbon cartridge. Batch MEK / MeOH / H2O Purity Chiral Isolation ML loss KF GC-HS No ratio (V / V / V) (a%) Purity yield (a%) (%)1(wt / wt%) (wt%) (ppm) MEK: 343 AA221 / 6 / 0.5 100 100 80 6 0.01 MeOH:<200 THF: <200 1V / 6V / 0.5V MEK: 412 CC22(starting material was treated with 10% 3M-R55 99.91 100 81 4 0.01 MeOH:<200 carbon cartridge with 328 g scale) THF: <200 1 / 6 / 0.5 MEK: 480 EE22(starting material was treated with pre-treated 100 100 83 4 0.02 MeOH<200 3M-R55 carbon cartridge with TEA) THF<200 1 / 6 / 0.5 MEK: 411 DD22(starting material was treated with 10% 3M-R55 99.92 100 81 (crude dge with 328 g scale, 100g scale) yiel 6 0.01 MeOH:<200 carbon cartri d) THF: <200 MEK: 406 BB221 / 6 / 1 V / V / V 100 100 84 4 0.01 MeOH:<200 THF: <200 1 / 6 / 1.0 V / V / V, MEK: 40 (starting material was treated with 10% 3M-R55 99.92 100 83 (cr 6 FF22ude cale) yie 3 0.02 MeOH:<200 carbon cartridge with 328 g s ld) THF: <200 Note: 1. Based on input amount (including Form 30 and racemate corrected for the added seeds). 2. XRPD Form 30. Table 23. Racemate rejection procedures in MEK / MeOH / water - crude solution was treated with other types of carbon cartridges. Batch No Starting material Procedure Result 1. Crude solution (10.4 V THF) was concentrated to 3 V, then adding 3.4 V MEK / Crude Solution, 2. Concentrating to 3 V, then adding 3.4 V MEK, solid purity: 99.4% nucleation / GG1 , chiral purity: 92.7%, 3. Repeating step 2 two times / 85.4% Form 30 Cake:racemate 4. Filtering the suspension Chiral purity: 51.1%, material loss: ~0.4%Batch NoStarting material Procedure ResultFiltrate: Chiral purity: 99.6% Yield of enantiomer: 85% 5. Concentrating filtrate to 2.1 vol RS of THF: 0.42% 1. Crude solution (11.0 V THF) was concentrated to 3 V, then adding 3.4 V MEK / 2. Concentrating to 3 V, solid nucleation, then add 3.4 V MEK / Crude Solution, purity: 3. Repeating step 2 two times / 1 99. Cake:racemate HH 0%, chiral purity: 94.2%, Chiral purity: 51.5%, 88.2% Form 30 material loss: ~0.4% 4. Filtering the suspension Filtrate: Chiral purity: 99.4% Yield of enantiomer: 88% 5. Concentrating filtrate to 2.1 vol RS of THF: 0.47% 1. Crude solution (11.2 V THF) was concentrated to 3 V, then adding 3.4 V MEK / 2. Concentrating to 3 V, adding 3.4 V MEK / 3. Concentrating to 3 V, solid nucleation, then adding 3.4 V MEK / Crude Solution, 4. Repeating step 1 once / II1 chiral purity: 94.5 Cake:racemate 89.0% Form 30 Chiral purity: 52.7%, material loss: ~0.8% 5. Filtering the suspension Filtrate: Chiral purity: 99.7% Yield of enantiomer: 89% 6. Concentrating filtrate to 2.1 vol RS of THF: 0.22% 1. Crude solution (10.6 V THF) was concentrated to 3 V, then adding 3.4 V MEK / 2. Concentrating to 3 V, solid nucleation, then adding 3.4 V MEK / Crude Solution, 3. Repeating step 2 two times / puri Cake:racemate JJ1 ty: 98.7%, chiral purity:94.2%, Chiral purity: 52.3%, 88.4% Form 30 material loss: ~0.7% 4. Filtering the suspension Filtrate: Chiral purity: 99.5% Yield of enantiomer: 88% 5. Concentrating filtrate to 2.1 vol RS of THF: 0.08%Table 24. Crystallization procedures of Form 30 in MEK / MeOH / water - crude solution was treated with other types of carbon. Initial Batch No point1Seeding & aging4Anti-solvent addition Cooling MEK / MeOH / water Filtrate Seed T Ratio (V / V / V) source Ratio Loading2Solvent ra Time (°C) Carbon treatment tio T= 40 °C (wt%) (h) Time (h) 1stMeOH addition 1 B (MEK / MeOH 10 GG atch 1 / 6 / 0.5 GG1, M 2.1 V / 12.6 V) Unifiltech cartridge Table 2 EK30 °C 10% 3 2.1 V 2% Aging 4 6 treatment 2.1 vol 2nd.7 h water addition MEK (MEK / MeOH / water 2 2.1 V / 12.6 V / 1.05 V) 1stMeOH addition HH1 Batch (MEK / MeOH 10 HH1, 2.1 V / 12.6 V) 1 / 6 / 0.5 Table 23 MEK 2%3Ag 0°C 10% Nuchar AquaGuard® 2 ing 4 loose carbon treatment 2.1 vol .1 V 2nd6.7h water addition MEK (MEK / MeOH / water 2 2.1 V / 12.6 V / 1.05 V) 1stMeOH addition II1 Batch II1, (MEK / MeOH 10 2.1 V / 12.6 V) 1 / 6 / 0.5 Table 23 MEK 10%Nuchar carbon cartridge treatment 2.1 vol 2.1 v 2%3Aging 4 6.7h at 0 °C MEK 2ndwater addition (MEK / MeOH / water 2 2.1 V / 12.6 V / 1.05 V) 1stMeOH addition Batc (MEK / MeOH 10 JJ1 h JJ1 2.1 V / 12.6 V) 1 / 6 / 0.5 , Table 23 MEK 2%30°C 10% RGC loose 2.1 v Aging 4 6.7 arbon treatment 2.1 vol 2ndwa h c ter addition MEK (MEK / MeOH / water 2 2.1 V / 12.6 V / 1.05 V) Note: 1: Volume was based on input of Form 30 and racemate 2: Seed loading based on Form 30 (wt% seed of Form 30 based on the amount of Form 30 present in the filtrate) 3: A little of solid nucleation before seed addition. 4: Aging for 4 hours. Table 25. Results of crystallization experiment in MEK / MeOH / water - crude solution was treated with other types of carbon. Batch Starting Material Purity Chiral Isolation yield ML loss KF GC-HS No Carbon Treatment (a%) purity (a%) (%)1(%) (wt%) (ppm) 10% 3M-R55 carbo MEK: 412 CC22n cartridge 99.91 100 81 4 0.01 MeOH:<200 THF: <200 GG2 10 MEK: 554 MeOH: 2 % Unifiltech cartridge treatment 99.90 100 80 5 0.02 <200 THF: <200Batch Starting Material Purity Chiral Isolation yield ML loss KF GC-HS No Carbon Treatment (a%) (%)1(%) (wt%) (ppm) 10% Nuchar MEK: 670 HH22AquaGuard® loose 99.87 100 84 4 0.03 MeOH: <200 carbon THF: <200 10%Nuc MEK: 300 II22har carbon cartridge treatment 99.9 100 82(crude yield) 4 0.03 MeOH:<100 THF: <100 10% RGC loose MEK: 319 JJ22carbon 99.90 100 83 5 0.02 MeOH: <200 THF: <200 Note: 1. Based on input amount (including Form 30 and racemate corrected for the added seeds). 2. XRPD Form 30. Table 26. Racemate rejection procedures in MEK / MeOH / water - crude solution was treated with Nuchar AquaGuard®. Batch No Starting material Procedure Result 1. Crude solution (12 V THF) was concentrated to 3 V, / then adding 3.4 V MEK 2. Concentrating to 3 V, Crude Solution solid nucleation, then adding 3.4 V MEK RS of THF: 19.5% purity: 99.5%, chiral purity: 94.3%, 88.6% 3. Concentrating to 3 V, then addiRS of THF: 6.2%KK1 Form 30,ng 3.4 V MEK10% Nuchar AquaGuard® Cake:racemate loose carbon chiral purity: 52.6%, treatment 4. Filtering the suspension material loss:~0.7% Filtrate: Chiral purity: 99.4% Yield of enantiomer: 86% 5. Concentrating filtrate to 2.1 vol RS of THF: 2.2 % 1. Crude solution (19.3 V THF) was concentrated to 3 V, / then adding 3.4 V MEK 2. Concentrating to 3 V, then adding 3.4 V MEK, a little solid came RS of THF: 12.5% out Cake: Crude Solution Chiral purity: 53.8% purity: 99.5%, 3. Filtering the suspension Filtrate: LL1 chiral purity: 94.3%, 88.6% Form 30, Chiral purity: 97.0% ; 10% Nuchar AquaGuard® 4. Concentrating filtrate to 2.1 vol, atment more solid n / loose carbon tre ucleation Cake:racemate Chiral purity: 59.4%, material loss: 1.3% 4. Filtering the suspension Filtrate: Chiral purity: 99.6% Yield of enantiomer: 85% RS of THF: 1.8%Table 27. Crystallization procedures of Form 30 in MEK / MeOH / water - crude solution was treated with Nuchar AquaGuard®. Initial point Seeding (2 wt%) Anti-solvent Cooling Batch No & aging (4 hours) addition Filtrate source Time T ( 40 °C Solvent So °C) T= lvent ratio (h) Time (h) 1stMeOH addition (MEK / MeOH 10 KK1 Batch KK1, 2.1 V / 12.6 V) Tabl 2.1 V 0°C (concentration 3 times) e 26 Aging 4 2.1 vol MEK MEK 6.7 2ndh water addition (MEK / MeOH / water 2 2.1 V / 12.6 V / 1.05 V) 1stMeOH addition (MEK / MeOH 10 LL1 Batch LL1, 2.1 V / 12.6 V) (concentration 2 times Table 26 2.1 V Aging 0°C and filter at 2.1v) 2.1 vol MEK MEK 4 2nd6.7h water addition (MEK / MeOH / water 2 2.1 V / 12.6 V / 1.05 V) Table 28. Results of crystallization experiment in MEK / MeOH / water - crude solution was treated with other types of carbon at the chiral hydrogenation step. Batch Chiral Key pPurityIsolation ML loss KF GC-HS Nooint(a%) purity yield (%1(a%) ) (%) (wt%) (ppm) MEK: 670 HH22Standard process 99.87 100 84 4 0.03 MeOH: <200 THF: <200 Concentration 3 times, ME rystallization with higher THF 100 100 7 K: 300 KK22c 8 ent (6.2%)(cr5 0.01MeOH: 200 contude yield)THF: <200 Concentration 2 times, L2 crystallization with higher THF 100 100 7 MEK: 300 L20* 5 0.04 MeOH: <20 5%) (crude yield 0 content (12. ) THF: <200 Note: 1. Based on input amount (including Form 30 and racemate corrected for the added seeds). 2. XRPD Form 30. Example 9: Racemate rejection and form 30 crystallization in MEK / methanol (MeOH) / water (H2O) – diluted racemate rejection The below general procedure was followed: 1. Concentrating the THF crude reaction solution at temperatures between 25 – 40 °C 2. Adding MEK (3.4 – 12 V) 3. Repeating steps 1-2 one to five times until the amount of THF was below < 2% by weight 4. Filtering the suspension to remove racemate and collecting the filtrate 5. Concentrating filtrate to 2.1 V and heating to 40 °C6. Adding seeds of form 30 of Compound A (2 wt% seed of Form 30 based on the amount of Form 30 present in the filtrate) 7. Adding anti-solvent MeOH (12.6 V) and crystallizing Compound A as non-solvated form 30 8. Adding water 1.05 V and cool to 0 °C 9. Isolating, washing and drying the resulting solids Table 29. Racemate rejection procedures in MEK / MeOH / water – diluted racemate rejection Batch No Starting material Procedure Result 1. Crude solution (12 V THF) was concentrated to 3 V, then adding 12 V MEK / Crude Solution, 2. Concentrating to 7.2 V, solid nucleation, purity: 99.5%,then adding 7.8 V MEKRS of THF: 15.1%chiral purity: 94.3%, 3. Concentrated to 7.2 V RS of THF: 3.6% NN1 88.6% Form 30, Cake:racemate 10% Nuchar Chiral purity: 55.1%, material AquaGuard® 4. Filter loss: 1.2% loose carbon ing the suspension Filtrate: treatment Chiral purity: 99.6% Yield of enantiomer: 83% 5. Concentrating filtrate to 2.1 vol RS of THF: 1.6% 1. Charging 6.2 g Form 30 and 0.8 g racemate / 2. Charging 12 V THF, stirring at 25C to clear solution / 3. Concentrating to 3 V, then adding 12 V MEK / Crude Solution, 4. Concentrating to 7.2 V, then adding 7.8 V chiral purity: 94.3%, MEK RS of THF: 14.5% OO1 88.6% Form 30, 5. Concentrating to 7.2 V, solid nucleation RS of THF: 4.6% Starting material Cake:racemate from 10% 3M-R55 Chiral purity: 52.6%, cartridge treatment 6. Filtering the suspension material loss: 0.4%; Filtrate: Chiral purity: 99.3% Yield of enantiomer: 83% 7. Concentrating filtrate to 2.1 vol RS of THF: 1.6% 1. Crude solution (12 V THF) was concentrated to 3 V, then adding 3.4 V MEK / 2. Concentrating to 3 V, solid nucleation, then adding 3.4 V MEK / Crude Solution, 3. Concentrate to 3 V, then adding 3.4 V MEK / purity: 99.5%, chiral purity: 94.3%, 4. Concentrating to 3 V, then adding 4.2 V MEK / PP1 88.6% Form 30, 5. Stirring for 20h at 25C / 10% Nuchar Cake:racemate AquaGuard® loose Chiral purity: 52.4%, material carbon treatment 6. Filtering the suspension loss: 0.51% Filtrate: Chiral purity: 99.4% Yield of enantiomer: 83% 7. Concentrating filtrate to 2.1 vol RS of THF: 1.2% QQ1 Crude Solution, 1. Crude solution (12 V THF) was concentrated purity: 99.5%, to 3 V, then adding 3.4 V MEK / Batch NoStarting material Procedure Resultchiral purity: 94.2%, 2. Concentrating to 3 V, then adding 3.4 V MEK, 88.4% Form 30, solid nucleation / starting material was 3. Concentrating to 3 V, then adding 3.4 V MEK / treated with 10% 4. Concentrating to 3 V, then adding 4.2 V MEK RS of THF: 1.3% Nuchar Cake:racemate AquaGuard® Chiral purity: 55.8%, cartridge 6. Filtering the suspension material loss: 1.6% Filtrate: Chiral purity: 99.5% Yield of enantiomer: 86% 7. Concentrating filtrate to 2.1 vol RS of THF: 0.26% 1. Charging 6.2 g Form 30 and 0.8 g racemate / 2. Charging 12 V THF, stirring at 25C to clear solution / 3. Concentrating to 3 V, then adding 3.4 V MEK / Crude Solution, 4. Concentrating to 3 V, solid nucleation, then rity: 94.3%, adding 3.4 / chiral pu V MEK 88.6% Form 30, 5. Concentrating to 3 V, then adding 3.4 V MEK / RR1 Starting material 6. Concentrating to 3 V, then adding 4.2 V MEK / from 7. Stirring for 20h at 25C / 10% 3M-R55 Cake:racemate cartridge treatment Chiral purity: 53.1%, material 8. Filtering the suspension loss: 0.73% Filtrate: Chiral purity: 99.4% 9. Concentrating filtrate to 2.1 vol RS of THF: 0.7% Table 30. Crystallization procedures of Form 30 in MEK / MeOH / water - diluted racemate rejection Initial point1Seeding2& aging3Anti-solvent addition Cooling Batch No Filtrate source Sol Time T (°C) T=40 °C vent Solvent ratio (h) Time (h) MEK / MeOH 2.1 V / 1210NN1Batch NN1, Table 29,.6 V0°C 2.1 vol MEK 2.1 V MEK Aging 4 6.7h MEK / MeOH / water 2.1 V / 12.6 V / 1.05 V 2 MEK / MeOH Batch OO1, Table 29, 2.1 V / 12.6 V 10 OO1 (solid product inputs form 0° mate), 2.1 vol 2.1 V MEK A C 30 + race ging 4 6.7h MEK MEK / MeOH / water 2.1 V / 12.6 V / 1.05 V2MEK / MeOH 2.1 V / 12.6 V 10 PP1 Batch PP1,Table 29, 2.1V 0°C 2.1 vol MEK MEK Aging 4 6.7h MEK / MeOH / water 2.1 V / 12.6 V / 1.05 V 2 Batch QQ1, Tab MEK / MeOH QQ1 le 29, 2 2.1 V / 12.6 V100°C2.1 vol MEK .1V MEK Aging 4 6.7hInitial point1Seeding2& aging3Anti-solvent addition Cooling Batch No Filtrate source Solvent Solvent rat Time T (°C) T=40 °C io (h) Time (h) MEK / MeOH / water 2.1 V / 12.6 V / 1.05 V 2 MEK / MeOH 2.1 V / 10 Batch RR1 12.6 V RR1 , Table 29, 2.1V MEK Agin 0°C 2.1 vol MEK g 4 MEK / MeOH / water 6.7h 2.1 V / 12.6 V / 1.05 V 2 Note: 1. Volume was based on input of Form 30 and racemate. 2. Seed loading 2% based on Form 30 (wt% seed of Form 30 based on the amount of Form 30 present in the filtrate). 3. Aging for 4 hours. Table 31. Results of crystallization experiment in MEK / MeOH / water - diluted racemate rejection Batch Key point Purity Chiral pur Isolation ML loss KF GC-HS No (a%) ity (a%) yield (%)1(wt%) (wt%) (ppm) Increase minimum volume in all MEK: 300 NN22concentration steps, crude 100 100 74* 5 0.02 MeOH: 100 solution as input THF: 0 Increase minimum volume in all MEK: 200 OO22concentration steps, Form 30 and 100 100 74* 5 0.01 MeOH: 0 racemate as input THF: 0 Filtra MEK: 300 PP22tion at 7.2v MEK, crude 10*solution as input 0 100 74 4 0.02 MeOH: 100 THF<LOQ(200ppm) 76(crude MEK: 500 QQ22Repeat MM1 100 100 yield) 5 0.02 MeOH: 100 THF: <200 Filtration aMEK: 200 RR22t 7.2V MEK, Form 30100 100*and racemate as input 75 5 0.01 MeOH: <200 THF: <200 Note: 1. Based on input amount (including Form 30 and racemate corrected for the added seeds). * Low yield due to sampling. 2. XRPD Form 30. Example 10: Racemate rejection and form 30 crystallization in THF based systems This procedure involved the separation of racemic material from a crude solution comprising a mixture of racemic material and enantiopure Compound A in THF. The racemate was precipitated by addition of suitable anti-solvent to the solution (e.g. n-heptane) after which filtration was used to remove the racemic solid. Subsequently, the enantiomerically enriched filtrate was crystallized by suitable anti-solvent (e.g. n-heptane) as the non-solvated free form 30 of Compound A. The below general procedure was followed:1. Concentrating the THF crude reaction solution at 25 – 40 °C 2. Adding n-heptane (1.5 – 6 V) 3. Filtering the suspension thereby removing the racemate and collecting the filtrate 4. Adding the anti-solvent (e.g. n-heptane 4.5 - 10.5 V) and crystallizing Compound A as non- solvated form 30 5. Isolating, washing and drying the resulting solids Table 32. Racemate rejection procedures in THF / n-heptane system with seeding of the racemate starting from crude reaction solution. Seeding Concentration Anti-solvent point addition 2% Filter cake Filtrate Batch No Starting material Loading Solvent S Chiral Chiral Yield of system olventAging (hPurity Material Purity Form 30 T= 25 °Csystem)(a%) loss (%) (a%) (%) SS11 3 57.2 / 99.1 / Crude Solution, 7.5 vol purity: 99.2%, chiral 11 V→6 V THF THF / n-hep purity: 92.5%, 85 wt% (4 / 1 V / V) 24 58.3 2 99.2 81 Form 30 TT1 4 57.0 / 99.0 / Crude Solution purity: al purity: 10.7 V→ 7.5 vol 94.4%, chir 6 V t% Form THF THF / n-hep (4 / 1 V / V) 2192.6%, 85.2 w 4 59.2 3 99.0 75 30) UU1 on, 10.0 V→6 7.5 vol Crude Soluti V THF THF / n-hep 24 60.3 / 99.2 78 chiral purity: 94.4% (4 / 1 V / V) Table 33. Procedures for crystallization of Form 30 in THF / n-heptane system. Initial point Seeding point and Aging2Anti-solvent ch addit Cooling Bat ion No Objective Filtrate THF / n-hep Sup Seed THF / n-hep source1Solvent ratio er- Loading Solvent rati T (°C) C T= 40 °C saturation o T=25 ° (wt%) Time (h) Time (h) Batch PP1, SS1 Repeat with Table 32, 6 V / 6 V 7.1 2 6 V / 12 V 25°C crude solution THF / n-hep 8h 2.5h 6 V / 1.5 V Batch TT1, 5 5 TT1 wt% micronized Table 32, 6 V / 6 V 7.1 (mi 6 V / 12 V 25°C seed THF / n-hep cronized 8h / 1.5 V s 2.5h 6 V eed) 5 wt% 3M-R55 Batch UU1, UU1 charcoal Table 32,6 V / 6 V6 V / 12 V25°C treatment at 25 ºC THF / n-hep7.1 28h 2.5h for 2 h 6 V / 1.5 VInitial point Seeding point and Aging2Anti-solvent additionCoolingBatch No Objective Filtrate THF / n-hep ce Solvent ratio Super Seed THF / n-hep sour1- T (°C) saturati Loading Solvent ratio T=25 °C T= 40 °C on (wt%) Time (h) Time (h) Note: 1: Volume based on input (Form 30 and racemate) 2: Aging for 4 hours. Table 34. Results of crystallization of Form 30 in THF / n-heptane system. Purity Chiral Isola GC-HS (ppm) Batch NoSolventPu tion system (a%) rity (a%) yield (%) ML loss (wt / wt%) THF n-heptane THF / n2135 SS2**-hep 6V / 12 V 99.9 100.0 74 5 (50 ºC by 157 oven) THF / n 1732 TT2** -hep 6 V / 12 V99.7 99.9 69 6(50 ºC by 191 oven) THF / n-h 1553 UU2 ep 6 V / 12 V 99.9 99.9 67* 8 (50 ºC by <200 oven) Example 11: XRPD pattern of Form 30 of Compound A (Pattern B) The XRPD pattern of Form 30 of Compound A (Pattern B) is depicted in Figure 1. X-ray power diffraction (XRPD) analysis was carried out on a PANalytical Emyrean diffractometer. The instrument was equipped with a Cu-Kα X-ray tube using iCore and dCore tunable optics for the incident and the diffracted beam respectively. The compound was spread on a zero background sample holder. Instrument Parameters: Generator voltages: 45 kV Generator amperage: 40 mA Geometry: Bragg-Brentano Stage: spinner stage Measurement Conditions: Scan mode: continuous Scan range: 3-50° 2θ Step size: 0.0131 ° / step Counting time: 30 sec / step Spinner revolution time: 1 sec Radiation type: Cu- Kα (1.541874 Å)Incident beam path (iCore):Diffracted Beam Path (dCore)Program divergence slit: automatic Anti scatter slit: automatic(Irradiated length) 7mm 7mm Soller slit: 0.03 rad slit: 0.04 rad Mask 1: 14 mm Detector: PIXcel3D- Medipix31x1 Mask 2: 6 mm (width) 7.7 mm Peak list: Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 7.57 4901.12 0.0640 11.67906 52.31 8.31 180.65 0.0640 10.64487 1.93 8.89 180.12 0.0768 9.94655 1.92 9.33 631.86 0.0512 9.47603 6.74 9.52 237.76 0.0895 9.28854 2.54 10.08 836.02 0.0895 8.77870 8.92 10.58 227.00 0.0768 8.36197 2.42 11.57 196.20 0.1023 7.65011 2.09 12.04 612.11 0.0768 7.35152 6.53 12.30 274.69 0.0512 7.19394 2.93 12.50 229.99 0.0768 7.08002 2.45 13.57 244.83 0.0895 6.52556 2.61 14.13 766.66 0.0640 6.26894 8.18 14.36 3476.45 0.0895 6.16756 37.10 14.74 842.92 0.1023 6.01183 9.00 15.29 235.86 0.2558 5.79485 2.52 15.90 5664.62 0.1023 5.57305 60.46 16.34 798.29 0.0895 5.42631 8.52 16.67 408.73 0.0768 5.31677 4.36 17.35 743.70 0.0512 5.11026 7.94 17.57 2092.82 0.1023 5.05180 22.34 17.99 527.93 0.1279 4.93114 5.63 18.11 454.04 0.0768 4.89930 4.85 18.75 485.02 0.0895 4.73277 5.18 19.14 1189.22 0.0768 4.63647 12.69 19.35 3786.37 0.1023 4.58694 40.41 19.58 3294.37 0.1023 4.53443 35.16 20.18 1982.37 0.0624 4.39782 21.16 20.25 2781.84 0.0640 4.38584 29.69 20.44 4938.99 0.1023 4.34480 52.71 20.98 9369.43 0.1151 4.23497 100.00 21.24 2494.10 0.1023 4.18411 26.62 21.58 758.95 0.0768 4.11773 8.10 21.83 2597.30 0.1151 4.07196 27.72Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 22.06 981.64 0.0895 4.02950 10.48 22.52 302.72 0.0768 3.94846 3.23 23.21 2634.37 0.1023 3.83215 28.12 23.38 4293.98 0.0640 3.80528 45.83 23.73 1663.03 0.1151 3.74910 17.75 24.09 2103.26 0.1023 3.69436 22.45 24.325 980.34 0.0895 3.66045 10.46 24.54 2443.00 0.0768 3.62691 26.07 24.69 2806.41 0.1023 3.60528 29.95 24.99 2715.64 0.0895 3.56337 28.98 25.60 1538.41 0.0895 3.47971 16.42 25.88 2093.73 0.0895 3.44239 22.35 26.94 1921.51 0.0895 3.30911 20.51 27.24 879.41 0.1151 3.27429 9.39 27.83 2233.80 0.0895 3.20605 23.84 28.24 893.04 0.0895 3.16032 9.53 28.97 712.36 0.0895 3.08235 7.60 29.38 1263.62 0.0640 3.03990 13.49 29.57 1371.98 0.1023 3.02140 14.64 30.27 653.33 0.1535 2.95310 6.97 30.72 730.61 0.0895 2.91059 7.80 31.12 541.16 0.1023 2.87418 5.78 32.16 993.97 0.1151 2.78314 10.61 33.01 630.82 0.0768 2.71341 6.73 33.88 1429.07 0.0895 2.64604 15.25 34.58 395.63 0.1023 2.59396 4.22 Maximum divergence = 0.63 Scan Axis Gonio Start Position [°2θ] 3.0081 End Position [°2θ] 34.9881 Step Size [°2θ] 0.0130 Scan Step Time [s] 29.0700 Scan Type Continuous PSD Mode Scanning PSD Length [°2θ] 3.35 Offset [°2θ] 0.0000 Divergence Slit Type Automatic Irradiated Length [mm] 10.00 Specimen Length [mm] 10.00 Measurement Temperature [°C] 25.00 Anode Material CuIntended Wavelength Type K-Alpha K-Alpha1 [Å] 1.54060 K-Alpha2 [Å] 1.54443 K-Beta [Å] 1.39225 K-A2 / K-A1 Ratio 0.50000 Generator Settings 40 mA, 45 kV Diffractometer Type 0000000011241495 Diffractometer Number 0 Goniometer Radius [mm] 240.00 Dist. Focus-Diverg. Slit [mm] 144.50 Incident Beam Monochromator No Spinning Yes Crystal data Chemical Formula: C26H22ClF3N2O6S Dx= 1.481 Mg m-3Mr = 582.92 Cu Kα radiation, λ = 1.54184 Å orthorhombic, P212121Cell parameters from 9216 reflections a = 11.88930(10) Å θ = 7.602 to 133.186 b = 23.2602(3) Å µ = 2.636 mm-1c = 18.9063(2) Å T = 293(2) K V = 5228.49(10) Å3block, colorless Z = 8 0.20 × 0.10 × 0.05 mm F(000) = 2400.0 Summary of X-ray Crystallographic Data. Crystal size / mm30.20 × 0.10 × 0.05 Radiation Type CuKα (λ = 1.54184) Crystal system orthorhombic Space group P212121a / Å 11.88930(10) b / Å 23.2602(3) c / Å 18.9063(2) α / ° 90 β / ° 90 γ / ° 90 Cell Volume / Å35228.49(10) Cell Formula Units Z 8 Crystal Density calc g / cm31.481 Crystal F(000) 2400.0 Absorption Coefficient μ / mm-12.636 Index ranges -13 ≤ h ≤ 14, -27 ≤ k ≤ 27, -22 ≤ l ≤ 22 Cell Measurement Temperature / K 293(2) 2θ range for data collection / ° 7.602 to 133.186Goodness-of-fit on F21.025 Final R indexes [I>=2σ (I)] = 0.0570, wR2= 0.1606 Final R indexes [all data] R1= 0.0595, wR2= 0.1637 Largest diff. peak / hole / e Å-31.58 / -0.56 Reflections collected / unique 102108 / 9216 [Rint = 0.0540] Flack parameter 0.012(8) Example 12 : ATR-FTIR spectrum of Form 30 of Compound A

[0161] The ATR-FTIR spectrum of Form 30 of Compound A is depicted in Figure 2, and was measured pursuant to the following measurement conditions. The sample was analyzed using a suitable microATR accessory. Number of scans: 32 Resolution: 2 cm-1Wavelength range: 4000 to 400 cm-1Apparatus: Thermo iS50 FTIR spectrometer Detector: DTGS with KBr windows Beamsplitter: Ge on KBr Micro ATR accessory: Harrick Split Pea with Si crystal ATR-FTIR peak list (peaks in cm-1): 3400, 3292, 3111, 3027, 2943, 1650, 1599, 1582, 1497, 1486, 1456, 1435, 1332, 1281, 1249, 1237, 1222, 1173, 1155, 1120, 1091, 1054, 1026, 1003, 964, 945, 896, 881, 841826, 757, 737, 710, 657. Example 13 : DSC thermogram of Form 30 of Compound A

[0162] The DSC thermogram of Form 30 of Compound A is depicted in Figure 3. The DSC curve of compound A, Form 30 shows the melting of the product at 236.9 ºC with a heat of fusion of 94J / g. The thermogram was measured pursuant to the following measurement conditions: About 3 mg of the compound were transferred into a standard aluminum TA- Instrument sample pan. The sample pan was closed with the appropriate cover and the DSC thermogram was recorded on a TA-Instruments DSC 2500 equipped with a RCS cooling unit. The following parameters were used: Initial temperature: 25 °C Heating rate: 10 °C / min Final temperature: 300 °C Nitrogen flow: 50 ml / minExample 14 : Crystallographic stability of Form 30 of Compound A

[0163] The TGA thermogram of Form Compound A is depicted in Figure 4. The TG curve was recorded on a TA Instruments TGA 550 thermogravimeter using the following parameters: Initial temperature: room temperature Heating rate: 20 °C / min Resolution factor: 4 Final condition: 300 °C or <80 [(w / w)%]

[0164] The crystal structure stability and appearance of Form 30 of Compound A was studied after storage of the compound in various open conditions for a period of 6 weeks. TGA weight Condition loss %w / w XRD IR DSC Appeara -260 °C Max nce 210 (°C) 0 days 0.1 Cryst., Ref Cryst., Ref 236.9 white RT / <5% RH 0.1 ~Ref ~Ref 238.4 white RT / 56% RH 0.1 ~Ref ~Ref 236.7 white RT / 75% RH 0.1 ~Ref ~Ref 238.1 white 50 °C 0.1 ~Ref ~Ref 241.1 white 40 °C / 75% RH 0.1 ~Ref ~Ref 237.9 white ~Ref: comparable with reference Cryst.: crystalline

[0165] DSC curves of Form 30 of Compound A showed the melting of a crystalline product as an endothermal signal in a temperature range of 237 up to 241 °C. No changes were observed with XRD and IR. An absorption / desorption study was performed indicating that form 30 of compound A did not show a hydroscopic behavior. Example 15:1H-NMR spectrum of Form 30 of Compound A

[0166] 1H-NMR spectrum of Form 30 of Compound A is depicted in Figure 5, and showed no detectable residual solvent. It was measured pursuant to the following measurement conditions: Instrument: Bruker Avance-AV 400M. Frequency: 400MHz. Probe: 5 mm PABBO BB / 19F-1H / D Z-GRD Z108618 / 0406. Number of scan: 8. Temperature: 297.6K. Relaxation delay: 1 second. Example 16 : XRPD pattern of Form 1 of Compound A (Pattern A)

[0167] The XRPD pattern of Form 1 of Compound A (Pattern A) is depicted in Figure 6 and shows high crystallinity. X-ray power diffraction (XRPD) analysis was carried out on a PANalytical Emyrean diffractometer. The instrument was equipped with a Cu-Kα X-ray tube using iCore and dCore tunable optics for the incident and the diffracted beam respectively. The compound was spread on a zero background sample holder.Instrument Parameters: Generator voltages: 45 Generator amperage: 40 mA Geometry: Bragg-Brentano Stage: spinner stage Measurement Conditions: Scan mode: continuous Scan range: 3-50° 2θ Step size: 0.02 ° / step Counting time: 30 sec / step Spinner revolution time: 1 sec Radiation type: Cu- Kα (1.541874 Å) Incident beam path (iCore): Diffracted Beam Path (dCore) Program divergence slit: 15 mm Long anti scatter shield: + Soller slit: 0.04 rad Soller slit: 0.04 rad Beam Mask: 15 mm Ni filter: + Anti scatter slit: 1º Detector: X’Celerator Bean knife + Peak list: Pos. [°2θ] Height [cts] FWHM Left [°2θ] d-spacing [Å] Rel. Int. [%] 5.48 517.51 0.2007 16.12184 1.95 9.63 1548.80 0.1004 9.18013 5.83 12.53 2634.10 0.1673 7.06520 9.92 13.29 996.10 0.0836 6.66001 3.75 13.91 852.72 0.1004 6.36495 3.21 15.94 12936.84 0.0836 5.56031 48.70 16.09 12558.27 0.1004 5.50983 47.28 16.66 1960.45 0.1171 5.32188 7.38 17.75 8815.77 0.1004 4.99801 33.19 17.96 17365.99 0.1840 4.93886 65.38 18.68 5969.65 0.1004 4.75010 22.47 18.78 5643.50 0.0669 4.72587 21.25 19.15 4480.26 0.1171 4.63362 16.87 19.70 6140.27 0.1004 4.50576 23.12 19.83 6870.09 0.0836 4.47785 25.86 20.22 9177.94 0.2342 4.39256 34.55 20.70 8352.50 0.1840 4.29095 31.44 21.03 9047.73 0.2007 4.22443 34.06 21.33 9516.22 0.0836 4.16634 35.83 21.48 6095.62 0.0669 4.13664 22.95Pos. [°2θ] Height [cts] FWHM Left [°2θ] d-spacing [Å] Rel. Int. [%] 22.43 21485.88 0.0816 3.96079 80.89 22.51 26562.54 0.0816 3.94646 100.00 22.59 24976.08 0.0612 3.94275 94.03 22.69 15820.18 0.0816 3.91528 59.56 23.26 2115.75 0.2040 3.82033 7.97 24.30 2117.86 0.1020 3.65975 7.97 25.39 3910.96 0.0816 3.50584 14.72 25.54 5980.87 0.1428 3.48431 22.52 26.66 5761.92 0.1020 3.34079 21.69 26.76 6792.23 0.1020 3.32924 25.57 27.14 4650.53 0.1224 3.28316 17.51 27.26 4542.11 0.1224 3.26934 17.10 27.99 3806.15 0.1632 3.18476 14.33 28.63 1809.87 0.1224 3.11506 6.81 29.08 4344.24 0.1428 3.06831 16.35 30.07 9641.81 0.1020 2.96924 36.30 30.15 8782.83 0.1224 2.96171 33.06 31.22 3983.38 0.1224 2.86284 15.00 31.50 1728.69 0.6528 2.83779 6.51 32.23 2094.44 0.1224 2.77554 7.88 33.17 2230.66 0.1836 2.69904 8.40 33.60 946.63 0.2040 2.66493 3.56 34.12 1397.75 0.3264 2.62564 5.26 34.65 896.22 0.2040 2.58698 3.37 35.05 1302.42 0.2040 2.55786 4.90 36.21 1531.10 0.0816 2.47898 5.76 36.81 797.37 0.1632 2.43969 3.00 37.79 1840.95 0.1020 2.37843 6.93 38.76 1127.43 0.1632 2.32121 4.24 39.11 1049.14 0.3264 2.30130 3.95 40.23 1216.00 0.2448 2.23963 4.58 41.30 1654.15 0.2448 2.18427 6.23 41.96 1465.42 0.1632 2.15156 5.52 42.11 1302.03 0.1224 2.14933 4.90 43.51 2472.81 0.0816 2.07820 9.31 45.22 2043.63 0.1020 2.00382 7.69 45.90 825.12 0.3264 1.97565 3.11 46.49 695.13 0.3264 1.95197 2.62 47.43 838.87 0.2856 1.91542 3.16 47.80 754.60 0.2448 1.90148 2.84 48.61 492.05 0.2448 1.87134 1.85 49.27 793.72 0.2856 1.84798 2.99 Scan Axis GonioStart Position [°2θ] 2.9994 End Position [°2θ] 49.9874 Step Size [°2θ] 0.0170 Scan Step Time [s] 29.8450 Scan Type Continuous PSD Mode Scanning PSD Length [°2θ] 2.12 Offset [°2θ] 0.0000 Divergence Slit Type Automatic Irradiated Length [mm] 15.00 Specimen Length [mm] 10.00 Measurement Temperature [°C] 25.00 Anode Material Cu Intended Wavelength Type K-Alpha K-Alpha1 [Å] 1.54060 K-Alpha2 [Å] 1.54443 K-Beta [Å] 1.39225 K-A2 / K-A1 Ratio 0.50000 Generator Settings 40 mA, 45 kV Diffractometer Type 0000000011085924 Diffractometer Number 0 Goniometer Radius [mm] 240.00 Dist. Focus-Diverg. Slit [mm] 100.00 Incident Beam Monochromator No Spinning Yes Example 17: DSC thermogram of Form 1 of Compound A

[0168] The DSC thermogram of Form 1 of Compound A is depicted in Figure 7 and shows a melting Tonsetof 194.3 °C. The DSC curve of Form 1 of Compound A shows the melting of a crystalline product at 196.5 ºC with a heat of fusion of 65J / g. The thermogram was measured pursuant to the following measurement conditions: About 3 mg of the compound were transferred into a standard aluminum TA-Instrument sample pan. The sample pan was closed with the appropriate cover and the DSC thermogram was recorded on a TA-Instruments DSC 1000 equipped with a RCS cooling unit. The following parameters were used: Initial temperature: 25 °C Heating rate: 10 °C / min Final temperature: 300 °C Nitrogen flow: 50 ml / min.Example 18 : ATR-FTIR spectrum of Form 1 of Compound A

[0169] The ATR-FTIR spectrum of of Compound A is depicted in Figure 8, and was measured pursuant to the following measurement conditions. The sample was analyzed using a suitable microATR accessory. Number of scans: 32 Resolution: 1 cm-1Wavelength range: 4000 to 400 cm-1Apparatus: Thermo Nexus 670 FTIR spectrometer Detector: DTGS with KBr windows Beamsplitter: Ge on KBr Micro ATR accessory: Harrick Split Pea with Si crystal ATR-FTIR peak list : 3333, 3276, 3136, 3070, 3011, 2978, 2947, 2916, 1641, 1623, 1595, 1585, 1491, 1462, 1440, 1375, 1318, 1259, 1245, 1225, 1159, 1094, 1085, 1050, 1030, 989, 976, 961, 889, 871, 856, 846, 817, 807, 772, 762, 720. Example 19: TGA data for Form 1 of Compound A

[0170] The TGA of Form 1 of Compound A is depicted in Figure 9. The TGA of Form 1 of Compound A showed no weight loss up to 210 ºC. The TG curve was recorded on a TA Instruments TGA 550 thermogravimeter using the following parameters: Initial temperature: room temperature Heating rate: 20 °C / min Resolution factor: 4 Final condition: 300 °C or <80 [(w / w)%] Example 20:1H-NMR spectrum of Form 1 of Compound A

[0171] The1H-NMR spectrum of form 1 of Compound A is depicted in Figure 10 and was measured pursuant to the following measurement conditions: Instrument: Bruker Avance-AV 400M. Frequency: 400MHz. Probe: 5 mm PABBO BB / 19F-1H / D Z-GRD Z108618 / 0406. Number of scan: 8. Temperature: 297.6K. Relaxation delay: 1 second. Example 21 : XRPD pattern of the acetone solvate of Compound A (Pattern C)

[0172] The XRPD pattern of the acetone solvate of Compound A (Pattern C) is depicted in Figure 11. It was measured pursuant to the following measurement conditions: Instrument: Bruker D8 Advance X-ray geometry: Reflection Detector: LYNXEYE_XE_T(1D mode)Open angle: Max Radiation: Cu / K-Alpha1 (λ=1.5406Å) X-ray generator power: 40kV, 40mA Primary beam path slits: Twin_Primary motorized slit 10.0mm by sample length; SollerMount axial soller 2.5° Secondary beam path slits: Detector OpticsMount soller slit 2.5°; Twin_Secondary motorized slit 5.2mm Scan mode: Continuous scan Scan type: Locked coupled Step size: 0.02° Time per step: 0.12 second per step Scan range: 3° to 40° Sample rotation: speed 15rpm Sample holder: Monocrystalline silicon, flat surface. Peak list: Pos. [°2θ] Height [cts] FWHM Left [°2θ] d-spacing [Å] Rel. Int. [%] 7.82 157.33 0.0984 11.30594 42.77 8.15 67.50 0.1181 10.85247 18.35 8.92 367.83 0.1181 9.91298 100.00 10.37 107.02 0.1378 8.52672 29.09 13.09 119.75 0.1574 6.76560 32.56 14.33 77.21 0.2362 6.17910 20.99 15.74 138.43 0.1771 5.63115 37.63 16.23 75.88 0.2362 5.45993 20.63 17.95 43.71 0.6298 4.94181 11.88 19.56 111.64 0.2362 4.53809 30.35 20.16 170.26 0.1574 4.40389 46.29 20.72 215.38 0.2755 4.28715 58.55 21.62 158.02 0.1181 4.11054 42.96 21.99 274.29 0.1574 4.04229 74.57 22.64 115.99 0.3149 3.92760 31.53 26.20 162.26 0.1968 3.40081 44.11 26.91 113.51 0.1574 3.31346 30.86 30.04 13.50 0.9446 2.97467 3.67 35.25 31.85 0.2362 2.54594 8.66 Scan Axis Gonio Start Position [°2θ] 3.0000 End Position [°2θ] 40.0200 Step Size [°2θ] 0.0200 Scan Step Time [s] 23.0400Scan Type Pre-set time Offset [°2θ] 0.0000 Divergence Slit Type Fixed Divergence Slit Size [°] 9999.0000 Specimen Length [mm] 10.00 Receiving Slit Size [mm] 0.1000 Measurement Temperature [°C] 25.00 Anode Material Cu Intended Wavelength Type K-Alpha K-Alpha1 [Å] 1.54060 K-Alpha2 [Å] 1.54443 K-Beta [Å] 1.39225 K-A2 / K-A1 Ratio 0.50000 Generator Settings 40 mA, 40 kV Diffractometer Number 0 Goniometer Radius [mm] 240.00 Dist. Focus-Diverg. Slit [mm] 91.00 Incident Beam Monochromator No Spinning No Example 22: DSC thermogram of the acetone solvate of Compound A

[0173] DSC thermogram of the acetone solvate of Compound A is depicted in Figure 12. It was measured pursuant to the following measurement conditions: Instrument: TA Discovery 2500 Sample pan: Tzero pan and Tzero hermetic lid with a pin hole of 0.7mm in diameter Temperature range: 0 to 250°C Heating rate: 10°C / min Nitrogen flow: 50mL / min Sample mass: About 0.5-2mg

[0174] DSC thermogram of the acetone solvate of Compound A (Figure 12) showed a desolvation peak at Tonsetof 89.5 °C with an enthalpy of about 101 J / g and an exothermic recrystallization peak at Tonsetof 157.4 °C with an enthalpy of about 43 J / g. The formed product melts at Tonsetof 199.7 °C with an enthalpy of about 42 J / g. Also an additional endothermic signal was observed at Tonsetof 211.2 °C with an enthalpy of about 14 J / g. Example 23: TGA data for the acetone solvate of Compound A

[0175] TGA thermogram of the acetone solvate of Compound A is depicted in Figure 13. It was measured pursuant to the following measurement conditions:Instrument: Discovery 5500 Sample pan: Aluminum, open Start temperature: Ambient condition (below 35°C) Final temperature: 300°C or abort next segment if weight < 80% (w / w) (The weight loss of the compound is no more than 20% (w / w)) Heating rate: 10°C / min Nitrogen flow Balance: 10mL / min; sample chamber 25mL / min Sample mass: About 2-10mg Karl Fischer (KF) Instrument: Mettler Toledo Coulometric KF Titrator C30 Method: Coulometric Sample mass: about 1-10 mg.

[0176] TGA for the acetone solvate of Compound A showed about 10.4% weight loss at about 150 °C. Example 24:1H-NMR spectrum of the acetone solvate of Compound A

[0177] 1H-NMR spectrum of the acetone solvate of Compound A is depicted in Figure 14. It was measured pursuant to the following measurement conditions: Instrument: Bruker Avance-AV 400M. Frequency: 400MHz. Probe: 5 mm PABBO BB / 19F-1H / D Z-GRD Z108618 / 0406. Number of scan: 8. Temperature: 297.6K. Relaxation delay: 1 second.

[0178] 1H-NMR spectrum of the acetone solvate of Compound A showed that it contained about 1.2 equivalents (10.7% by weight) of acetone. Example 25 : XRPD pattern for the IPA solvate (Form 2) of Compound A (Pattern D)

[0179] XRPD pattern for the IPA solvate (Form 2) of Compound A (Pattern D), is depicted in Figure 15. It was measured pursuant to the following measurement conditions: Instrument: Bruker D8 Advance X-ray geometry: Reflection Detector: LYNXEYE_XE_T(1D mode) Open angle: Max Radiation: Cu / K-Alpha1 (λ=1.5406Å) X-ray generator power: 40kV, 40mA Primary beam path slits: Twin_Primary motorized slit 10.0mm by sample length; SollerMount axial soller 2.5° Secondary beam path slits: Detector OpticsMount soller slit 2.5°; Twin_Secondary motorized slit 5.2mm Scan mode: Continuous scanScan type: Locked coupled Step size: 0.02° Time per step: 0.12 second per step Scan range: 3° to 40° Sample rotation: speed 15rpm Sample holder: Monocrystalline silicon, flat surface. Peak list: Pos. [°2θ] Height [cts] FWHM Left [°2θ] d-spacing [Å] Rel. Int. [%] 7.05 2593.85 0.0787 12.54448 100.00 7.24 1567.86 0.0984 12.21418 60.45 7.56 579.45 0.0787 11.68711 22.34 8.42 254.98 0.1378 10.49597 9.83 11.73 139.33 0.0590 7.54730 5.37 12.19 181.58 0.1574 7.25814 7.00 13.75 175.57 0.1181 6.43900 6.77 14.28 235.49 0.1574 6.20336 9.08 14.68 64.82 0.1181 6.03602 2.50 15.11 81.50 0.1181 5.86239 3.14 15.47 186.35 0.1574 5.72769 7.18 15.89 346.64 0.1378 5.57795 13.36 16.40 148.12 0.0787 5.40545 5.71 16.89 111.45 0.1968 5.24832 4.30 17.52 195.53 0.1181 5.06234 7.54 18.41 71.34 0.1574 4.81867 2.75 18.95 438.18 0.2362 4.68355 16.89 20.59 484.63 0.1378 4.31340 18.68 21.08 2152.23 0.0984 4.21379 82.97 21.62 939.60 0.0787 4.11054 36.22 22.28 222.61 0.2362 3.99094 8.58 22.75 137.35 0.1181 3.90876 5.30 23.14 141.18 0.1968 3.84344 5.44 24.76 695.10 0.1181 3.59595 26.80 25.69 830.98 0.1378 3.46907 32.04 27.68 113.92 0.2362 3.22242 4.39 28.20 296.71 0.1181 3.16440 11.44 28.52 460.77 0.0984 3.12997 17.76 29.15 137.15 0.2362 3.06358 5.29 31.88 92.82 0.1574 2.80760 3.58 32.85 27.52 0.4723 2.72630 1.06 34.11 37.62 0.4723 2.62891 1.45 38.14 52.16 0.2362 2.35945 2.01 Scan Axis GonioStart Position [°2θ] 3.0000 End Position [°2θ] 40.0200 Step Size [°2θ] 0.0200 Scan Step Time [s] 23.0400 Scan Type Pre-set time Offset [°2θ] 0.0000 Divergence Slit Type Fixed Divergence Slit Size [°] 9999.0000 Specimen Length [mm] 10.00 Receiving Slit Size [mm] 0.1000 Measurement Temperature [°C] 25.00 Anode Material Cu Intended Wavelength Type K-Alpha K-Alpha1 [Å] 1.54060 K-Alpha2 [Å] 1.54443 K-Beta [Å] 1.39225 K-A2 / K-A1 Ratio 0.50000 Generator Settings 40 mA, 40 kV Diffractometer Number 0 Goniometer Radius [mm] 240.00 Dist. Focus-Diverg. Slit [mm] 91.00 Incident Beam Monochromator No Spinning No Example 26: DSC thermogram of the IPA solvate (Form 2) of Compound A

[0180] DSC thermogram of the IPA solvate (Form 2) of Compound A is depicted in Figure 16. It was measured pursuant to the following measurement conditions. Instrument: TA Discovery 2500 Sample pan: Tzero pan and Tzero hermetic lid with a pin hole of 0.7mm in diameter Temperature range: 0 to 250°C Heating rate: 10°C / min Nitrogen flow: 50mL / min Sample mass: About 0.5-2mg.

[0181] DSC for the IPA solvate (Form 2) of Compound A showed a desolvation peak at Tonsetof 108.6 °C with an enthalpy of about 23 J / g and an exothermic peak at Tonsetof 133.1 °C with an enthalpy of about 69 J / g. The formed product melts at Tonsetof 239.6 °C with an enthalpy of about 79 J / g. Example 27: TGA data for the IPA solvate (Form 2) of Compound A

[0182] TGA thermogram for the IPA solvate (Form 2) of Compound A is depicted in Figure 17. It was measured pursuant to the conditions: Instrument: Discovery 5500 Sample pan: Aluminum, open Start temperature: Ambient condition (below 35°C) Final temperature: 300°C or abort next segment if weight < 80% (w / w) (The weight loss of the compound is no more than 20% (w / w)) Heating rate: 10°C / min Nitrogen flow Balance: 10mL / min; sample chamber 25mL / min Sample mass: About 2-10mg Karl Fischer (KF) Instrument: Mettler Toledo Coulometric KF Titrator C30 Method: Coulometric Sample mass: about 1-10 mg.

[0183] TGA for the IPA solvate (Form 2) of Compound A showed about 1.3% weight loss at about 90 °C and 5.4% weight loss from 90 °C to 160 °C. After desolvation by heating to 180 °C and cooling to 25 °C, it converted to Form 30. Example 28:1H-NMR spectrum of the IPA solvate (Form 2) of Compound A

[0184] 1H-NMR spectrum of the IPA solvate (Form 2) of Compound A is depicted in Figure 18. The 1H-NMR was recorded pursuant to the following measurement conditions: Instrument: Bruker Avance-AV 400M. Frequency: 400MHz. Probe: 5 mm PABBO BB / 19F-1H / D Z-GRD Z108618 / 0406. Number of scan: 8. Temperature: 297.6K. Relaxation delay: 1 second.

[0185] 1H-NMR spectrum of the IPA solvate (Form 2) of Compound A showed that it contained about 1.0 equivalents (9.4% by weight) of IPA. Example 29 : XRPD pattern for the amorphous free form of Compound A obtained from 1,4-dioxane

[0186] XRPD pattern for the amorphous free form of Compound A obtained from 1,4- dioxane is illustrated in Figure 19. It was measured pursuant to the following measurement conditions: Instrument: Bruker D8 Advance X-ray geometry: Reflection Detector: LYNXEYE_XE_T(1D mode) Open angle: Max Radiation: Cu / K-Alpha1 (λ=1.5406Å) X-ray generator power: 40kV, 40mAPrimary beam path slits: Twin_Primary motorized slit 10.0mm by sample length; SollerMount axial soller 2.5° Secondary beam path slits: Detector OpticsMount soller slit 2.5°; Twin_Secondary motorized slit 5.2mm Scan mode: Continuous scan Scan type: Locked coupled Step size: 0.02° Time per step: 0.12 second per step Scan range: 3° to 40° Sample rotation: speed 15rpm Sample holder: Monocrystalline silicon, flat surface. Example 30: DSC thermogram of the amorphous free form of Compound A obtained from 1,4-dioxane

[0187] DSC thermogram of the amorphous free form of Compound A obtained from 1,4 dioxane is illustrated in Figure 20. It was measured pursuant to the following measurement conditions: Instrument: TA Discovery 2500 Sample pan: Tzero pan and Tzero hermetic lid with a pin hole of 0.7mm in diameter Temperature range: 0 to 250°C Heating rate: 10°C / min Nitrogen flow: 50mL / min Sample mass: About 0.5-2mg. Example 31: TGA data for the amorphous free form of Compound A obtained from 1,4- dioxane

[0188] TGA thermogram for the amorphous free form of Compound A obtained from 1,4 dioxane is depicted in Figure 21. TGA thermogram was measured pursuant to the following measurement conditions: Instrument: Discovery 5500. Sample pan: Aluminum, open. Start temperature: Ambient condition (below 35°C). Final temperature: 300°C or abort next segment if weight < 80% (w / w) (The weight loss of the compound is no more than 20% (w / w)) Heating rate: 10°C / min. Nitrogen flow Balance: 10mL / min; sample chamber 25mL / min. Sample mass: About 2-10mg.Karl Fischer (KF) Instrument: Mettler Toledo Coulometric C30. Method: Coulometric. Sample mass: about 1-10 mg.

[0189] TGA for the amorphous free form of Compound A obtained from 1,4-dioxane showed about 2.6% weight loss at about 130 °C. Example 33:1H-NMR spectrum of the amorphous free form of Compound A obtained from 1,4-dioxane

[0190] 1H-NMR spectrum for the amorphous free form of Compound A obtained from 1,4- dioxane is depicted in Figure 22. The1H-NMR was recorded pursuant to the following measurement conditions: Instrument: Bruker Avance-AV 400M. Frequency: 400MHz. Probe: 5 mm PABBO BB / 19F-1H / D Z-GRD Z108618 / 0406. Number of scan: 8. Temperature: 297.6 K. Relaxation delay: 1 second.

[0191] 1H-NMR spectrum for the Amorphous Free Form of Compound A obtained from 1,4-dioxane showed that it contained about 0.8% 1,4-dioxane residue by weight. Example 34: Preparation of the different forms of Compound A Preparation of crystalline Form 1 of Compound A

[0192] The THF crude solution, from step 6 of the above described synthesis 1, was solvent switched to EtOH, followed by crystallization of an EtOH solvate from EtOH / Water (ethanol solvate as 94:6 enantiomeric ratio (er) mixture). The next step comprised the racemate crystallization, and filtration of the racemate to obtain the enantiomerically enriched filtrate, >99% ee. Racemate crystallization was performed in a THF / Heptane system. Solvent switch and crystallization of Compound A from methanol / water 70:30 allowed obtaining Form 1. The XRPD pattern for Form 1 of Compound A (Form 2) (Pattern A) is shown in Figure 6. The DSC thermogram of Form 1 of Compound A is shown in Figure 7. The IR spectrum of Form 1 of Compound A is shown in Figure 8. The TGA data of Form 1 of Compound A is shown in Figure 9. The1H-NMR spectrum of Form 1 of Compound A is shown in Figure 10. Preparation of crystalline Form 30 of Compound A

[0193] The THF crude solution, from step 6 of the above described synthesis 1, was solvent switched to EtOH, followed by crystallization of an EtOH solvate from EtOH / Water.15 V of THF were added to the EtOH solvate and the solution was purified using a CUNO activated carbon filter cartridge at 20-302°C for 12 hours. After CUNO filtration the THF filtrate was concentrated to 10V. The temperature was adjusted to 40°C and 10V of heptane were added. The mixture was stirred for 16h at 40°C. The racemate was filtered off. The filtrate had a chiral purity of 99.46. The filtrate was then passed through silica gel columns which were eluted withTHF / heptane (1V / 1V, 8V). The filtrate was concentrated and the solvent switched to methanol. Crystallization from methanol gave Form XRPD pattern for Form 30 of Compound A (Pattern B) is shown in Figure 1. The IR spectrum of Form 30 of Compound A is shown in Figure 2. The DSC thermogram of Form 30 of Compound A is shown in Figure 3. The TGA data of Form 30 of Compound A is shown in Figure 4. The 1H-NMR spectrum of Form 30 of Compound A is shown in Figure 5. Preparation of the Amorphous Free Form of Compound A

[0194] Amorphous free form obtained from 1,4-dioxane was prepared using the following procedure: About 50 mg of Form 30 of compound A was weighed into a 40mL glass vial and dissolved in 25.0 mL of 1,4-dioxane at 25°C. (clear solution). The clear solution was pre-frozen by ethanol / dry ice mixture for about 45 min, and then the sample was lyophilized in the freeze dryer for about 7 days (powder). About 49 mg of amorphous free form obtained from 1,4- dioxane, was obtained as a white solid in 99% yield. The XRPD pattern for the amorphous free from of Compound A obtained from 1,4-dioxane is shown in Figure 19. The DSC thermogram for the amorphous free from of Compound A obtained from 1,4-dioxane is shown in Figure 20. The TGA thermogram for the amorphous free from of Compound A obtained from 1,4-dioxane is shown in Figure 21. The1H-NMR data for the amorphous free from of Compound A obtained from 1,4-dioxane is shown in Figure 22. Preparation of IPA Solvate (Form 2) of Compound A

[0195] About 40mg of the amorphous free form of compound A obtained from 1,4-dioxane, was equilibrated in 0.1-0.2 mL of isopropyl alcohol at 25°C for 2 weeks with a stirring bar on a magnetic stirring plate at a rate of 300-400 rpm. The thus obtained suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. Solid parts (wet cakes) were investigated by XRPD, which allowed the identification of the IPA Solvate (Form 2) of Compound A. The XRPD pattern for the isopropyl alcohol (IPA) solvate of Compound A (Form 2) (Pattern D) is shown in Figure 15. The DSC thermogram for the IPA solvate of Compound A (Form 2) is shown in Figure 16. The TGA thermogram for the IPA solvate of Compound A (Form 2) is shown in Figure 17. The1H-NMR spectrum for the IPA solvate of Compound A (Form 2) is shown in Figure 18. Preparation of the acetone solvate of Compound A

[0196] About 50 mg of Form 30 of compound A was equilibrated in 0.2 mL of acetone at 60°C for about 1 week with stirring at 300-400 rpm. The obtained suspension was then filtered through a 0.45 µm nylon membrane filter by centrifugation at 14,000 rpm. Solid part (wet cake) was investigated by XRPD. The XRPD pattern for the acetone solvate of Compound A (Pattern c) is shown in Figure 11. The DSC thermogram of the acetone solvate of Compound A is shown in Figure 12.The TGA thermogram of the acetone solvate of Compound A is shown inFigure 13. The1H-NMR spectrum of the acetone solvate of Compound A is shown in Figure 14. Example 35: Color measurements

[0197] Color analysis of the solution samples (solution concentration 100 mg / mL in THF) was measured using a commercial digital camera. Color was measured by extracting the RGB color values from the digital image and converting to the CIELAB color space (L*a*b*). Delta E* (or ∆E*) is a calculation of the change in color as measured in the CIELAB color space on a three-dimensional axes L* a* b*. The image processing was performed using “imager” package in R language. The results are shown in Table 35. Table 35 Isolation System solvent at isolation and carbon treatments yield Appearance results (%)1Batch Color card No Comment Solvent isolation Carbon treatment Image analysis Yellowish Brown MEK / MeOH / water (V / V / V) before before hydrogenationcrystallizationL* a* b* dE* L1-L9A-144 / 1 / 3 / 0.2 10% 3M-R55 NO 68 66.2 -16.711.317.3 L4 A-159 / 1 / 6 / 0.5 10% 3M-R55 NO 80 68.4 -16.614.618.5 L4 A-157 / 1 / 3 / 0.5 10% 3M-R5510% 3M-R55 73 64.5 -16.817.923.6 L4 A-160 / 1 / 6 / 1 10% 3M-R55 NO 84 66.1 -17.019.523.6 L5 A-158 Double charcoal1 / 3 / 1 10% 3M-R55 10% 3M-R55 75 63.9 -16.918.824.5 L5B-6 1 / 3 / 0.2 NO NO 62 62.9 -18.219.125.2 L5A-155 / 1 / 3 / 0.5 10% Norit A Supra NO 88 62.2 -19.623.830.1 L5 add more B-9 water 1 / 3 / 0.4 NO NO 64 61.7 -19.625.632.0 L5 after MeOH A-151 / 1 / 3 / 0.5 10% Nuchar Aqua NO 83 60.2 -17.826.933.0 L5 A-138 / 1 / 3 / 0.5 10% 3M-R55 NO 78 59.1 -18.429.535.7 L5 B-8 / 1 / 3 / 0.5 NO NO 71 57.0 -18.133.439.7 L5 A-145 / 1 / 3 / 1 10% 3M-R55 NO 86 58.1 -17.931.137.4 L5 MEK / MeOH / water (V / V / V) before before hydrogenation crystallization L* A* B* dE* L1-L9 A-162 Double charcoal 1 / 6 10% 3M-R5510% 3M-R55 75 69.8 -14.45.6 9.2 L3 A-146 / 1 / 3 10% 3M-R55 NO 46 70.0 -15.47.311.1 L3 5% A-97 micronized 1 / 3 NO NO 43 69.0 -16.010.314.2 L4 seeds used A-139 / 1 / 6 10% 3M-R55 NO 76 69.5 -16.312.216.1 L3 B-11 / 1 / 6 NO NO 76 67.6 -18.421.425.6 L5

Claims

CLAIMS 1. A process for the preparation of - (4-chloro-2 methoxyphenyl)-2-((3-methoxy-5- (methylsulfonyl)phenyl)amino)-1-(5-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-one (Compound A): A comprising the stepsa) separating a and enantiopure Compound A to produce an enantiomerically enriched filtrate, wherein said mixture is in solvent A; b) crystallizing the enantiomerically enriched filtrate to produce enantiopure compound A, preferably wherein enantiopure compound A has an enantiomeric excess greater than 99%.

2. The process of claim 1, wherein step a) further comprises: a1) precipitating the racemic material to produce a solid racemic material via one or both of: i) solvent switch the mixture from solvent A to solvent B ii) addition of an anti-solvent; and a2) removing the solid racemic material via filtration.

3. The process of claim 2, wherein solvent B is a solvent in which a solubility ratio of a solubility of the enantiopure Compound A in solvent B at 25°C (Solubilityenantiopure) to a solubility of the racemic material in solvent B at 25 °C (Solubilityracemic) is at least 4: ௌ^^௨^^^^௧௬^^ೌ^^^^^ೠ^^ ^ 4.4.one of claims 2-3, wherein solvent B is selected from the group comprising methyl ethyl ketone (MEK), dimethyl sulfoxide (DMSO), 1,4-dioxane, dimethylacetamide (DMAc), THF, and cyclohexanone.

5. The process of any one of claims 1-5, wherein step b) comprises crystallization of the enantiomerically enriched filtrate with an anti-solvent to produce enantiopure compound A.

6. The process of any one of claims 2-5, wherein the anti-solvent is selected from the group comprising n-heptane, methanol, water, cyclopentanone, dichloromethane, n-hexane, ethyl acetate, isopropyl alcohol, propyl, polyethylene glycol 400 and a mixture thereof, preferably from the group comprising n-heptane, methanol, water, and a mixture thereof.

7. The process of any one of claims 2-6, wherein the ratio by volume of solvent B to the anti- solvent ranges from 1:30 to 10:7; from 1.5:28 to 8:6; preferably from 2:27 to 7:5; preferably from 2.5:26.5 to 7:5; preferably from 1:1 - 1:6, preferably from 1:2 - 1:

4.

8. The process of any one of claims 1-7, wherein enantiopure compound A is a crystalline form of Compound A designated as Form 30, characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, or more peaks at diffraction angles selected from the group comprising 10.08, 19.35, 23.73, 24.09, 24.99, 29.57, and 30.72, degrees two theta ± 0.2 degrees two theta (°2θ ± 0.2° 2θ), with XRPD pattern obtained using copper K-α1 X-rays at a wavelength of 1.541 Angstroms.

9. (S)-2-(4-chloro-2 methoxyphenyl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)amino)-1-(5- (trifluoromethoxy)-1H-indol-3-yl)ethan-1-one (Compound A) of formula A or acompound A is in amorphous free form characterized by an X-ray powder diffraction pattern as depicted in Figure 19, or in a crystalline form characterized by an X-ray powder diffraction pattern obtained using copper K-α1 X-rays at a wavelength of 1.541 Angstroms, which: comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 10.08, 19.35, 23.73, 24.09, 24.99, 29.57, and 30.72, degrees two theta ± 0.2 degrees two theta; or comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 7.0, 8.4, 12.2, 16.9, 20.6, 24.8, and 28.5 degrees two theta ± 0.2 degrees two theta; or comprises one, two, three, or more peaks at diffraction angles selected from the group comprising 9.6, 12.5, 13.3, 13.9, 22.7, 30.2, and 31.5 degrees two theta ± 0.2 degrees two theta; or comprises one, two, or three peaks at diffraction angles selected from the group comprising 10.4, 13.1, and 26.2 degrees two theta ± 0.2 degrees two theta.

10. The compound of claim 9, wherein said compound is crystalline Form 30 of Compound A characterized by an XRPD pattern comprising two, three or more peaks, preferably three or more peaks, preferably four or more peaks, preferably five or more peaks at 10.08, 19.35, 23.73, 24.09, 24.99, 29.57, 30.72, degrees two theta ± 0.2 degrees two theta.

11. The compound of any one of claims 9 or 10, wherein said compound is crystalline Form 30 of Compound A characterized by an pattern comprising one, two, three or more peaks at diffraction angles selected from the group comprising at 10.08, 23.73, 24.09, 24.99 degrees two theta ± 0.2 degrees two theta, preferably two, three or more peaks, preferably three or more peaks at 10.08, 23.73, 24.09, 24.99 degrees two theta ± 0.2 degrees two theta.

12. The compound of any one of claims 9-11, wherein said compound is crystalline Form 30 of Compound A characterized by an XRPD pattern comprising peaks at 7.57, 8.31, 8.89, 9.33, 9.52, 10.08, 10.58, 11.57, 12.04, 12.30, 12.50, 13.57, 14.13, 14.36, 14.74, 15.29, 15.90, 16.34, 16.67, 17.35, 17.57, 17.99, 18.11, 18.75, 19.14, 19.35, 19.58, 20.18, 20.25, 20.44, 20.98, 21.24, 21.58, 21.83, 22.06, 22.52, 23.21, 23.38, 23.73, 24.09, 24.325, 24.54, 24.69, 24.99, 25.60, 25.88, 26.94, 27.24, 27.83, 28.24, 28.97, 29.38, 29.57, 30.27, 30.72, 31.12, 32.16, 33.01, 33.88, and 34.58 degrees two theta ± 0.2 degrees two theta.

13. The compound of any one of claims 9-12, wherein said compound is crystalline Form 30 of Compound A characterized by an XRPD pattern comprising as depicted in Figure 1.

14. A pharmaceutical composition comprising the compound A of any one of claims 9-13 or the compound A prepared by the process of any one of claims 1-8 and one or more pharmaceutically acceptable excipients.

15. The compound A prepared by the process of any one of claims 1-8 or the compound A of any one of claims 9-13 or the pharmaceutical composition of claim 14 for use in the treatment or prophylaxis of dengue viral infection in a subject.

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