Solid forms of a HSV helicase primase inhibitor

Abstract

The present disclosure provides crystalline forms, solvates and hydrates of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihy dro-lH-indene-2-carbonyl)indoline-6- sulfonamide, and methods of making.

Description

SOLID FORMS OF A HSV HELICASE PRIMASE INHIBITORCROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 600,285, filed November 17, 2023, which is incorporated herein in its entireties for all purposes.FIELD

[0002] The present disclosure relates to solid forms of indolinyl compounds. The present disclosure also relates to use of those solid forms in the treatment of viral infections.BACKGROUND

[0003] Herpesviruses have a very high global prevalence and disease burden. Herpesviruses include herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), varicella-zoster virus, Epstein-Barr virus, and cytomegalovirus. HSV-1 and HSV-2 are contagious human pathogens. HSV-1 is mainly transmitted by oral-to-oral contact to cause oral herpes, while HSV-2 is a sexually transmitted infection that causes genital herpes. These infections are lifelong and characterized by periodic re-activation and viral shedding, which can cause symptoms such as painful blisters or ulcers and transmissions to others. Currently available medications to treat these infections are largely based on nucleoside analogs such as acyclovir, famciclovir, and valacyclovir. Although effective at reducing severity and frequency of the symptoms, these compounds do not eliminate viral shedding and thus a risk of transmission. In addition, dosing regimens are complex and inconvenient.

[0004] Herpesvirus encodes its own helicase and primase for synthesis of viral DNA. The helicase-primase complex performs a key role in viral DNA replication. The helicase separates the viral DNA double helix, and the primase synthesizes RNA primers on the single-stranded DNA which initiates DNA synthesis directed by the DNA polymerase (Kleymann G. 2004).

[0005] There is a need for new agents that are more effective and safer with improved pharmacokinetics. Inhibition of viral helicase-primase interferes with viral replication and thus could lead to the development of drugs with desirable selectivity, potency, metabolic stability, or reduced detrimental effects.SUMMARY

[0006] In one embodiment, the present disclosure provides a crystalline form of Compound 1 having the structure:and salts, solvates or hydrates thereof.

[0007] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):that is: Compound 1 Form I, Compound 1 Form II, Compound 1 Form III, Compound 1 Form IV, Compound 1 Form V, Compound 1 monohydrate, Compound 1 dihydrate, Compound 1 methyl-tetrahydrofuran (MeTHF) solvate, Compound 1 methyl t-butyl ether solvate 1, Compound 1 methyl t-butyl ether solvate 2, Compound 1 2-butanol solvate, Compound 1 t- butanol solvate, Compound 1 p-dioxane solvate, Compound 1 cyclopentyl methyl ether solvate, Compound 1 dimethyl acetamide solvate, Compound 1 hydrochloride Form I, Compound 1 hydrochloride Form II, Compound 1 hemisulfate Form I, Compound 1 sulfate Form I, Compound 1 mesylate Form I, Compound 1 esylate Form I, Compound 1 besylate Form I, Compound 1 besylate Form II, Compound 1 tosylate Form I, Compound 1 napsylate Form I, Compound 1 maleate Form I, Compound 1 L-tartrate Form I, Compound 1 L-tartrate Form II, or Compound 1 L-tartrate Form III.

[0008] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2 -methyl- 1 -((R)-5-(pyri din-2 -yl)-2, 3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5° 26 (± 0.2° 29), Form I.

[0009] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 12.6, 13.9, 15.3, 18.5, 19.2, 19.7, 22.3, 23.4, or 24.3° 26 (± 0.2° 29), Form II.

[0010] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 10.0, 12.2, 17.3, 18.3, 20.1, 22.0, 23.7, 25.3, or 25.9° 26 (± 0.2° 29), Form III.

[0011] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 5.7, 11.2, 16.8, 17.1, 18.7, 21.4, 22.4, 23.3, or 23.8° 29 (± 0.2° 29), Form IV.

[0012] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 10.0, 11.8, 13.9, 17.6, 18.1, 18.5, 18.9, 19.6, or 26.0° 26 (± 0.2° 29), Form V.

[0013] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 12.2, 14.9, 17.5, 20.0, 20.6, 21.8, 23.6, 25.4, or 26.0° 26 (± 0.2° 29), monohydrate.

[0014] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 8.1, 9.6, 11.7, 16.3, 18.8, 24.5, 25.7, 25.9, or 27.9° 29 (± 0.2° 29), dihydrate.

[0015] In another embodiment, the present disclosure provides Compound 1 MeTHF solvate, characterized by an XRPD pattern substantially as shown in FIG. 26.

[0016] In another embodiment, the present disclosure provides Compound 1 MTBE solvate 1, characterized by an XRPD pattern substantially as shown in FIG. 29.

[0017] In another embodiment, the present disclosure provides Compound 1 MTBE solvate 2, characterized by an XRPD pattern substantially as shown in FIG. 30.

[0018] In another embodiment, the present disclosure provides Compound 1 2-BuOH solvate, characterized by an XRPD pattern substantially as shown in FIG. 33

[0019] In another embodiment, the present disclosure provides Compound 1 t-BuOH solvate, characterized by an XRPD pattern substantially as shown in FIG. 35.

[0020] In another embodiment, the present disclosure provides Compound 1 p-Dioxane solvate, characterized by an XRPD pattern substantially as shown in FIG. 36.

[0021] In another embodiment, the present disclosure provides Compound 1 CPME solvate, characterized by an XRPD pattern substantially as shown in FIG. 37.

[0022] In another embodiment, the present disclosure provides Compound 1 DMAc solvate, characterized by an XRPD pattern substantially as shown in FIG. 39.

[0023] In another embodiment, the present disclosure provides Compound 1 Mesophase, characterized by an XRPD pattern substantially as shown in FIG. 42.

[0024] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 8.9, 12.5, 18.9, 19.6, 20.8, 23.8, 24.4, 24.8, or 28.8° 29 (± 0.2° 29), hydrochloride Form I.

[0025] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2 -methyl- 1 -((R)-5-(pyri din-2 -yl)-2, 3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 8.3, 12.4, 15.3, 19.2, 22.6, 24.0, 24.8, 26.3, or 28.3° 29 (± 0.2° 29), hydrochloride Form II.

[0026] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 9.6, 11.9, 16.5, 19.4, 20.1, 22.6, 23.8, or 25.8° 29 (± 0.2° 29), hemisulfate Form I.

[0027] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 9.6, 19.1, 19.4, 20.4, 22.3, 23.6, or 25.5° 29 (± 0.2° 20), sulfate Form I .

[0028] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, or 29.6° 29 (± 0.2° 29), mesylate Form I.

[0029] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 7.0, 17.9, 18.4, 20.1, 20.8, 23.0, 23.4, 24.0, or 25.8° 29 (± 0.2° 29), esylate Form I.

[0030] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 11.3, 14.9, 16.1, 18.4, 19.8, 21.0, 22.8, or 24.9° 20 (± 0.2° 20), besylate Form I.

[0031] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.2, 18.0, 19.3, and 21.7° 29 (± 0.2° 29), besylate Form II.

[0032] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at4.1, 8.1, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5, or 24.5° 29 (± 0.2° 29), tosylate Form I.

[0033] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at6.6, 12.3, 17.8, 19.0, 21.2, 22.2, 23.9, 25.8, or 26.6° 29 (± 0.2° 20), napsylate Form I.

[0034] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at10.6, 16.9, 18.0, 20.0, 21.7, 22.6, 24.5, 25.5, or 27.3° 26 (± 0.2° 29), maleate Form I.

[0035] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at9.4, 14.4, 16.2, 17.4, 17.9, 18.9, 20.3, 21.5, or 24.3° 29 (± 0.2° 29), L-tartrate Form I.

[0036] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 11.7, 13.9, 18.6, 21.8, 23.1, 24.5, 26.1, 28.8, or 29.5° 26 (± 0.2° 29), L-tartrate Form II.

[0037] In another embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 4.9, 9.8, 17.1, 18.6, 19.6, 20.2, 20.8, 22.0, or 24.6° 29 (± 0.2° 29), L-tartrate Form III.

[0038] In some embodiments, provided herein are pharmaceutical compositions comprising a crystalline form of Compound 1 of the present disclosure and a pharmaceutically acceptable carrier.

[0039] In some embodiments, provided herein is a method of treating a herpesvirus infection comprising administering to a patient a therapeutically effective amount of a crystalline form of Compound 1 provided herein, or a pharmaceutical composition provided herein, to a patient in need thereof.

[0040] In some embodiments, provided herein is a method of treating a disorder induced, exacerbated, or accelerated by herpesviruses, comprising administering to a patient a therapeutically effective amount of a crystalline form of Compound 1 provided herein, or a pharmaceutical composition provided herein, to a patient in need thereof.

[0041] In some embodiments, provided herein is use of a crystalline form of Compound 1 provided herein, or a pharmaceutical composition provided herein, in the manufacture of a medicament for treating or preventing a HSV infection.

[0042] In some embodiments, provided herein is use of a crystalline form of Compound 1 provided herein, or a pharmaceutical composition provided herein, in the treatment of a viral infection.

[0043] In some embodiments, provided herein is use of a crystalline form of Compound 1 provided herein, or a pharmaceutical composition provided herein, in the treatment of a viral infection caused by herpesviruses

[0044] In some embodiments, provided herein is use of a crystalline form of Compound 1 provided herein, or a pharmaceutical composition provided herein, in the treatment of a viral infection caused by HSV-1 or HSV-2.

[0045] In some embodiments, provided herein is use of a crystalline form of Compound 1 provided herein, or a pharmaceutical composition provided herein, for the preparation of a medicament for preventing / treating a viral infection.

[0046] In some embodiments, provided herein is use of a crystalline form of Compound 1 provided herein, or a pharmaceutical composition provided herein, for the preparation of a medicament for preventing / treating a viral infection caused by herpesviruses.

[0047] In some embodiments, provided herein is use of a crystalline form of Compound 1 provided herein, or a pharmaceutical composition provided herein, for the preparation of a medicament for preventing / treating a viral infection caused by HSV-1 or HSV-2.

[0048] In some embodiments, provided herein is the crystalline form of Compound 1 provided herein, or a pharmaceutical composition provided herein, for use in a method of treating a viral infection caused by HSV-1 or HSV-2.

[0049] In one embodiment, there is provided a process to prepare Compound 1 Form I.

[0050] In one embodiment, there is provided Compound 1 Form I obtainable by the process described herein.

[0051] In one embodiment, there is provided a process to prepare Compound 1 Mesylate Form I.

[0052] In one embodiment, there is provided Compound 1 Mesylate Form I obtainable by the process described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0053] FIG. 1 shows a XRPD pattern of Compound 1 Form I.

[0054] FIG. 2 shows a DSC thermogram of Compound 1 Form I.

[0055] FIG. 3 shows a TGA thermogram of Compound 1 Form I.

[0056] FIG. 4 shows a DVS analysis of Compound 1 Form I.

[0057] FIG. 5 shows a XRPD pattern of Compound 1 Form II.

[0058] FIG. 6 shows a DSC thermogram of Compound 1 Form II.

[0059] FIG. 7 shows a TGA thermogram of Compound 1 Form II.

[0060] FIG. 8 shows a DVS analysis of Compound 1 Form II.

[0061] FIG. 9 shows a XRPD pattern of Compound 1 Form III.

[0062] FIG. 10 shows a DSC thermogram of Compound 1 Form III.

[0063] FIG. 11 shows a TGA thermogram of Compound 1 Form III.

[0064] FIG. 12 shows a DVS analysis of Compound 1 Form III.

[0065] FIG. 13 shows a XRPD pattern of Compound 1 Form IV.

[0066] FIG. 14 shows a DSC thermogram of Compound 1 Form IV.

[0067] FIG. 15 shows a TGA thermogram of Compound 1 Form IV.

[0068] FIG. 16 shows a DVS analysis of Compound 1 Form IV.

[0069] FIG. 17 shows a XRPD pattern of Compound 1 Form V.

[0070] FIG. 18 shows a DSC thermogram of Compound 1 Form V.

[0071] FIG. 19 shows a TGA thermogram of Compound 1 Form V.

[0072] FIG. 20 shows a XRPD pattern of Compound 1 monohydrate.

[0073] FIG. 21 shows a DSC thermogram of Compound 1 monohydrate.

[0074] FIG. 22 shows a TGA thermogram of Compound 1 monohydrate.

[0075] FIG. 23 shows a XRPD pattern of Compound 1 dihydrate.

[0076] FIG. 24 shows a DSC thermogram of Compound 1 dihydrate.

[0077] FIG. 25 shows a TGA thermogram of Compound 1 dihydrate.

[0078] FIG. 26 shows a XRPD pattern of Compound 1 MeTHF solvate.

[0079] FIG. 27 shows a DSC thermogram of Compound 1 MeTHF solvate.

[0080] FIG. 28 shows a TGA thermogram of Compound 1 MeTHF solvate.

[0081] FIG. 29 shows a XRPD pattern of Compound 1 MTBE solvate 1.

[0082] FIG. 30 shows a XRPD pattern of Compound 1 MTBE solvate 2.

[0083] FIG. 31 shows a DSC thermogram of Compound 1 MTBE solvate 2.

[0084] FIG. 32 shows an overlay of the XRPD patterns of the solids before and after drying Compound 1 2-BuOH solvate (from top to bottom): wet cake, dried at 50 °C, dried at 100 °C, and dried at 180 °C.

[0085] FIG. 33 shows a XRPD pattern of Compound 1 2-BuOH solvate.

[0086] FIG. 34 shows a DSC thermogram of Compound 1 2-BuOH solvate.

[0087] FIG. 35 shows a XRPD pattern of Compound 1 t-BuOH solvate.

[0088] FIG. 36 shows a XRPD pattern of Compound 1 p-di oxane solvate.

[0089] FIG. 37 shows a XRPD pattern of Compound 1 CPME solvate.

[0090] FIG. 38 shows a DSC thermogram of Compound 1 CPME solvate.

[0091] FIG. 39 shows a XRPD pattern of Compound 1 DMAc solvate.

[0092] FIG. 40 shows a DSC thermogram of Compound 1 DMAc solvate.

[0093] FIG. 41 shows a TGA thermogram of Compound 1 DMAc solvate.

[0094] FIG. 42 shows a XRPD patterns of Compound 1 mesophase.

[0095] FIG. 43 shows a XRPD pattern of Compound 1 hydrochloride Form I.

[0096] FIG. 44 shows a DSC thermogram of Compound 1 hydrochloride Form I.

[0097] FIG. 45 shows a TGA thermogram of Compound 1 hydrochloride Form I.

[0098] FIG. 46 shows a DVS analysis of Compound 1 hydrochloride Form I.

[0099] FIG. 47 shows a XRPD pattern of Compound 1 hydrochloride Form II.

[0100] FIG. 48 shows a DSC thermogram of Compound 1 hydrochloride Form II.

[0101] FIG. 49 shows a TGA thermogram of Compound 1 hydrochloride Form II.

[0102] FIG. 50 shows a DVS analysis of Compound 1 hydrochloride Form II.

[0103] FIG. 51 shows a XRPD pattern of Compound 1 hemisulfate Form I.

[0104] FIG. 52 shows a DSC thermogram of Compound 1 hemisulfate Form I.

[0105] FIG. 53 shows a XRPD pattern of Compound 1 sulfate Form I.

[0106] FIG. 54 shows a DSC thermogram of Compound 1 sulfate Form I.

[0107] FIG. 55 shows a XRPD pattern of Compound 1 mesylate Form I.

[0108] FIG. 56 shows a DSC thermogram of Compound 1 mesylate Form I.

[0109] FIG. 57 shows a TGA thermogram of Compound 1 mesylate Form I.

[0110] FIG. 58 shows a DVS analysis of Compound 1 mesylate Form I.[OHl] FIG. 59 shows a XRPD pattern of Compound 1 esylate Form I.

[0112] FIG. 60 shows a DSC thermogram of Compound 1 esylate Form I.

[0113] FIG. 61 shows a TGA thermogram of Compound 1 esylate Form I.

[0114] FIG. 62 shows a DVS analysis of Compound 1 esylate Form I.

[0115] FIG. 63 shows a XRPD pattern of Compound 1 besylate Form I.

[0116] FIG. 64 shows a DSC thermogram of Compound 1 besylate Form I.

[0117] FIG. 65 shows a XRPD pattern of Compound 1 besylate Form II.

[0118] FIG. 66 shows a DSC thermogram of Compound 1 besylate Form II.

[0119] FIG. 67 shows a XRPD pattern of Compound 1 tosylate Form I.

[0120] FIG. 68 shows a DSC thermogram of Compound 1 tosylate Form I.

[0121] FIG. 69 shows a XRPD pattern of Compound 1 napsylate Form I.

[0122] FIG. 70 shows a DSC thermogram of Compound 1 napsylate Form I.

[0123] FIG. 71 shows a XRPD pattern of Compound 1 maleate Form I.

[0124] FIG. 72 shows a DSC thermogram of Compound 1 maleate Form I.

[0125] FIG. 73 shows a TGA thermogram of Compound 1 maleate Form I.

[0126] FIG. 74 shows a DVS analysis of Compound 1 maleate Form I.

[0127] FIG. 75 shows a XRPD pattern of Compound 1 L-tartrate Form I.

[0128] FIG. 76 shows a DSC thermogram of Compound 1 L-tartrate Form I.

[0129] FIG. 77 shows a XRPD pattern of Compound 1 L-tartrate Form II.

[0130] FIG. 78 shows a DSC thermogram of Compound 1 L-tartrate Form II.

[0131] FIG. 79 shows a XRPD pattern of Compound 1 L-tartrate Form III.

[0132] FIG. 80 shows a DSC thermogram of Compound 1 L-tartrate Form III.

[0133] FIG. 81 shows a XRPD overlay of Compound 1 Form I stability study samples.

[0134] FIG. 82 shows a XRPD overlay of Compound 1 mesylate Form I stability study samples.

[0135] FIG. 83 shows the PK profiles for Compound 1 Form I (freebase) and Compound 1 mesylate Form I (MSA salt) powder in capsule - pentagastrin pre-treated.

[0136] Fig. 84 shows a DCS thermogram of Compound 1 Form I.

[0137] Fig. 85 shows a DCS thermogram of Compound 1 Mesylate Form I.DETAILED DESCRIPTIONI. GENERAL

[0138] The present disclosure results from the surprising discoveries of the solid forms of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-IH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):and salts, solvates or co-crystals thereof. Compound 1 can adopt a variety of crystalline forms, including, but not limited to, Form I, Form II, Form III, Form IV, Form V, monohydrate, dihydrate, methyl -tetrahydrofuran (MeTHF) solvate, methyl t-butyl ether (MTBE) solvate 1, MTBE solvate 2, 2-butanol solvate, t-butanol solvate, p-dioxane solvate, cyclopentyl methyl ether (CPME) solvate, dimethyl acetamide (DMAc) solvate, hydrochloride Form I, hydrochloride Form II, hemisulfate Form I, sulfate Form I, mesylate Form I, esylate Form I, besylate Form I, besylate Form II, tosylate Form I, napsylate Form I, maleate Form I, L-tartrate Form I, L-tartrate Form II, or L-tartrate Form III. Compound 1 can form a mixture of two or more crystalline forms, or form a single crystalline form substantially free of other crystalline forms.

[0139] The X-ray powder diffraction (XRPD) patterns provided herein of the solid forms of (R)- 5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1) were collected using Cu Ka radiation (1.5419 A).H. DEFINITIONS

[0140] The description below is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout thisdisclosure are provided for convenience and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0141] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It must be noted that as used herein and in the appended claims, the singular forms “a”, “and”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art, and so forth.

[0142] As used in the present specification, the following terms and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0143] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0144] At various places in the present specification, values are disclosed in groups or in ranges. It is specifically intended that the description include all individual sub-combination of the members of such groups and ranges and any combination of the various endpoints of such groups or ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 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, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0145] The use of any and all examples, or exemplary language herein, for example, "such as," "including," or "for example," is intended merely to illustrate better the present teachings and does not pose a limitation on the scope of the invention unless claimed.

[0146] A "crystalline form" is a solid material wherein the constituents of the solid material are arranged in a highly ordered microscopic structure, thereby forming a crystal lattice which extendsin all directions. Crystalline forms can include anhydrous crystalline forms, solvated crystalline forms and / or hydrated crystalline forms. Salts of a compound can also exist in crystalline forms.

[0147] "Polymorphism" is when a solid material can exist in more than one crystalline form.

[0148] As used herein, the term "amorphous" refers to a solid material having no long-range order in the position of its molecules. Amorphous solids are substances in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long-range order. Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points. For example, an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid.

[0149] “Hydrate” refers to a complex formed by the combining of Compound 1 and water. The term includes stoichiometric (such as monohydrate and dihydrate) as well as non-stoichiometric hydrates. As the term is used herein a "hydrate" refers to a solid form, i.e., Compound 1 in water solution, while it may be hydrated, is not a hydrate as the term is used herein. Hydrates may be crystalline, wherein both the compound and water form part of the crystal lattice.

[0150] “Solvate” refers to a complex formed by the combining of Compound 1 and a solvent. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric. As the term is used herein a "solvate" refers to a solid form, i.e., a Compound 1 in solvent solution, while it may be solvated, is not a solvate as the term is used herein. Solvates may be crystalline, wherein both the compound and solvent form part of the crystal lattice.

[0151] “Desolvated” refers to a Compound 1 form that is a solvate as described herein, and from which solvent molecules have been partially or completely removed. Desolvation techniques to produce desolvated forms include, without limitation, exposure of a Compound 1 Form (solvate) to vacuum, subjecting the solvate to elevated temperature, exposing the solvate to a stream of gas, such as air or nitrogen, or any combination thereof. Thus, a desolvated Compound 1 form can be completely without solvent molecules, or partially solvated wherein solvent molecules are present in stoichiometric or non-stoichiometric amounts.

[0152] "Anhydrous" means the solid form of the compound does not have water incorporated into its structure. For example, an anhydrous crystalline form does not have water forming part of the crystal structure. The skilled person would be aware of techniques which can be used to quantify the amount of water associated with a solid. For example, water content can bedetermined by either Karl Fischer Titration or Thermogravimetric Analysis (TGA). Suitably, an anhydrous solid form of the compound comprises less than about 2% by weight, such as less than about 1.5%, less than about 1%, such as less than about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05%, or about 0.01% by weight of water.

[0153] "Un-solvated" or "non-solvated" means the solid form of the compound does not have solvent(s) incorporated into its structure. For example, an un-solvated crystalline form does not have solvent(s) forming part of the crystal structure. The skilled person would be aware of techniques which can quantify the amount of solvent associated with a solid. For example, solvent content can be determined by Gas Chromatography (GC). Suitably, an un-solvated or nonsolvated solid form of the compound comprises less than about 2% by weight, such as less than about 1.5%, less than about 1%, such as less than about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05%, or about 0.01% by weight of solvent.

[0154] A “mesophase” or “mesomorphic” phase is a phase of matter intermediate between solid and liquid.

[0155] “Alcohol” refers to a solvent having a hydroxy group. Representative alcohols can have any suitable number of carbon atoms, such as Ci-Cs, and any suitable number of hydroxy groups, such as 1-3. Exemplary alcohols include, but are not limited to, methanol, ethanol, w-propanol, i- propanol, etc.

[0156] “Substantially free of other crystalline forms of Compound 1” refers to a crystalline form of Compound 1 that contains less than 10% of other crystalline forms of Compound 1. For example, substantially free can refer to a crystalline form of Compound 1 that contains less than 9, 8, 7, 6, 5, 4, 3, 2, or 1% of other crystalline forms of Compound 1. Preferably, substantially free refers to a crystalline form of Compound 1 that contains less than 5% of other crystalline forms of Compound 1. Preferably, substantially free refers to a crystalline form of Compound 1 that contains less than 1% of other crystalline forms of Compound 1.

[0157] The disclosures illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc., shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure claimed.

[0158] Furthermore, the present disclosure provides pharmaceutical compositions comprising a crystalline form of Compound 1 of the present disclosure as active ingredient together with a pharmaceutically acceptable carrier.

[0159] “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure can encompass any composition made by admixing at least one compound of the present disclosure and a pharmaceutically acceptable carrier.

[0160] As used herein, “pharmaceutically acceptable carrier” includes excipients or agents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like that are not deleterious to the disclosed compound or use thereof. The use of such carriers and agents to prepare compositions of pharmaceutically active substances is well known in the art (see, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985); and Modem Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds ).

[0161] “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition, and / or delaying the spread (e.g., metastasis) of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival. In some embodiments, the term “treatment” or “treating” means administering a crystalline form of Compound 1 of the present disclosure for the purpose of: (i) delaying the onset of a disease, that is, causing the clinical symptoms of the disease not to develop or delaying the development thereof; (ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and / or (iii) relieving the disease, that is, causing the regression of clinical symptoms or the severity thereof.

[0162] “Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0163] The terms “individual,” “patient,” or “subject” are used interchangeably. “Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. The mammal treated in the methods of the disclosure is desirably a mammal in which treatment of HSV infection is desired.

[0164] The term “therapeutically effective amount” or “effective amount” of a crystalline form of Compound 1 described herein means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition responsive to herpesvirus helicase- primase inhibitor. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art.

[0165] Herein, where a composition is said to "consist essentially of a particular component, said composition suitably comprises at least 70 wt% of said component, suitably at least 80 wt% thereof, suitably at least 90 wt% thereof, suitably at least 95 wt% thereof, most suitably at least 99 wt% thereof. Suitably, a composition said to "consist essentially of a particular component consists of said component save for one or more trace components.

[0166] The phrase "substantially as shown in figure" refers to an X-ray powder diffraction pattern or DSC thermogram with at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95% or at least 99% of its features appearing in the figure.

[0167] The term “relative volumes” refers to the volume of a liquid (in mL) used relative to the mass of Compound 1 (in g). For example, 10 relative volumes of solvent equates to 10 mL for every gram of Compound 1.

[0168] The phrase “FIG.” is short for Figure.HI. SOLID FORMS OF COMPOUND 1

[0169] The present disclosure provides solid forms of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin- 2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1; see Example 35 of PCT Application No. PCT / US2023 / 022679, publication reference of WO 2023 / 225162 Al), including crystalline and mesophase forms, as well as salts, solvate and hydrate forms. In some embodiments, the present disclosure provides a crystalline form of Compound 1 having the structure:and salts, solvates or hydrates thereof.

[0170] Compound 1 can adopt a variety of crystalline forms, including, but not limited to, Form I, Form II, Form III, Form IV, Form V, monohydrate, dihydrate, methyl-tetrahydrofuran (MeTHF) solvate, methyl t-butyl ether (MTBE) solvate 1, MTBE solvate 2, 2-butanol solvate, t- butanol solvate, p-dioxane solvate, cyclopentyl methyl ether (CPME) solvate, dimethyl acetamide (DMAc) solvate, hydrochloride Form I, hydrochloride Form II, hemisulfate Form I, sulfate Form I, mesylate Form I, esylate Form I, besylate Form I, besylate Form II, tosylate Form I, napsylate Form I, maleate Form I, L-tartrate Form I, L-tartrate Form II, or L-tartrate Form III. Compound 1 can form a mixture of two or more crystalline forms, or form a single crystalline form substantially free of other crystalline forms.

[0171] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1):or pharmaceutically acceptable salts or co-crystals thereof. The crystalline forms of Compound 1 can be anhydrous, salts, solvates, hydrates, or co-crystals. In some embodiments, the crystal form of Compound 1 can be a salt or co-crystal. In some embodiments, the crystal form ofCompound 1 can be anhydrous or solvated. In some embodiments, the crystal form of Compound 1 can be hydrated.

[0172] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1):that is: Compound 1 Form I, Compound 1 Form II, Compound 1 Form III, Compound 1 Form IV, Compound 1 Form V, Compound 1 monohydrate, Compound 1 dihydrate, Compound 1 methyl-tetrahydrofuran (MeTHF) solvate, Compound 1 methyl t-butyl ether solvate 1, Compound 1 methyl t-butyl ether solvate 2, Compound 1 2-butanol solvate, Compound 1 t- butanol solvate, Compound 1 p-dioxane solvate, Compound 1 cyclopentyl methyl ether solvate, Compound 1 dimethyl acetamide solvate, Compound 1 hydrochloride Form I, Compound 1 hydrochloride Form II, Compound 1 hemisulfate Form I, Compound 1 sulfate Form I, Compound 1 mesylate Form I, Compound 1 esylate Form I, Compound 1 besylate Form I, Compound 1 besylate Form II, Compound 1 tosylate Form I, Compound 1 napsylate Form I, Compound 1 maleate Form I, Compound 1 L-tartrate Form I, Compound 1 L-tartrate Form II, or Compound 1 L-tartrate Form III.

[0173] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is Compound 1 Form I, Compound 1 Form II, Compound 1 Form III, Compound 1 Form IV, or Compound 1 Form V.

[0174] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is Compound 1 monohydrate, or Compound 1 dihydrate.

[0175] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is Compound 1 methyl-tetrahydrofuran (MeTHF) solvate, Compound 1 methyl t-butyl ether solvate 1, Compound 1 methyl t-butyl ether solvate 2, Compound 1 2-butanol solvate, Compound 1 t-butanol solvate, Compound 1 p-dioxane solvate, Compound 1 cyclopentyl methyl ether solvate, or Compound 1 dimethyl acetamide solvate.

[0176] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is Compound 1 hydrochloride Form I, Compound 1 hydrochloride Form II, Compound 1 hemisulfate Form I, Compound 1 sulfate Form I, Compound 1 mesylate Form I, Compound 1 esylate Form I, Compound 1 besylate Form I, Compound 1 besylate FormII, Compound 1 tosylate Form I, Compound 1 napsylate Form I, Compound 1 maleate Form I, Compound 1 L-tartrate Form I, Compound 1 L-tartrate Form II, or Compound 1 L-tartrate FormIII,

[0177] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is Compound 1 Form I, Compound 1 Form III, Compound 1 FormIV, Compound 1 monohydrate, Compound 1 hydrochloride Form I, Compound 1 hydrochloride Form II, Compound 1 mesylate Form I, or Compound 1 maleate Form I.

[0178] In a preferred embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide, wherein the crystalline form is Compound 1 Form I. Advantageously, Compound 1 Form I is chemically and physically stable and has pharmacokinetic properties suitable for use in a pharmaceutical product.

[0179] In a preferred embodiment, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide, wherein the crystalline form is Compound 1 mesylate Form I. Advantageously, Compound 1 Mesylate Form I is chemically and physically stable when stored at a number of stability and forced degradation conditions, and has pharmacokinetic properties suitable for use in a pharmaceutical product.

[0180] There are a number of analytical methods one of ordinary skill in the art in solid-state chemistry can use to characterize solid forms. The term "characterize" as used herein means to obtain information about the solid-state structure of solid forms. For example, powder X-ray diffraction (PXRD / XRPD) is a suitable technique for differentiating amorphous solid forms from crystalline solid forms and for characterizing and identifying particular crystalline solid forms of a compound.

[0181] Due to differences in X-Ray diffraction instruments, samples, and sample preparation, peak values are often reported with the modifiers "± 0.2 °20" or "± 0.1 °29". This is common practice in the solid-state chemical arts because of the variation inherent in peak values. Variability in peak intensity is a result of how individual crystals are oriented in the sample container with respect to the external X-ray source (known as "preferred orientation"). This orientation effect does not provide structural information about the crystal.

[0182] When the modifiers “± 0.2 °20" and "± 0.1 °20" are used at the end of a list of X-Ray diffraction peaks, it is to be understood that the modifier applies to each peak specified in that list.

[0183] X-ray powder diffraction is just one of several analytical techniques one may use to characterize and / or identify crystalline solid forms. Differential scanning calorimetry (DSC) may be used to characterize and / or identity crystalline solid forms. A typical variability for a value associated with a differential scanning calorimetry onset temperature is of the order of ± 2°C.

[0184] It should be noted that unless noted otherwise, thermal data (DSC and TGA) presented herein were acquired using a heating rate of 10°C / min. Furthermore, DSC data was acquired using T zero aluminum pans.Compound 1 Form I

[0185] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is Form I (herein designated and characterized as Compound 1 Form I). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2- methyl- 1 -((R)-5 -(pyri din-2-yl)-2, 3 -dihydro- 1 H-indene-2-carb onyl)indoline-6-sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5° 20 (± 0.2° 20), Form I.

[0186] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, and 26.5° 20 (± 0.2° 20). In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 12.3, 12.5, 13.3, 14.4, 16.6, 17.3,18.0, 18.5, 19.8, 20.3, 21.2, 22.8, 23.2, 24.0, 24.6, 25.0, 25.3, 26.5, 27.6, 28.1, 28.7, 29.5, 30.9, 31.5, 32.2, 36.4, and 37.1° 20 (± 0.2° 20). In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 12.3, 12.5, 13.3, 14.4, 16.6, 17.3, 18.0, 18.5, 19.8, 20.3, 21.2, 22.8, 23.2, 24.0, 24.6, 25.0, 25.3, 26.5, 27.6, 28.1, 28.7, 29.5, 30.9, 31.5, 32.2, 36.4, and 37.1° 20 (± 0.2° 20).

[0187] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising five or more peaks at 12.3, 12.5, 17.3, 18.0, 18.5,21.2, 23.2, 24.0, or 26.5° 20 (± 0.1° 20). In some embodiments, the present disclosure provides Compound 1 Form I Compound 1 Form I, characterized by an XRPD pattern comprising peaks at12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, and 26.5° 20 (± 0.1° 20). In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 12.3, 12.5, 13.3, 14.4, 16.6, 17.3, 18.0, 18.5, 19.8, 20.3, 21.2, 22.8, 23.2, 24.0, 24.6, 25.0,25.3, 26.5, 27.6, 28.1, 28.7, 29.5, 30.9, 31.5, 32.2, 36.4, and 37.1° 20 (± 0.1° 20). In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 12.3, 12.5, 13.3, 14.4, 16.6, 17.3, 18.0, 18.5, 19.8, 20.3, 21.2, 22.8, 23.2, 24.0, 24.6, 25.0, 25.3, 26.5, 27.6, 28.1, 28.7, 29.5, 30.9, 31.5, 32.2, 36.4, and 37.1° 20 (± 0.1° 20).

[0188] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 18.0, 21.2 and 23.2020 (± 0.2° 20). In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 18.0, 21.2 and 23.2 ° 20 (± 0.2° 20) and further comprising at least one, two or three specific peaks selected from the peaks at 12.5, 18.5 and 22.8020 (± 0.2° 20).

[0189] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 18.0, 21.2 and 23.2 ° 20 (± 0.1° 20). In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 18.0, 21.2 and 23.2020 (± 0.1° 20) and further comprising at least one, two or three specific peaks selected from the peaks at 12.5, 18.5 and 22.8 ° 20 (± 0.1° 20).

[0190] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 18.0, 18.5, 21.2, 22.8 and 23.2020 (± 0.2° 20). In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 18.0, 18.5, 21.2, 22.8 and 23.2 ° 20 (± 0.1° 20).

[0191] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 18.0, 21.2 and 23.2029 (± 0.2° 29) and further comprising at least two, five, ten, fifteen or twenty specific peaks selected from the peaks at 12.3, 12.5, 13.3, 14.4, 16.6, 17.3, 18.5, 19.8, 20.3, 22.8, 24.0, 24.6, 25.0, 25.3, 26.5, 27.6, 28.1, 28.7, 29.5, 30.9, 31.5, 32.2, 36.4, and 37.1° 29 (± 0.2° 29).

[0192] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 18.0, 18.5, 21.2, 22.8 and 23.2 ° 20 (± 0.2° 20) and further comprising at least two, five, ten, fifteen or twenty specific peaks selected from the peaks at 12.3, 12.5, 13.3, 14.4, 16.6, 17.3, 19.8, 20.3, 24.0, 24.6, 25.0, 25.3, 26.5, 27.6, 28.1, 28.7, 29.5, 30.9, 31.5, 32.2, 36.4, and 37.1° 20 (± 0.2° 20).

[0193] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern substantially as shown in FIG. 1.

[0194] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by a unit cell as determined by single crystal X-ray crystallography of the following dimensions: a = 19.6326(18) A; b = 7.6161(7) A; c = 14.8409(14) A, a = 90°; = 104.029(8)°; and y = 90°.

[0195] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 230 °C. In some embodiments, the present disclosure provides Compound 1 Form I, characterized by a differential scanning calorimetry (DSC) thermogram having no thermal events between 25 and 200 °C and an endotherm with an onset of about 230 °C. In some embodiments, the present disclosure provides Compound 1 Form I, characterized by a DSC thermogram substantially as shown in FIG. 2.

[0196] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 225 °C. In some embodiments, the present disclosure provides Compound 1 Form I, characterized by a differential scanning calorimetry (DSC) thermogram having no thermal events between 25 and 200 °C and an endotherm with an onset of about 225 °C. In some embodiments, the present disclosure provides Compound 1 Form I, characterized by a DSC thermogram substantially as shown in FIG. 84.

[0197] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 225 to about 230 °C.

[0198] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising five or more peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5° 29 (± 0.2° 20) and a DSC thermogram having an endotherm onset of about 225°C to about 230 °C. In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising five or more peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5° 20 (± 0.2° 20) and a DSC thermogram having an endotherm onset of about 225°C. In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising five or more peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5° 29 (± 0.2° 20) and a DSC thermogram having an endotherm onset of about 230°C.

[0199] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 18.0, 21.2 and 23.2020 (± 0.2° 20) and a DSC thermogram having an endotherm onset of about 225°C to about 230 °C. In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 18.0, 21.2 and 23.2020 (± 0.2° 20) and further comprising at least one, two or three specific peaks selected from the peaks at 12.5, 18.5 and 22.8 ° 20 (± 0.2° 20) and a DSC thermogram having an endotherm onset of about 225°C to about 230 °C.

[0200] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 18.0, 21.2 and 23.2020 (± 0.1° 20) and a DSC thermogram having an endotherm onset of about 225°C to about 230 °C. In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 18.0, 21.2 and 23.2020 (± 0.1° 20) and further comprising at least one, two or three specific peaks selected from the peaks at 12.5, 18.5 and 22.8 ° 20 (± 0.1° 20) and a DSC thermogram having an endotherm onset of about 225°C to about 230 °C.

[0201] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 18.0, 18.5, 21.2, 22.8 and 23.2 ° 20 (± 0.2° 20) and a DSC thermogram having an endotherm onset of about 225°C to about 230 °C. In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising peaks at 18.0, 18.5, 21.2, 22.8 and 23.2 ° 20 (± 0.1° 20) and a DSC thermogram having an endotherm onset of about 225°C to about 230 °C.

[0202] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 0.4%. In some embodiments, the present disclosure provides Compound 1 Form I, characterized by athermal gravimetric analysis (TGA) having a weight loss of about 0.4% between 40 and 200 °C. In some embodiments, the present disclosure provides Compound 1 Form I, characterized by a TGA substantially as shown in FIG. 3.

[0203] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 0.1%. In some embodiments, the present disclosure provides Compound 1 Form I, characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 0.1% between about 0 and 90%RH. In some embodiments, the present disclosure provides Compound 1 Form V, characterized by a DVS analysis substantially as shown in FIG. 4.

[0204] Suitably, Compound 1 Form I is unsolvated and anhydrous. Suitably Compound 1 Form I comprises less than about 2% by weight solvent and / or water, such as less than about 1.5% by weight, less than about 1%, or less than about 0.5% by weight. The skilled person would know of suitable analytical techniques which can quantify the amount of solvent / water associated with a solid. For example, water content can be determined by Karl Fischer Titration. Residual solvents can be determined by Gas Chromatography. Thermogravimetric Analysis (TGA) can also quantify the amount of volatile material (i.e., solvent and water) associated with a solid (either surface bound or incorporated into the crystal structure).

[0205] In some embodiments, the present disclosure provides Compound 1 Form I, characterized by an XRPD pattern comprising five or more peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5° 20 (± 0.2° 20) and wherein Compound 1 Form I comprises less than about 2% weight solvent and / or water.Compound 1 Form II

[0206] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is Form II (herein designated and characterized as Compound 1 Form II). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2- methyl- 1 -((R)-5 -(pyri din-2-yl)-2, 3 -dihydro- 1 H-indene-2-carb onyl)indoline-6-sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 12.6, 13.9, 15.3, 18.5, 19.2, 19.7, 22.3, 23.4, or 24.3° 29 (± 0.2° 20), Form II.

[0207] In some embodiments, the present disclosure provides Compound 1 Form II, characterized by an XRPD pattern comprising peaks at 12.6, 13.9, 15.3, 18.5, 19.2, 19.7, 22.3,23.4, and 24.3° 20 (± 0.2° 29). In some embodiments, the present disclosure provides Compound 1 Form II, characterized by an XRPD pattern comprising peaks at 9.4, 12.6, 13.9, 15.3, 16.7, 17.3,18.5, 19.2, 19.7, 22.3, 23.4, 24.3, 25.1, 25.7, 26.4, 28.0, 29.0, 29.7, 31.5, 33.7, and 35.3° 29 (± 0.2° 20).

[0208] In some embodiments, the present disclosure provides Compound 1 Form II, characterized by an XRPD pattern substantially as shown in FIG. 5.

[0209] In some embodiments, the present disclosure provides Compound 1 Form II, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with onsets of about 223 and 245 °C. In some embodiments, the present disclosure provides Compound 1 Form II, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 223 °C. In some embodiments, the present disclosure provides Compound 1 Form II, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 245 °C. In some embodiments, the present disclosure provides Compound 1 Form II, characterized by a DSC thermogram substantially as shown in FIG. 6.

[0210] In some embodiments, the present disclosure provides Compound 1 Form II, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 0.6%. In some embodiments, the present disclosure provides Compound 1 Form II, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 0.6% between 25 and 150 °C. In some embodiments, the present disclosure provides Compound 1 Form II, characterized by a TGA substantially as shown in FIG. 7.

[0211] In some embodiments, the present disclosure provides Compound 1 Form II, characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 0.6%. In some embodiments, the present disclosure provides Compound 1 Form II, characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 0.6% between about 0 and about 90%RH. In some embodiments, the present disclosure provides Compound 1 Form II, characterized by a DVS analysis substantially as shown in FIG. 8.Compound 1 Form III

[0212] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is Form III (herein designated and characterized as Compound 1 Form III). In some embodiments, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 10.0, 12.2, 17.3, 18.3, 20.1, 22.0, 23.7, 25.3, or 25.9° 26 (± 0.2° 29), Form III.

[0213] In some embodiments, the present disclosure provides Compound 1 Form III, characterized by an XRPD pattern comprising peaks at 10.0, 12.2, 17.3, 18.3, 20.1, 22.0, 23.7, 25.3 and 25.9° 29 (± 0.2° 29). In some embodiments, the present disclosure provides Compound 1 Form III, characterized by an XRPD pattern comprising peaks at 10.0, 12.2, 12.7, 13.3, 14.7, 15.0, 15.8, 17.3, 18.3, 19.1, 20.1, 20.3, 20.8, 22.0, 23.0, 23.7, 24.4, 25.3, 25.9, 27.0, 28.0, 28.5, 28.9, and 30.3° 29 (± 0.2° 29).

[0214] In some embodiments, the present disclosure provides Compound 1 Form III, characterized by an XRPD pattern substantially as shown in FIG 9.

[0215] In some embodiments, the present disclosure provides Compound 1 Form III, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 246 °C. In some embodiments, the present disclosure provides Compound 1 Form III, characterized by a DSC thermogram substantially as shown in FIG 10.

[0216] In some embodiments, the present disclosure provides Compound 1 Form III, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 3.5%. In some embodiments, the present disclosure provides Compound 1 Form III, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 3.5% between 25 and 60 °C. In some embodiments, the present disclosure provides Compound 1 Form III, characterized by a TGA substantially as shown in FIG. 11.

[0217] In some embodiments, the present disclosure provides Compound 1 Form III, characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 4.6%. In some embodiments, the present disclosure provides Compound 1 Form III, characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 4.6% between about 0 and about 90%RH. In some embodiments, the present disclosure provides Compound 1 Form III, characterized by a DVS analysis substantially as shown in FIG. 12.Compound 1 Form IV

[0218] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is Form IV (herein designated and characterized as Compound 1 Form IV). In some embodiments, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 5.7, 11.2, 16.8, 17.1, 18.7, 21.4, 22.4, 23.3, or 23.8° 29 (± 0.2° 29), Form IV.

[0219] In some embodiments, the present disclosure provides Compound 1 Form IV, characterized by an XRPD pattern comprising peaks at 5.7, 11.2, 16.8, 17.1, 18.7, 21.4, 22.4, 23 3, and 23.8° 29 (± 0.2° 29). In some embodiments, the present disclosure provides Compound 1 Form IV, characterized by an XRPD pattern comprising peaks at 5.7, 8.6, 11.2, 11.7, 13.8, 16.2, 16.8, 17.1, 17.6, 18.2, 18.7, 19.7, 20.4, 21.4, 21.8, 22.4, 23.3, 23.8, 24.5, 25.7, 26.5, 27.7, 29.2, 30.0, 31.4, 32.7, 33.2, 33.7, 34.8, 35.3, and 38.3° 29 (± 0.2° 29). In some embodiments, the present disclosure provides Compound 1 Form IV, characterized by an XRPD pattern substantially as shown in FIG. 13.

[0220] In some embodiments, the present disclosure provides Compound 1 Form IV, characterized by a unit cell as determined by single crystal X-ray crystallography of the following dimensions: a - 6.09120(10) A; b = 11.01750(10) A; c = 31.8714(4) A; a = 90°; 0 = 90°; and y - 90°.

[0221] In some embodiments, the present disclosure provides Compound 1 Form IV, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 242 °C. In some embodiments, the present disclosure provides Compound 1 Form IV, characterized by a DSC thermogram substantially as shown in FIG. 14.

[0222] In some embodiments, the present disclosure provides Compound 1 Form IV, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 0.7%. In some embodiments, the present disclosure provides Compound 1 Form IV, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 0.7% between 25 and 75 °C. In some embodiments, the present disclosure provides Compound 1 Form IV, characterized by a TGA substantially as shown in FIG. 15.

[0223] In some embodiments, the present disclosure provides Compound 1 Form IV, characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 0.8%. In some embodiments, the present disclosure provides Compound 1 Form IV, characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 0.8% between about 0% and 90%RH. In some embodiments, the present disclosure provides Compound 1 Form IV, characterized by a DVS analysis substantially as shown in FIG. 16.Compound 1 Form V

[0224] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is Form V (herein designated and characterized as Compound 1 Form V). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2- methyl- 1 -((R)-5 -(pyri din-2-yl)-2, 3 -dihydro- 1 H-indene-2-carb onyl)indoline-6-sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 10.0, 11.8, 13.9, 17.6, 18.1, 18.5, 18.9, 19.6, or 26.0° 26 (± 0.2° 29), Form V.

[0225] In some embodiments, the present disclosure provides Compound 1 Form V, characterized by an XRPD pattern comprising peaks at 10.0, 11.8, 13.9, 17.6, 18.1, 18.5, 18.9, 19.6, and 26.0° 26 (± 0.2° 29). In some embodiments, the present disclosure provides Compound1 Form V, characterized by an XRPD pattern comprising peaks at 9.2, 10.0, 11.8, 12.5, 13.9, 15.3, 15.8, 16.8, 17.3, 17.6, 18.1, 18.5, 18.9, 19.6, 20.4, 21.2, 21.7, 22.4, 23.8, 25.0, 26.0, 27.0, and 28.4° 29 (± 0.2° 29).

[0226] In some embodiments, the present disclosure provides Compound 1 Form V, characterized by an XRPD pattern substantially as shown in FIG. 17.

[0227] In some embodiments, the present disclosure provides Compound 1 Form V, characterized by a DSC thermogram substantially as shown in FIG. 18.

[0228] In some embodiments, the present disclosure provides Compound 1 Form V, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 2%. In some embodiments, the present disclosure provides Compound 1 Form V, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 2% between 25 and 100 °C. In some embodiments, the present disclosure provides Compound 1 Form V, characterized by a TGA substantially as shown in FIG. 19.Compound 1 Monohydrate

[0229] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the monohydrate (herein designated and characterized as Compound 1 Monohydrate). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-l -((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2- carbonyl)indoline-6-sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at12.2, 14.9, 17.5, 20.0, 20.6, 21.8, 23.6, 25.4, or 26.0° 26 (± 0.2° 29), monohydrate.

[0230] In some embodiments, the present disclosure provides Compound 1 Monohydrate, characterized by an XRPD pattern comprising peaks at 12.2, 14.9, 17.5, 20.0, 20.6, 21.8, 23.6, 25.4, and 26.0° 26 (± 0.2° 26). In some embodiments, the present disclosure provides Compound 1 Monohydrate, characterized by an XRPD pattern comprising peaks at 10.0, 12.2, 12.5, 13.2,14.9, 16.3, 17.5, 18.7, 19.0, 19.4, 20.0, 20.6, 21.1, 21.8, 23.0, 23.6, 24.5, 25.4, 26.0, 27.8, 28.3, 28.6, 30.1, 31.4, 32.1, 32.8, 34.3, 35.9, 36.9, 38.3, and 39.0° 20 (± 0.2° 29).

[0231] In some embodiments, the present disclosure provides Compound 1 Monohydrate, characterized by an XRPD pattern substantially as shown in FIG. 20.

[0232] In some embodiments, the present disclosure provides Compound 1 Monohydrate, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with onsets of about 33 and about 246 °C. In some embodiments, the present disclosure provides Compound 1 Monohydrate, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 33 °C. In some embodiments, the present disclosure provides Compound 1 Monohydrate, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 246 °C. In some embodiments, the present disclosure provides Compound 1 Monohydrate, characterized by a DSC thermogram substantially as shown in FIG. 21.

[0233] In some embodiments, the present disclosure provides Compound 1 Monohydrate, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 3.7%. In some embodiments, the present disclosure provides Compound 1 Monohydrate, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 3.7% between 25 and 100 °C. In some embodiments, the present disclosure provides Compound 1 Monohydrate, characterized by a TGA substantially as shown in FIG. 22.Compound 1 Dihydrate

[0234] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the dihydrate (herein designated and characterized as Compound 1 Dihydrate). In some embodiments, the present disclosure provides a crystalline form of (R)-5- fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 8.1, 9.6, 11.7, 16.3, 18.8, 24.5, 25.7, 25.9, or 27.9° 20 (± 0.2° 20), dihydrate.

[0235] In some embodiments, the present disclosure provides Compound 1 Dihydrate, characterized by an XRPD pattern comprising peaks at 8.1, 9.6, 11.7, 16.3, 18.8, 24.5, 25.7, 25.9, and 27.9° 29 (± 0.2° 20). In some embodiments, the present disclosure provides Compound 1 Dihydrate, characterized by an XRPD pattern comprising peaks at 8.1, 9.6, 10.5, 11.7, 12.2, 15.1, 16.3, 17.6, 18.1, 18.8, 19.2, 20.9, 21.7, 22.4, 22.8, 23.4, 23.8, 24.5, 25.0, 25.7, 25.9, 26.4, 26.6, 27.2, 27.9, 29.1, 29.6, and 34.5° 29 (± 0.2° 29).

[0236] In some embodiments, the present disclosure provides Compound 1 Dihydrate, characterized by an XRPD pattern substantially as shown in FIG. 23.

[0237] In some embodiments, the present disclosure provides Compound 1 Dihydrate, characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 24.

[0238] In some embodiments, the present disclosure provides Compound 1 Dihydrate, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 7.4%. In some embodiments, the present disclosure provides Compound 1 Dihydrate, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 7.4% between 25 and 100 °C. In some embodiments, the present disclosure provides Compound 1 Dihydrate, characterized by a TGA substantially as shown in FIG. 25.Compound 1 MeTHF solvate

[0239] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the MeTHF solvate (herein designated and characterized as Compound 1 MeTHF solvate).

[0240] In some embodiments, the present disclosure provides Compound 1 MeTHF solvate, characterized by an XRPD pattern substantially as shown in FIG. 26.

[0241] In some embodiments, the present disclosure provides Compound 1 MeTHF solvate, characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 27.

[0242] In some embodiments, the present disclosure provides Compound 1 MeTHF solvate, characterized by a TGA substantially as shown in FIG. 28.Compound 1 MTBE solvate 1

[0243] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the MTBE solvate 1 (herein designated and characterized as Compound 1 MTBE solvate 1).

[0244] In some embodiments, the present disclosure provides Compound 1 MTBE solvate 1, characterized by an XRPD pattern substantially as shown in FIG. 29.Compound 1 MTBE solvate 2

[0245] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the MTBE solvate 2 (herein designated and characterized as Compound 1 MTBE solvate 2).

[0246] In some embodiments, the present disclosure provides Compound 1 MTBE solvate 2, characterized by an XRPD pattern substantially as shown in FIG. 30.

[0247] In some embodiments, the present disclosure provides Compound 1 MTBE solvate 2, characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 31.Compound 1 2-BuOH solvate

[0248] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the 2-BuOH solvate (herein designated and characterized as Compound 1 2-BuOH solvate).

[0249] In some embodiments, the present disclosure provides Compound 1 2-BuOH solvate, characterized by an XRPD pattern substantially as shown in FIG. 33.

[0250] In some embodiments, the present disclosure provides Compound 1 2-BuOH solvate, characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 34.Compound 1 t-BuOH solvate

[0251] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide,wherein the crystalline form is the t-BuOH solvate (herein designated and characterized as Compound 1 t-BuOH solvate).

[0252] In some embodiments, the present disclosure provides Compound 1 t-BuOH solvate, characterized by an XRPD pattern substantially as shown in FIG. 35.Compound 1 p-Dioxane solvate

[0253] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the p-dioxane solvate (herein designated and characterized as Compound 1 p-Dioxane solvate).

[0254] In some embodiments, the present disclosure provides Compound 1 p-Dioxane solvate, characterized by an XRPD pattern substantially as shown in FIG. 36.Compound 1 CPME solvate

[0255] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the CPME solvate (herein designated and characterized as Compound 1 CPME solvate).

[0256] In some embodiments, the present disclosure provides Compound 1 CPME solvate, characterized by an XRPD pattern substantially as shown in FIG. 37.

[0257] In some embodiments, the present disclosure provides Compound 1 CPME solvate, characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 38.Compound 1 DMAc solvate

[0258] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the DMAc solvate (herein designated and characterized as Compound 1 DMAc solvate).

[0259] In some embodiments, the present disclosure provides Compound 1 DMAc solvate, characterized by an XRPD pattern substantially as shown in FIG. 39.

[0260] In some embodiments, the present disclosure provides Compound 1 DMAc solvate, characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 40.

[0261] In some embodiments, the present disclosure provides Compound 1 DMAc solvate, characterized by a TGA substantially as shown in FIG. 41.Compound 1 Mesophase

[0262] In some embodiments, the present disclosure provides a solid form of (R)-5-fluoro-2- methyl- 1 -((R)-5 -(pyri din-2-yl)-2, 3 -dihydro- 1 H-indene-2-carb onyl)indoline-6-sulfonamide, wherein the solid form is the mesophase (herein designated and characterized as Compound 1 Mesophase).

[0263] In some embodiments, the present disclosure provides Compound 1 Mesophase, characterized by an XRPD pattern substantially as shown in FIG. 42.Compound 1 Hydrochloride Form I

[0264] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the hydrochloride Form I (herein designated and characterized as Compound 1 Hydrochloride Form I). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2- carbonyl)indoline-6-sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 8.9, 12.5, 18.9, 19.6, 20.8, 23.8, 24.4, 24.8, or 28.8° 29 (± 0.2° 29), hydrochloride Form I.

[0265] In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form I, characterized by an XRPD pattern comprising peaks at 8.9, 12.5, 18.9, 19.6, 20.8, 23.8,24.4, 24.8, and 28.8° 20 (± 0.2° 20). In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form I, characterized by an XRPD pattern comprising peaks at 8.9,12.5, 15.2, 15.9, 18.9, 19.2, 19.6, 20.8, 21.5, 23.8, 24.4, 24.8, 25.9, 26.2, 26.9, 27.7, 28.8, 30.4, 31.2, 32.5, 33.8, and 38.9° 20 (± 0.2° 20).

[0266] In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form I, characterized by an XRPD pattern substantially as shown in FIG. 43.

[0267] In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form I, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 221°C. In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form I, characterized by a DSC thermogram substantially as shown in FIG. 44.

[0268] In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form I, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 0.2%. In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form I, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 0.2% between 25 and 125 °C. In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form I, characterized by a TGA substantially as shown in FIG. 45.

[0269] In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form I, characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 0.4%. In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form I, characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 0.4% between about 0 and about 90% RH In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form I, characterized by a DVS analysis substantially as shown in FIG. 46.Compound 1 Hydrochloride Form II

[0270] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the hydrochloride Form II (herein designated and characterized as Compound 1 Hydrochloride Form II). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2- carbonyl)indoline-6-sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 8.3, 12.4, 15.3, 19.2, 22.6, 24.0, 24.8, 26.3, or 28.3° 29 (± 0.2° 29), hydrochloride Form II.

[0271] In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form II, characterized by an XRPD pattern comprising peaks at 8.3, 12.4, 15.3, 19.2, 22.6, 24.0,24.8, 26.3, and 28.3° 29 (± 0.2° 29). In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form II, characterized by an XRPD pattern comprising peaks at 8.3,9.8, 11.8, 12.4, 15.3, 17.0, 17.8, 18.4, 19.2, 19.5, 20.5, 21.1, 21.6, 22.6, 23.2, 23.4, 24.0, 24.8, 25.1, 25.4, 26.3, 26.8, 27.4, 28.3, 29.5, 29.9, 30.6, 32.4, and 33.4° 29 (± 0.2° 29).

[0272] In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form II, characterized by an XRPD pattern substantially as shown in FIG. 47.

[0273] In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form II, characterized by a unit cell as determined by single crystal X-ray crystallography of the following dimensions: a = 10.83810(10) A; b = 17.4553(2) A; c = 12.44620(10) A; a = 90°; 0 = 93.4720(10)°; and y = 90°.

[0274] In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form II, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 177 °C. In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form II, characterized by a DSC thermogram substantially as shown in FIG 48.

[0275] In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form II, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 3.8%. In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form II, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 3.8% between 40 and 150 °C. In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form II, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 2.1% between 150 and 200 °C. In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form II, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 5.9% between 40 and 200 °C. In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form II, characterized by a TGA substantially as shown in FIG. 49.

[0276] In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form II, characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 0.7%. In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form II,characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 0.7% between about 0 and about 90% RH. In some embodiments, the present disclosure provides Compound 1 Hydrochloride Form II, characterized by a DVS analysis substantially as shown in FIG. 50.Compound 1 Hemisulfate Form I

[0277] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the hemisulfate Form I (herein designated and characterized as Compound 1 Hemisulfate Form I). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2- carbonyl)indoline-6-sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 9.6, 11.9, 16.5, 19.4, 20.1, 22.6, 23.8, or 25.8° 26 (± 0.2° 26), hemisulfate Form I.

[0278] In some embodiments, the present disclosure provides Compound 1 Hemisulfate Form I, characterized by an XRPD pattern comprising peaks at 9.6, 11.9, 16.5, 19.4, 20.1, 22.6, 23.8, and 25.8° 29 (± 0.2° 26). In some embodiments, the present disclosure provides Compound 1 Hemisulfate Form I, characterized by an XRPD pattern comprising peaks at 9 6, 11.9, 14.6, 16.5, 19.4, 20.1, 22.6, 23.8, 25.8, and 28.7° 29 (± 0.2° 29).

[0279] In some embodiments, the present disclosure provides Compound 1 Hemisulfate Form I, characterized by an XRPD pattern substantially as shown in FIG. 51.

[0280] In some embodiments, the present disclosure provides Compound 1 Hemisulfate Form I, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 153 °C. In some embodiments, the present disclosure provides Compound 1 Hemisulfate Form I, characterized by a DSC thermogram substantially as shown in FIG. 52.Compound 1 Sulfate Form I

[0281] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide,wherein the crystalline form is the sulfate Form I (herein designated and characterized as Compound 1 Sulfate Form I). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2- carbonyl)indoline-6-sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 9.6, 19.1, 19.4, 20.4, 22.3, 23.6, or 25.5° 29 (± 0.2° 29), sulfate Form I.

[0282] In some embodiments, the present disclosure provides Compound 1 Sulfate Form I, characterized by an XRPD pattern comprising peaks at 9.6, 19.1, 19.4, 20.4, 22.3, 23.6, and 25.5° 29 (± 0.2° 29). In some embodiments, the present disclosure provides Compound 1 Sulfate Form I, characterized by an XRPD pattern comprising peaks at 9.6, 12.7, 14.1, 15.5, 16.6, 18.4, 19.1, 19.4, 20.4, 22.0, 22.3, 22.9, 23.6, 24.3, 25.5, 26.8, and 27.6° 29 (± 0.2° 29).

[0283] In some embodiments, the present disclosure provides Compound 1 Sulfate Form I, characterized by an XRPD pattern substantially as shown in FIG. 53.

[0284] In some embodiments, the present disclosure provides Compound 1 Sulfate Form I, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 165 °C. In some embodiments, the present disclosure provides Compound 1 Sulfate Form I, characterized by a DSC thermogram substantially as shown in FIG. 54.Compound 1 Mesylate Form I

[0285] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the mesylate Form I (herein designated and characterized as Compound 1 Mesylate Form I). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2- carbonyl)indoline-6-sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, or 29.6° 29 (± 0.2° 29), mesylate Form I.

[0286] In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by an XRPD pattern comprising peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, and 29.6° 29 (± 0.2° 29). In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by an XRPD pattern comprising peaks at 7.2, 8.9, 11.6, 12.8, 14.3, 16.1, 16.4, 17.3, 18.1, 18.5, 19.1, 19.5, 20.2, 20.6, 20.9, 20.9, 21.4, 22.2, 22.5, 23.2, 24.0, 24.7, 25.4, 25.7, 26.1, 26.8, 27.7, 29.6, 31.0, 31.5, 32.4, 34.0, 35.4, 35.9, 36.3, 37.2, and 37.9° 29 (± 0.2° 29).

[0287] In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by an XRPD pattern comprising five or more peaks at 7.2, 11.6, 14.3, 18.5, 19.1,20.9, 24.0, 26.8, or 29.6° 29 (± 0.1° 29). In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by an XRPD pattern comprising peaks at 7.2, 11.6,14.3, 18.5, 19.1, 20.9, 24.0, 26.8, and 29.6° 29 (± 0.1° 29). In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by an XRPD pattern comprising peaks at 7.2, 8.9, 11.6, 12.8, 14.3, 16.1, 16.4, 17.3, 18.1, 18.5, 19.1, 19.5, 20.2, 20.6, 20.9, 20.9,21.4, 22.2, 22.5, 23.2, 24.0, 24.7, 25.4, 25.7, 26.1, 26.8, 27.7, 29.6, 31.0, 31.5, 32.4, 34.0, 35.4,35.9, 36.3, 37.2, and 37.9° 29 (± 0.1° 29).

[0288] In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by an XRPD pattern comprising peaks at 7.2, 11.6, 14.3, 17.3 and 18.5° 29 (± 0.2° 29). In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by an XRPD pattern comprising peaks at 7.2, 11.6, 14.3, 17.3 and 18.5° 29 (± 0.1° 29).

[0289] In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by an XRPD pattern comprising peaks at 7.2, 11.6, 14.3, 17.3 and 18.5° 29 (± 0.2° 29) and further comprising at least two, five, ten, fifteen, twenty or twenty-five specific peaks selected from 8.9, 12.8, 16.1, 16.4, 18.1, 19.1, 19.5, 20.2, 20.6, 20.9, 20.9, 21.4, 22.2, 22.5, 23.2, 24.0, 24.7, 25.4, 25.7, 26.1, 26.8, 27.7, 29.6, 31.0, 31.5, 32.4, 34.0, 35.4, 35.9, 36.3, 37.2, and 37.9° 29 (± 0.2° 29).

[0290] In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by an XRPD pattern comprising peaks at 7.2, 11.6, 14.3, 17.3 and 18.5° 20 (± 0.1° 20) and further comprising at least two, five, ten, fifteen, twenty or twenty-five specific peaks selected from 8.9, 12.8, 16.1, 16.4, 18.1, 19.1, 19.5, 20.2, 20.6, 20.9, 20.9, 21.4, 22.2, 22.5, 23.2, 24.0, 24.7, 25.4, 25.7, 26.1, 26.8, 27.7, 29.6, 31.0, 31.5, 32.4, 34.0, 35.4, 35.9, 36.3, 37.2, and 37.9° 20 (± 0.1° 20).

[0291] In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by an XRPD pattern substantially as shown in FIG. 55.

[0292] In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 250 °C. In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by a differential scanning calorimetry (DSC) thermogram having no thermal events between 25 and 200 °C and an endotherm with an onset of about 250 °C. In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by a DSC thermogram substantially as shown in FIG. 56.

[0293] In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 254 °C In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by a differential scanning calorimetry (DSC) thermogram having no thermal events between 25 and 200 °C and an endotherm with an onset of about 254 °C. In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by a DSC thermogram substantially as shown in FIG. 85.

[0294] In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by an XRPD pattern comprising five or more peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, or 29.6° 20 (± 0.2° 20) and a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 250 °C. In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by an XRPD pattern comprising peaks at 7.2, 11.6, 14.3, 17.3 and 18.5° 20 (± 0.2° 20) and a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 250 °C.

[0295] In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by an XRPD pattern comprising five or more peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, or 29.6° 20 (± 0.2° 20) and a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 254 °C. In some embodiments, the present disclosureprovides Compound 1 Mesylate Form I, characterized by an XRPD pattern comprising peaks at 7.2, 11.6, 14.3, 17.3 and 18.5° 20 (± 0.2° 20) and a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 254 °C.

[0296] In some embodiments, the present disclosure provides Compound 1 Mesylate Form ICompound 1 Mesylate Form I, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 0.1%. In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 0.1% between 25 and 150 °C. In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by a TGA substantially as shown in FIG. 57.

[0297] In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 2.3%. In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 2.3% between about 0 and about 90%RH. In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by a DVS analysis substantially as shown in FIG. 58.

[0298] Suitably, Compound 1 Mesylate Form I is unsolvated and anhydrous. Suitably Compound 1 Mesylate Form I comprises less than about 2% by weight solvent and / or water, such as less than about 1.5, 1, 0.5, 0.2, or 0.1% by weight. The skilled person would know of suitable analytical techniques which can quantify the amount of solvent / water associated with a solid. For example, water content can be determined by Karl Fischer Titration. Residual solvents can be determined by Gas Chromatography. Thermogravimetric Analysis (TGA) can also quantify the amount of volatile material (i.e., solvent and water) associated with a solid (either surface bound or incorporated into the crystal structure).

[0299] In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by an XRPD pattern comprising five or more peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, or 29.6° 20 (± 0.2° 20) and wherein Compound 1 Mesylate Form I comprises less than about 2% weight solvent and / or water.

[0300] In some embodiments, the present disclosure provides Compound 1 Mesylate Form I, characterized by an XRPD pattern comprising peaks at 7.2, 11.6, 14.3, 17.3 and 18.5° 20 (± 0.2° 20) and wherein Compound 1 Mesylate Form I comprises less than about 2% weight solvent and / or water.Compound 1 Esylate Form I

[0301] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is esylate Form I (herein designated and characterized as Compound 1 Esylate Form I). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 7.0, 17.9, 18.4, 20.1, 20.8, 23.0, 23.4, 24.0, or 25.8° 29 (± 0.2° 29), esylate Form I.

[0302] In some embodiments, the present disclosure provides Compound 1 Esylate Form I, characterized by an XRPD pattern comprising peaks at 7.0, 17.9, 18.4, 20.1, 20.8, 23.0, 23.4, 24.0, and 25.8° 20 (± 0.2° 20). In some embodiments, the present disclosure provides Compound 1 Esylate Form I, characterized by an XRPD pattern comprising peaks at 7.0, 8.7, 11.6, 12.3, 13.9, 14.5, 16.3, 17.0, 17.9, 18.4, 18.9, 19.5, 20.1, 20.6, 20.8, 21.9, 22.2, 23.0, 23.4, 24.0, 24.6, 25.2, 25.8, 27.1, 27.8, 28.4, 29.8, 30.6, 31.1, 32.3, 34.7, 35.5, and 36.2° 20 (± 0.2° 20).

[0303] In some embodiments, the present disclosure provides Compound 1 Esylate Form I, characterized by an XRPD pattern substantially as shown in FIG 59.

[0304] In some embodiments, the present disclosure provides Compound 1 Esylate Form I, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 258 °C. In some embodiments, the present disclosure provides Compound 1 Esylate Form I, characterized by a DSC thermogram substantially as shown in FIG. 60

[0305] In some embodiments, the present disclosure provides Compound 1 Esylate Form I, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 0.1%. In some embodiments, the present disclosure provides Compound 1 Esylate Form I, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 0.1% between 25 and 150 °C. In some embodiments, the present disclosure provides Compound 1 Esylate Form I, characterized by a TGA substantially as shown in FIG. 61.

[0306] In some embodiments, the present disclosure provides Compound 1 Esylate Form I, characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 3.3%. In some embodiments, the present disclosure provides Compound 1 Esylate Form I, characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 3.3% between about 0 and about 90% RH. In some embodiments, the present disclosure provides Compound 1 Esylate Form I, characterized by a DVS analysis substantially as shown in FIG. 62.Compound 1 Besylate Form I

[0307] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is besylate Form I (herein designated and characterized as Compound 1 Besylate Form I). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6- sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 11.3, 14.9, 16.1, 18.4, 19.8, 21.0, 22.8, or 24.9° 20 (± 0.2° 20), besylate Form I.

[0308] In some embodiments, the present disclosure provides Compound 1 Besylate Form I, characterized by an XRPD pattern comprising peaks at 11.3, 14.9, 16.1, 18.4, 19.8, 21.0, 22.8, and 24.9° 20 (± 0.2° 20). In some embodiments, the present disclosure provides Compound 1 Besylate Form I, characterized by an XRPD pattern comprising peaks at 10.0, 10.5, 11.3, 14.4, 14.9, 16.1, 17.1, 18.4, 19.8, 21.0, 22.8, 24.9, 25.8, 27.0, and 31.5° 20 (± 0.2° 20).

[0309] In some embodiments, the present disclosure provides Compound 1 Besylate Form I, characterized by an XRPD pattern substantially as shown in FIG. 63.

[0310] In some embodiments, the present disclosure provides Compound 1 Besylate Form I, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 148 °C. In some embodiments, the present disclosure provides Compound 1 Besylate Form I, characterized by a DSC thermogram substantially as shown in FIG. 64.Compound 1 Besylate Form II

[0311] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the besylate Form II (herein designated and characterized as Compound 1 Besylate Form II). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2- carbonyl)indoline-6-sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.2, 18.0, 19.3, and 21.7° 26 (± 0.2° 26), besylate Form II.

[0312] In some embodiments, the present disclosure provides Compound 1 Besylate Form II, characterized by an XRPD pattern comprising five or more peaks at 12.2, 14.4, 16.0, 18.0, 19.3, 21.7, 22.5, 24.9, 27.1, or 28.2° 26 (± 0.2° 26). In some embodiments, the present disclosure provides Compound 1 Besylate Form II, characterized by an XRPD pattern comprising peaks at 12.2, 14.4, 16.0, 18.0, 19.3, 21.7, 22.5, 24.9, 27.1, and 28.2° 26 (± 0.2° 26).

[0313] In some embodiments, the present disclosure provides Compound 1 Besylate Form II, characterized by an XRPD pattern substantially as shown in FIG. 65.

[0314] In some embodiments, the present disclosure provides Compound 1 Besylate Form II, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 148 °C. In some embodiments, the present disclosure provides Compound 1 Besylate Form II, characterized by a DSC thermogram substantially as shown in FIG. 66.Compound 1 Tosylate Form I

[0315] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the tosylate Form I (herein designated and characterized as Compound 1 Tosylate Form I). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2- carbonyl)indoline-6-sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 4.1, 8.1, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5, or 24.5° 29 (± 0.2° 20), tosylate Form I.

[0316] In some embodiments, the present disclosure provides Compound 1 Tosylate Form I, characterized by an XRPD pattern comprising peaks at 4.1, 8.1, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5, and 24.5° 26 (± 0.2° 20). In some embodiments, the present disclosure provides Compound 1 Tosylate Form I, characterized by an XRPD pattern comprising peaks at 4.1, 5.0, 6.7, 8.1, 9.3, 9.9, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5, 20.4, 22.2, and 24.5° 26 (± 0.2° 26).

[0317] In some embodiments, the present disclosure provides Compound 1 Tosylate Form I, characterized by an XRPD pattern substantially as shown in FIG. 67.

[0318] In some embodiments, the present disclosure provides Compound 1 Tosylate Form I, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 164 °C. In some embodiments, the present disclosure provides Compound 1 Tosylate Form I, characterized by a DSC thermogram substantially as shown in FIG. 68.Compound 1 Napsylate Form I

[0319] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the napsylate Form I (herein designated and characterized as Compound 1 Napsylate Form I). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2- carbonyl)indoline-6-sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at6.6, 12.3, 17.8, 19.0, 21.2, 22.2, 23.9, 25.8, or 26.6° 20 (± 0.2° 20), napsylate Form I.

[0320] In some embodiments, the present disclosure provides Compound 1 Napsylate Form I, characterized by an XRPD pattern comprising peaks at 6.6, 12.3, 17.8, 19.0, 21.2, 22.2, 23.9, 25.8, and 26.6° 20 (± 0.2° 20). In some embodiments, the present disclosure provides Compound 1 Napsylate Form I, characterized by an XRPD pattern comprising peaks at 6.6, 8.9, 12.3, 13.2,14.5, 16.3, 16.8, 17.8, 18.4, 19.0, 19.9, 20.4, 20.7, 21.2, 21.4, 22.2, 22.9, 23.9, 25.0, 25.8, 26.6, 27.2, 27.7, 28.3, 29.1, 29.9, 30.8, 32.1, 32.7, and 33.3° 20 (± 0.2° 20).

[0321] In some embodiments, the present disclosure provides Compound 1 Napsylate Form I, characterized by an XRPD pattern substantially as shown in FIG. 69.

[0322] In some embodiments, the present disclosure provides Compound 1 Napsylate Form I, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 215 °C. In some embodiments, the present disclosure provides Compound 1 Napsylate Form I, characterized by a DSC thermogram substantially as shown in FIG. 70.Compound 1 Maleate Form I

[0323] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the maleate Form I (herein designated and characterized as Compound 1 Maleate Form I). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-l -((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2- carbonyl)indoline-6-sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at10.6, 16.9, 18.0, 20.0, 21.7, 22.6, 24.5, 25.5, or 27.3° 20 (± 0.2° 20), maleate Form I.

[0324] In some embodiments, the present disclosure provides Compound 1 Maleate Form I, characterized by an XRPD pattern comprising peaks at 10.6, 16.9, 18.0, 20.0, 21.7, 22.6, 24.5, 25.5, and 27.3° 20 (± 0.2° 20). In some embodiments, the present disclosure provides Compound 1 Maleate Form I, characterized by an XRPD pattern comprising peaks at 9.1, 10.0, 10.6, 12.9,13.7, 15.0, 15.5, 16.1, 16.9, 17.2, 18.0, 18.4, 19.2, 20.0, 21.7, 22.6, 24.5, 24.8, 25.5, 25.9, 26.1, 27.3, 30.0, 30.6, 31.8, 33.1, and 38.3° 29 (± 0.2° 29).

[0325] In some embodiments, the present disclosure provides Compound 1 Maleate Form I, characterized by an XRPD pattern substantially as shown in FIG. 71.

[0326] In some embodiments, the present disclosure provides Compound 1 Maleate Form I, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 198 °C. In some embodiments, the present disclosure provides Compound 1 Maleate Form I, characterized by a DSC thermogram substantially as shown in FIG. 72.

[0327] In some embodiments, the present disclosure provides Compound 1 Maleate Form I, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 0.04%. In some embodiments, the present disclosure provides Compound 1 Maleate Form I, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 0.04% between 25 and 150 °C. In some embodiments, the present disclosure provides Compound 1 Maleate Form I, characterized by a TGA substantially as shown in FIG. 73.

[0328] In some embodiments, the present disclosure provides Compound 1 Maleate Form I, characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 0.17%. In some embodiments, the present disclosure provides Compound 1 Maleate Form I, characterized by a dynamic vapor sorption (DVS) analysis having a water uptake of about 0.17% between about 0 and about 90% RH. In some embodiments, the present disclosure provides Compound 1 Maleate Form I, characterized by a DVS analysis substantially as shown in FIG. 74Compound 1 L-tartrate Form I

[0329] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the L-tartrate Form I (herein designated and characterized as Compound 1 L-tartrate Form I). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2- carbonyl)indoline-6-sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at9.4, 14.4, 16.2, 17.4, 17.9, 18.9, 20.3, 21.5, or 24.3° 29 (± 0.2° 29), L-tartrate Form I.

[0330] In some embodiments, the present disclosure provides Compound 1 L-tartrate Form I, characterized by an XRPD pattern comprising peaks at 9.4, 14.4, 16.2, 17.4, 17.9, 18.9, 20.3, 21.5, and 24.3° 20 (± 0.2° 20). In some embodiments, the present disclosure provides Compound 1 L- tartrate Form I, characterized by an XRPD pattern comprising peaks at 8.2, 8.7, 9.4, 12.7, 13.5,14.4, 14.7, 15.2, 16.2, 17.4, 17.9, 18.9, 19.2, 19.7, 20.3, 21.5, 21.9, 23.0, 23.8, 24.3, 24.8, 25.4,26.5, 27.5, 29.0, 29.7, and 33.4° 20 (± 0.2° 20).

[0331] In some embodiments, the present disclosure provides Compound 1 L-tartrate Form I, characterized by an XRPD pattern substantially as shown in FIG. 75.

[0332] In some embodiments, the present disclosure provides Compound 1 L-tartrate Form I, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 113 °C. In some embodiments, the present disclosure provides Compound 1 L- tartrate Form I, characterized by a DSC thermogram substantially as shown in FIG. 76.Compound 1 L-tartrate Form II

[0333] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the L-tartrate Form II (herein designated and characterized as Compound 1 L-tartrate Form II). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2- carbonyl)indoline-6-sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at11.7, 13.9, 18.6, 21.8, 23.1, 24.5, 26.1, 28.8, or 29.5° 20 (± 0.2° 20), L-tartrate Form II.

[0334] In some embodiments, the present disclosure provides Compound 1 L-tartrate Form II, characterized by an XRPD pattern comprising peaks at 11.7, 13.9, 18.6, 21.8, 23.1, 24.5, 26.1,28.8, and 29.5° 20 (± 0.2° 20). In some embodiments, the present disclosure provides Compound 1 L-tartrate Form II, characterized by an XRPD pattern comprising peaks at 7.7, 8.0, 8.3, 11.3, 11.7, 13.9, 14.3, 15.6, 16.6, 16.9, 18.0, 18.6, 18.9, 20.2, 20.5, 21.8, 22.2, 22.6, 23.1, 23.6, 24.5, 25.2, 26.1, 26.7, 27.6, 28.8, 29.5, 30.0, 30.9, 31.4, 32.0, 33.5, 34.8, 36.3, 37.5, and 38.0° 20 (± 0.2° 20).

[0335] In some embodiments, the present disclosure provides Compound 1 L-tartrate Form II, characterized by an XRPD pattern substantially as shown in FIG. 77.

[0336] In some embodiments, the present disclosure provides Compound 1 L-tartrate Form II, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 26, 97, and 172 °C. In some embodiments, the present disclosure provides Compound 1 L-tartrate Form II, characterized by a DSC thermogram substantially as shown in FIG. 78.Compound 1 L-tartrate Form III

[0337] In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro- 2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is the L-tartrate Form III (herein designated and characterized as Compound 1 L-tartrate Form III). In some embodiments, the present disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2- carbonyl)indoline-6-sulfonamide (Compound 1):characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at4.9, 9.8, 17.1, 18.6, 19.6, 20.2, 20.8, 22.0, or 24.6° 20 (± 0.2° 20), L-tartrate Form III.

[0338] In some embodiments, the present disclosure provides Compound 1 L-tartrate Form III, characterized by an XRPD pattern comprising peaks at 4.9, 9.8, 17.1, 18.6, 19.6, 20.2, 20.8, 22.0, and 24.6° 20 (± 0.2° 20). In some embodiments, the present disclosure provides Compound 1 L- tartrate Form III, characterized by an XRPD pattern comprising peaks at 4.9, 9.8, 12.2, 13.7, 15.4, 17.1, 17.9, 18.6, 19.6, 20.2, 20.8, 22.0, 23.4, 24.6, 25.2, 26.5, 28.2, 29.2, 29.9, 30.6, 32.1, 33.9, 36.3, and 38.5° 20 (± 0.2° 20).

[0339] In some embodiments, the present disclosure provides Compound 1 L-tartrate Form III, characterized by an XRPD pattern substantially as shown in FIG. 79.

[0340] In some embodiments, the present disclosure provides Compound 1 L-tartrate Form III, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 20, 114 and 170 °C. In some embodiments, the present disclosure providesCompound 1 L-tartrate Form III, characterized by a DSC thermogram substantially as shown in FIG. 80.

[0341] When it is stated herein that the specification relates to a crystalline form of Compound 1 the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, yet more conveniently greater than about 90% and preferably greater than 95%, 98% or 99% by weight.

[0342] In one embodiment, Compound 1 Form I is pure or substantially pure. As used herein, the term “substantially pure” means that the solid state form of Compound 1 contains about 20% by weight or less, or about 15% by weight or less, or about 10% by weight or less, or about 5% by weight or less, or about 2% by weight or less, or about 1% by weight or less, or about 0.5% by weight or less of any impurities or other solid forms of Compound 1, including alternative crystalline forms, hydrates, solvates, salts or amorphous forms, for example as measured by XRPD. Thus, substantially pure Compound 1 Form I described herein would be understood to contain greater than about 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 95% by weight, greater than 98% by weight, greater than 99% by weight, greater than 99.5% by weight of Compound 1 Form I. Suitably, there is provided Compound 1 Form I wherein when Compound 1 Form I is analyzed by a solid-state technique, such as by X- Ray Powder diffraction and / or Raman spectroscopy, no other solid forms (amorphous and / or other crystalline forms) are detected. Suitably, there is provided a crystalline form of Compound 1 essentially consisting of Compound 1 Form I. Suitably, there is provided a crystalline form of Compound 1 consisting of Compound 1 Form I.

[0343] In one embodiment, Compound 1 Mesylate Form I is pure or substantially pure. As used herein, the term “substantially pure” means that the solid state form of Compound 1 contains about 20% by weight or less, or about 15% by weight or less, or about 10% by weight or less, or about 5% by weight or less, or about 2% by weight or less, or about 1% by weight or less, or about 0.5% by weight or less of any impurities or other solid forms of Compound 1, including alternative crystalline forms, hydrates, solvates, salts or amorphous forms, for example as measured by XRPD. Thus, substantially pure Compound 1 Mesylate Form I described herein would be understood to contain greater than about 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 95% by weight, greater than 98% by weight, greater than 99% by weight, greater than 99.5% by weight of Compound 1 Mesylate Form I. Suitably, there is provided Compound 1 Mesylate Form I wherein when Compound 1 Mesylate Form I is analyzed by a solid- state technique, such as by X-Ray Powder diffraction and / or Raman spectroscopy, no other solid forms (amorphous and / or other crystalline forms) are detected. Suitably, there is provided acrystalline form of Compound 1 essentially consisting of Compound 1 Mesylate Form I. Suitably, there is provided a crystalline form of Compound 1 consisting of Compound 1 Mesylate Form I.

[0344] In one embodiment, Compound 1 Form II, Compound 1 Form III, Compound 1 Form IV, Compound 1 Form V, Compound 1 monohydrate, Compound 1 dihydrate, Compound 1 methyltetrahydrofuran (MeTHF) solvate, Compound 1 methyl t-butyl ether solvate 1, Compound 1 methyl t-butyl ether solvate 2, Compound 1 2-butanol solvate, Compound 1 t-butanol solvate, Compound 1 p-dioxane solvate, Compound 1 cyclopentyl methyl ether solvate, Compound 1 dimethyl acetamide solvate, Compound 1 hydrochloride Form I, Compound 1 hydrochloride Form II, Compound 1 hemisulfate Form I, Compound 1 sulfate Form I, Compound 1 esylate Form I, Compound 1 besylate Form I, Compound 1 besylate Form II, Compound 1 tosylate Form I, Compound 1 napsylate Form I, Compound 1 maleate Form I, Compound 1 L-tartrate Form I, Compound 1 L-tartrate Form II, or Compound 1 L-tartrate Form III is pure or substantially pure. As used herein, the term “substantially pure” means that the solid state form of Compound 1 contains about 20% by weight or less, or about 15% by weight or less, or about 10% by weight or less, or about 5% by weight or less, or about 2% by weight or less, or about 1% by weight or less, or about 0.5% by weight or less of any impurities or other solid forms of Compound 1, including alternative crystalline forms, hydrates, solvates, salts or amorphous forms, for example as measured by XRPD. Thus, substantially pure Compound 1 Form II, Compound 1 Form III, Compound 1 Form IV, Compound 1 Form V, Compound 1 monohydrate, Compound 1 dihydrate, Compound 1 methyl-tetrahydrofuran (MeTHF) solvate, Compound 1 methyl t-butyl ether solvate 1, Compound 1 methyl t-butyl ether solvate 2, Compound 1 2-butanol solvate, Compound 1 t- butanol solvate, Compound 1 p-dioxane solvate, Compound 1 cyclopentyl methyl ether solvate, Compound 1 dimethyl acetamide solvate, Compound 1 hydrochloride Form I, Compound 1 hydrochloride Form II, Compound 1 hemisulfate Form I, Compound 1 sulfate Form I, Compound 1 esylate Form I, Compound 1 besylate Form I, Compound 1 besylate Form II, Compound 1 tosylate Form I, Compound 1 napsylate Form I, Compound 1 maleate Form I, Compound 1 L- tartrate Form I, Compound 1 L-tartrate Form II, or Compound 1 L-tartrate Form III described herein would be understood to contain greater than about 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 95% by weight, greater than 98% by weight, greater than 99% by weight, greater than 99.5% by weight of Compound 1 Form II, Compound 1 Form III, Compound 1 Form IV, Compound 1 Form V, Compound 1 monohydrate, Compound 1 dihydrate, Compound 1 methyl-tetrahydrofuran (MeTHF) solvate, Compound 1 methyl t-butyl ether solvate 1, Compound 1 methyl t-butyl ether solvate 2, Compound 1 2-butanol solvate, Compound 1 t-butanol solvate, Compound 1 p-dioxane solvate, Compound 1 cyclopentyl methyl ether solvate, Compound 1 dimethyl acetamide solvate, Compound 1 hydrochloride Form I,Compound 1 hydrochloride Form II, Compound 1 hemisulfate Form I, Compound 1 sulfate Form I, Compound 1 esylate Form I, Compound 1 besylate Form I, Compound 1 besylate Form II, Compound 1 tosylate Form I, Compound 1 napsylate Form I, Compound 1 maleate Form I, Compound 1 L-tartrate Form I, Compound 1 L-tartrate Form II, or Compound 1 L-tartrate Form III respectively. Suitably, there is provided Compound 1 Form II, Compound 1 Form III, Compound 1 Form IV, Compound 1 Form V, Compound 1 monohydrate, Compound 1 dihydrate, Compound 1 methyl-tetrahydrofuran (MeTHF) solvate, Compound 1 methyl t-butyl ether solvate 1, Compound 1 methyl t-butyl ether solvate 2, Compound 1 2-butanol solvate, Compound 1 t- butanol solvate, Compound 1 p-dioxane solvate, Compound 1 cyclopentyl methyl ether solvate, Compound 1 dimethyl acetamide solvate, Compound 1 hydrochloride Form I, Compound 1 hydrochloride Form II, Compound 1 hemisulfate Form I, Compound 1 sulfate Form I, Compound 1 esylate Form I, Compound 1 besylate Form I, Compound 1 besylate Form II, Compound 1 tosylate Form I, Compound 1 napsylate Form I, Compound 1 maleate Form I, Compound 1 L- tartrate Form I, Compound 1 L-tartrate Form II, or Compound 1 L-tartrate Form III wherein when Compound 1 Form II, Compound 1 Form III, Compound 1 Form IV, Compound 1 Form V, Compound 1 monohydrate, Compound 1 dihydrate, Compound 1 methyl-tetrahydrofuran (MeTHF) solvate, Compound 1 methyl t-butyl ether solvate 1, Compound 1 methyl t-butyl ether solvate 2, Compound 1 2-butanol solvate, Compound 1 t-butanol solvate, Compound 1 p-dioxane solvate, Compound 1 cyclopentyl methyl ether solvate, Compound 1 dimethyl acetamide solvate, Compound 1 hydrochloride Form I, Compound 1 hydrochloride Form II, Compound 1 hemisulfate Form I, Compound 1 sulfate Form I, Compound 1 esylate Form I, Compound 1 besylate Form I, Compound 1 besylate Form II, Compound 1 tosylate Form I, Compound 1 napsylate Form I, Compound 1 maleate Form I, Compound 1 L-tartrate Form I, Compound 1 L- tartrate Form II, or Compound 1 L-tartrate Form III is analyzed by a solid-state technique, such as by X-Ray Powder diffraction and / or Raman spectroscopy, no other solid forms (amorphous and / or other crystalline forms) are detected. Suitably, there is provided a crystalline form of Compound 1 essentially consisting of Compound 1 Form II, Compound 1 Form III, Compound 1 Form IV, Compound 1 Form V, Compound 1 monohydrate, Compound 1 dihydrate, Compound 1 methyl-tetrahydrofuran (MeTHF) solvate, Compound 1 methyl t-butyl ether solvate 1, Compound 1 methyl t-butyl ether solvate 2, Compound 1 2-butanol solvate, Compound 1 t- butanol solvate, Compound 1 p-dioxane solvate, Compound 1 cyclopentyl methyl ether solvate, Compound 1 dimethyl acetamide solvate, Compound 1 hydrochloride Form I, Compound 1 hydrochloride Form II, Compound 1 hemisulfate Form I, Compound 1 sulfate Form I, Compound 1 esylate Form I, Compound 1 besylate Form I, Compound 1 besylate Form II, Compound 1 tosylate Form I, Compound 1 napsylate Form I, Compound 1 maleate Form I, Compound 1 L-tartrate Form I, Compound 1 L-tartrate Form II, or Compound 1 L-tartrate Form III. Suitably, there is provided a crystalline form of Compound 1 consisting of Compound 1 Form II, Compound 1 Form III, Compound 1 Form IV, Compound 1 Form V, Compound 1 monohydrate, Compound 1 dihydrate, Compound 1 methyl -tetrahydrofuran (MeTHF) solvate, Compound 1 methyl t-butyl ether solvate 1, Compound 1 methyl t-butyl ether solvate 2, Compound 1 2-butanol solvate, Compound 1 t-butanol solvate, Compound 1 p-dioxane solvate, Compound 1 cyclopentyl methyl ether solvate, Compound 1 dimethyl acetamide solvate, Compound 1 hydrochloride Form I, Compound 1 hydrochloride Form II, Compound 1 hemisulfate Form I, Compound 1 sulfate Form I, Compound 1 esylate Form I, Compound 1 besylate Form I, Compound 1 besylate Form II, Compound 1 tosylate Form I, Compound 1 napsylate Form I, Compound 1 maleate Form I, Compound 1 L-tartrate Form I, Compound 1 L-tartrate Form II, or Compound 1 L-tartrate Form III.METHODS OF PREPARING SOLID FORMS OF COMPOUND 1

[0345] The solid forms of Compound 1 can be prepared by a variety of methods. For example, Compound 1 can be dissolved in a single solvent system and allowed to crystallize. Alternatively, Compound 1 can be crystallized from a two-solvent system by dissolving Compound 1 in a solvent (a good solvent), and then adding an anti-solvent (a bad solvent) to the mixture causing Compound 1 to crystallize.

[0346] The solvent can be any solvent suitable to form a solution. Typically the solvent can be a polar solvent, which in some embodiments is a protic solvent. Other suitable solvents include non-polar solvents. Suitable solvents include, but are not limited to, water, alkanes such as heptanes, hexanes, and cyclohexane, petroleum ether, C1-C3 alcohols (methanol, ethanol, propanol, isopropanol), ethylene glycol and polyethylene glycol such as PEG400, alkanoates such as ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate, acetonitrile, alkanones such as acetone, butanone, methyl ethyl ketone (MEK), methyl propyl ketone (MPK) and methyl isobutyl ketone (MIBK), ethers such as cyclopentyl methyl ether diethyl ether, methyl-t-butyl ether, tetrahydrofuran, methyl-tetrahydrofuran, 1,2-dimethoxy ethane and 1,4-di oxane, aromatics such as benzene and toluene, halogenated solvents such as methylene chloride, chloroform and carbon tetrachloride, dimethyl sulfoxide (DMSO), and dimethylformamide (DMF). Suitable solvents also include, but are not limited to halogenated C1-C3 alcohols (trifluoromethanol, trifluoroethanol (TFE), hexafluoroisopropanol (HFIPA)). For example, the solvent can be a polar aprotic solvent such as di chloromethane, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetone, methyl ethyl ketone, dimethylformamide (DMF), acetonitrile (ACN), dimethyl sulfoxide (DMSO),among others. The solvent can also be a polar protic solvent such as t-butanol, n-propanol, isopropanol, ethanol, methanol, acetic acid, water, among others. The solvent can also be a nonpolar solvent, such as hexane, pentanes, petroleum ether, benzene, toluene, diethyl ether, methyl- t-butyl ether, tetrahydrofuran, methyl -tetrahydrofuran, 1 ,2-dimethoxy ethane and 1,4-di oxane, chloroform, and carbon tetrachloride.

[0347] Two or more solvents can be used in a solvent mixture in any suitable ratio. For example, the ratio of a first solvent and a second solvent can be from 10:1 to about 1:10 (volume / volume or weight / weight), or about 10: 1 to 1 :5, or 10: 1 to 1 :1, or 10: 1 to 5:1, or 5: 1 to 1:5, or 5:1 to 1: 1, or 4:1 to 1 : 1, or 3: 1 to 1 :1, or 2: 1 to 1:1. Other solvent ratios include about 10: 1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1 :1, 1:2, 1:3, 1:4, 1:5, 1:6, 1 :7, 1 :8, 1 :9 or about 1:10 (volume / volume or weight / weight).

[0348] The methods of preparing solid forms of Compound 1 can be performed under any suitable reaction conditions. For example, the methods of preparing the crystalline forms of Compound 1 can be performed at any suitable temperature, such as, but not limited to, below room temperature, at room temperature, or above room temperature. In some embodiments, the temperature can be from about -78 °C to about 100 °C, or from about 0 °C to about 50 °C, or from about 10 °C to about 30 °C. For example, the reaction mixture be at a temperature of about 20 °C, or 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100 °C. The reaction mixture can also be at a temperature of about 20 °C, 15, 10, 5, 0, -5, -10, -20, -30, -40, -50, -60, - 70 or about -78 °C. In some embodiments, the temperature can be the reflux temperature of the particular solvent used in the method. In other embodiments, crystalline forms of Compound 1 can be heated above about 100 °C such that one crystalline form of Compound 1 forms a second crystalline form of Compound 1.

[0349] The methods of preparing solid forms of Compound 1 can include a variety of other steps. For example, the solvent can be evaporated, a seed crystal can be added to the mixture, the mixture can be heated and cooled a single time or repeatedly, etc. For example, the methods can include heating the reaction mixture to a temperature of about 20 °C, or 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100 °C. The methods can also include cooling the reaction mixture to a temperature of about 20 °C, 15, 10, 5, 0, -5, -10, -20, -30, -40, -50, -60, -70 or about -78 °C. The temperature of the reaction mixture can be changed at any suitable rate. For example, the rate of temperature change can be from about 0.1 °C / min to about 10 °C / min.

[0350] The methods of preparing crystalline forms of Compound 1 can be performed for any suitable time. For example, the time can be for minutes, hours or days. In some embodiments,the time can be several hours, such as overnight. The methods of preparing crystalline forms of Compound 1 can be also be performed at any suitable pressure. For example, the pressure can be below atmospheric pressure, at about atmospheric pressure, or above atmospheric pressure.

[0351] Crystallization can be induced by methods known in the art, for example by mechanical means such as scratching or rubbing the contact surface of the reaction vessel with e.g. a glass rod. Optionally the saturated or supersaturated solution may be inoculated with seed crystals. The method preparing solid forms of Compound 1 can also include a seed crystal of crystalline Compound 1.

[0352] Isolation of the desired crystalline form can be accomplished by removing the solvent and precipitating solvent from the crystals. Generally this is carried out by known methods, such as, filtration, suction filtration, decantation or centrifugation. Further isolation can be achieved by removing any excess of the solvent(s) from the crystalline form by methods known to the one skilled in the art as for example application of a vacuum, and / or by heating.

[0353] In some embodiments, the present disclosure provides a method of preparing a crystalline Compound 1 Form I of the present disclosure, including forming a mixture of Compound 1 of the present disclosure and a first solvent, and adding a second solvent to the mixture, under conditions suitable to prepare Form I. In some embodiments, Compound 1 is dissolved in the first solvent, a good solvent. In some embodiments, the first solvent can be a polar protic solvent. In some embodiments, the first solvent can be ethanol. In some embodiments, the second solvent is an anti-solvent. In some embodiments, the second solvent can be water.

[0354] The mixture can include any suitable ratio of the first solvent and the second solvent. For example, the ratio of the first solvent and the second solvent can be from 10:1 to about 1:10 (volume / volume or weight / weight), or about 10:1 to 1:5, or 10:1 to 1: 1, or 10:1 to 5:1, or 5:1 to 1:5, or 5:1 to 1 :1, or 4:1 to 1: 1, or 3: 1 to 1:1, or 2:1 to 1:1. Other solvent ratios include about 10:1, 9:1, 8:1, 7:1, 6:1, 5: 1, 4:1, 3: 1, 2: 1, 1: 1, 1 :2, 1 :3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or about 1:10 (volume / volume or weight / weight). In some embodiments, the ratio of the first solvent and the second solvent can be about 2:1 (weight / weight). In some embodiments, the ratio of the first solvent and the second solvent can be about 1 :1 (weight / weight). In some embodiments, the ratio of the ethanol and water is about 2:1 (weight / weight). In some embodiments, the ratio of the ethanol and water is about 1:1 (weight / weight).

[0355] The method of preparing crystalline Compound 1 can include a variety of other steps. In some embodiments, the reaction mixture can be heated to a temperature of about 75 °C. In some embodiments, the method also includes cooling the reaction mixture to a temperature of about 22°C. In some embodiments, the method of preparing crystalline Compound 1 also includes heating the mixture to dissolve Compound 1, and cooling the mixture.

[0356] The method can be performed under any suitable reaction conditions. For example, the reaction mixture can be at a temperature of about 0 °C, about -40 °C, -40 °C or about -78 °C. In some embodiments, the reaction mixture can be at a temperature of about -78 °C.Method to prepare Compound 1 Form I

[0357] In one embodiment of the present disclosure, there is provided a process to prepare Compound 1 Form I.

[0358] In one embodiment, the process to prepare Compound 1 Form I comprises the steps of: a) providing a solution of Compound 1 in a first solvent system; b) concentrating the solution from step a) and / or adding a second solvent system to the solution from step a); c) mixing the mixture obtained from step b); d) optionally, isolating the solids formed from step c); and e) optionally, drying the solids isolated from step d).

[0359] In one embodiment, the first solvent system comprises a solvent wherein Compound 1 has a solubility of at least 10 mg / mL at room temperature, such as at least 20 mg / mL. Suitably, the first solvent system comprises a polar solvent. Suitably, the first solvent system comprises an aprotic polar solvent. Suitably, the first solvent system comprises dimethyl sulfoxide (DMSO), N,,N-dimethylformamide (DMF), tetrahydrofuran (THF), dimethylacetamide (DMAc) and / or acetone. Suitably, the first solvent system comprises acetone. Suitably, Compound 1 is dissolved in 1 to 40 relative volumes of the first solvent system, such as 20 to 40 relative volumes. Suitably, Compound 1 is dissolved in about 30 relative volumes of acetone.

[0360] Suitably, step a) is performed at 25 to 75 °C, such as 40 to 55 °C.

[0361] Suitably, in step a) Compound 1 is dissolved in 20 to 40 relative volumes of acetone at a temperature of 40 to 55 °C.

[0362] Suitably, in step b) the solution from step a) is concentrated to 1-10 relative volumes, such as 2.5-7.5 relative volumes.

[0363] Suitably, the second solvent system comprises a solvent wherein Compound 1 has a solubility of less than 10 mg / mL at room temperature, such as less than 5 mg / mL or less than 2mg / L. Suitably, the second solvent system comprises a protic polar solvent, Suitably, the second solvent system comprises ethanol and / or isopropyl alcohol. Suitably, the second solvent system comprises ethanol. Suitably, 5-40 relative volumes of the second solvent system are added to the solution from step a), such as 5-20 or 10-15 relative volumes. Suitably, 5-40 relative volumes of ethanol are added to the solution from step a), such as 5-20 or 10-15 relative volumes. Suitably, in step b) the second solvent is added at a temperature of 25 to 75 °C, such as 40 to 50 °C.

[0364] Suitably, the addition of the second solvent system in step b) is over a time period of at least 1 hour, such as at least 2 hours. Suitably, the addition of the second solvent in step b) is over a time period of about 3 hours.

[0365] Suitably, the first solvent system comprises acetone and the second solvent system comprises ethanol.

[0366] Suitably, the second solvent system is an anti-solvent system.

[0367] Suitably, step b) comprises concentrating the solution from step a) and adding a second solvent system to the solution from step a). Suitably, step b) comprises concentrating the solution from step a) and adding a second solvent system to the concentration mixture.

[0368] Suitably, step c) comprises mixing the solution from step b) for at least 10 minutes. Suitably, step c) further comprises mixing the solution from step b) for 20 to 240 minutes, such as for about 120 minutes. Suitably the mixing is carried out at the same temperature as step b), such as at 25 to 75 °C, or more suitably at 40 to 50 °C.

[0369] Suitably, step c) further comprises cooling the mixture. Suitably, the mixture is cooled to less than 25 °C, such as less than 0 °C. Suitably, the mixture is cooled to about -10 °C.

[0370] Suitably, step c) further comprises mixing the cooled solution for 20 to 240 minutes, such as for about 120 minutes. Suitably the mixing is carried out at a temperature of less than 25 °C, such as less than 0 °C. Suitably, the mixing is carried out at a temperature of about -10 °C.

[0371] Suitably, step d) comprises isolating the solids by filtration.

[0372] Suitably, step e) comprises drying the solids at a temperature greater than room temperature, such as greater than 30 °C, or greater than 40 °C.

[0373] In an aspect of the present invention there is provided a crystalline form of Compound 1 Form I obtainable by the process described above.Method to prepare Compound 1 Mesylate Form I

[0374] In one embodiment of the present disclosure, there is provided a process to prepare Compound 1 Mesylate Form I.

[0375] In one embodiment, the process to prepare Compound 1 Mesylate Form I comprises the steps of: a) providing a solution of Compound 1 in a first solvent system; b) adding methanesulfonice acid in a second solvent system to the solution from step a); c) optionally, cooling the mixture obtained from step b); d) optionally, isolating the solids formed from step c); and e) optionally, drying the solids isolated from step d).

[0376] In one embodiment, the first solvent system comprises a solvent wherein Compound 1 has a solubility of at least 0.1 mg / mL at room temperature, such as at least 1 mg / mL, 5 mg / mL, lOmg / mL or 20 mg / mL. Suitably, the first solvent system comprises a polar solvent. Suitably, the first solvent system comprises an aprotic polar solvent. Suitably, the first solvent system comprises acetone, acetonitrile, anisole, butanone, dichloromethane, dimethylacetamide (DMAc), dimethylsulfoxide, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, N-methyl- 2-pyrrolidone, methyl tert-butyl ether, methyl isobutyl ketone, tetrahydrofuran (THF), and / or toluene. Suitably, the first solvent system comprises acetone. Suitably, the first solvent system comprises a protic polar solvent. Suitably, the first solvent system comprises ethanol and / or isopropyl alcohol. Suitably, Compound 1 is dissolved in 1 to 50 relative volumes of the first solvent system, such as 20-40 relative volumes or 25-35 relative volumes. Suitably, Compound 1 is dissolved in 25-35 relative volumes of acetone.

[0377] Suitably, step a) is performed at 25 to 75 °C, such as 40 to 60 °C or 45 to 55 °C.

[0378] Suitably, in step a) Compound 1 is dissolved in 25-35 relative volumes of acetone at a temperature of 45 to 55 °C.

[0379] Suitably, step a) further comprises an additional step (step a2)) of adding a seed of Compound 1 Mesylate Form I to the solution. Suitably, 0.01 to 10% by weight of the seed relative to the amount of Compound 1 present in the solution in step a) is added. Suitably, 0.1 to 5% by weight of seed is added, such as 0.1 to 2% by weight. Suitably step a2) is carried out at the same temperature as step a), such as at 25 to 75 °C, or more suitably at 40 to 60 °C or 45 to 55°C.

[0380] Suitably, step a) further comprises an additional step (step a3)) of mixing the solution from step a) for 10 to 120 minutes, such as for about 30 minutes. Suitably step a3) is carried outat the same temperature as step a), such as at 25 to 75 °C, or more suitably at 40 to 60 °C or 45 to 55 °C.

[0381] Suitably step a) comprises step a2) and step a3).

[0382] Suitably step a) comprises step a2).

[0383] Suitably step a) comprises step a3).

[0384] Steps a), a2) and / or a3) may provide a suspension of Compound 1 and / or Compound 1 Mesylate in the first solvent system, therefore, step b) may comprise adding a second solvent system to the suspension resulting from steps a), a2) or step a3).

[0385] Suitably, the second solvent system comprises a solvent in which methanesulfonic acid is soluble at ambient temperature. Suitably, the second solvent system comprises a polar solvent. Suitably, the second solvent system comprises an aprotic polar solvent. Suitably, the second solvent system comprises acetone, acetonitrile, anisole, butanone, di chloromethane, dimethylacetamide (DMAc), dimethylsulfoxide, ethyl acetate, isopropyl acetate, 2- methyltetrahydrofuran, N-methyl-2 -pyrrolidone, methyl tert-butyl ether, methyl isobutyl ketone, tetrahydrofuran (THF), and / or toluene. Suitably, the second solvent system comprises acetone. Suitably, the second solvent system comprises a protic polar solvent. Suitably, the second solvent system comprises ethanol and / or isopropyl alcohol. Suitably, the second solvent system comprises the same solvent as the first solvent system. Suitably, the second solvent system comprises acetone. Suitably 1.0 to 1.5, such as 1.0 to 1.2, or about 1.0 molar equivalents of methanesulfonic acid are used in step b). Suitably methanesulfonic acid is dissolved in 1-10 relative volumes of the second solvent system, such as 1-5 or 1-3 relative volumes. Suitably methanesulfonic acid is dissolved in 1-10 relative volumes of acetone, such as 1-5 relative volumes or about 2 relative volumes of acetone.

[0386] Suitably, in step b) the methanesulfonic acid in the second solvent system is added to the solution from step a) at 25 to 75 °C. Suitably, step b) is performed at 40 to 60 °C, 45 to 55 °C.

[0387] Suitably, in step b) the methanesulfonic acid in the second solvent system is added to the solution from step a) over a period of at least 30 minutes, such as at least 1 hour. Suitably, in step b) the methanesulfonic acid in the second solvent system is added to the solution from step a) over a period of about 2 hours.

[0388] Suitably, step b) comprises an additional step (step b2)) of adding an additional portion of the second solvent system. Suitably, 1 to 5 relative volumes of the second solvent system are added, such as about 2 relative volumes.

[0389] Suitably, step b) comprises an additional step (step b3)) of mixing the solution for 10 to 240 minutes, such as for about 120 minutes. Suitably the mixing is carried out at 25 to 75 °C, 40 to 60 °C, or more suitably at 45 to 55 °C. Suitably, step b2) is performed after the addition of methanesulfonic acid in a second solvent system.

[0390] Suitably, step b) comprises step b2) and step b3).

[0391] Suitably, step b) comprises step b2).

[0392] Suitably, step b) comprises step b3).

[0393] Suitably, in step c) the mixture is cooled to less than 45 °C. Suitably, in step c) the mixture is cooled to less than 30 °C. Suitably, the mixture is cooled to about 15 to 25 °C. Suitably, the mixture is cooled over a time period of at least 30 minutes, such as at least a hour. Suitably, the mixture is cooled over a time period of about 2 hours.

[0394] Suitably, step c) comprises an additional step (step c2)) of mixing the cooled solution for 10 to 240 minutes, such as for about 120 minutes. Suitably the mixing is carried out at the same temperature as step c), such as at 15 to 25 °C.

[0395] Suitably, step d) comprises isolating the solids by filtration.

[0396] Suitably, step e) comprises drying the solids at a temperature greater than room temperature, such as greater than 30 °C, or greater than 40 °C.

[0397] In an aspect of the present invention there is provided a crystalline form of Compound 1 Mesylate Form I obtainable by the process described above.IV. COMPOSITIONS AND KITS

[0398] Crystalline forms of Compound 1 provided herein, are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that comprise one or more of the crystalline forms of Compound 1 provided herein and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. The crystalline forms of Compound 1 provided herein, may be the sole active ingredient or one of the active ingredients of the pharmaceutical compositions. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0399] In some embodiments, provided herein are pharmaceutical compositions comprising a crystalline form of Compound 1 of the present disclosure and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions comprise a therapeutically effective amount of a crystalline form of Compound 1 provided herein, and a pharmaceutically acceptable carrier.

[0400] In one embodiment, provided herein is a pharmaceutical composition comprising a pure or substantially pure crystalline form of Compound 1 of the present disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, provided herein is a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient wherein the crystalline form of Compound 1 consists essentially of crystalline Compound 1 Form I, Form II, Form III, Form IV, Form V, monohydrate, dihydrate, methyl-tetrahydrofuran (MeTHF) solvate, methyl t-butyl ether (MTBE) solvate 1, MTBE solvate 2, 2-butanol solvate, t-butanol solvate, p-dioxane solvate, cyclopentyl methyl ether (CPME) solvate, dimethyl acetamide (DMAc) solvate, hydrochloride Form I, hydrochloride Form II, hemisulfate Form I, sulfate Form I, mesylate Form I, esylate Form I, besylate Form I, besylate Form II, tosylate Form I, napsylate Form I, maleate Form I, L- tartrate Form I, L-tartrate Form II, or L-tartrate Form III. In one embodiment, provided herein is a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient wherein the crystalline form of Compound 1 consists of crystalline Compound 1 Form I, Form II, Form III, Form IV, Form V, monohydrate, dihydrate, methyl-tetrahydrofuran (MeTHF) solvate, methyl t-butyl ether (MTBE) solvate 1, MTBE solvate 2, 2-butanol solvate, t-butanol solvate, p-dioxane solvate, cyclopentyl methyl ether (CPME) solvate, dimethyl acetamide (DMAc) solvate, hydrochloride Form I, hydrochloride Form II, hemisulfate Form I, sulfate Form I, mesylate Form I, esylate Form I, besylate Form I, besylate Form II, tosylate Form I, napsylate Form I, maleate Form I, L-tartrate Form I, L-tartrate Form II, or L-tartrate Form III.

[0401] In some embodiments, provided herein is a pharmaceutical composition comprising Compound 1 Form I and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of Compound 1 Form I and a pharmaceutically acceptable carrier, diluent or excipient.

[0402] In one embodiment, provided herein is a pharmaceutical composition comprising pure or substantially pure Compound 1 Form I and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, provided herein is a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipientwherein the crystalline form of Compound 1 consists essentially of crystalline Compound 1 Form I. In one embodiment, provided herein is a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient wherein the crystalline form of Compound 1 consists of crystalline Compound 1 Form I.

[0403] In some embodiments, provided herein is a pharmaceutical composition comprising Compound 1 mesylate Form I and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of Compound 1 mesylate Form I and a pharmaceutically acceptable carrier, diluent or excipient.

[0404] In one embodiment, provided herein is a pharmaceutical composition comprising pure or substantially pure Compound 1 mesylate Form I and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, provided herein is a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient wherein the crystalline form of Compound 1 consists essentially of crystalline Compound 1 mesylate Form I. In one embodiment, provided herein is a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient wherein the crystalline form of Compound 1 consists of crystalline Compound 1 mesylate Form I.

[0405] When it is stated herein that the pharmaceutical composition relates to a crystalline form of Compound 1, the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, yet more conveniently greater than about 90% and preferably greater than 95%, 98% or 99% by weight of that crystalline form.

[0406] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of the one or more (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof. In some embodiments, the one of more therapeutic agents are selected from Complement receptor 2 antagonists; Duffy antigen chemokine receptor modulators; Envelope glycoprotein GP350 modulators; Glucocorticoid receptor agonists; Helicase inhibitors; helicase-primase inhibitor; HIV gpl60 protein inhibitors; HIV gp41 protein inhibitors; HIV-1 reverse transcriptase inhibitors; HLA class I antigen A-2 alpha modulators; HLA class I antigen A-24 alpha modulators; Human cytomegalovirus glycoprotein B modulators; Human cytomegalovirus glycoprotein H modulators; Humancytomegalovirus glycoprotein inhibitors; Human cytomegalovirus glycoprotein L modulators; Immunoglobulin G agonists; Interferon alpha 2 ligands; Interferon gamma receptor antagonists; Latent membrane protein 1 modulators; Latent membrane protein 2 modulators; Latent membrane protein 2 stimulators; Progesterone receptor agonists; Secreted protein BARF1 modulators; Serine threonine protein kinase UL97 modulators; T-cell surface glycoprotein CD8 stimulators; Thymidine kinase inhibitors; Trans acting transcription protein ICP4 modulators; Transferase inhibitors; Unspecified gene inhibitors; Adenosylhomocysteinase inhibitors; Basigin inhibitors; Basigin modulators; CCR5 chemokine modulators; CD4 agonists; CD4 modulators; CD89 agonists; CMV 65kDa lower matrix phosphoprotein modulators; CRISPR associated endonuclease Cas9 modulators; Cyclin dependent kinase inhibitors; Cyclin dependent kinase inhibitors; Cyclin-dependent kinase-9 inhibitors; DNA polymerase inhibitors; DNA primase inhibitors; Endonuclease modulators; Epstein-Barr nuclear antigen 1 inhibitors; Epstein-Barr nuclear antigen 1 modulators; Epstein-Barr nuclear antigen 1 stimulators; Fatty acid synthase inhibitors; Herpesvirus envelope glycoprotein B stimulators; Herpesvirus envelope glycoprotein D inhibitors; Herpesvirus envelope glycoprotein D modulators; HIV gp!20 protein inhibitors; HLA class I antigen A-l l alpha modulators; Hsp 90 inhibitors; Human cytomegalovirus glycoprotein B inhibitors; Human cytomegalovirus glycoprotein B modulators; Human cytomegalovirus glycoprotein inhibitors; Hyaluronidase inhibitors; Immunoglobulin agonists; Interferon alpha 1 ligands; Interferon alpha 2 ligands; Interferon alpha ligand inhibitors; Interferon alpha ligand modulators; Interferon beta ligands; Large terminase protein inhibitors; LAT gene inhibitors; NAD-dependent deacetylase sirtuin modulators; Nicotinic acetylcholine receptor antagonists; NKG2D ligand modulators; Nucleotidyltransferase inhibitors; Protein Jumonji inhibitors; Ribonuclease stimulators; Serine threonine protein kinase UL97 inhibitors; Syntaxin- 5 inhibitors; TAT protein modulators; T-cell surface glycoprotein CD8 stimulators; TLR-4 agonists; and viral ribonucleotide reductase inhibitors. In some embodiments, the one of more therapeutic agents are selected from famciclovir, acyclovir, and valacyclovir.

[0407] In some embodiments, provided herein are pharmaceutical compositions comprising a therapeutically effective amount of a crystalline form of Compound 1 provided herein, and a pharmaceutically acceptable carrier.

[0408] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical compositions may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In some embodiments, the pharmaceutical compositions may be administered by intra-arterial injection, intravenously,intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0409] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, com oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. In some embodiments, the crystalline forms of Compound 1, and pharmaceutical compositions disclosed herein are administered by subcutaneous injection.

[0410] The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

[0411] In some embodiments, the sterile injectable preparation disclosed herein may also be a sterile injectable solution or suspension prepared from a reconstituted lyophilized powder in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

[0412] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. In certain embodiments the suspension is a microsuspension. In certain embodiments the suspension is a nanosuspension.

[0413] In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) will include one or more excipients. Excipients should be compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof. Examples of suitable excipients are well known to the person skilled in the art of parenteral formulation and may be found e.g., in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009. Examples of solubilizing excipients in a parenteral formulation (e.g., an SC or IM formulation) include, but are not limited to, polysorbates (such as polysorbate 20 or 80) and poloxamers (such as poloxamer 338, 188, or 207). In some embodiments, the crystalline forms of Compound 1, and pharmaceutical compositions disclosed herein are administered with implants.

[0414] Oral administration may be another route for administration of the crystalline forms of Compound 1 provided herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one crystalline form of Compound 1 provided herein, the active ingredient (such as a crystalline form of Compound 1 provided herein) is usually diluted by an excipient and / or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the pharmaceutical compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active crystalline form of Compound 1, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0415] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose or any combinations thereof. The pharmaceutical compositions can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents; or any combinations thereof.

[0416] The pharmaceutical compositions that include at least one crystalline form of Compound 1 described herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient (such as a crystalline form of Compound 1 provided herein) after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containingpolymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present disclosure employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the crystalline forms of Compound 1 provided herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0417] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a crystalline form of Compound 1 described herein or a mixture thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0418] The tablets or pills of the crystalline forms of Compound 1 provided herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0419] Pharmaceutical compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

[0420] In one embodiment, provided herein are kits that comprise a crystalline form of Compound 1 provided herein, and suitable packaging. In some embodiments, the kit further comprises instructions for use. In some embodiments, the kit comprises a crystalline form of Compound 1 provided herein and a label and / or instructions for use of the crystalline forms of Compound 1 in the treatment of the indications, including the diseases or conditions, described herein.

[0421] In some embodiments, the kits further comprise one or more (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0422] In one embodiment, provided herein are articles of manufacture that comprise a crystalline form of Compound 1 described herein in a suitable container. In some embodiments, the container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag.V. METHODS

[0423] The methods provided herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living individual, as within an animal or human. In this context, the methods provided herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. In this context, the present disclosure may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the present disclosure may be used ex vivo to determine the optimal schedule and / or dosing of administration of a crystalline form of Compound 1 as disclosed herein for a given cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the present disclosure may be suited are described below or will become apparent to those skilled in the art. The selected crystalline forms of Compound 1 may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.

[0424] In some embodiments, the present disclosure provides a method of treating or preventing a herpesvirus (conveniently a HSV) infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a crystalline form of Compound 1 providedherein, or a pharmaceutical composition provided herein. In some embodiments, the present disclosure provides a method of treating or preventing a herpesvirus (conveniently a HSV) infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of Compound 1 Form I, or a pharmaceutical composition comprising Compound 1 Form I and a pharmaceutically acceptable carrier, dilute or excipient. In some embodiments, the present disclosure provides a method of treating or preventing a herpesvirus (conveniently a HSV) infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of Compound 1 mesylate Form I, or a pharmaceutical composition comprising Compound 1 mesylate Form I and a pharmaceutically acceptable carrier, dilute or excipient.

[0425] In some embodiments, the present disclosure provides a method of treating a herpesvirus (conveniently a HSV) infection comprising administering to a patient a therapeutically effective amount of a crystalline form of Compound 1 provided herein, or a pharmaceutical composition provided herein, to a patient in need thereof. In some embodiments, the present disclosure provides a method of treating a herpesvirus (conveniently a HSV) infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of Compound 1 Form I, or a pharmaceutical composition comprising Compound 1 Form I and a pharmaceutically acceptable carrier, dilute or excipient. In some embodiments, the present disclosure provides a method of treating a herpesvirus (conveniently a HSV) infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of Compound 1 mesylate Form I, or a pharmaceutical composition comprising Compound 1 mesylate Form I and a pharmaceutically acceptable carrier, dilute or excipient.

[0426] In some embodiments, the methods provided herein further comprise administering a therapeutically effective amount of one, two, three, or four additional therapeutic agents, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods provided herein wherein the herpesvirus is HSV-1 or HSV-2.

[0427] The disclosure further relates to the use of crystalline forms of Compound 1 disclosed herein for the treatment and / or prophylaxis of diseases and / or conditions through inhibiting the helicase primase of herpesviruses by said crystalline forms of Compound 1. Further, the present disclosure relates to the use of said crystalline forms of Compound 1 for the preparation of a medicament for the treatment and / or prophylaxis of a herpesvirus associated disease and / or condition through inhibiting helicase primase of herpesviruses by said crystalline forms of Compound 1. In some embodiments the herpesvirus associated disease or condition is alleviated by inhibiting herpesvirus helicase primase. In some embodiments, the present disclosure relatesto the use of the crystalline forms of Compound 1 disclosed herein for the preparation of a medicament for the treatment and / or prophylaxis of HSV-1 or HSV-2 associated disease and / or condition through inhibiting the helicase primase by said crystalline forms of Compound 1. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0428] Medicaments as referred to herein can be prepared by conventional processes, including the combination of a crystalline form of Compound 1 according to the present disclosure and a pharmaceutically acceptable carrier.

[0429] In some embodiments, provided herein is a method of the inhibiting the helicase primase of herpesviruses comprising administering to a patient in need thereof (e.g, a patient having a herpesvirus associated disease or condition) a therapeutically effective amount of a crystalline form of Compound 1, or a composition comprising a crystalline form of Compound 1. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0430] In some embodiments, provided herein is a method of inhibiting the helicase primase of HSV-1 or HSV-2 comprising administering to a patient in need thereof (e.g, a patient having a HSV-1 or HSV-2 associated disease or condition) a therapeutically effective amount of a crystalline form of Compound 1, or a composition comprising a crystalline form of Compound 1. In some embodiments, provided herein is a method of inhibiting the helicase primase of HSV-1 or HSV-2 comprising administering to a patient in need thereof (e.g, a patient having a HSV-1 or HSV-2 associated disease or condition) a therapeutically effective amount of a crystalline form of Compound 1 disclosed herein, or a composition comprising a crystalline form of Compound 1 disclosed herein. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0431] In one embodiment, there is provided a method for inhibiting HSV replication in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1. In one embodiment, there is provided a method for inhibiting HSV replication in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0432] In some embodiments, provided herein is a method of reducing the proliferation of a virus comprising contacting the virus with a crystalline form of Compound 1, and inhibiting helicase primase in the virus. In some embodiments, provided herein is a method of reducing the proliferation of herpesviruses comprising contacting the virus with a crystalline form of Compound 1, and inhibiting helicase primase in the virus. In some embodiments, provided herein is a method of reducing the proliferation of HSV-1 or HSV-2 comprising contacting the virus with a crystalline form of Compound 1 disclosed herein, and inhibiting helicase primase in the virus. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0433] In some embodiments, provided herein is a method of treating a disorder induced, exacerbated, or accelerated by herpesviruses, comprising administering to a patient a therapeutically effective amount of a crystalline form of Compound 1, or a pharmaceutical composition comprising a crystalline form of Compound 1, to a patient in need thereof. In some embodiments, provided herein is a method of treating a disorder induced, exacerbated, or accelerated by HSV-1 or HSV-2, comprising administering to a patient a therapeutically effective amount of a crystalline form of Compound 1, or a pharmaceutical composition comprising a crystalline form of Compound 1, to a patient in need thereof. In some embodiments, the disorder is genital herpes, herpes labialis, HSV keratitis, HSV encephalitis, or disseminated HSV. In some embodiments, the disorder is genital herpes. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0434] In one embodiment, there is provided a method for reducing the likelihood or severity of symptoms of a HSV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 provided herein. In one embodiment, there is provided a method for reducing the likelihood or severity of symptoms of a HSV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound 1 provided herein and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0435] In one embodiment, there is provided a method for inhibiting the development or progression of a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof, the method comprising administering to the subject a therapeutically effectiveamount of a crystalline form of Compound 1 provided herein. In one embodiment, there is provided a method for inhibiting the development or progression of a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound 1 provided herein and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0436] In one embodiment, there is provided a method for treating or preventing a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 provided herein. In one embodiment, there is provided a method for treating or preventing a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound 1 provided herein and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0437] In a particular embodiment, the crystalline forms of Compound 1 according to the present disclosure, or the pharmaceutical compositions according to the present disclosure, can reduce time to healing of lesions (e.g., time to full recovery of lesions) and duration of symptoms resulting from HSV infections in diseases or disorders, such as herpes labialis or genital herpes. The time to lesion healing may be defined as complete epithelization of mucocutaneous HSV lesion(s) within the treatment period and no appearance of new lesions, e.g., as assessed by a physician.

[0438] In one embodiment, the crystalline forms of Compound 1 according to the present disclosure, or the pharmaceutical compositions according to the present disclosure can reduce pain or pain intensity (for example, at a lesion site) caused as a consequence of HSV infections in diseases or disorders, such as herpes labialis or genital herpes.

[0439] In some embodiments, provided herein is the use of a crystalline form of Compound 1, in the treatment of a viral infection. In some embodiments, provided herein is the use of a crystalline form of Compound 1, in the treatment of a viral infection caused by herpesviruses. In some embodiments, provided herein is the use of a crystalline form of Compound 1, in the treatment of a viral infection caused by HSV-1 or HSV-2. In one embodiment, the crystalline formof Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0440] In one embodiment, there is provided the use of a crystalline form of Compound 1, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1, for the inhibition of HSV replication in a subject. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0441] In one embodiment, there is provided the use of a crystalline form of Compound 1, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1, for reducing the likelihood or severity of symptoms of a HSV infection in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0442] In one embodiment, there is provided the use of a crystalline form of Compound 1, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1, in inhibiting the development or progression of a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0443] In one embodiment, there is provided the use of a crystalline form of Compound 1, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1, in treating or preventing a disease or disorder caused by, or associated with, HSV infection. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0444] In some embodiments, provided herein is the use of a crystalline form of Compound 1, for the preparation of a medicament for preventing / treating a viral infection. In some embodiments, provided herein is the use of a crystalline form of Compound 1, for the preparation of a medicament for preventing / treating a viral infection caused by herpesviruses. In some embodiments, provided herein is the use of a crystalline form of Compound 1, for the preparation of a medicament for preventing / treating a viral infection caused by HSV-1 or HSV-2. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0445] In one embodiment, there is provided the use of a crystalline form of Compound 1, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1, in themanufacture of a medicament for inhibiting HSV replication in a subject. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0446] In one embodiment, there is provided the use of a crystalline form of Compound 1, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1, in the manufacture of a medicament for reducing the likelihood or severity of symptoms of a HSV infection in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0447] In one embodiment, there is provided the use of a crystalline form of Compound 1, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1, in the manufacture of a medicament for inhibiting the development or progression of a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0448] In one embodiment, there is provided the use of a crystalline form of Compound 1 or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 in the manufacture of a medicament for treating or preventing a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0449] In some embodiments, provided herein is a crystalline form of Compound 1 for use as a medicament. In some embodiments, provided herein is Compound 1 Form I for use as a medicament. In some embodiments, provided herein is Compound 1 mesylate Form I for use as a medicament.

[0450] In one embodiment, provided herein is a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient for use as a medicament. In one embodiment, provided herein is a pharmaceutical composition comprising Compound 1 Form I and a pharmaceutically acceptable carrier, diluent or excipient for use as a medicament. In one embodiment, provided herein is a pharmaceutical composition comprising Compound 1 mesylate Form I and a pharmaceutically acceptable carrier, diluent or excipient for use as a medicament.

[0451] In some embodiments, provided herein is a crystalline form of Compound 1, for use in therapy. In one embodiment, provided herein is Compound 1 Form I for use in therapy. In another embodiment, provided herein is Compound 1 mesylate Form I for use in therapy.

[0452] In one embodiment, provided herein is a pharmaceutical composition comprising a crystalline form of Compound 1 provided herein and a pharmaceutically acceptable carrier, diluent or excipient for use in therapy. In one embodiment, provided herein is a pharmaceutical composition comprising Compound 1 Form I provided herein and a pharmaceutically acceptable carrier, diluent or excipient for use in therapy. In one embodiment, provided herein is a pharmaceutical composition comprising Compound 1 mesylate Form I and a pharmaceutically acceptable carrier, diluent or excipient for use in therapy.

[0453] In another aspect, there is provided a crystalline form of Compound 1 for use in the treatment of a herpes virus (conveniently a HSV) infection. In another aspect, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1, and a pharmaceutically acceptable carrier, diluent or excipient for use in the treatment of a herpes virus (conveniently a HSV) infection. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In one embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0454] In some embodiments, provided herein is a crystalline form of Compound 1 for use in a method of treating a viral infection caused by HSV-1 or HSV-2. In some embodiments, provided herein is Compound 1 Form I for use in a method of treating a viral infection caused by HSV-1 or HSV-2. In some embodiments, provided herein is Compound 1 mesylate Form I for use in a method of treating a viral infection caused by HSV-1 or HSV-2.

[0455] In one embodiment, there is provided a crystalline form of Compound 1 for use in the inhibition of HSV replication in a subject. In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1, and a pharmaceutically acceptable carrier, diluent or excipient for use in the inhibition of HSV replication in a subject. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In one embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0456] In one embodiment, there is provided a crystalline form of Compound 1 for use in reducing the likelihood or severity of symptoms of a HSV infection in a subject in need thereof. In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1, and a pharmaceutically acceptable carrier, diluent or excipient for use in reducing the likelihood or severity of symptoms of a HSV infection in a subject in need thereof. In oneembodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0457] In one embodiment, there is provided a crystalline form of Compound 1 for use in inhibiting the development or progression of a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1, and a pharmaceutically acceptable carrier, diluent or excipient for use in inhibiting the development or progression of a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0458] In one embodiment, there is provided a crystalline form of Compound 1 for use in treating or preventing a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof. In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1, and a pharmaceutically acceptable carrier, diluent or excipient for use in treating or preventing a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 is Compound 1 Form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0459] In an embodiment, the patient being treated is a human. Besides being useful for human treatment, the crystalline forms of the present invention may be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. Conveniently, such animals include horses, dogs and cats.

[0460] In a particular embodiment, the disease or disorder caused by, or associated with, HSV infection, is selected from herpes labialis (e.g., oro-labial cold sores or Whitlow’s), genital herpes, HSV-related ocular keratitis, HSV-related encephalitis, herpes gladiatorum, primary HSV gingivostomatitis, Mollaret's meningitis and Bell's palsy.

[0461] In a particular embodiment, the disease or disorder caused by, or associated with, HSV infection, is selected from herpes labialis (e g., oro-labial cold sores or Whitlow’s) or genital herpes. In one embodiment, the disease or disorder is recurrent herpes labialis or recurrent genital herpes. Individuals with a history of multiple recurrences of herpes labialis or recurrent genital herpes, e.g., HSV which recurs six times or more annually, may be regarded as having recurrent HSV.

[0462] In one embodiment, the herpes virus being treated is HSV-2. In a further embodiment, the herpes virus being treated is HSV-2 and the subject in need of the treatment has HSV-2 recurrent genital herpes.

[0463] In one embodiment, the herpes virus being treated is HSV-1. In yet a further embodiment, both herpes virus HSV-1 and HSV-2 are being treated.

[0464] In one embodiment, the herpes virus being treated or prevented is resistant to nucleosidic anti-viral therapy, e.g., acyclovir-resistant mucocutaneous HSV infection. In one embodiment, the nucleosidic antiviral therapy is selected from therapy with the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir and valacyclovir.

[0465] In a further embodiment, the HSV infection being treated is a mucocutaneous HSV infection resistant to therapy with antiviral therapy with nucleoside analogues, such as acyclovir, penciclovir, famciclovir, ganciclovir or valacyclovir.

[0466] In a particular embodiment, the subject in need of the methods disclosed herein, is immunocompromised. The subject may be immunocompromised due to conditions including HIV infection, cancer, hematopoietic cell or solid organ transplantation and chronic glucocorticoid use or a genetic immunodeficiency.

[0467] In a particular embodiment, the subject in need of the methods disclosed herein, is a neonate or an infant.

[0468] In a particular embodiment, the subject is a herpes-positive patient.

[0469] In a particular embodiment, the subject in need of the methods disclosed herein, has acyclovir-resistant mucocutaneous HSV infection. This subject may have been diagnosed with condition on the basis of clinical failure, e.g., no improvement after oral or iv doses for at least 7 days with approved doses of acyclovir.

[0470] In a particular embodiment, the subject in need of the methods disclosed herein, has a primary genital HSV-related herpes infection. In one aspect, the subject in need of the methods disclosed herein, has severe or progressive genital HSV-related herpes infection.VI. ADMINISTRATION

[0471] The crystalline forms of Compound 1 of the present disclosure (also referred to herein as the active ingredients) can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal,intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with, for example, the condition of the recipient. An advantage of certain crystalline forms of Compound 1 disclosed herein, is that they are orally bioavailable and can be dosed orally.

[0472] A crystalline form of Compound 1 of the present disclosure, may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about one week, at least about 2 weeks, at least about 3 weeks, at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In some embodiments, the crystalline form of Compound 1 is administered on a daily or intermittent schedule for the duration of the individual’s life.

[0473] In some embodiments, the crystalline form of Compound 1 of the present disclosure, is administered to a patient in need thereof once a week, twice a month, once a month, once every two months, once every 3 months, once every six months, or once every year. In some embodiments, the crystalline form of Compound 1 of the present disclosure, is administered to a patient in need thereof once every 3 months, once every six months, or once every year.

[0474] The specific dose level of a crystalline form of Compound 1 of the present disclosure for any particular subject will depend upon a variety of factors including the activity of the specific crystalline form of Compound 1 employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a crystalline form of Compound 1 provided herein per kilogram of the subject’s body weight (mg / kg). Dosages of between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg / kg may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.

[0475] The dosage may also be described as a total amount of a crystalline form of Compound 1 described herein administered per dose. The dosage or dosing frequency of a crystalline form of Compound 1 of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician.

[0476] The crystalline forms of Compound 1 of the present disclosure, may be administered to an individual (e.g., a human) in a therapeutically effective amount. In some embodiments, the crystalline form of Compound 1 is administered once daily, once weekly, once monthly, once every two months, once every three months, or once every six months. In some embodiments, the crystalline form of Compound 1 is administered once daily. In some embodiments, the crystalline form of Compound 1 is administered once weekly. In some embodiments, the crystalline form of Compound 1 is administered once monthly. In some embodiments, the crystalline form of Compound 1 is administered once every two months. In some embodiments, the crystalline form of Compound 1 is administered once every three months. In some embodiments, the crystalline form of Compound 1 is administered once every six months.

[0477] The crystalline forms of Compound 1 provided herein can be administered by any useful route and means, such as by oral or parenteral (e g., intravenous) administration. Therapeutically effective amounts of the crystalline form of Compound 1 may include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, such as from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or such as from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day. In some embodiments, a therapeutically effective amount of the crystalline forms of Compound 1 provided herein include from about 30 pg to about 300 pg per day, from about 0.3 mg to about 30 mg per day, or from about 30 mg to about 300 mg per day, or from about 300 mg to about 1000 mg per day.

[0478] A crystalline form of Compound 1 of the present disclosure may be combined with one or more additional therapeutic agents in any dosage amount of the crystalline form of Compound 1 of the present disclosure (e.g., from 1 mg to 1000 mg of crystalline form of Compound 1). The one or more additional therapeutic agents can be administered before, after, or simultaneous with, the administration of the crystalline form of Compound 1 of the present disclosure, or the pharmaceutical composition of the present disclosure. In some embodiments, the one or more additional therapeutic agents are administered before the crystalline form of Compound 1 or the pharmaceutical composition. In some embodiments, the one or more additional therapeutic agents are administered after the crystalline form of Compound 1 or the pharmaceutical composition. In some embodiments, the one or more additional therapeutic agents are administered simultaneously with the crystalline form of Compound 1 or the pharmaceutical composition.

[0479] Therapeutically effective amounts may include from about 0.1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or such as from about100 mg per dose to about 400 mg per dose, or such as from about 150 mg per dose to about 350 mg per dose, or such as from about 200 mg per dose to about 300 mg per dose, or such as from about 0.01 mg per dose to about 1000 mg per dose, or such as from about 0.01 mg per dose to about 100 mg per dose, or such as from about 0.1 mg per dose to about 100 mg per dose, or such as from about 1 mg per dose to about 100 mg per dose, or such as from about 1 mg per dose to about 10 mg per dose, or such as from about 1 mg per dose to about 1000 mg per dose. Other therapeutically effective amounts of the crystalline form of Compound 1 of the present disclosure, are about 50, 100, 125, 150, 175, 200, 225, 250, 275, or 300 mg per dose. Other therapeutically effective amounts of the crystalline form of Compound 1 of the present disclosure, are about 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or about 1000 mg per dose.

[0480] In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1 mg to about 1000 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1 mg to about 900 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1 mg to about 800 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1 mg to about 700 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1 mg to about 600 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1 mg to about 500 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1 mg to about 400 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1 mg to about 300 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1 mg to about 200 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1 mg to about 100 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1 mg to about 75 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1 mg to about 50 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1 mg to about 25 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1 mg to about 20 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1 mg to about15 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1 mg to about 10 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1 mg to about 5 mg.

[0481] In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, or about 1050 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 5 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 100 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 150 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 200 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 250 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 300 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 350 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 400 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 450 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 500 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 550 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 600 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 650 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 700 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 750 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 800 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 850 mg. In some embodiments, a therapeuticallyeffective amount of the crystalline form of Compound 1 of the present disclosure, is about 900 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 950 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1000 mg. In some embodiments, a therapeutically effective amount of the crystalline form of Compound 1 of the present disclosure, is about 1050 mg. When administered orally, the total weekly dosage for a human subject may be between about 1 mg and 1,000 mg / week, between about 10-500 mg / week, between about 50-300 mg / week, between about 75-200 mg / week, or between about 100-150 mg / week. In some embodiments, the total weekly dosage for a human subject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg / week administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 100 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 150 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 200 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 250 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 300 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 350 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 400 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 450 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 500 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 600 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 700 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 800 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a crystalline form ofCompound 1 of the present disclosure, may be about 900 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 1000 mg administered in a single dose.

[0482] When administered orally, the total monthly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be between about 500 mg and 1,000 mg / month, between about 600-900 mg / month, or between about 700-800 mg / month. In some embodiments, the total weekly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg / week administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 500 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject may be about 550 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 600 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 650 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 700 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 750 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 800 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 850 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 900 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 950 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a crystalline form of Compound 1 of the present disclosure, may be about 1000 mg administered in a single dose.

[0483] A single dose can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16 or once every 24 hours. A single dose can also be administered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. A single dose can also be administered once every 1 week, 2, 3, or once every 4 weeks. In certain embodiments, a single dose can be administered once every week. A single dose can also beadministered once every month. In some embodiments, a crystalline form of Compound 1 provided herein is administered once daily in a method disclosed herein. In some embodiments, a crystalline form of Compound 1 provided herein is administered twice daily in a method disclosed herein.

[0484] In some embodiments, a crystalline form of Compound 1 provided herein is administered once daily in a method disclosed herein. In some embodiments, a crystalline form of Compound 1 provided herein is administered once weekly in a method disclosed herein. In some embodiments, a crystalline form of Compound 1 provided herein is administered once monthly in a method disclosed herein. In some embodiments, a crystalline form of Compound 1 provided herein is administered once every two months in a method disclosed herein. In some embodiments, a crystalline form of Compound 1 provided herein is administered once every three months in a method disclosed herein. In some embodiments, a crystalline form of Compound 1 provided herein is administered once every six months in a method disclosed herein.

[0485] In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 100 mg once weekly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 150 mg once weekly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 200 mg once weekly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 250 mg once weekly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 300 mg once weekly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 350 mg once weekly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 400 mg once weekly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 450 mg once weekly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 500 mg once weekly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 600 mg once weekly.

[0486] In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 500 mg once monthly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 550 mg once monthly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 600 mg once monthly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about650 mg once monthly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 700 mg once monthly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 750 mg once monthly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 800 mg once monthly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 850 mg once monthly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 900 mg once monthly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 950 mg once monthly. In some embodiments, a crystalline form of Compound 1 provided herein is administered orally in a single dose of about 1000 mg once monthly.

[0487] The frequency of dosage of the crystalline form of Compound 1 of the present disclosure will be determined by the needs of the individual patient and can be, for example, once per day, once per week, once per month, once per every two months, once per every three months, or once per every six months. Administration of the crystalline form of Compound 1 continues for as long as necessary to treat the herpesvirus infection, including an HSV-1 and an HSV-2 infection, or any other indication described herein. For example, a crystalline form of Compound 1 can be administered to a human suffering from a herpesvirus infection, including an HSV-1 and an HSV- 2 infection, for the duration of the human’s life.

[0488] Administration can be intermittent, with a period of several or more days during which a patient receives a daily dose of the crystalline form of Compound 1 of the present disclosure followed by a period of several or more days during which a patient does not receive a daily dose of the crystalline form of Compound 1. For example, a patient can receive a dose of the crystalline form of Compound 1 every other day, or three times per week. Again by way of example, a patient can receive a dose of the crystalline form of Compound 1 each day for a period of from 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the crystalline form of Compound 1 followed by a subsequent period (e.g., from 1 to 14 days) during which the patient again receives a daily dose of the crystalline form of Compound 1. Alternating periods of administration of the crystalline form of Compound 1 followed by non-administration of the crystalline form of Compound 1 can be repeated as clinically required to treat the patient.

[0489] The crystalline forms of Compound 1 of the present disclosure or the pharmaceutical compositions of the present disclosure may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the crystalline forms of Compound 1 may be continued for a number of days; for example, commonly treatmentwould continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known for herpesvirus infections, including an HSV-1 and an HSV-2 infection. In some embodiments, treatment cycles are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous.

[0490] The effective dosage of active ingredient employed may vary depending on the particular crystalline form of Compound 1 employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.VII. COMBINATION THERAPY

[0491] The crystalline forms of Compound 1 provided herein or the pharmaceutical compositions of the present invention may be administered alone as a sole therapy, or can be administered in addition with one or more other substances and or treatments. Such conjoint treatment may be achieved by way of simultaneous, sequential or separate administration of the individual components of the treatment.

[0492] In some embodiments, a crystalline form of Compound 1, or a pharmaceutical composition provided herein, is administered in combination with one or more additional therapeutic agents to treat or prevent a disease or condition disclosed herein. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.

[0493] In some embodiments, the pharmaceutical compositions provided herein have a crystalline form of Compound 1 and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.

[0494] Also contemplated herein are methods that include administering a second active agent. For example, in addition to being infected with HSV, a subject or patient can further have HSV infection-related co-morbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected with HSV. Contemplated herein are also disclosed pharmaceutical compositions in combination with at least one other agent that has previously been shown to treat these HSV-infection-related conditions. Such conjoint treatment may be achieved independently (by way of simultaneous, sequential or separate administration of the individual components of the treatment) and / or via pharmaceutical compositions of the present invention that include a second active agent.

[0495] Therefore, provided herein is a method for treating or preventing HSV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1, and co-administering to the subject a therapeutically effective amount of an additional therapeutic agent. Suitably, the crystalline form of Compound 1 is Compound 1 Form I. Suitably, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0496] Also, provided herein is a method for treating or preventing HSV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient and co-administering to the subject a therapeutically effective amount of an additional therapeutic agent. Suitably, the crystalline form of Compound 1 is Compound 1 Form I. Suitably, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0497] In some embodiments, the one or more additional therapeutic agents include, e.g., DNA polymerase inhibitors such as, brincidofovir; Protein Jumonji inhibitors such as, ML-324, dimethyloxaloylglycine; Interferon alpha 2 ligand modulators such as, interferon alfa-2b, Alpharekin®, recombinant human interferon alfa-2b follow-on biologic, Herpferon®, Anterferon®; Nicotinic acetylcholine receptor antagonists such as, RPI-MN; Virus specific T cell therapies such as off-the-shelf single-virus specific T-cell (VST) therapy, ALVR-108, multi-virus- specific T cells TH; Other drugs for the treatment of Herpesvirus infection such as, BOR- 15001L7, lidocaine, Bryostatin-23 ; or any combination thereof.

[0498] In some embodiments, the one or more additional therapeutic agents include, e g., antiHerpesvirus envelope glycoprotein D antibodies such as m27f; Progesterone receptor agonists such as, levonorgestrel; or HIV-1 reverse transcriptase inhibitors such as, tenofovir; or any combination thereof.

[0499] In some embodiments, the one or more additional therapeutic agents include, e.g., Endonuclease modulators such as, meganucleases; Interferon alpha ligand / Interferon gamma receptor antagonists such as, Anaferon®, or any combination thereof.

[0500] In some embodiments, the one or more additional therapeutic agents include, e.g., CCR5 chemokine modulators; DNA polymerase inhibitors; DNA primase inhibitors; Fatty acid synthase inhibitors; Glucocorticoid receptor agonists; Helicase inhibitors; Herpesvirus envelope glycoprotein D inhibitors; Hsp 90 inhibitors; Human cytomegalovirus glycoprotein inhibitors; Hyaluronidase inhibitors; Interferon alpha 1 ligands; Interferon alpha 2 ligands; Interferon beta ligands; T-cell surface glycoprotein CD8 stimulators; or Cyclin dependent kinase inhibitors, or any combination thereof.

[0501] In some embodiments, the one or more additional therapeutic agents include, e.g., DNA primase-helicase inhibitors such as, amenamevir, pritelivir, IM-250; DNA polymerase inhibitors such as famciclovir, penciclovir, valaciclovir, acyclovir, foscamet sodium; CCR5 chemokine modulators / Human cytomegalovirus glycoprotein inhibitors such as, MB-66; Hsp 90 inhibitors such as, BJ-B11; Glucocorticoid receptor agonists such as, hydrocortisone; Interferon alpha 1 ligand modulators such as, interferon alpha lb, recombinant human interferon alpha lb; Interferon alpha 2 ligand modulators such as, recombinant human interferon alpha-2b, KW-045; Interferon beta ligand modulators such as, interferon beta-la (RebiSmart™); anti-HSV envelope glycoprotein D antibodies, such as UB-621; T-cell surface glycoprotein CD8 stimulators such as, immunogenic peptides, Fatty acid synthase inhibitors such as, TVB-2640; anti-herpes simplex virus monoclonal antibodies such as, HDIT-101; or other drugs for the treatment of Herpes simplex virus infection such as, idoxuridine, BTL-TML-HSV, docosanol, MAR-8644, MAR- 8658, NV-HHV-101, PRL-01, HN-0037; or any combination thereof.

[0502] In some embodiments, the one or more additional therapeutic agents include, e.g., Hyaluronidase inhibitors such as, astodrimer (SPL-7013); Live-attenuated HSV vaccines such as, RVx-101 HSV-1; Live-attenuated HSV vaccine with deletions in UL20 and UL53 such as, VC2; Live-attenuated HSV vaccine mutated in R2 coding region of UL37 such as, R2; or HSV-2 subunit trivalent vaccine (containing gC2, gD2, gE2) such as, HSV-2 Trivalent Vaccine; or any combination thereof.

[0503] In some embodiments, the one or more additional therapeutic agents include, e.g., live attenuated recombinant vaccines such as, AuroVax; HSV-2 replication-defective vaccine with UL5 and UL29 deleted such as, HSV-529; mRNA vaccine targeted against HSV-2 disease such as, mRNA-1608; or any combination thereof.

[0504] In some embodiments, the one or more additional therapeutic agents include, e.g., CD4 agonists; CD89 agonists; Duffy antigen chemokine receptor modulators; Herpesvirus envelope glycoprotein D inhibitors; HIV gpl20 protein inhibitors; HIV gpl60 protein inhibitors; HIV gp41 protein inhibitors; Immunoglobulin G agonists; Nicotinic acetylcholine receptor antagonists; TAT protein modulators; T-cell surface glycoprotein CD8 stimulators; or TLR-4 agonist; or any combination thereof.

[0505] In some embodiments, the one or more additional therapeutic agents include, e.g., Nicotinic acetylcholine receptor antagonists such as, RPI-78M; anti-herpes simplex virus monoclonal antibodies such as, HDIT-101; anti -herpesvirus envelope glycoprotein D antibodies such as, UB-621; TLR-4 agonists such as, IDC-G103 vaccines; Inactivated HSV-1 and HSV-2 vaccines such as, Vitaherpavac®; live Inactivated HSV-1 and HSV-2 vaccines such as, Theravax- HSV-2 vaccine; formalin-inactivated herpesvirus (FI-HSV2) vaccine; or RBT-26 T-cell-based subunit vaccine; DNA vaccines such as, pDNA / rVSV vector vaccine; or other drugs for the treatment of HSV-2 such as, EBT-105, Alloferon™; or any combination thereof.

[0506] In some embodiments, the one or more additional therapeutic agents include, e.g., HIV gpl20 / gpl60 / gp41 protein inhibitors such as, griffithsin; Hyaluronidase inhibitors such as, astodrimer (SPL-7013); CD4 agonist / T-cell surface glycoprotein CD8 vaccine such as GENO-2; TAT protein modulators such as HerpesVaxTat® vaccines; CD89 agonist / Duffy antigen chemokine receptor modulator / Immunoglobulin G agonist such as, glycoprotein D + liposome encapsulated glycoprotein D boost vaccine; or vaccines such as, Profavax-HSV-2 vaccine; HSV- 2 mRNA vaccine; glycoprotein D DNA vaccine; or any combination thereof.

[0507] In some embodiments, the one or more additional therapeutic agents include, e.g., DNA vaccines such as, HSV-2 vaccine Admedus; RNA vaccines such as, GSK-4108771A; Live attenuated vims vaccines such as, EXD-12; live-attenuated delta-gD2 based viral vaccines; Vaccines such as, NE-gD2 intranasal nanoemulsion NE-based adjuvanted HSV-2 vaccine; or other drugs for the treatment of HSV-2 such as, EBT-105, Alloferon™; or any combination thereof.

[0508] In some embodiments, the one or more additional therapeutic agents include, e.g., antimicrobial peptoids; CD4 modulators; CRISPR associated endonuclease Cas9 modulators; Cyclin-dependent kinase-9 inhibitors; DNA polymerase inhibitors; Nicotinic acetylcholine receptor antagonists; TAT protein modulators; Thymidine kinase inhibitors; or viral envelope protein inhibitors; or any combination thereof.

[0509] In some embodiments, the one or more additional therapeutic agents include, e.g., DNA polymerase inhibitors / Thymidine kinase inhibitors such as acyclovir; CRISPR associated endonuclease Cas9 modulators such as, EBT-104; Nicotinic acetylcholine receptor antagonists such as, RPI-78M; Cyclin-dependent kinase-9 inhibitors such as, FIT-039; Other drugs for HSV- 1 treatment such as, ZEP-3Na, MXB-009; CD4 modulator peptide vaccine such as, CEL-1000; Vaccines such as, Inactivated HSV-1 and HSV-2 vaccines such as, Vitaherpavac® (anti-herpes vaccine); live Inactivated HSV-1 and HSV-2 vaccines such as, Theravax-HSV-1 vaccine; or Viral envelope protein inhibitors such as, MXB-005; or a combination thereof.

[0510] In some embodiments, the one or more additional therapeutic agents include, e.g., TAT protein modulators such as HerpesVaxTat® vaccine; or Vaccines such as, Profavax-HSV-1 vaccine; or a combination thereof.

[0511] In some embodiments, the one or more additional therapeutic agents include, e g., Live attenuated virus vaccines such as, EXD-12; or live-attenuated delta-gD2 based viral vaccines; or a combination thereof.

[0512] In some embodiments, the one or more additional therapeutic agents include, e.g., DNA polymerase inhibitors; Herpesvirus envelope glycoprotein D inhibitors; or Interferon alpha 2 ligand; or a combination thereof.

[0513] In some embodiments, the one or more additional therapeutic agents include, e.g., DNA polymerase inhibitors such as, famciclovir, penciclovir; Interferon alpha 2 ligand modulators such as, Yallaferon®; anti -Herpesvirus envelope glycoprotein D antibodies such as, UB-621; or other drugs for treatment of genital herpes such as, interferon gamma, Alloferon™, ZEP-3Na; or a combination thereof.

[0514] In some embodiments, the one or more additional therapeutic agents include, e.g., Vaccines such as, NE-gD2 intranasal nanoemulsion NE-based adjuvanted vaccine; or other drugs for the treatment and prevention of genital herpes such as, SQX-77, anti-STI antibodies; or a combination thereof.

[0515] In some embodiments, the one or more additional therapeutic agents include, e.g., SAPNs (self-assembling protein nanoparticles) based herpes vaccine.

[0516] In some embodiments, the one or more additional therapeutic agents include, e g., CMV 65kDa lower matrix phosphoprotein modulators; DNA polymerase inhibitors; G protein coupled receptor homolog US28 antagonists; Herpesvirus envelope glycoprotein B stimulators; HLA class I antigen A-l 1 alpha modulators; HLA class I antigen A-2 alpha modulators; HLA class I antigenA-24 alpha modulators; Human cytomegalovirus glycoprotein B inhibitors; Human cytomegalovirus glycoprotein B modulators; Human cytomegalovirus glycoprotein H modulators; Human cytomegalovirus glycoprotein inhibitors; Large terminase protein inhibitors; Ribonuclease stimulators; Serine threonine protein kinase UL97 modulators; Syntaxin-5 inhibitors; Transferase inhibitors; or Viral ribonucleotide reductase inhibitors; or a combination thereof.

[0517] In some embodiments, the one or more additional therapeutic agents include, e.g., DNA polymerase inhibitors such as, ganciclovir, fomivirsen, fomivirsen sodium, valganciclovir; DNA polymerase inhibitor / Serine threonine protein kinase UL97 modulators such as, filociclovir; G protein coupled receptor homolog US28 antagonists such as, SYN-002; Large terminase protein inhibitors such as, AIC-387, AIC-476; Serine threonine protein kinase UL97 inhibitors such as, maribavir; Viral ribonucleotide reductase inhibitors such as, didox; Ribonuclease stimulators such as, ranpirnase; HLA class I antigen A-l l alpha modulators / HLA class I antigen A-2 alpha modulators / HLA class I antigen A-24 alpha modulators such as, allogenic anti-CMV-TCR-T-cell therapy, YT-CMV-22, YT-CMV-27 and YT-CMV-45; Human cytomegalovirus glycoprotein B inhibitors such as, CMV-345; Other drugs for treatment of CMV such as, USC-505, USC-596, CMV pp65 and ppM83 derived peptides, artemifone (BAY-44-9585), PG-36, CMX-16669, HN- 0141, ALVR-105, NPP-669, CMV pH4 human immunoglobulin, Cytovir™, anti-viral cytotoxic T-cell therapy, CMV TCR-transduced T-cells, adimlecleucel; or Polyclonal antibodies such as, Cytogam®; or a combination thereof.

[0518] In some embodiments, the one or more additional therapeutic agents include, e.g., Syntaxin-5 inhibitors such as, Retro-94; Large terminase protein inhibitors such as, letermovir; DNA polymerase inhibitors such as, valganciclovir; anti -CMV antibodies such as, BT-084 (Cytotect® CP); Human cytomegalovirus glycoprotein B and glycoprotein H modulator vaccines such as mRNA-1647; CMV 65kDa lower matrix phosphoprotein vaccines such as, IRB-12022; or Vaccines such as, mRNA-based vaccine; BD-03 plasmid DNA vaccine; V-212 heat-treated varicella zoster virus vaccine; protein subunit vaccines such as, VBL1501A; CMV-MVA pentamer vaccine (RhUL128C-MVA); CMV-MVA Triplex vaccine; VLP based vaccine SPYVLP-102; or any combination thereof.

[0519] In some embodiments, the one or more additional therapeutic agents include, e.g., Human cytomegalovirus glycoprotein inhibitors such as, CMV-IVIG; Additional drugs for the treatment or prevention of CMV such as, artemisinin derivatives, NPC-21; Herpesvirus envelope glycoprotein B stimulator vaccine such as, HB-101; CMV 65kDa lower matrix phosphoproteinmodulator vaccine such as, AVX-601; Vaccines such as, CMV vaccine; CMVpp65 peptide vaccine; V-160; or Multivirus-specific cytotoxic T-cell therapy; or any combination thereof.

[0520] In some embodiments, the one or more additional therapeutic agents include, e.g., DNA polymerase inhibitors such as, ganciclovir, fomivirsen, cidofovir, valganciclovir, or foscarnet sodium, or any combination thereof

[0521] In some embodiments, the one or more additional therapeutic agents include, e.g., DNA polymerase inhibitors; Helicase inhibitors; Immunoglobulin agonists; Interferon alpha 2 ligands; Interferon alpha ligand modulators; Interferon beta ligands; or TLR-4 agonists; or any combination thereof.

[0522] In some embodiments, the one or more additional therapeutic agents include, e.g., DNA polymerase inhibitors such as, penci cl ovir, famciclovir, valaciclovir, acyclovir, USC-373; DNA primase inhibitor-helicase inhibitor such as, amenamevir; Interferon alpha 2 ligand modulators such as, interferon alfa-2b, Yallaferon®, pegylated interferon alpha-lb, INTEFEN®, interferon alpha-2a, Anterferon®; Interferon beta ligand modulators such as, Rebi Smart™; Immunoglobulin agonists such as, Varicellon®, Zoster Immunoglobulin-VF, Vaccines such as, varicella vaccine (live attenuated); MMRV vaccine; herpes zoster vaccine; zoster recombinant adjuvanted vaccine; or Drugs for treatment of Varicella zoster virus infection such as, HerpeCide™; or any combination thereof.

[0523] In some embodiments, the one or more additional therapeutic agents include, e.g., Vaccines such as, ProQuad®; Priorix-Tetra® (MeMuRu-OKA); protein subunit TLR-4 agonist vaccines such as, CRV-101; VZV ORF29 mutant-based vaccine; varicella vaccine (live attenuated); chickenpox vaccine Sinovac; Varilrix® vaccine (VZV-OKA-strain); attenuated recombinant subunit vaccine containing gE such as, GSK-137173A; protein subunit vaccines such as, SP-0204; pneumococcal conjugate vaccines such as, SP-0202; triple live-attenuated vaccines such as, M-M-RvaxPRO®; adenovirus-vectored vaccine such as, VTP-400; recombinant varicella-zoster virus vaccine; recombinant herpes zoster vaccine; inactivated varicella-zoster vaccine; Live attenuated viral vaccines such as, NBP-608, Suduvax® II, VZV-7D; or antiVaricella Zoster virus antibodies such as, VariZIG®; or any combination thereof.

[0524] In some embodiments, the one or more additional therapeutic agents include, e.g., drugs for treatment or prevention of Varicella zoster virus infection such as, OV-02; or vaccines such as, EG-HZ; or any combination thereof.

[0525] In some embodiments, the one or more additional therapeutic agents include, e.g., interferon alpha 2 ligand; DNA polymerase inhibitors; transferase inhibitors; CRISPR associatedendonuclease Cas9 modulators; LAT gene inhibitor; or gene inhibitors; or any combination thereof.

[0526] In some embodiments, the one or more additional therapeutic agents include, e.g., DNA polymerase inhibitors such as, acyclovir, ganciclovir; Interferon alpha 2 ligand modulators such as, interferon alfa-2b, Anterferon®; CRISPR associated endonuclease Cas9 modulator / gene inhibitors such as, HSV-1 -targeted CRISPR / Cas9 gene therapy; LAT gene inhibitors such as, IFNy / LAT siRNA gene therapy (rdHSVl vector, herpes simplex keratitis); additional drugs for the treatment of herpetic keratitis such as, EKC-Cide™; or any combination thereof.

[0527] In some embodiments, the one or more additional therapeutic agents include, e.g., Basigin inhibitors; Envelope glycoprotein GP350 modulators; Epstein-Barr nuclear antigen 1 inhibitors; Epstein-Barr nuclear antigen 1 stimulators; HLA class I antigen A-l l alpha modulators; HLA class I antigen A-2 alpha modulators; HLA class I antigen A-24 alpha modulators; Human cytomegalovirus glycoprotein B modulators; Human cytomegalovirus glycoprotein H modulators; Human cytomegalovirus glycoprotein L modulators; Latent membrane protein 1 modulators; Latent membrane protein 2 stimulators; NKG2D ligand modulators; or Secreted protein BARF1 modulators; or any combination thereof.

[0528] In some embodiments, the one or more additional therapeutic agents include, e.g., NKG2D ligand modulators such as, pamidronic acid; Epstein-Barr nuclear antigen 1 inhibitors such as, VK-2019, anti -Epstein-Barr virus (EBV) peptides; HLA class I antigen A-l l alpha / HLA class I antigen A-2 alpha / HLA class I antigen A-24 alpha modulators such as, allogenic anti-EBV- TCR-T-cells, YT-EBV-44; Additional drugs for EBV treatment such as, ALVR-105, anti-viral cytotoxic T-cell therapy; Epstein-Barr nuclear antigen / Latent membrane protein 1 and protein 2 / Secreted protein BARF1 modulators such as, baltaleucel-T (CMD-003); or mRNA vaccines such as, mRNA-1195; or any combination thereof.

[0529] In some embodiments, the one or more additional therapeutic agents include, e.g., basigin modulators such as, EBV gH / gL / gp42 vaccine; or basigin modulator / Envelope glycoprotein GP350 modulator / Human cytomegalovirus glycoprotein B modulator / Human cytomegalovirus glycoprotein H modulator / Human cytomegalovirus glycoprotein L modulator such as, mRNA- 1189 vaccine; vaccines such as, EBV gH / gL vaccine; P-989; mRNA vaccine; or EBV cancer vaccine (mRNA, LPP nanoparticle); or any combination thereof.

[0530] In some embodiments, the one or more additional therapeutic agents include, e.g., Epstein-Barr nuclear antigen 1 / Latent membrane protein 2 stimulators such as MVA-basedvaccines; Multivirus-specific cytotoxic T-cell therapy; or vaccines such as, EBV-VLP vaccine; or any combination thereof.

[0531] In some embodiments, the one or more additional therapeutic agents include, e.g., DNA polymerase inhibitors.

[0532] In some embodiments, the one or more additional therapeutic agents include, e.g., DNA polymerase inhibitors such as, brincidofovir; Drugs for herpesvirus type 6 treatment such as, ALVR-105; Multivirus-specific cytotoxic T-cell therapy; or HHV-6B glycoprotein complex gH / gL / gQl / gQ2 subunit vaccine; or any combination thereof.

[0533] In one embodiment, the one or more additional therapeutic agent is selected from one or more of the following agents: i. nucleoside polymerase inhibitors, such as acyclovir, valacyclovir, famciclovir, penci cl ovir and ganciclovir; ii. pyrophosphate polymerase inhibitors, such as foscamet; iii. saturated aliphatic alcohols, such as docosanol; iv. agents such as idoxuridine, trifluridine and vidarabine; v. a corticosteroid; and vi. other helicase-primase inhibitors, such as amenamevir.

[0534] In some cases, a crystalline form of Compound 1 provided herein may be administered in a first amount as part of a combination therapy in conjunction with one or more antivirals, including nucleoside analogues such as acyclovir, foscarnet, ganciclovir or penciclovir or the respective prodrugs valacyclovir or famciclovir, which antiviral agents may be administered in a second amount. Suitably, the crystalline form of Compound 1 is Compound 1 Form I. Suitably, the crystalline form of Compound 1 is Compound 1 mesylate Form I.

[0535] In some embodiments, the first and second amounts together comprise a pharmaceutically effective amount. The first amount, the second amount, or both may be the same, more, or less than effective amounts of each compound administered as monotherapies. Therapeutically effective amounts of a disclosed compound and antiviral may be co-administered to the subject, i.e., administered to the subject simultaneously or separately, in any given order and by the same or different routes of administration. In some instances, it may be advantageous to initiate administration of a crystalline form of Compound 1 first, for example one or more days or weeks prior to initiation of administration of the antiviral. Moreover, additional drugs may be given in conjunction with the above combination therapy.

[0536] Suitably, in the combination therapies described hereinabove, the crystalline form of Compound 1 is Compound 1 Form I. Suitably, in the combination therapies described hereinabove, the crystalline form of Compound 1 is Compound 1 mesylate Form I.VIII. EXAMPLES

[0537] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that these examples are exemplary and not exhaustive. Many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

[0538] Abbreviations as used herein have respective meanings as follows:

[0539] The solid forms (polymorphs, solvates and hydrates) of Compound 1 were characterized by a variety of the following methods.

[0540] XRPD patterns were collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu Ka radiation produced using a long, fine-focus source and a nickel filter. The diffractometer was configured using the symmetric Bragg-Brentano geometry. Prior to the analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A specimen of the sample was prepared as a thin, circular layer centered on a silicon zero-background substrate. Antiscatter slits (SS) were used to minimize the background generated by air. Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the sample and Data Collector software v. 2.2b.

[0541] Differential Scanning Calorimetry (DSC) data were collected using a TA Instruments 2920 and Q2000 differential scanning calorimeter. Temperature calibration was performed using NIST-traceable indium metal. The sample was placed into a T zero aluminum DSC pan, covered with a lid and crimped. The weight was then accurately recorded. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The sample was heated from 20°C to 300°C at 10°C / minute.

[0542] Thermogravimetric Analysis (TGA) data were collected using a TA Instruments Discovery thermogravimetric analyzer. Temperature calibration was performed using nickel and Alumel™ Each sample was placed in an aluminum pan and inserted into the TG furnace. The furnace was heated under a nitrogen purge. The sample was heated from ambient to 350 °C at 10°C / minute.

[0543] Moisture sorption / desorption data were collected on a Model Q5000 SA (TA Instruments). NaCl and PVP were used as calibration standards. Samples were not dried prior to analysis. Sorption and desorption data were collected over a range from 5% to 95% RH at 10% RH increments under a nitrogen purge. The equilibrium criterion used for analysis was less than 0.0100% weight change in 5 minutes with a maximum equilibration time of 3 hours. Weight percentages reported in the data section are relative to the total sample mass introduced prior to equilibration at 5% RH as measured on the instrument.A. Compound ExamplesExample 1. Preparation of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3-dihvdro-lH- indene-2-carbonyl)indoline-6-sulfonamide (Compound 1)

[0544] Compound 1 was prepared according to the procedures described in Example 35 of PCT Application No. PCT / US2023 / 022679, publication reference of WO 2023 / 225162 ALPreparation of Intermediate 21:.

[0545] Preparation of Intermediate 21.1 : 5 -fluoro-2 -methylindoline (40 g, 268 mmol, 1 eq) was taken up in acetic acid (200 mL, 5V). NaBILCN (50 g, 815 mmol, 3 eq) was added portion-wise while maintaining the temperature below 10° C. The resulting solution was warmed to RT and stirred for 3 h, at which time the reaction was diluted with ice-cold water (500 mL). The reaction was then extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (750 mL), dried over NaiSO4 and concentrated in vacuo. The crude Intermediate 21.1 was isolated as a thick yellow oil and used in the next step without further purification. LC / MS: 151.2 [M+H],

[0546] Preparation of Intermediate 21.2: To a stirred solution of Intermediate 21.1 (35 g, 86.6 mmol) in DCM (300 mL) was added tri ethylamine (35 mL, 1 vol) followed by acetyl chloride (35mL, 1 vol) at 0 °C. The reaction mixture was stirred at RT for 2 h. The residue was quenched with cold water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (750 mL), dried over NaiSCL and concentrated in vacuo. The crude residuewas purified by column chromatography (100-200 silica gel, eluted 8% EtOAc-Hexane) to afford Intermediate 21.2. LC / MS: 193.2 [M+H],

[0547] Preparation of Intermediate 21.3: To a stirred solution of Intermediate 21.2 (35 g, 0.011 mol) in chlorosulfonic acid (250 mL, 10 V) at 0 °C under nitrogen and the reaction mixture was stirred at 50 °C for 3h. Upon completion of the reaction, the mixture was diluted with ice-cold water. The precipitate was filtered, taken up in dichloromethane (50 mL), and added to a solution of concentrated ammonium hydroxide (20 mL). After vigorous stirring for 15 minutes at RT, the solvent was removed under pressure and the resulting solid was filtered and rinsed with water to afford Intermediate 21.3. LC / MS: 272.3 [M+H],

[0548] Preparation of Intermediates (R)-21 and (5 -21: A racemic mixture of Intermediate 21.3 (30 g, 110 mmol, 1 equiv) in 500 mL of 2N sodium hydroxide was heated at 100°C for 3 hours. The reaction was cooled to RT and the pH was adjusted to 7 with acetic acid. The precipitate was filtered, washed with water, and dried under vacuum. The resulting de-acetylated racemic mixture was then subjected to chiral SFC purification using a ChiralPak IG 240 x 4.6 mm column with a mobile phase consisting of 70:20:10 hexane: methanol: MTBE. Intermediate fR ~21 was collected as the second eluent (retention time 13.1 min). LC / MS: 230.1 [M+H], Intermediate (S)- 21 was collected as the first eluent (retention time 10.5 min). LC / MS: 230.1 [M+H],Preparation of Intermediate 19:Preparation of Intermediate 2: 5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carboxylic acid

[0549] Preparation of Intermediate 2.1: To a stirred suspension of 60% NaH (22.72 g, 2 equiv) in THF (1000 mL) at 0 °C was added diethyl carbonate (86 mL, 1.5 equiv). To this was added 5- bromo-indan-l-one (100 g, 473.1 mmol) portion wise at this temperature. The reaction mixture continued to stir at this temperature until gas evolution subsided. The reaction mixture was slowly heated to 50 °C and maintained stirring for 2h. Progress of the reaction was monitored by TLC, and after consumption of starting material, the reaction mixture was allowed to cool to RT. Thereaction was diluted with EtOAc (10V). To this was added 3N aq HC1 dropwise. Both layers were separated. Aqueous layer was extracted with EtOAc (2 x 5V). The combined organic layer was washed with brine solution (5 V), dried (Na2SO4) and evaporated to obtain the crude, which was purified by column chromatography on silica gel to afford Intermediate 2.1. LCMS: 283.0 [M+H],

[0550] Preparation of Intermediate 2.2: To a solution of Intermediate 2.1 (56 g, 197.9 mmol) in TFA (280 mL) at 0 °C was added triethyl silane (224 mL) dropwise and the reaction mixture was stirred at rt for 24 h. Progress of the reaction was monitored by TLC. After consumption of starting materials, the reaction mixture was evaporated to dryness under reduced pressure to obtain the crude. The crude was purified by column chromatography on silica gel to obtain Intermediate 2.2. LC / MS: 269.0 [M+H],

[0551] Preparation of Intermediate 2.3: A stirred solution of Intermediate 2.2 (40 g, 148.7 mmol) and 2-tributylstannylpyridine (57.5 g, 1.05 equiv) in 1,4 dioxane (400 mL) was degassed for 10 min using argon, at which time Pd(PPhs)4 (8.6 g, 5 mol%) was added and again degassed for another 10 min. The reaction mixture was heated to 90 °C for 16h. The reaction mixture was filtered through Celite pad and the Celite pad was washed with ethyl acetate twice. The combined filtrate was evaporated to dryness to obtain crude. The crude was purified by column chromatography on silica gel to afford Intermediate 2.3. LC / MS: 268.1 [M+H],

[0552] Preparation of Intermediate 2: To a stirred solution of Intermediate 2.3 (35 g, 131.1 mmol) in methanol (350 mL) at 0 °C was added 2N aq NaOH solution (140 mL, 2.2 equiv) and the reaction mixture was stirred at rt for 4h After completion of the reaction, the reaction mixture was concentrated under reduced pressure to 100 mL. The residue was diluted with water (10V) and the aqueous layer washed with ethyl acetate (2 x 2V). The aqueous phase was neutralized with 2N aq HC1 solution and extracted with 10% Methanol / DCM (3 x 5V). The organic layer was dried over sodium sulfate and concentrated to afford the crude. Then the crude was taken with 10% isopropanol / toluene (10V) solution and treated with activated carbon. The solvent was then removed under reduced pressure. The residue was taken in 30% toluene / hexane, stirred for 30 min and filtered, and then dried under vacuum. This process was repeated two additional times to afford Intermediate 2. LC / MS: 238.1 [M-H],

[0553] Preparation of Intermediate 19: (R)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2- carboxylic acid

[0554] Intermediate 19 was obtained as the first eluent of SFC purification of Intermediate 2 using a Chiralpak AD-H column with 20% methanol as co-solvent. LC / MS: 238.1 [M-H].Preparation of Compound 1

[0555] Intermediate (7? -21 was taken up in THF (10 V) and dimethylformamide dimethyl acetal (1.2 equiv) was added at once. The solution was stirred at RT for 30 minutes and the solvent was then removed under reduced pressure to afford the crude residue Intermediate (7?)-21a (LC / MS: 286.1 [M+H]) which was used directly in the next step without further purification.

[0556] Intermediate (7?)-21a was taken up in acetonitrile (10 V). Intermediate 19 (1 equiv) was added, followed by TCFH (2 equiv). The suspension was placed in a RT water bath and N- methylimidazole (5 equiv) was added dropwise. The solution stirred at RT for 1 hour, at which time LC / MS analysis indicated complete conversion to Intermediate (7?)-21b (LC / MS: 507.2 [M+H]). Hydrazine hydrate (50 equiv) was then added at once and allowed to stir at RT for 30 minutes, after which time water was added (5 V). The resulting precipitate was filtered and dried under reduced pressure to afford Compound 1. ’H NMR (400 MHz, DMSO-d6) 6 8.69 (d, J = 4.9 Hz, 1H), 8.54 (d, J = 6.6 Hz, 1H), 8.10 - 7.84 (m, 4H), 7.58 (s, 2H), 7.51 - 7.24 (m, 3H), 4.90 (t, J = 7.5 Hz, 1H), 3.77 (p, J = 8.2 Hz, 1H), 3.46 (ddt, J = 34.0, 17.5, 8.7 Hz, 3H), 3.20 (ddd, J = 59.1, 16.3, 8.3 Hz, 2H), 2.80 (d, J = 16.9 Hz, 1H), 1.30 (d, J = 6.2 Hz, 3H). LC / MS: 452.1 [M+H],Example 2. Compound 1 Form I

[0557] (A,E)-A"-((5-fluoro-2-methylindolin-6-yl)sulfonyl)-A,A-dimethylformimidamide(20.3 g, 71.1 mmol) and (A)-5-(pyridin-2-yl)-2,3-dihydro-lH-indene-2-carboxylic acid (17.0 g, 71.0 mmol) were dissolved in di chloromethane (170 mL). The mixture was cooled to 10 °C, and 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide in dichloromethane (50 wt%, 85.3 mL, 142 mmol) was added slowly to the mixture. The mixture was warmed to 20 °C and stirred for 1 h, and then triethylamine (80.0 mL, 574 mmol) was added slowly to the mixture. The mixture was left stirring at 20 °C. After complete consumption of (A)-5-(pyridin-2-yl)-2,3- dihydro-lH-indene-2-carboxylic acid, the mixture was cooled to 10 °C and water (85 mL) was slowly added to the mixture. The stirring was stopped, and the resulting layers were separated. The organic layer was concentrated by distillation at reduced pressure to a minimum volume, then acetonitrile (170 mL) was charged; this was repeated one additional time. To the resulting mixture was slowly added aqueous ammonium hydroxide (23 wt%, 351 mL, 4.26 mol). Following complete consumption of intermediate (E)-A-(((A)-5-fluoro-2-methyl-l-((A)-5-(pyridin-2-yl)- 2, 3-dihydro-l H-indene-2 -carbonyl )indolin-6-yl)sulfonyl)-A,JV-dimethylformimidamide, a slurry was formed. The slurry was filtered, and the solids were washed twice with water (2 x 170 mL). The solids were dried to constant weight (29.1 g, 91% yield). XRPD analysis of the solids showed that it was crystalline (designated as Compound 1 Form I).

[0558] A representative XRPD pattern of Compound 1 Form I is shown in FIG. 1. Peak positions present in the XRPD diffractogram acquired from Compound 1 Form I are presented in Table 1.Table 1 Peak list of Compound 1 Form I

[0559] The DSC thermogram (FIG. 2) indicates a melting onset at about 230 °C.

[0560] The TGA thermogram shows a weight loss of about 0.4% from 40 to 200 °C, indicating an unsolvated form (FIG. 3).

[0561] The DVS analysis is shown in FIG. 4 and indicates that the form is non-hygroscopic with about 0.1% water uptake from 0 to 90% RH at 25 °C.

[0562] Single crystals of Compound 1 Form I were prepared by dissolving about 40 mg of Compound 1 in 1 mL of acetone at about 50 °C and then held for 3 days. A slurry formed and the sample was subjected to SCXRD analysis at about 100 K. The result (see Table 2) was consistent with Compound 1 Form I with the following parameters.Table 2 Crystal Lattice Parameters of Compound 1 Form IExample 3. Compound 1 Form II

[0563] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, about 100 mg of amorphous Compound 1 free base was stirred with about 1 m of toluene at about 22 °C. After stirring for 3 days, XRPD analysis of the wet solids showed a new pattern (designated as Compound 1 Form II). After drying at 50 °C under vacuum, its XRPD pattern was unchanged.

[0564] A representative XRPD pattern for Form II is shown in FIG. 5. Peak positions present in the XRPD diffractogram acquired from Compound 1 Form II are presented in Table 3.Table 3 Peak list of Compound 1 Form II

[0565] The DSC thermogram (FIG. 6) of Compound 1 Form II indicates a melting onset at about 223 °C, followed by the melting onset of at about 245 °C associated with Compound 1 Form IV.

[0566] The TGA thermogram of Compound 1 Form II indicates a weight loss of about 0.6% from 25 to 150 °C (FIG. 7).

[0567] The DVS analysis is shown in FIG. 8 and indicates that the form is slightly hygroscopic with around 0.6% water uptake from 0 to 90% RH at 25 °C.Example 4. Compound 1 Form III

[0568] Compound 1 Form III was obtained after drying Compound 1 monohydrate at 50 °C under vacuum.

[0569] A representative XRPD pattern of Compound 1 Form III is shown in FIG. 9. Peak positions present in the XRPD diffractogram acquired from Compound 1 Form III are presented in Table 4.Table 4 Peak list of Compound 1 Form III

[0570] The DSC thermogram (FIG. 10) indicates a small endothermic transition below 50 °C, and an exothermic event with onset at about 206 °C. The final endothermic event at about 246 °C onset temperature.

[0571] The TGA thermogram shows substantial weight loss of about 3.5% from 25 to 60 °C, caused by the hygroscopic nature of Form III (FIG. 11).

[0572] The DVS analysis is shown in FIG. 12 and indicates that the form is hygroscopic with about 4.6% water uptake from 0 to 90% RH at 25 °C.Example 5. Compound 1 Form IV

[0573] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, about 150 mg of Compound 1 mesylate base Form I was stirred with about 1.5 mL of water at about 22 °C. The sample first became a gel-like mesophase in an hour or so and then a mobile slurry after stirring overnight. It was filtered and XRPD analysis of the wet solids showed a new pattern (FIG. 13). After drying at about 50 °C under vacuum, its XRPD pattern was unchanged. Proton NMR analysis showed the dried solid contained no detectable methanesulfonic acid content. This new form is designated as Compound 1 Form IV.

[0574] A representative XRPD pattern for Form IV is shown in FIG. 13. Peak positions present in the XRPD diffractogram acquired from Compound 1 Form IV are presented in Table 5.Table 5 Peak list of Compound 1 Form IV

[0575] The DSC thermogram (FIG. 14) indicates an endotherm with onset at about 242 °C.

[0576] The TGA thermogram (FIG. 15) shows weight loss of about 0.7% from 25 to 75 °C.

[0577] The DVS analysis is shown in FIG. 16 and indicates that the form is slightly hygroscopic with about 0.8% water uptake from 0 to 90% RH at 25 °C.

[0578] Single crystals of Compound 1 Form IV were prepared by holding about 50 mg of Compound 1 HC1 salt Form I in 0.5 mL of a mixture of EtOH and water (1:1 by volume) at 45 °C for a few hours. A slurry formed and the sample was subjected to SCXRD analysis at about 299 K. The result was consistent with Compound 1 Form IV when comparing the predicted powder diffraction data with experimental data, and there is no solvent in the crystal lattice. The crystal lattice parameters are shown in Table 6 below.Table 6 Crystal Lattice Parameters of Compound 1 Form TVExample 6. Compound 1 Form V

[0579] A sample of Compound 1 dihydrate was further dried at 50 °C under vacuum for 3 hours, and its XRPD pattern changed. The new form is designated as Compound 1 Form V.

[0580] A representative XRPD pattern of Compound 1 Form V is shown in FIG. 17. Peak positions present in the XRPD diffractogram acquired from Compound 1 Form V are presented in Table 7.Table 7 Peak list of Compound 1 Form V

[0581] The DSC thermogram (FIG. 18) was similar to that of Compound 1 Dihydrate.

[0582] The TGA thermogram (FIG. 19) shows a weight loss of about 2%.Example 7. Compound 1 Monohydrate

[0583] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, about 50 mg of Compound 1 mesylate base Form I was stirred with about 1 mL of water at about 22 °C. After two weeks, XRPD analysis of the wet solids showed a new pattern (FIG. 20, designated as Compound 1 monohydrate). Proton NMR analysis of the dried solid showed it had no detectable methanesulfonic acid content.

[0584] A representative XRPD pattern of Compound 1 monohydrate is shown in FIG. 20. Peak positions present in the XRPD diffractogram acquired from Compound 1 Monohydrate are presented in Table 8.Table 8 Peak list of Compound 1 Monohydrate

[0585] The DSC thermogram (FIG. 21) indicates an endothermic transition with onset temperature at about 33 °C attributed to a loss of water, and an exothermic event with onset at about 203 °C. The final endothermic event at about 246 °C onset temperature.

[0586] The TGA thermogram shows substantial weight loss of about 3.7% from 25 to 100 °C, indicating a monohydrate (theoretical monohydrate water content is 3.8%) (FIG. 22).Example 8. Compound 1 Dihydrate

[0587] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, about 120 mg of Compound 1 mesylate base Form I was stirred with about 3 mL of water at about 22 °C. The sample became a mobile slurry after a total of 4 hours. It was filtered and dried under vacuum at about 22 °C for about 16 h.

[0588] A representative XRPD pattern of Compound 1 dihydrate is shown in FIG. 23. Peak positions present in the XRPD diffractogram acquired from Compound 1 Dihydrate are presented in Table 9.Table 9 Peak list of Compound 1 Dihydrate

[0589] The DSC thermogram is provided in FIG. 24 and includes: an endothermic transition below 110 °C; an endothermic event with onset at about 137 °C; an exothermic event with onset at about 170 °C; and an endothermic event at about 247 °C onset temperature.

[0590] The TGA thermogram shows a weight loss of about 7.4%, indicating a dihydrate (theoretical water content for dihydrate is 7.4%) (FIG. 25).Example 9. Compound 1 MeTHF solvate

[0591] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, about 100 mg of Compound 1 Form I was stirred with about 1 mb of MeTHF at about 22 °C. After stirring for one day, XRPD analysis of the wet solids showed a new pattern (FIG. 26, designated as Compound 1 MeTHF solvate).

[0592] A representative XRPD pattern of Compound 1 MeTHF solvate is shown in FIG. 26.

[0593] The DSC thermogram (FIG. 27) of Compound 1 MeTHF solvate after drying at 50 °C under vacuum indicates an endothermic transition at about 82 °C, and at about 228 °C.

[0594] The TGA thermogram of Compound 1 MeTHF solvate (after drying at 50 °C under vacuum) shows a weight loss of about 12% from 25 to 106 °C, indicating solvent loss of MeTHF (FIG. 28).Example 10. Compound 1 MTBE solvate 1

[0595] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, about 50 mg of amorphous Compound 1 free base was stirred with about 1 mL of MTBE at about 22 °C. After stirring for 3 days, XRPD analysis of the wet solids showed a new pattern (FIG. 29, designated as Compound 1 MTBE solvate 1).

[0596] A representative XRPD pattern of Compound 1 MTBE solvate 1 is shown in FIG. 29.Example 11. Compound 1 MTBE solvate 2

[0597] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, about 50 mg of amorphous Compound 1 free base was stirred with about 1 mL of MTBE at about 22 °C. After stirring for 2 weeks, XRPD analysis of the wet solids showed a new pattern (FIG. 30, designated as Compound 1 MTBE solvate 2). After drying at 50 °C under vacuum, its XRPD pattern was unchanged.

[0598] A representative XRPD pattern of Compound 1 MTBE solvate 2 is shown in FIG. 30.

[0599] The DSC thermogram (FIG. 31) of Compound 1 MTBE solvate 2 after drying at 50 °C under vacuum indicates an endothermic transition at about 94 °C, and at 216 °C onset temperature, an exotherm at 225 °C, and final endotherm at about 243 °C.Example 12. Compound 1 2-BuOH solvate

[0600] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, about 50 mg of amorphous Compound 1 free base was stirred with about 1 mL of 2-BuOH at about 22 °C. After stirring for 3 days, XRPD analysis of the wet solids showed a new pattern (FIG. 33, designated as Compound 1 2-BuOH solvate).

[0601] A representative XRPD pattern of Compound 1 2-BuOH solvate is shown in FIG. 33.

[0602] The DSC thermogram (FIG. 34) of Compound 1 2-BuOH solvate after drying at 50 °C under vacuum indicates an endothermic transition at about 88 °C, followed by an exotherm at about 139 °C, and endotherm at about 243 °C.Example 13. Compound 1 t-BuOH solvate

[0603] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, about 50 mg of amorphous Compound 1 free base was stirred with about 1 mL of t-BuOH at about 22 °C. After stirring for 3 days, XRPD analysis of the wet solids showed a new pattern (FIG. 35, designated as Compound 1 t-BuOH solvate).

[0604] A representative XRPD pattern of Compound 1 t-BuOH solvate is shown in FIG. 35.Example 14. Compound 1 p-Dioxane solvate

[0605] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, about 100 mg of amorphous Compound 1 free base was stirred with about 0.5 mL of p-dioxane at about 22 °C. After stirring for 3 days, XRPD analysis of the wet solid showed a new pattern (FIG. 36, designated as Compound 1 p-dioxane solvate).

[0606] A representative XRPD pattern of Compound 1 p-dioxane solvate is shown in FIG. 36.Example 15. Compound 1 CPME solvate

[0607] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, about 50 mg of amorphous Compound 1 free base was stirred with about 1 mL of CPME at about 22 °C. After stirring for 3 days, XRPD analysis of the wet solid showed a new pattern (FIG. 37, designated asCompound 1 CPME solvate). After drying at 50 °C under vacuum, its XRPD pattern was unchanged.

[0608] A representative XRPD pattern of Compound 1 CPME solvate is shown in FIG. 37.

[0609] The DSC thermogram (FIG. 38) of Compound 1 CPME solvate after drying at 50 °C under vacuum indicates an endothermic transitions with onset at about 79 °C, and at about 245 °C. The DSC thermogram (FIG. 38) of Compound 1 CPME solvate after drying at 50 °C under vacuum indicate endothermic transitions with onsets at about 79 °C, about 223 °C and about 245 °C.Example 16. Compound 1 DMAc solvate

[0610] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, about 200 mg of amorphous Compound 1 free base was stirred with about 0.5 mL of DMAc at about 22 °C. After stirring for 17 days, XRPD analysis of the wet solids showed a new pattern (FIG. 39, designated as Compound 1 DMAc solvate). After drying at 50 °C under vacuum, its XRPD pattern was unchanged.

[0611] A representative XRPD pattern of Compound 1 DMAc solvate is shown in FIG. 39.

[0612] The DSC thermogram (FIG. 40) of Compound 1 DMAc solvate after drying at 50 °C under vacuum indicates two endothermic transition with onset at about 125 °C, and at about 246 °C.

[0613] The TGA thermogram (FIG. 41) shows substantial weight loss of about 16.3% from 25 to 200 °C, close to the theoretical value of one equivalent of DMAc (16.2%).Example 17. Compound 1 Mesophase

[0614] Compound 1 mesophase may be obtained soon after stirring Compound 1 mesylate Form I in water. It appeared as gel. XRPD pattern (FIG. 42) shows two broad peaks at about 3.9 and 15.8 ±0.2° 20.Example 18. Compound 1 Hydrochloride Form I

[0615] To a 20-mL vial equipped with a Teflon coated magnetic stir bar, about 500 mg of Compound 1 free base Form I was stirred with 1.1 equivalents of concentrated HC1 in 10 mL of acetone. A slurry formed soon afterwards, and was filtered, washed with 0.5 mL of acetone, then 1 mL of heptanes, and dried in the vacuum oven at 50 °C for two hours. XRPD analysis showed that the dry solid has a unique pattern was designated as Compound 1 hydrochloride Form I.

[0616] A representative XRPD pattern of Compound 1 Hydrochloride Form I is shown in FIG. 43. Peak positions present in the XRPD diffractogram acquired from Compound 1 Hydrochloride Form I are presented in Table 10.Table 10 Peak list of Compound 1 Hydrochloride Form I

[0617] The DSC thermogram (FIG. 44) indicates an endotherm with onset at about 221 °C

[0618] The TGA thermogram shows a weight loss of about 0.2% from 25 to 125 °C, indicating an unsolvated form (FIG. 45).

[0619] The DVS analysis is shown in FIG. 46 and indicates that the form is slightly hygroscopic with about 0.4% water uptake from 0 to 90% RH at 25 °C.Example 19. Compound 1 Hydrochloride Form II

[0620] Compound 1 hydrochloride Form II was obtained by stirring Compound 1 hydrochloride Form I in water or EtOH / water mixtures with water contents (by volume) about 3% or above at about 21 °C for 16 hours or more.

[0621] A representative XRPD pattern of Compound 1 hydrochloride Form II is shown in FIG. 47. Peak positions present in the XRPD diffractogram acquired from Compound 1 Hydrochloride Form II are presented in Table 11.Table 11 Peak list of Compound 1 Hydrochloride Form II

[0622] The DSC thermogram (FIG. 48) indicates a melting onset at about 177 °C. The DSC thermogram also shows an endothermic event with an onset at about 46 °C.

[0623] The TGA thermogram shows a weight loss of about 3.8% from 40 to 150 °C, and about 2.1% from 150 °C to 200 °C (FIG. 49).

[0624] The DVS analysis is shown in FIG. 50 and indicates that the form is slightly hygroscopic with about 0.7% water uptake from 0 to 90% RH at 25 °C.

[0625] Single crystals of Compound 1 hydrochloride Form II were prepared by dissolving about 20 mg of Compound 1 HC1 salt Form I in a mixture of 0.4 mb of EtOH and 0.2 mL of water at about 22 °C and then let the solvent to evaporate naturally in a vial without lid. The sample dried out with some crystals on the bottom of the vial. One of the crystals was subjected to SCXRD analysis at about 299 K. The result was consistent with Compound 1 hydrochloride Form II when comparing the predicted powder diffraction data with experimental data. The crystal lattice parameters are shown below in Table 12.Table 12 Crystal Lattice Parameters of Compound 1 Hydrochloride Form IIExample 20. Compound 1 Hemisulfate Form

[0626] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, a mixture of Compound 1 free base, 0.5 equivalents of sulfuric, and 0.5 mL of MeCN was stirred at about 22 °C for about one day. XRPD analysis of the solids that was dried at 50 °C under vacuum showed a new pattern, which was designated as Compound 1 hemisulfate Form I.

[0627] A representative XRPD pattern of Compound 1 hemisulfate Form I is shown in FIG. 51. Peak positions present in the XRPD diffractogram acquired from Compound 1 Hemi sulfate Form I are presented in Table 13.Table 13 Peak list of Compound 1 Hemisulfate Form I

[0628] The DSC thermogram (FIG. 52) indicates an endotherm event with onset at about 153°C.Example 21. Compound 1 Sulfate Form I

[0629] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, a mixture of Compound 1 free base, 1 equivalent of sulfuric, and 0.5 mL of MeOH was stirred at about 22 °C for about one day. XRPD analysis of the solids that was dried at 50 °C under vacuum showed a new pattern, which was designated as Compound 1 sulfate Form I.

[0630] A representative XRPD pattern of Compound 1 sulfate Form I is shown in FIG. 53. Peak positions present in the XRPD diffractogram acquired from Compound 1 Sulfate Form I are presented in Table 14.Table 14 Peak list of Compound 1 Sulfate Form I

[0631] The DSC thermogram (FIG. 54) indicates an endotherm event with onset at about 165 °C.Example 22. Compound 1 Mesylate Form I

[0632] To a 4-rnL vial equipped with a Teflon coated magnetic stir bar, about 50 mg of Compound 1 free base Form I was stirred with 1 equivalent of methanesulfonic acid in 0.5 mL of MeCN at about 22 °C. After stirring for 4 hours, XRPD analysis of the wet solids showed a new pattern, which was unchanged after drying at 50 °C under vacuum. The new salt was designated as Compound 1 mesylate Form I.

[0633] This form may also be obtained from other solvents such as MeCN, EtOH, IP A, acetone, MEK, MIBK, DCM, THF, MeTHF, EtOAc, IP Ac, MTBE, and toluene.

[0634] A representative XRPD pattern of Compound 1 Mesylate Form I is shown in FIG. 55. Peak positions present in the XRPD diffractogram acquired from Compound 1 Mesylate Form I are presented in Table 15.Table 15 Peak list of Compound 1 Mesylate Form I

[0635] The DSC thermogram (FIG. 56) indicates a melting onset at about 250 °C.

[0636] The TGA thermogram shows a weight loss of about 0.1% from 25 to 150 °C, indicating an unsolvated form (FIG. 57).

[0637] The DVS analysis is shown in FIG. 58 and indicates that the form is hygroscopic with about 2.3% water uptake from 0 to 90% RH at 25 °C.Example 23. Compound 1 Esylate Form I

[0638] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, a solution consists of about 50 mg of Compound 1 in 1 mL of acetone was stirred with 1 equivalent of ethanesulfonic acid at about 22 °C. After stirring for about 16 hours, XRPD analysis of the wet solids showed a new pattern, which was unchanged after drying at 50 °C under vacuum. The new salt was designated as Compound 1 esylate Form I.

[0639] A representative XRPD pattern of Compound 1 esylate Form I is shown in FIG. 59. Peak positions present in the XRPD diffractogram acquired from Compound 1 Esylate Form I are presented in Table 16.Table 16 Peak list of Compound 1 Esylate Form I

[0640] The DSC thermogram (FIG. 60) indicates a melting onset at about 258 °C.

[0641] The TGA thermogram shows a weight loss of about 0.1% from 25 to 150 °C, indicating an unsolvated form (FIG. 61).

[0642] The DVS analysis is shown in FIG. 62 and indicates that the form is hygroscopic with around 3.3% water uptake from 0 to 90% RH at 25 °C.Example 24. Compound 1 Besylate Form I

[0643] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, about 50 mg of Compound 1 free base Form I was stirred with 1 equivalent of benzenesulfonic acid in 0.5 mL of acetone at about 22 °C. After stirring for 1 day, the solution was dried in the vacuum oven at 50°C and was dissolved in 0.5 mL of MeOH. After stirring for 2 days, it crystallized. An aliquot of the slurry was filtered and dried in the vacuum oven at 50 °C. XRPD analysis of the solids dried at 50 °C under vacuum showed a new pattern, which was designated as Compound 1 besylate Form I.

[0644] A representative XRPD pattern of Compound 1 besylate Form I is shown in FIG. 63. Peak positions present in the XRPD diffractogram acquired from Compound 1 Besylate Form I are presented in Table 17.Table 17 Peak list of Compound 1 Besylate Form I

[0645] The DSC thermogram (FIG. 64) indicates a melting onset at about 148 °C.Example 25. Compound 1 Besylate Form II

[0646] An aliquot of the slurry of Compound 1 besylate in methanol from the previous example was dried in the vacuum oven at 50 °C, and then stirred with 0.5 mL of MeCN. After stirring for about 16 hours, XRPD analysis of the solids dried at 50 °C under vacuum showed a new pattern, which was designated as Compound 1 besylate Form II.

[0647] A representative XRPD pattern of Compound 1 besylate Form II is shown in FIG. 65. Peak positions present in the XRPD diffractogram acquired from Compound 1 Besylate Form II are presented in Table 18.Table 18 Peak list of Compound 1 Besylate Form II

[0648] The DSC thermogram (FIG. 66) indicates a melting onset at about 148 °C.Example 26. Compound 1 Tosylate Form I

[0649] To a 4-rnL vial equipped with a Teflon coated magnetic stir bar, about 50 mg of Compound 1 free base Form I was stirred with 1 equivalent of p-toluenesulfonic acid in 0.5 mL of acetone at about 22 °C. After stirring for 1 day, the solution was dried in the vacuum oven at 50 °C and was dissolved in 0.5 mL of MeOH. After stirring for 2 days, it crystallized, and the slurry was filtered and dried in the vacuum oven at 50 °C. XRPD analysis of the solid dried at 50 °C under vacuum showed a new pattern, which was designated as Compound 1 tosylate Form I.

[0650] A representative XRPD pattern of Compound 1 tosylate Form I is shown in FIG. 67. Peak positions present in the XRPD diffractogram acquired from Compound 1 Tosylate Form I are presented in Table 19.Table 19 Peak list of Compound 1 Tosylate Form I

[0651] The DSC thermogram (FIG. 68) indicates a melting onset at about 164 °C.Example 27. Compound 1 Napsylate Form I

[0652] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, about 50 mg of Compound 1 free base Form I was stirred with 1 equivalent of napthylene-2-sulfonic acid in 0.5 mL of acetone at about 22 °C. After stirring for 1 day, the solution was dried in the vacuum oven at 50 °C and was dissolved in 0.5 mL of MeOH. After stirring for 2 days, it crystallized. The slurry was filtered and dried in the vacuum oven at 50 °C. XRPD analysis of the dried solids showed a new pattern, which was designated as Compound 1 napsylate Form I.

[0653] A representative XRPD pattern of Compound 1 napsylate Form I is shown in FIG. 69. Peak positions present in the XRPD diffractogram acquired from Compound 1 Napsylate Form I are presented in Table 20.Table 20 Peak list of Compound 1 Napsylate Form I

[0654] The DSC thermogram (FIG. 70) indicates a melting onset at about 215 °C.Example 28. Compound 1 Maleate Form I

[0655] To a 4-mL vial equipped with a Teflon coated magnetic stir bar, about 50 mg of Compound 1 free base Form I was stirred with 1 equivalent of maleic acid in 0.5 mL of acetone at about 50 °C for about 30 min and then cooled to about 21 °C. After stirring for about 16 hours, XRPD analysis of the wet solids showed a new pattern, which was unchanged after drying at 50 °C under vacuum. The new salt was designated as Compound 1 maleate Form I.

[0656] A representative XRPD pattern of Compound 1 maleate Form I is shown in FIG. 71. Peak positions present in the XRPD diffractogram acquired from Compound 1 Maleate Form I are presented in Table 21.Table 21 Peak list of Compound 1 Maleate Form I

[0657] The DSC thermogram (FIG. 72) indicates an endotherm with onset at about 198 °C

[0658] The TGA thermogram shows a weight loss of about 0.04% from 25 to 150 °C, indicating an unsolvated form (FIG. 73). Weight loss at higher temperature was probably due to loss of maleic acid (theoretical malic acid content is 20.5%).

[0659] The DVS analysis is shown in FIG. 74 and indicates that the form is non-hygroscopic with about 0.17% water uptake from 0 to 90% RH at 25 °C.Example 29. Compound 1 L-tartrate Form I

[0660] Compound 1 L-tartrate Form I was obtained by stirring a mixture of 0.4 g of Compound 1 and 0.2 g of L-tartaric acid, (about 1.5 eq) in 7 mL of acetone. The mixture was stirred at 70 °C in a sealed vial for a few minutes and then cooled to about 21 °C. After a few hours, the slurry was fdtered and the solid was dried in the vacuum oven at 50 °C. The solid was characterized by XRPD and DSC, and designated as Compound 1 L-tartrate Form I.

[0661] A representative XRPD pattern of Compound 1 L-tartrate Form I is shown in FIG. 75. Peak positions present in the XRPD diffractogram acquired from Compound 1 L-tartrate Form I are presented in Table 22.Table 22 Peak list of Compound 1 L-tartrate Form I

[0662] The DSC thermogram (FIG. 76) indicates a major endotherm with onset at about 113 °C.Example 30. Compound 1 L-tartrate Form II

[0663] Compound 1 L-tartrate Form II was obtained by stirring Compound 1 L-tartrate Form I from section 3.28 in MeCN. After two days, the slurry was filtered and the solid was dried in the vacuum oven at 50 °C. The solid was characterized by XRPD and DSC, and designated as Compound 1 L-tartrate Form II. Proton NMR shows about 1 eq of L-tartaric acid and about 0.6 eq of MeCN.

[0664] A representative XRPD pattern of Compound 1 L-tartrate Form II is shown in FIG. 77. Peak positions present in the XRPD diffractogram acquired from Compound 1 L-tartrate Form II are presented in Table 23.Table 23 Peak list of Compound 1 L-tartrate Form II

[0665] The DSC thermogram (FIG. 78) indicates three major endothermic events with onsets at about 26, 97, and 172 °C, respectively.Example 31. Compound 1 L-tartrate Form HI

[0666] Compound 1 L-tartrate Form II was obtained by stirring Compound 1 L-tartrate Form I in MeCN for 3 days, fdtering, drying the solids in a vacuum oven at 50 °C. The solid was characterized by XRPD and DSC, and designated as Compound 1 L-tartrate Form III. Proton NMR shows about 1 eq of L-tartaric acid and about 0.1 eq of MeCN.

[0667] A representative XRPD pattern of Compound 1 L-tartrate Form III is shown in FIG. 79. Peak positions present in the XRPD diffractogram acquired from Compound 1 L-tartrate Form III are presented in Table 24.Table 24 Peak list of Compound 1 L-tartrate Form III

[0668] The DSC thermogram (FIG. 80) indicates three major endothermic events with onsets at about 20, 114, and 170 °C.B. Biological assaysExample 32. Biological assaysHSV-2 Cellomics Assay

[0669] Compounds were tested for their ability to inhibit HSV-2 replication by monitoring the expression of the HSV protein gD using a high-throughput immunofluorescence-based assay. 10- dose, 3-fold serial dilutions of compounds were prepared at starting concentrations of 0.2 or 2 mMin 100% DMSO. 250 nL of compounds were spotted in quadruplicates onto black collagen-coated 384-well microplates with clear bottom (Greiner cat# 781956) using a Labcyte ECHO acoustic dispenser. The final starting concentration in the assay was either 1 or 10 pM. DMSO (no compound) and pritelivir were included on each microplate as negative and positive controls, respectively.

[0670] ARPE-19 cells (ATCC cat# CRL-2302) were maintained DMEM / F-12 Glutamax medium (Thermo Fisher Scientific cat# 10565018) supplemented with 10% FBS (Coming cat# 35-011-CV) and 1% Penicillin-Streptomycin (cat# 30-002-CI). Prior to confluence, cells were transferred to a centrifuge tube and spun for 5 minutes at 1000 rpm. Cells were resuspended in assay medium (DMEM / F-12 Glutamax, 2% FBS, 1% Penicillin-Streptomycin) and counted. Cell density was adjusted to 150,000 cells / ml and infected with HSV-2 vims (MS strain, ATCC cat# VR-540) at a MOI of 0.06 in a 50 ml conical tube for 1 hour under constant rocking. Cells were then spun for 5 minutes at 1000 rpm and the media replaced with assay medium containing either 2% FBS or 10% human serum (EMD Millipore cat# S1-100ML). 50 pL of the infection suspension were added into microplate wells that were pre-spotted with compounds (7,500 cells per well). Plates were incubated for 16 hours at 37°C.

[0671] Cell culture medium was aspirated using a Biomek Fx and 50 pL of a paraformaldehyde solution (Electron Microscopy Sciences cat# 15712-S) diluted to 4% in DPBS (Corning cat# 21- 031 -CM) were added per well. After a 30-minute incubation at room temperature, plates were washed 4 times with 100 pL / well of PBS using a Biotek plate washer. A 1:500 solution of primary antibody (anti-HSV gD, Virusys cat# Pl 103) was prepared in permeabilization buffer (Invitrogen cat# 00-8333-56) and 50 pL were added into wells. After a 1-hour incubation at room temperature, 50 pL of a 1 :1000 solution of secondary antibody (Alexa Fluor 488 goat anti-mouse, Thermo Fisher Scientific cat# Al 1001) and DAPI (Thermo Fisher Scientific cat# 62248) in permeabilization buffer were added into wells and plates were incubated in the dark at room temperature for 1 hour. Plates were washed 4 times again and 50 pL of DPBS were added to all wells prior to sealing the plates with a black adhesive seal. Fluorescence was measured on a Cellomics plate reader.

[0672] Data analysis was carried out using the Thermo Scientific HCS Studio software. Briefly, cells were identified using the DAPI nuclear stain and thresholds were set to filter cells out based on shape and size. A second threshold based on green fluorescence intensity (detection of HSV-2 gD) was set to identify HSV-2 infected cells. Data was reported as the average fluorescence intensity of HSV-2 infected cells. EC50 values were defined as the compound concentration thatcaused a 50% decrease in the average fluorescence intensity and was calculated using a sigmoidal dose-response model to generate curve fits. EC50 for pritelivir in this assay was 150 nM.MT-4 CC50 Assay

[0673] Compounds were tested in 384-well plates: 18 compounds in duplex. Compounds were diluted in 7 points, 3 -fold with DMSO by Bravo. Assay plate, which contains 20 pL medium with compounds, was seeded 2000 MT-4 cells in 20 pL / well by Multi-drop to start the assay. The plate was incubated at 37°C for 5 days. On 6th day, the CellTiter Gio 40 pL was added in each well. Luminescence was read by Victor II. CCso values are defined as the compound concentration that causes a 50% decrease in luminescence signal, and were calculated using a sigmoidal doseresponse model to generate curve fits.HSV qPCR Assay

[0674] HSV replication in the presence or absence of compounds was measured by qPCR according to the following procedure: DMSO stock compound solutions (1-10 mM) were serially diluted (2.5-fold) in DMSO in clear round bottom 96-well plates. Compounds were then diluted 1:20 in assay medium (DMEM / F12 Glutamax + 2% Fetal bovine serum + 1% Penicillin Streptomycin) and 10 pL of these dilutions were added to 96-well tissue culture plates for final starting concentrations between 0.5 and 5 pM.

[0675] ARPE-19 cells (ATCC cat # CRL-2302) that were maintained in growth medium (DMEM / F12 Glutamax + 10% FBS + 1% Penicillin streptomycin) were transferred to a centrifuge tube and spun for 5 minutes at 1000 rpm. Cells were resuspended in assay medium, counted, and cell density was adjusted to 2.8E+05 cells / ml with assay medium. Cells were then infected with HSV-1 (KOS strain, ATCC cat# VR-1493) or HSV-2 virus (MS strain, ATCC cat# VR-540) at a MOI 0.05 in a 50-mL conical tube for 1 hour under constant rocking. 90 pL of the infection suspension (25,000 cells) were added to assay plates in which compounds were already added. After an overnight incubation at 37°C, cell culture medium was removed, and cell lysis was performed using the prepGEM Universal kit (MicroGEM cat# PUN1000). Specifically, 100 pL of prepGEM master mix (94.75 pL Water, 5 pL buffer, 0.25 pL enzyme stock) were added to each well and plates were incubated at room temperature for 15 minutes, with the 5 last minutes on a plate shaker. The cell lysates were then transferred to a 96-well PCR compatible microplate (Applied Biosystems, Cat #N8010560). Plates were sealed with a heat resistant plastic sealer and heated on a thermal cycler using the following conditions: 75°C for 10 min, 95°C for 5 minutes. Finally, plates were cooled down to room temperature with light shaking before proceeding to the qPCR setup.

[0676] qPCR reactions were carried out in a total reaction volume of 20 pL, using the QuantiNova multiplex PCR kit (Qiagen Cat #208456). 15 pL of reagent mix (5pL of 4X QuantiNova Master Mix, 0.1 pL of QN Rox reference dye, 1 pL of 20X HSV primer / probe mix and 8.9 pL PCR grade water) and 5 pL of cell lysate were added to wells of a 96-well fast optical microplate (Applied Biosystems cat# 4246906). Plates were sealed with a clear sealer, spun down, and qPCR reactions were performed in an Applied Biosystems Quantstudio 7 Flex instrument using the following conditions: 95°C for 2 minutes, then 40 cycles alternating between 95°C for 5 seconds and 60°C for 30 seconds.

[0677] Analysis was performed using dCT method where dCT = CT (test)- CT (DMSO). Fold change was calculated using the 2A'dCTequation. This fold change was then converted to percentage relative to DMSO control (no drug). EC50s were determined by non-linear regression analysis using GraphPad Prism software.

[0678] EC50 for both pritelivir and amenamevir in this assay were 14 nM. EC50 for acyclovir was 1250 nM.Carbonic anhydrase (esterase) biochemical assay

[0679] Compounds were tested in a high-throughput 384-well assay format for their ability to inhibit the human carbonic anhydrase (hCA)-mediated hydrolysis of 4-nitrophenyl acetate (4NPA) (Verpoorte et al, JBC, 1967). 10-dose, 3-fold serial dilutions of compounds were prepared at starting concentrations of 10 mM in 100% DMSO. 200 nL of compounds were then spotted in quadruplicates onto clear 384-well microplates (Perkin Elmer cat# 6007640) using a Labcyte ECHO acoustic dispenser. Final starting concentration in the assay was 50 pM. DMSO (no compound) and acetazolamide were included on each microplate as negative and positive controls, respectively.

[0680] A 1.5 pM solution of hCAI (R&D systems cat# 2180-CA) or a 1 pM solution of hCAII (Genscript cat# U3256FL150-4 / P5GA002) was prepared in assay buffer (25 mM Tris (pH 7.5), 100 mM NaCl, 1% DMSO) and 20 pL were added to compounds using a Biotek Micro Flo. Following a preincubation at room temperature for 15 minutes, 20 pL of a 4 mM solution of 4NPA substrate (Sigma cat# N8130) in assay buffer were added to start the reaction. Microplates were incubated at room temperature for 60 min after which absorbance at 405 nM was read on an Envision plate-reader. IC50 values were defined as the compound concentration that caused a 50% decrease in absorbance signal and were calculated using a sigmoidal dose-response model to generate curve fits. IC50 of acetazolamide was 0.04 pM in the hCAII assay and 1.1 pM in the hCAI assay.Plasma Stability Assay

[0681] The test compound was incubated at 2 pM in either rat or human plasma (BioIVT, Westbury, NY) up to 4 hours at 37°C. At specified time points, an aliquot from the incubation was quenched by addition of 9 volumes of 100% acetonitrile containing internal standard. Following the last collection, samples were centrifuged at 4500 rpm for 10 min and supernatants were transferred to a new plate containing an equal volume of water for analysis by liquid chromatography coupled to triple quadrupole mass spectrometry (LC-MS / MS). The percentage of test compound remaining (analyte to internal standard peak area ratio) in plasma after incubation was plotted versus incubation time and plasma half-life (t 1 / 2) was calculated from the linear fit of the natural logarithm of the curve.Stability Assay in Cryopreserved Hepatocytes

[0682] Test compound was incubated at 1 pM with either rat or human cryopreserved hepatocytes (BioIVT, Westbury, NY) up to 6 hours at 37°C in a 24-well plate format (IxlO6cells / mL per well). At specified time points, samples were transferred to a 96-well plate and quenched with 2 volumes of a solution containing 90% acetonitrile 10% methanol 0.1% formic acid and internal standard. Sample plate was centrifuged at 3200 rpm for 15 min and supernatants transferred to a new plate containing half volume of water. The resulting solution was analyzed by LC-MS / MS. Data (analyte to internal standard peak area ratio) was plotted on a semi -log scale and fitted using an exponential fit. Assuming first order kinetics, the half-life (tl / 2) and rate of metabolism were determined. Predicted hepatic clearance was calculated from the half-life using the well-stirred model.C. Large scale synthesis of Compound 1 Form I and Compound 1 mesylate Form IExample 33. Large scale manufacture of Compound 1 Form I

[0683] Compound 1 (5.61 kg) is dissolved in acetone (30V) at 45 - 50 °C. The solution is concentrated to 5 V and ethanol (12V) is added over 3 hours at 45 °C. After aging for 2h, the slurry is cooled to -10 °C over 3h. After aging for 2h, the slurry is filtered and washed with ethanol (1.5V). The product is dried at 50 °C to afford 4.95 kg Compound 1 Form I (88% yield, 99.9% area purity).Example 34. Large scale manufacture of Compound 1 mesylate Form I

[0684] A mixture of Compound 1 (4.90 kg) in acetone (31.5V) is heated to 45 - 55 °C for 2h. The resulting solution is filtered through a cartridge filter, rinsed with acetone (2V) and Compound 1 mesylate Form I seed (0.014X) is charged. After aging the mixture for 0.5h at 45 - 55 °C, a solution of methanesulfonic acid (1.03 eq) in acetone (2. IV) is slowly added over 2h. Rinse with acetone (2 V). The mixture is aged for 2h and cooled to 15 - 25 °C over 2h and aged for 2h. The resulting slurry is filtered, and the cake is washed with acetone (3.9V). The product is dried at 50 °C, then sieved to afford 5.76 kg Compound 1 mesylate Form I (96% yield, 99.9% area purity). The polymorphic form was confirmed by XRPD. The solid was also analysed by DSC (see FIG. 85).D Stability studiesExample 35. Stability studies for Compound 1 Form I

[0685] The chemical and physical stability of Compound 1 Form I was assessed under the following stability conditions: 25°C closed, 25°C / 60%RH open, 40°C closed, 40°C / 75%RH open, 60°C closed and 60°C open, for 1 week, 2 weeks, 1 month, 2 months and 3 months. The stability samples were analyzed by UPLC and XRPD at the different time points. The stability study showed that Compound 1 Form I remained stable at the stability conditions tested. There were no significant increases in impurities or other parameters over the duration of the study and the solid form remained as Compound 1 Form I (see FIG. 81).

[0686] Further stability studies of Compound 1 Form I were performed at the following conditions: 25°C / 60%RH closed and 40°C / 75%RH closed, wherein the packaging was double LDPE bags, both secured with cable ties, wherein for each stability condition the bags were stored in a HDPE drum. Samples were tested for appearance, assay and related substances by UPLC, chiral purity by UPLC, XRPD, water content by Karl Fischer titration, and melting point by DSC at 1 and 3 months. FIG. 84 shows a representative DSC thermogram obtained forCompound 1 Form I. The stability data acquired showed that Compound 1 Form I remained chemically and physically stable for 3 months at the 25°C / 60%RH and 40°C / 75%RH conditions.

[0687] In both stability studies, Compound 1 Form I was shown to be physically and chemically stable for up to 3 months at the accelerated and stressed conditions tested.Example 36. Stability studies for Compound 1 Mesylate Form

[0688] The chemical and physical stability of Compound 1 mesylate Form I was assessed under the following stability conditions: 25°C closed, 25°C / 60%RH open, 40°C closed, 40°C / 75%RH open, 60°C closed and 60°C open, for 2 weeks, 4 weeks and 2 months. The stability samples were analyzed by UPLC and XRPD at the different time points. The stability study showed that Compound 1 mesylate Form I remained stable at the stability conditions tested. There was no signification increases in impurities or other parameters over the duration of the study. The solid form remained as Compound 1 mesylate Form I (see FIG. 82). Compound 1 mesylate Form I was shown to be physically and chemically stable for up to 2 months at the accelerated and stressed conditions tested.

[0689] Further stability studies of Compound 1 Mesylate Form I were performed at the following conditions: 25°C / 60%RH closed and 40°C / 75%RH closed, wherein the packaging was double LDPE bags, both secured with cable ties, wherein for each stability condition the bags were stored in a HDPE drum. Samples will be tested for appearance, assay and related substances by UPLC, chiral purity by UPLC, XRPD, water content by Karl Fischer titration, melting point by DSC, ion chromatography and particle size distribution at different time points throughout the duration of the study. The stability data acquired at 3 months shows that Compound 1 Mesylate Form I is chemically and physically stable at the 25°C / 60%RH and 40°C / 75%RH conditions.F Forced degradation study for Compound 1 mesylate Form IExample 37. Forced degradation study for Compound 1 mesylate Form I

[0690] Compound 1 mesylate Form I was assessed under the following forced degradation conditions:• Solution: acid, basic, oxidation, thermal and simulated sunlight; and• Solid: simulated sunlight, thermal, thermal and humidity, and natural light.Methodology:Solution forced degradation conditions:Acidic Stress / 1 N HCl, ambient temperature, 7 days.

[0691] Transfer 8.33 mL 12 N HC1 standard solution to a 100-mL volumetric flask with 50 mL diluent, then dilute to volume with diluent and mix well, label it as 1 N HC1 solution. Weigh 50 mg sample into 50mL volumetric flask, dissolve and dilute with above 1 N HC1 solution and mix well. Keep it at ambient temperature for 7 days. Take out 1 mL of this solution to centrifuge tube and add 1 mL 1 N NaOH solution neutralize.Basic Stress / 1 N NaOH, ambient temperature, 5 days

[0692] Weigh 10 g Sodium hydroxide to a beaker, dissolve with 225 mL MeOH:water=50:50(v:v), label it as 1 N NaOH solution. Transfer 50 mg sample into a 50-mL volumetric flask, dissolve with above IN NaOH solution, dilute to volume. Keep it at ambient temperature for 5 days. Take out 1 mL of this solution to centrifuge tube and add 1 mL 1 N HCL solution neutralize.Oxidative Stress / 3% H2O2, room temperature, 7 days.

[0693] Transfer 10 mL 30% H2O2 to a 100 mL volumetric flask with 50 mL diluent, dilute to volume with diluent and mix well, label it as 3% H2O2 solution. Weigh 25 mg sample into 50 mL volumetric flask, dissolve and dilute with above 3% solution diluent, mix well. Keep this solution at ambient temperature for 7 days.Thermal Stress / 70 °C, solution, 7 days.

[0694] Weigh 25 mg sample into 50 mL volumetric flask. Dilute to volume with diluent and mix well. Seal and set it at 70 °C for 7 days.

[0695] Weigh 25 mg sample into 50 mL volumetric flask. Dilute to volume with diluent and mix well. And take other sample wrapped with foil as control. Seal and irradiation at 25* 103lux for 96 hours and UV 20 W / m2for 20 hours.Solid forced degradation conditions:Thermal and Humidity Stress / 70 °C and 75% RH, solid, 7 days.

[0696] Take 200 mg of sample in a glass dish. Keep it open and set it at 70 °C and 75% RH for 7 days in a temperature / humidity controlled stability chamber. Then weigh 25 mg stress samples into 50-mL volumetric flask. Dilute to volume with diluent and mix well.Thermal Stress / 70 °C, solid, 7 days.

[0697] Take 200 mg of sample in a glass dish. Keep it closed and set it at 70 °C for 7 days. Then weigh 25 mg stress sample into 50 mL volumetric flask. Dilute to volume with diluent and mix well.

[0698] Take 200 mg of sample in a glass dish and seal it. And take other sample wrapped with foil as control. Irradiation these two samples at 25*103lux for 96 hours and UV 20 W / m2for 20 hours. Then weigh 25 mg stress sample into 50 mL volumetric flask. Dilute to volume with diluent and mix well.Unstressed Samples

[0699] Weigh 25 mg sample into 50 mL volumetric flask. Dilute to volume with diluent and mix well.Results:

[0700] The forced degradation samples were analyzed by UPLC. Individual impurity increases > 0.2% were observed for the acid, base and photostability solution conditions.Acceptable peak purity of the Compound 1 freebase peak in the UPLC was shown under all forced degradations conditions studied. Compound 1 Mesylate Form I was shown to be stable under the oxidative stress conditions tested. Compound 1 Mesylate Form I was shown to be stable in the solid state at the thermal and humidity stress, thermal stress, and simulated light stress conditions tested.G Pharmocokinetic studies for Compound 1 Form I and Compound 1 mesylate Form IExample 38. Pharmocokinetic studies

[0701] A pharmacokinetic study in dogs was performed using Compound 1 Form I and Compound 1 mesylate Form I.Formulation Preparation:

[0702] For all of these studies, the formulation comprised of a 50:50 (w / w) mixture of Compound 1 (Compound Form I or Compound 1 Mesylate Form I) and pregelatinized starch. To prepare the powder blend, the individual components were weighed and triturated in a mortarand pestle for ~ 1 min. Once a uniform blend was obtained, the required amount of blend was weighed and manually filled into Capsugel coni-snap size 1 hard-gelatin capsules.PK Methodology:

[0703] Fasting / Food Return: Male beagle dogs were fasted overnight and had food returned approximately 4 hours post-dose.

[0704] Pentagastrin pretreatment: to simulate gastric secretion, each animal was received a single 6 pg / kg intramuscular injection of pentagastrin approximately 30 minutes prior to test article administration. The intramuscular dose was administered in a thigh muscle using a needle and syringe.

[0705] Famotidine pretreatment: to suppress gastric secretion, each animal was received a single 20 mg tablet of famotidine approximately 1 hour prior to test article administration. The tablet was administered orally followed by approximately 5-10 mL of water.

[0706] Dose administration: oral doses of capsules were administered by hand by deep throat deposition. Following each dose, the animals were offered approximately 10 mL of water to assist in swallowing. This was done by depositing ~l-3 mL at a time into the back of the throat and holding the mouth closed until swallowing is observed. This is repeated until all 10 mL of water has been given.

[0707] Serial blood samples were collected via cephalic or jugular vein. Blood samples were collected into K2EDTA tubes and stored on wet ice until processed. Whole blood was processed to plasma by centrifugation (3500 rpm for 10 minutes at 5 °C) within 30 minutes of collection. Plasma samples were stored at -70 °C as soon as possible and remain at -70°C until analyzed.

[0708] The results from this PK study are presented in Table 25 and FIG. 83.

[0709] The results are presented in Table 25 and FIG. 83.Table 25 - Pharmacokinetic study in dogs* * *

[0710] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0711] Thus, it should be understood that although the present disclosure has been specifically disclosed by preferred embodiments and optional features, modification, improvement and variation of the disclosures embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications, improvements and variations are considered to be within the scope of this disclosure. The materials, methods, and examples provided here are representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure.

[0712] The disclosure has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the disclosure. This includes the generic description of the disclosure with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0713] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims

WHAT IS CLAIMED IS:

1. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3- dihydro-lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1):or a pharmaceutically acceptable salt or co-crystal thereof.

2. The crystalline form of claim 1 that is:Compound 1 Form I,Compound 1 Form II,Compound 1 Form III,Compound 1 Form IV,Compound 1 Form V,Compound 1 monohydrate,Compound 1 dihydrate,Compound 1 methyl-tetrahydrofuran (MeTHF) solvate,Compound 1 methyl t-butyl ether solvate 1,Compound 1 methyl t-butyl ether solvate 2,Compound 1 2-butanol solvate,Compound 1 t-butanol solvate,Compound 1 p-dioxane solvate,Compound 1 cyclopentyl methyl ether solvate,Compound 1 dimethyl acetamide solvate,Compound 1 hydrochloride Form I,Compound 1 hydrochloride Form II,Compound 1 hemi sulfate Form I,Compound 1 sulfate Form I,Compound 1 mesylate Form I,Compound 1 esylate Form I,Compound 1 besylate Form I,Compound 1 besylate Form II,Compound 1 tosylate Form I,Compound 1 napsylate Form I,Compound 1 maleate Form I,Compound 1 L-tartrate Form I, Compound 1 L-tartrate Form II, or Compound 1 L-tartrate Form III.

3. The crystalline form of claim 2 that is: Compound 1 Form I,Compound 1 Form II, Compound 1 Form III, Compound 1 Form IV, or Compound 1 Form V.

4. The crystalline form of claim 2 that is: Compound 1 Form I.

5. The crystalline form of claim 2 that is: Compound 1 monohydrate, orCompound 1 dihydrate.

6. The crystalline form of claim 2 that is: Compound 1 methyl-tetrahydrofuran (MeTHF) solvate, Compound 1 methyl t-butyl ether solvate 1, Compound 1 methyl t-butyl ether solvate 2, Compound 1 2-butanol solvate,Compound 1 t-butanol solvate, Compound 1 p-dioxane solvate, Compound 1 cyclopentyl methyl ether solvate, or Compound 1 dimethyl acetamide solvate.

7. The crystalline form of claim 2 that is: Compound 1 hydrochloride Form I,Compound 1 hydrochloride Form II, Compound 1 hemi sulfate Form I,Compound 1 sulfate Form I,Compound 1 mesylate Form I,Compound 1 esylate Form I,Compound 1 besylate Form I,Compound 1 besylate Form II,Compound 1 tosylate Form I,Compound 1 napsylate Form I,Compound 1 maleate Form I,Compound 1 L-tartrate Form I, Compound 1 L-tartrate Form II, or Compound 1 L-tartrate Form III.

8. The crystalline form of claim 2 that is: Compound 1 mesylate Form I.

9. The crystalline form of claim 2 that is:Compound 1 Form I,Compound 1 Form III,Compound 1 Form IV,Compound 1 monohydrate,Compound 1 hydrochloride Form I,Compound 1 hydrochloride Form II,Compound 1 mesylate Form I, or Compound 1 maleate Form I.

10. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5° 29 (± 0.2° 29), Form I.

11. The crystalline form of claim 10, characterized by an XRPD pattern comprising peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, and 26.5° 29 (± 0.2° 20).

12. The crystalline form of claim 10 or 11, characterized by an XRPD pattern comprising peaks at 12.3, 12.5, 13.3, 14.4, 16.6, 17.3, 18.0, 18.5, 19.8, 20.3, 21.2, 22.8, 23.2, 24.0, 24.6, 25.0, 25.3, 26.5, 27.6, 28.1, 28.7, 29.5, 30.9, 31.5, 32.2, 36.4, and 37.1° 29 (± 0.2° 29).

13. The crystalline form of any one of claims 10-12, characterized by an XRPD pattern substantially as shown in FIG. 1.

14. The crystalline form of any one of claims 10-13, characterized by a unit cell as determined by single crystal X-ray crystallography of the following dimensions: a = 19.6326(18) A; b = 7.6161(7) A; c = 14.8409(14) A; a = 90°; 0 = 104.029(8)°; and = 90°.

15. The crystalline form of any one of claims 10-14, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 230 °C.

16. The crystalline form of any one of claims 10-15, characterized by a DSC thermogram substantially as shown in FIG. 2.

17. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 12.6, 13.9, 15.3, 18.5, 19.2, 19.7, 22.3, 23.4, or 24.3° 26 (± 0.2° 26), Form II.

18. The crystalline form of claim 17, characterized by an XRPD pattern comprising peaks at 12.6, 13.9, 15.3, 18.5, 19.2, 19.7, 22.3, 23.4, and 24.3° 26 (± 6.2° 26).

19. The crystalline form of claim 17 or 18, characterized by an XRPD pattern comprising peaks at 9.4, 12.6, 13.9, 15.3, 16.7, 17.3, 18.5, 19.2, 19.7, 22.3, 23.4, 24.3, 25.1, 25.7, 26.4, 28.6, 29.6, 29.7, 31.5, 33.7, and 35.3° 26 (± 6.2° 26).

26. The crystalline form of any one of claims 17-19, characterized by an XRPD pattern substantially as shown in FIG. 5.

21. The crystalline form of any one of claims 17-26, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 223 and 245°C.

22. The crystalline form of any one of claims 17-21, characterized by a DSC thermogram substantially as shown in FIG. 6.

23. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 10.0, 12.2, 17.3, 18.3, 20.1, 22.0, 23.7, 25.3, or 25.9° 20 (± 0.2° 20), Form III.

24. The crystalline form of claim 23, characterized by an XRPD pattern comprising peaks at 10.0, 12.2, 17.3, 18.3, 20.1, 22.0, 23.7, 25.3 and 25.9° 20 (± 0.2° 29).

25. The crystalline form of claim 23 or 24, characterized by an XRPD pattern comprising peaks at 10.0, 12.2, 12.7, 13.3, 14.7, 15.0, 15.8, 17.3, 18.3, 19.1, 20.1, 20.3, 20.8, 22.0, 23.0, 23.7, 24.4, 25.3, 25.9, 27.0, 28.0, 28.5, 28.9, and 30.3° 29 (± 0.2° 29).

26. The crystalline form of any one of claims 23-25, characterized by an XRPD pattern substantially as shown in FIG. 9.

27. The crystalline form of any one of claims 23-26, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 246°C.

28. The crystalline form of any one of claims 23-27, characterized by a DSC thermogram substantially as shown in FIG. 10.

29. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 5.7, 11.2, 16.8, 17.1, 18.7, 21.4, 22.4, 23.3, or 23.8° 26 (± 0.2° 29), Form IV.

30. The crystalline form of claim 29, characterized by an XRPD pattern comprising peaks at 5.7, 11.2, 16.8, 17.1, 18.7, 21.4, 22.4, 23.3, and 23.8° 29 (± 0.2° 26).

31. The crystalline form of claim 29 or 30, characterized by an XRPD pattern comprising peaks at 5.7, 8.6, 11.2, 11.7, 13.8, 16.2, 16.8, 17.1, 17.6, 18.2, 18.7, 19.7, 20.4, 21.4, 21.8, 22.4, 23.3, 23.8, 24.5, 25.7, 26.5, 27.7, 29.2, 30.0, 31.4, 32.7, 33.2, 33.7, 34.8, 35.3, and 38.3° 29 (± 0.2° 29).

32. The crystalline form of any one of claims 29-31, characterized by an XRPD pattern substantially as shown in FIG. 13.

33. The crystalline form of any one of claims 29-32, characterized by a unit cell as determined by single crystal X-ray crystallography of the following dimensions: a = 6.09120(10) A; b = 11.01750(10) A; c = 31.8714(4) A; a = 90°; 0 = 90°; and = 90°.

34. The crystalline form of any one of claims 29-33, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 242°C.

35. The crystalline form of any one of claims 29-34, characterized by a DSC thermogram substantially as shown in FIG. 14.

36. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 10.0, 11.8, 13.9, 17.6, 18.1, 18.5, 18.9, 19.6, or 26.0° 29 (± 0.2° 29), Form V.

37. The crystalline form of claim 36, characterized by an XRPD pattern comprising peaks at 10.0, 11.8, 13.9, 17.6, 18.1, 18.5, 18.9, 19.6, and 26.0° 29 (± 0.2° 20).

38. The crystalline form of claim 36 or 37, characterized by an XRPD pattern comprising peaks at 9.2, 10.0, 11.8, 12.5, 13.9, 15.3, 15.8, 16.8, 17.3, 17.6, 18.1, 18.5, 18.9, 19.6, 20.4, 21.2, 21.7, 22.4, 23.8, 25.0, 26.0, 27.0, and 28.4° 29 (± 0.2° 29).

39. The crystalline form of any one of claims 36-38, characterized by an XRPD pattern substantially as shown in FIG. 17.

40. The crystalline form of any one of claims 36-39, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 2%.

41. The crystalline form of any one of claims 36-40, characterized by a TGA substantially as shown in FIG. 19.

42. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 12.2, 14.9, 17.5, 20.0, 20.6, 21.8, 23.6, 25.4, or 26.0° 20 (± 0.2° 29), monohydrate.

43. The crystalline form of claim 42, characterized by an XRPD pattern comprising peaks at 12.2, 14.9, 17.5, 20.0, 20.6, 21.8, 23.6, 25.4, and 26.0° 29 (± 0.2° 20).

44. The crystalline form of claim 42 or 43, characterized by an XRPD pattern comprising peaks at 10.0, 12.2, 12.5, 13.2, 14.9, 16.3, 17.5, 18.7, 19.0, 19.4, 20.0, 20.6, 21.1, 21.8, 23.0, 23.6, 24.5, 25.4, 26.0, 27.8, 28.3, 28.6, 30.1, 31.4, 32.1, 32.8, 34.3, 35.9, 36.9, 38.3, and 39.0° 29 (± 0.2° 29).

45. The crystalline form of any one of claims 42-44, characterized by an XRPD pattern substantially as shown in FIG. 20.

46. The crystalline form of any one of claims 42-45, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 33 and 246°C.

47. The crystalline form of any one of claims 42-46, characterized by a DSC thermogram substantially as shown in FIG. 21.

48. The crystalline form of any one of claims 42-47, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 3.7%.

49. The crystalline form of any one of claims 42-48, characterized by a TGA substantially as shown in FIG. 22.

56. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 8.1, 9.6, 11.7, 16.3, 18.8, 24.5, 25.7, 25.9, or 27.9° 26 (± 0.2° 26), dihydrate.

51. The crystalline form of claim 56, characterized by an XRPD pattern comprising peaks at 8.1, 9.6, 11.7, 16.3, 18.8, 24.5, 25.7, 25.9, and 27.9° 26 (± 6.2° 26).

52. The crystalline form of claim 56 or 51, characterized by an XRPD pattern comprising peaks at 8.1, 9.6, 16.5, 11.7, 12.2, 15.1, 16.3, 17.6, 18.1, 18.8, 19.2, 26.9, 21.7, 22.4, 22.8, 23.4, 23.8, 24.5, 25.6, 25.7, 25.9, 26.4, 26.6, 27.2, 27.9, 29.1, 29.6, and 34.5° 26 (± 6.2° 26).

53. The crystalline form of any one of claims 56-52, characterized by an XRPD pattern substantially as shown in FIG. 23.

54. The crystalline form of any one of claims 56-53, characterized by a thermal gravimetric analysis (TGA) having a weight loss of about 7.4%.

55. The crystalline form of any one of claims 56-54, characterized by a TGA substantially as shown in FIG. 25.

56. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 8.9, 12.5, 18.9, 19.6, 20.8, 23.8, 24.4, 24.8, or 28.8° 20 (± 0.2° 29), hydrochloride Form I.

57. The crystalline form of claim 56, characterized by an XRPD pattern comprising peaks at 8.9, 12.5, 18.9, 19.6, 20.8, 23.8, 24.4, 24.8, and 28.8° 29 (± 0.2° 20).

58. The crystalline form of claim 56 or 57, characterized by an XRPD pattern comprising peaks at 8.9, 12.5, 15.2, 15.9, 18.9, 19.2, 19.6, 20.8, 21.5, 23.8, 24.4, 24.8, 25.9, 26.2, 26.9, 27.7, 28.8, 30.4, 31.2, 32.5, 33.8, and 38.9° 29 (± 0.2° 29).

59. The crystalline form of any one of claims 56-58, characterized by an XRPD pattern substantially as shown in FIG. 43.

60. The crystalline form of any one of claims 56-59, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 221 °C.

61. The crystalline form of any one of claims 56-60, characterized by a DSC thermogram substantially as shown in FIG. 44.

62. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 8.3, 12.4, 15.3, 19.2, 22.6, 24.0, 24.8, 26.3, or 28.3° 20 (± 0.2° 29), hydrochloride Form II.

63. The crystalline form of claim 62, characterized by an XRPD pattern comprising peaks at 8.3, 12.4, 15.3, 19.2, 22.6, 24.0, 24.8, 26.3, and 28.3° 29 (± 0.2° 20).

64. The crystalline form of claim 62or 63, characterized by an XRPD pattern comprising peaks at 8.3, 9.8, 11.8, 12.4, 15.3, 17.0, 17.8, 18.4, 19.2, 19.5, 20.5, 21.1, 21.6, 22.6, 23.2, 23.4, 24.0, 24.8, 25.1, 25.4, 26.3, 26.8, 27.4, 28.3, 29.5, 29.9, 30.6, 32.4, and 33.4° 29 (± 0.2° 29).

65. The crystalline form of any one of claims 62-64, characterized by an XRPD pattern substantially as shown in FIG. 47.

66. The crystalline form of any one of claims 62-65, characterized by a unit cell as determined by single crystal X-ray crystallography of the following dimensions: a = 10.83810(10) A; b = 17.4553(2) A; c = 12.44620(10) A; a = 90°; 0 = 93.4720(10)°; and = 90°.

67. The crystalline form of any one of claims 62-66, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 177°C.

68. The crystalline form of any one of claims 62-67, characterized by a DSC thermogram substantially as shown in FIG. 48.

69. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 9.6, 11.9, 16.5, 19.4, 20.1, 22.6, 23.8, or 25.8° 20 (± 0.2° 20), hemisulfate Form I.

70. The crystalline form of claim 69, characterized by an XRPD pattern comprising peaks at 9.6, 11.9, 16.5, 19.4, 20.1, 22.6, 23.8, and 25.8° 20 (± 0.2° 29).

71. The crystalline form of claim 69 or 70, characterized by an XRPD pattern comprising peaks at 9.6, 11.9, 14.6, 16.5, 19.4, 20.1, 22.6, 23.8, 25.8, and 28.7° 29 (± 0.2° 29).

72. The crystalline form of any one of claims 69-71, characterized by an XRPD pattern substantially as shown in FIG. 51.

73. The crystalline form of any one of claims 69-72, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 153°C.

74. The crystalline form of any one of claims 69-73, characterized by a DSC thermogram substantially as shown in FIG. 52.

75. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 9.6, 19.1, 19.4, 20.4, 22.3, 23.6, or 25.5° 20 (± 0.2° 20), sulfate Form I.

76. The crystalline form of claim 75, characterized by an XRPD pattern comprising peaks at 9.6, 19.1, 19.4, 20.4, 22.3, 23.6, and 25.5° 20 (± 0.2° 29).

77. The crystalline form of claim 75 or 76, characterized by an XRPD pattern comprising peaks at 9.6, 12.7, 14.1, 15.5, 16.6, 18.4, 19.1, 19.4, 20.4, 22.0, 22.3, 22.9, 23.6, 24.3, 25.5, 26.8, and 27.6° 29 (± 0.2° 29).

78. The crystalline form of any one of claims 75-77, characterized by an XRPD pattern substantially as shown in FIG. 53.

79. The crystalline form of any one of claims 75-78, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 165°C.

80. The crystalline form of any one of claims 75-79, characterized by a DSC thermogram substantially as shown in FIG. 54.

81. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, or 29.6° 29 (± 0.2° 29), mesylate Form I.

82. The crystalline form of claim 81, characterized by an XRPD pattern comprising peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, and 29.6° 29 (± 0.2° 20).

83. The crystalline form of claim 81 or 82, characterized by an XRPD pattern comprising peaks at 7.2, 8.9, 11.6, 12.8, 14.3, 16.1, 16.4, 17.3, 18.1, 18.5, 19.1, 19.5, 20.2, 20.6, 20.9, 20.9, 21.4, 22.2, 22.5, 23.2, 24.0, 24.7, 25.4, 25.7, 26.1, 26.8, 27.7, 29.6, 31.0, 31.5, 32.4, 34.0, 35.4, 35.9, 36.3, 37.2, and 37.9° 29 (± 0.2° 29).

84. The crystalline form of any one of claims 81-83, characterized by an XRPD pattern substantially as shown in FIG. 55.

85. The crystalline form of any one of claims 81-84, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 250°C.

86. The crystalline form of any one of claims 81-85, characterized by a DSC thermogram substantially as shown in FIG. 56.

87. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 7.0, 17.9, 18.4, 20.1, 20.8, 23.0, 23.4, 24.0, or 25.8° 20 (± 0.2° 29), esylate Form I.

88. The crystalline form of claim 87, characterized by an XRPD pattern comprising peaks at 7.0, 17.9, 18.4, 20.1, 20.8, 23.0, 23.4, 24.0, and 25.8° 29 (± 0.2° 20).

89. The crystalline form of claim 87 or 88, characterized by an XRPD pattern comprising peaks at 7.0, 8.7, 11.6, 12.3, 13.9, 14.5, 16.3, 17.0, 17.9, 18.4, 18.9, 19.5,20.1, 20.6, 20.8, 21.9, 22.2, 23.0, 23.4, 24.0, 24.6, 25.2, 25.8, 27.1, 27.8, 28.4, 29.8, 30.6,31.1, 32.3, 34.7, 35.5, and 36.2° 29 (± 0.2° 29).

90. The crystalline form of any one of claims 87-89, characterized by an XRPD pattern substantially as shown in FIG. 59.

91. The crystalline form of any one of claims 87-90, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 258°C.

92. The crystalline form of any one of claims 87-91, characterized by a DSC thermogram substantially as shown in FIG. 60.

93. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 11.3, 14.9, 16.1, 18.4, 19.8, 21.0, 22.8, or 24.9° 20 (± 0.2° 20), besylate Form I.

94. The crystalline form of claim 93, characterized by an XRPD pattern comprising peaks at 11.3, 14.9, 16.1, 18.4, 19.8, 21.0, 22.8, and 24.9° 20 (± 0.2° 29).

95. The crystalline form of claim 93 or 94, characterized by an XRPD pattern comprising peaks at 10.0, 10.5, 11.3, 14.4, 14.9, 16.1, 17.1, 18.4, 19.8, 21.0, 22.8, 24.9, 25.8, 27.0, and 31.5° 29 (± 0.2° 29).

96. The crystalline form of any one of claims 93-95, characterized by an XRPD pattern substantially as shown in FIG. 63.

97. The crystalline form of any one of claims 93-96, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 148°C.

98. The crystalline form of any one of claims 93-97, characterized by a DSC thermogram substantially as shown in FIG. 64.

99. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)-2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.2, 18.0, 19.3, and 21.7° 20 (± 0.2° 20), besylate Form II.

100. The crystalline form of claim 99, characterized by an XRPD pattern comprising five or more peaks at 12.2, 14.4, 16.0, 18.0, 19.3, 21.7, 22.5, 24.9, 27.1, or 28.2° 20 (± 0.2° 29).

101. The crystalline form of claim 99 or 100, characterized by an XRPD pattern comprising peaks at 12.2, 14.4, 16.0, 18.0, 19.3, 21.7, 22.5, 24.9, 27.1, and 28.2° 29 (± 0.2° 29).

102. The crystalline form of any one of claims 99-101, characterized by an XRPD pattern substantially as shown in FIG. 65.

103. The crystalline form of any one of claims 99-102, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 148°C.

104. The crystalline form of any one of claims 99-103, characterized by a DSC thermogram substantially as shown in FIG. 66.

105. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)- 2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 4.1, 8.1, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5, or 24.5° 29 (± 0.2° 29), tosylate Form I.

106. The crystalline form of claim 105, characterized by an XRPD pattern comprising peaks at 4.1, 8.1, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5, and 24.5° 29 (± 0.2° 20).

107. The crystalline form of claim 105 or 106, characterized by an XRPD pattern comprising peaks at 4.1, 5.0, 6.7, 8.1, 9.3, 9.9, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5, 20.4, 22.2, and 24.5° 29 (± 0.2° 29).

108. The crystalline form of any one of claims 105-107, characterized by an XRPD pattern substantially as shown in FIG. 67.

109. The crystalline form of any one of claims 105-108, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 164°C.

110. The crystalline form of any one of claims 105-109, characterized by a DSC thermogram substantially as shown in FIG. 68.

111. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)- 2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 6.6, 12.3, 17.8, 19.0, 21.2, 22.2, 23.9, 25.8, or 26.6° 29 (± 0.2° 29), napsylate Form I.

112. The crystalline form of claim 111, characterized by an XRPD pattern comprising peaks at 6.6, 12.3, 17.8, 19.0, 21.2, 22.2, 23.9, 25.8, and 26.6° 29 (± 0.2° 20).

113. The crystalline form of claim 111 or 112, characterized by an XRPD pattern comprising peaks at 6.6, 8.9, 12.3, 13.2, 14.5, 16.3, 16.8, 17.8, 18.4, 19.0, 19.9, 20.4,20.7, 21.2, 21.4, 22.2, 22.9, 23.9, 25.0, 25.8, 26.6, 27.2, 27.7, 28.3, 29.1, 29.9, 30.8, 32.1,32.7, and 33.3° 29 (± 0.2° 29).

114. The crystalline form of any one of claims 111-113, characterized by an XRPD pattern substantially as shown in FIG. 69.

115. The crystalline form of any one of claims 111-114, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 215°C.

116. The crystalline form of any one of claims 111-115, characterized by a DSC thermogram substantially as shown in FIG. 70.

117. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)- 2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 10.6, 16.9, 18.0, 20.0, 21.7, 22.6, 24.5, 25.5, or 27.3° 20 (± 0.2° 29), maleate Form I.

118. The crystalline form of claim 117, characterized by an XRPD pattern comprising peaks at 10.6, 16.9, 18.0, 20.0, 21.7, 22.6, 24.5, 25.5, and 27.3° 29 (± 0.2° 20).

119. The crystalline form of claim 117 or 118, characterized by an XRPD pattern comprising peaks at 9.1, 10.0, 10.6, 12.9, 13.7, 15.0, 15.5, 16.1, 16.9, 17.2, 18.0, 18.4, 19.2, 20.0, 21.7, 22.6, 24.5, 24.8, 25.5, 25.9, 26.1, 27.3, 30.0, 30.6, 31.8, 33.1, and 38.3° 29 (± 0.2° 29).

120. The crystalline form of any one of claims 117-119, characterized by an XRPD pattern substantially as shown in FIG. 71.

121. The crystalline form of any one of claims 117-120, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 198°C.

122. The crystalline form of any one of claims 117-121, characterized by a DSC thermogram substantially as shown in FIG. 72.

123. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)- 2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 9.4, 14.4, 16.2, 17.4, 17.9, 18.9, 20.3, 21.5, or 24.3° 29 (± 0.2° 29), L-tartrate Form I.

124. The crystalline form of claim 123, characterized by an XRPD pattern comprising peaks at 9.4, 14.4, 16.2, 17.4, 17.9, 18.9, 20.3, 21.5, and 24.3° 29 (± 0.2° 20).

125. The crystalline form of claim 123 or 124, characterized by an XRPD pattern comprising peaks at 8.2, 8.7, 9.4, 12.7, 13.5, 14.4, 14.7, 15.2, 16.2, 17.4, 17.9, 18.9, 19.2, 19.7, 20.3, 21.5, 21.9, 23.0, 23.8, 24.3, 24.8, 25.4, 26.5, 27.5, 29.0, 29.7, and 33.4° 29 (± 0.2° 29).

126. The crystalline form of any one of claims 123-125, characterized by an XRPD pattern substantially as shown in FIG. 75.

127. The crystalline form of any one of claims 123-126, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 113°C.

128. The crystalline form of any one of claims 123-127, characterized by a DSC thermogram substantially as shown in FIG. 76.

129. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)- 2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 11.7, 13.9, 18.6, 21.8, 23.1, 24.5, 26.1, 28.8, or 29.5° 26 (± 0.2° 26), L-tartrate Form II.

136. The crystalline form of claim 129, characterized by an XRPD pattern comprising peaks at 11.7, 13.9, 18.6, 21.8, 23.1, 24.5, 26.1, 28.8, and 29.5° 26 (± 6.2° 26).

131. The crystalline form of claim 129 or 136, characterized by an XRPD pattern comprising peaks at 7.7, 8.6, 8.3, 11.3, 11.7, 13.9, 14.3, 15.6, 16.6, 16.9, 18.6, 18.6,18.9, 26.2, 26.5, 21.8, 22.2, 22.6, 23.1, 23.6, 24.5, 25.2, 26.1, 26.7, 27.6, 28.8, 29.5, 36.6,36.9, 31.4, 32.6, 33.5, 34.8, 36.3, 37.5, and 38.6° 26 (± 6.2° 26).

132. The crystalline form of any one of claims 129-131, characterized by an XRPD pattern substantially as shown in FIG. 77.

133. The crystalline form of any one of claims 129-132, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 26, 97, and 172°C.

134. The crystalline form of any one of claims 129-133, characterized by a DSC thermogram substantially as shown in FIG. 78.

135. A crystalline form of (R)-5-fluoro-2-methyl-l-((R)-5-(pyridin-2-yl)- 2,3 -dihydro- lH-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 ) :characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 4.9, 9.8, 17.1, 18.6, 19.6, 20.2, 20.8, 22.0, or 24.6° 20 (± 0.2°29), L-tartrate Form III.

136. The crystalline form of claim 135, characterized by an XRPD pattern comprising peaks at 4.9, 9.8, 17.1, 18.6, 19.6, 20.2, 20.8, 22.0, and 24.6° 29 (± 0.2° 20).

137. The crystalline form of claim 135 or 136, characterized by an XRPD pattern comprising peaks at 4.9, 9.8, 12.2, 13.7, 15.4, 17.1, 17.9, 18.6, 19.6, 20.2, 20.8, 22.0, 23.4, 24.6, 25.2, 26.5, 28.2, 29.2, 29.9, 30.6, 32.1, 33.9, 36.3, and 38.5° 29 (± 0.2° 29).

138. The crystalline form of any one of claims 135-137, characterized by an XRPD pattern substantially as shown in FIG. 79.

139. The crystalline form of any one of claims 135-138, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 20, 114 and 170°C.

140. The crystalline form of any one of claims 135-139, characterized by a DSC thermogram substantially as shown in FIG. 80.

141. A pharmaceutical composition comprising a crystalline form of any one of claims 1-140, and at least one pharmaceutically acceptable carrier.

142. The pharmaceutical composition of claim 141, further comprising one, two, three, or four additional therapeutic agents.

143. The pharmaceutical composition of claim 142, wherein the additional therapeutic agents are selected from famciclovir, acyclovir, and valacyclovir.

144. A method of treating a herpesvirus infection comprising administering to a patient a therapeutically effective amount of a crystalline form of any one of claims 1- 140, or a pharmaceutical composition of any one of claims 141-143, to a patient in need thereof.

145. The method of claim 144, wherein the method comprises administering a crystalline form of any one of claims 1-140, or a pharmaceutical composition of any one of claims 141-143, in combination with one, two, three, or four additional therapeutic agents.

146. The method of claim 144 or 145, wherein the herpesvirus is HSV-1 or HSV-2.

147. A method of treating a disorder induced, exacerbated, or accelerated by herpesviruses, comprising administering to a patient a therapeutically effective amount of a crystalline form of any one of claims 1-140, or a pharmaceutical composition of any one of claims 141-143, to a patient in need thereof.

148. The method of claim 147, wherein the disorder is genital herpes, herpes labialis, HSV keratitis, HSV encephalitis, or disseminated HSV.

149. The method of claim 147 or 148, wherein the method comprises administering a crystalline form of any one of claims 1-140, or a pharmaceutical composition of any one of claims 141-143, in combination with one, two, three, or four additional therapeutic agents.

150. The method of claim 149, wherein the one or more additional therapeutic agents are administered simultaneously with the crystalline form or the pharmaceutical composition.

151. Use of a crystalline form of any one of claims 1-140, or a pharmaceutical composition of any one of claims 141-143, in the manufacture of a medicament for treating a HSV infection.

152. Use of a crystalline form of any one of claims 1-140, or a pharmaceutical composition of any one of claims 141-143, in the treatment of a viral infection.

153. Use of a crystalline form of any one of claims 1-140, or a pharmaceutical composition of any one of claims 141-143, in the treatment of a viral infection caused by herpesviruses.

154. Use of a crystalline form of any one of claims 1-140, or a pharmaceutical composition of any one of claims 141-143, in the treatment of a viral infection caused by HSV-1 or HSV-2.

155. Use of a crystalline form of any one of claims 1-140, or a pharmaceutical composition of any one of claims 141-143, for the preparation of a medicament for treating a viral infection.

156. Use of a crystalline form of any one of claims 1-140, or a pharmaceutical composition of any one of claims 141-143, for the preparation of a medicament for treating a viral infection caused by herpesviruses.

157. Use of a crystalline form of any one of claims 1-140, or a pharmaceutical composition of any one of claims 141-143, for the preparation of a medicament for treating a viral infection caused by HSV-1 or HSV-2.

158. The crystalline form of any one of claims 1-140, or a pharmaceutical composition of any one of claims 141-143, for use in a method of treating a viral infection caused by HSV-1 or HSV-2.

159. The crystalline form or pharmaceutical composition for use of claim 158, wherein the viral infection is genital herpes, herpes labialis, HSV keratitis, HSV encephalitis, or disseminated HSV.

160. The crystalline form or pharmaceutical composition for use of claim 158 or 159, wherein the compound thereof is administered in combination with an additional therapeutic agent.

161. The crystalline form of any one of claims 1-140, or a pharmaceutical composition of any one of claims 141-143, for use in therapy.

162. A process to prepare Compound 1 Form I, the process comprising the steps of: a) providing a solution of Compound 1 in a first solvent system; b) concentrating the solution from step a) and / or adding a second solvent system to the solution from step a); c) mixing the mixture obtained from step b); d) optionally, isolating the solids formed from step c); and e) optionally, drying the solids isolated from step d).

163. A process to prepare Compound 1 Mesylate Form I, the process comprising the steps of: a) providing a solution of Compound 1 in a first solvent system; b) adding methanesulfonice acid in a second solvent system to the solution from step a); c) optionally, cooling the mixture obtained from step b); d) optionally, isolating the solids formed from step c); and e) optionally, drying the solids isolated from step d).

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