Solid forms of hsv helicase-primase inhibitors

Abstract

The present disclosure provides crystalline forms, solvates, and hydrates of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-inden-2-carbonyl)indoline-6-sulfonamide and methods of preparation.

Description

Cross-reference to related applications

[0001] This application claims priority to U.S. Provisional Application 63 / 600,285, filed November 17, 2023, which is incorporated herein in its entirety for all purposes. Technical Field

[0002] This disclosure relates to solid forms of indolinel compounds. This disclosure also relates to the use of these solid forms in the treatment of viral infections. Background Technology

[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 infectious human pathogens. HSV-1 is primarily transmitted through oral-oral contact, causing oral herpes, while HSV-2 is a sexually transmitted infection causing genital herpes. These infections are lifelong and are characterized by periodic reactivation and viral shedding, which can lead to symptoms such as painful blisters or ulcers and spread to others. Currently available drugs for treating these infections are mainly based on nucleoside analogues such as acyclovir, famciclovir, and valacyclovir. While these compounds are effective in reducing the severity and frequency of symptoms, they do not eliminate viral shedding, thus posing a risk of transmission. Furthermore, the administration regimens are complex and inconvenient.

[0004] Herpesviruses encode their own helicases and primases for the synthesis of viral DNA. The helicase-primase complex plays a crucial role in viral DNA replication. The helicase severs the viral DNA double helix, and the primase synthesizes RNA primers on single-stranded DNA, which initiate DNA synthesis directed by 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, thus facilitating the development of drugs with desired selectivity, potency, metabolic stability, or reduced harmful effects. Summary of the Invention

[0006] In one embodiment, this disclosure provides a crystalline form of compound 1 having the following structure: And its salts, solvates or hydrates.

[0007] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): The crystalline forms are: 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-tert-butyl ether Solvate 1, Compound 1 Methyl-tert-butyl ether Solvate 2, Compound 1 2-Butanol Solvate, Compound 1 Tert-Butanol Solvate, Compound 1 p-Dioxane Solvate, Compound 1 Cyclopentylmethyl Ether Solvate, Compound 1 Dimethylacetamide Solvate, Compound 1 Hydrochloride Form I, Compound 1 Hydrochloride Form II, Compound 1 Hemisulfate Form I, Compound 1 Sulfate Form I, Compound 1 Methanesulfonate Form I, Compound 1 Ethylsulfonate Form I, Compound 1 Benzenesulfonate Form I, Compound 1 Benzenesulfonate Form II, Compound 1 Toluenesulfonate Form I, Compound 1 Naphthalenesulfonate 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, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5. o 2θ (±0.2) o An X-ray powder diffraction (XRPD) pattern with five or more peaks at 2θ, in form I.

[0009] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 12.6, 13.9, 15.3, 18.5, 19.2, 19.7, 22.3, 23.4, or 24.3.o 2θ (±0.2) o An X-ray powder diffraction (XRPD) pattern with five or more peaks at 2θ, form II.

[0010] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 10.0, 12.2, 17.3, 18.3, 20.1, 22.0, 23.7, 25.3, or 25.9. o 2θ (±0.2) o An X-ray powder diffraction (XRPD) pattern with five or more peaks at 2θ, type III.

[0011] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 5.7, 11.2, 16.8, 17.1, 18.7, 21.4, 22.4, 23.3, or 23.8. o 2θ (±0.2) o An X-ray powder diffraction (XRPD) pattern with five or more peaks at 2θ, in form IV.

[0012] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes values ​​of 10.0, 11.8, 13.9, 17.6, 18.1, 18.5, 18.9, 19.6, or 26.0. o 2θ (±0.2) o An X-ray powder diffraction (XRPD) pattern with five or more peaks at 2θ, in form V.

[0013] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes values ​​of 12.2, 14.9, 17.5, 20.0, 20.6, 21.8, 23.6, 25.4, or 26.0. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, monohydrate.

[0014] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 8.1, 9.6, 11.7, 16.3, 18.8, 24.5, 25.7, 25.9, or 27.9. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, dihydrate.

[0015] In another embodiment, this disclosure provides a MeTHF solvate of compound 1, characterized substantially as follows: Figure 26 The XRPD pattern shown.

[0016] In another embodiment, this disclosure provides compound 1, MTBE solvate 1, characterized in that it is substantially as follows: Figure 29 The XRPD pattern shown.

[0017] In another embodiment, this disclosure provides compound 1 MTBE solvate 2, characterized in that it is substantially as follows: Figure 30 The XRPD pattern shown.

[0018] In another embodiment, this disclosure provides a solvate of compound 1 2-BuOH, characterized substantially as follows: Figure 33 The XRPD pattern shown.

[0019] In another embodiment, this disclosure provides a solvate of compound 1 t-BuOH, characterized in that it is substantially as follows: Figure 35 The XRPD pattern shown.

[0020] In another embodiment, this disclosure provides compound 1 as a dioxane solvate, characterized substantially as follows: Figure 36 The XRPD pattern shown.

[0021] In another embodiment, this disclosure provides a CPME solvate of compound 1, characterized substantially as follows: Figure 37 The XRPD pattern shown.

[0022] In another embodiment, this disclosure provides a DMAc solvate of compound 1, characterized substantially as follows: Figure 39 The XRPD pattern shown.

[0023] In another embodiment, this disclosure provides an intermediate phase of compound 1, characterized substantially as follows: Figure 42 The XRPD pattern shown.

[0024] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes values ​​of 8.9, 12.5, 18.9, 19.6, 20.8, 23.8, 24.4, 24.8, or 28.8. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, hydrochloride form I.

[0025] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 8.3, 12.4, 15.3, 19.2, 22.6, 24.0, 24.8, 26.3, or 28.3. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, hydrochloride form II.

[0026] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes values ​​of 9.6, 11.9, 16.5, 19.4, 20.1, 22.6, 23.8, or 25.8. o 2θ (±0.2)o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, hemisulfate form I.

[0027] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 9.6, 19.1, 19.4, 20.4, 22.3, 23.6, or 25.5. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, in sulfate form I.

[0028] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, or 29.6. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, methanesulfonate form I.

[0029] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 7.0, 17.9, 18.4, 20.1, 20.8, 23.0, 23.4, 24.0, or 25.8. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, ethanesulfonate form I.

[0030] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 11.3, 14.9, 16.1, 18.4, 19.8, 21.0, 22.8, or 24.9. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, benzenesulfonate form I.

[0031] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features include 12.2, 18.0, 19.3, and 21.7. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of the peak at 2θ, benzenesulfonate form II.

[0032] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 4.1, 8.1, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5, or 24.5. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, toluenesulfonate form I.

[0033] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 6.6, 12.3, 17.8, 19.0, 21.2, 22.2, 23.9, 25.8, or 26.6. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, naphthalene sulfonate form I.

[0034] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes values ​​of 10.6, 16.9, 18.0, 20.0, 21.7, 22.6, 24.5, 25.5, or 27.3. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, maleate form I.

[0035] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 9.4, 14.4, 16.2, 17.4, 17.9, 18.9, 20.3, 21.5, or 24.3. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, L-tartrate form I.

[0036] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 11.7, 13.9, 18.6, 21.8, 23.1, 24.5, 26.1, 28.8, or 29.5. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, L-tartrate form II.

[0037] In another embodiment, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes values ​​of 4.9, 9.8, 17.1, 18.6, 19.6, 20.2, 20.8, 22.0, or 24.6.o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, L-tartrate form III.

[0038] In some embodiments, this document provides pharmaceutical compositions comprising the crystalline form of compound 1 of this disclosure and a pharmaceutically acceptable carrier.

[0039] In some embodiments, this document provides a method for treating herpes virus infection, comprising administering to a patient in need a therapeutically effective amount of the crystalline form of compound 1 provided herein or the pharmaceutical composition provided herein.

[0040] In some embodiments, this document provides a method for treating a condition induced, exacerbated, or accelerated by a herpes virus, the method comprising administering to a patient in need a therapeutically effective amount of the crystalline form of compound 1 provided herein or a pharmaceutical composition provided herein.

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

[0042] In some embodiments, this document provides the use of the crystalline form of compound 1 provided herein or the pharmaceutical composition provided herein in the treatment of viral infections.

[0043] In some embodiments, this document provides the use of the crystalline form of compound 1 provided herein or the pharmaceutical composition provided herein in the treatment of viral infections caused by herpesviruses.

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

[0045] In some embodiments, this document provides the use of the crystalline form of Compound 1 provided herein or the pharmaceutical composition provided herein for the preparation of a medicament for the prevention / treatment of viral infections.

[0046] In some embodiments, this document provides the use of the crystalline form of Compound 1 provided herein or the pharmaceutical composition provided herein for the preparation of a medicament for the prevention / treatment of viral infections caused by herpesviruses.

[0047] In some embodiments, this document provides the use of the crystalline form of Compound 1 provided herein or the pharmaceutical composition provided herein for the preparation of a medicament for the prevention / treatment of viral infections caused by HSV-1 or HSV-2.

[0048] In some embodiments, this document provides a crystalline form of compound 1 provided herein or a pharmaceutical composition provided herein for use in a method of treating viral infections caused by HSV-1 or HSV-2.

[0049] In one embodiment, a method for preparing compound 1 in form I is provided.

[0050] In one embodiment, compound form I, which can be obtained by the methods described herein, is provided.

[0051] In one embodiment, a method for preparing compound 1 in methanesulfonate form I is provided.

[0052] In one embodiment, compound 1 in methanesulfonate form I is provided, which can be obtained by the methods described herein. Attached Figure Description

[0053] Figure 1 The XRPD pattern of compound 1, form I, is shown.

[0054] Figure 2 The DSC thermogram of compound 1, form I, is shown.

[0055] Figure 3 The TGA thermogram of compound 1, form I, is shown.

[0056] Figure 4 DVS analysis of compound 1, form I, is shown.

[0057] Figure 5 The XRPD pattern of compound 1 form II is shown.

[0058] Figure 6 The DSC thermogram of compound 1, form II, is shown.

[0059] Figure 7 The TGA thermogram of compound 1, form II, is shown.

[0060] Figure 8 DVS analysis of compound 1, form II, is shown.

[0061] Figure 9 The XRPD pattern of compound form III is shown.

[0062] Figure 10 The DSC thermogram of compound 1, form III, is shown.

[0063] Figure 11 The TGA thermogram of compound 1, form III, is shown.

[0064] Figure 12 DVS analysis of compound 1, form III, is shown.

[0065] Figure 13 The XRPD pattern of compound 1 form IV is shown.

[0066] Figure 14 The DSC thermogram of compound 1 in form IV is shown.

[0067] Figure 15 The TGA thermogram of compound 1 in form IV is shown.

[0068] Figure 16 DVS analysis of compound 1 in form IV is shown.

[0069] Figure 17 The XRPD pattern of compound 1 in form V is shown.

[0070] Figure 18 The DSC thermogram of compound 1 in form V is shown.

[0071] Figure 19 The TGA thermogram of compound 1 in form V is shown.

[0072] Figure 20 The XRPD pattern of compound 1 hydrate is shown.

[0073] Figure 21 The DSC thermogram of compound 1 hydrate is shown.

[0074] Figure 22 The TGA thermogram of compound 1 hydrate is shown.

[0075] Figure 23 The XRPD pattern of compound 1 dihydrate is shown.

[0076] Figure 24 The DSC thermogram of compound 1 dihydrate is shown.

[0077] Figure 25 The TGA thermogram of compound 1 dihydrate is shown.

[0078] Figure 26 The XRPD pattern of the MeTHF solvate of compound 1 is shown.

[0079] Figure 27 The DSC thermogram of the solvate of compound 1 MeTHF is shown.

[0080] Figure 28 The TGA thermogram of the solvate of compound 1 MeTHF is shown.

[0081] Figure 29 The XRPD pattern of compound 1 MTBE solvate 1 is shown.

[0082] Figure 30 The XRPD pattern of compound 1 MTBE solvate 2 is shown.

[0083] Figure 31 The DSC thermogram of compound 1, MTBE solvate 2, is shown.

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

[0085] Figure 33 The XRPD pattern of the 2-BuOH solvate of compound 1 is shown.

[0086] Figure 34 The DSC thermogram of the solvate of compound 1, 2-BuOH, is shown.

[0087] Figure 35 The XRPD pattern of compound 1 t-BuOH solvate is shown.

[0088] Figure 36 The XRPD pattern of compound 1 with dioxane solvate is shown.

[0089] Figure 37 The XRPD pattern of the CPME solvate of compound 1 is shown.

[0090] Figure 38 The DSC thermogram of the CPME solvate of compound 1 is shown.

[0091] Figure 39 The XRPD pattern of the DMAc solvate of compound 1 is shown.

[0092] Figure 40 The DSC thermogram of the DMAc solvate of compound 1 is shown.

[0093] Figure 41 The TGA thermogram of the DMAc solvate of compound 1 is shown.

[0094] Figure 42 The XRPD pattern of the mesophase of compound 1 is shown.

[0095] Figure 43 An XRPD pattern of compound 1 hydrochloride form I is shown.

[0096] Figure 44 The DSC thermogram of compound 1 in hydrochloride form I is shown.

[0097] Figure 45 The TGA thermogram of compound 1 in hydrochloride form I is shown.

[0098] Figure 46 DVS analysis of compound 1 hydrochloride form I is shown.

[0099] Figure 47 The XRPD pattern of compound 1 hydrochloride form II is shown.

[0100] Figure 48 The DSC thermogram of compound 1 in hydrochloride form II is shown.

[0101] Figure 49 The TGA thermogram of compound 1 in hydrochloride form II is shown.

[0102] Figure 50 DVS analysis of compound 1 hydrochloride form II is shown.

[0103] Figure 51 An XRPD pattern of compound 1 in hemisulfate form I is shown.

[0104] Figure 52 The DSC thermogram of compound 1 in hemisulfate form I is shown.

[0105] Figure 53 An XRPD pattern of compound 1 in sulfate form I is shown.

[0106] Figure 54 The DSC thermogram of compound 1 in sulfate form I is shown.

[0107] Figure 55 An XRPD pattern of compound 1 in methanesulfonate form I is shown.

[0108] Figure 56 The DSC thermogram of compound 1 in its methanesulfonate form I is shown.

[0109] Figure 57 The TGA thermogram of compound 1 in its methanesulfonate form I is shown.

[0110] Figure 58 DVS analysis of compound 1 in its methanesulfonate form I is shown.

[0111] Figure 59 An XRPD pattern of compound 1 in ethanesulfonate form I is shown.

[0112] Figure 60 The DSC thermogram of compound 1 in ethanesulfonate form I is shown.

[0113] Figure 61 The TGA thermogram of compound 1 in ethanesulfonate form I is shown.

[0114] Figure 62 The DVS analysis of compound 1 in ethanesulfonate form I is shown.

[0115] Figure 63 An XRPD pattern of compound 1 benzenesulfonate form I is shown.

[0116] Figure 64 The DSC thermogram of compound 1 in benzenesulfonate form I is shown.

[0117] Figure 65 The XRPD pattern of compound 1 benzenesulfonate form II is shown.

[0118] Figure 66 The DSC thermogram of compound 1 in benzenesulfonate form II is shown.

[0119] Figure 67 An XRPD pattern of compound 1 in toluenesulfonate form I is shown.

[0120] Figure 68 The DSC thermogram of compound 1 in toluenesulfonate form I is shown.

[0121] Figure 69 An XRPD pattern of compound 1 naphthalene sulfonate form I is shown.

[0122] Figure 70 The DSC thermogram of compound 1 naphthalene sulfonate form I is shown.

[0123] Figure 71 An XRPD pattern of maleate form I of compound 1 is shown.

[0124] Figure 72 The DSC thermogram of maleate form I of compound 1 is shown.

[0125] Figure 73 The TGA thermogram of maleate form I of compound 1 is shown.

[0126] Figure 74 The DVS analysis of maleate form I of compound 1 is shown.

[0127] Figure 75 An XRPD pattern of compound 1 in L-tartrate form I is shown.

[0128] Figure 76 The DSC thermogram of compound 1 in L-tartrate form I is shown.

[0129] Figure 77 The XRPD pattern of compound 1 in L-tartrate form II is shown.

[0130] Figure 78 The DSC thermogram of compound 1 in L-tartrate form II is shown.

[0131] Figure 79 The XRPD pattern of compound 1 in L-tartrate form III is shown.

[0132] Figure 80 The DSC thermogram of compound 1 in L-tartrate form III is shown.

[0133] Figure 81 The XRPD overlay of the sample from the stability study of compound 1, form I, is shown.

[0134] Figure 82 The XRPD overlay image shows the stability study sample of compound 1 methanesulfonate form I.

[0135] Figure 83 The pharmacokinetic (PK) curves of compound 1 form I (free base) and compound 1 methanesulfonate form I (MSA salt) pretreated with pentagastrin are shown.

[0136] Figure 84 The DCS thermogram of compound 1, form I, is shown.

[0137] Figure 85 The DCS thermogram of compound 1 in its methanesulfonate form I is shown. Detailed Implementation

[0138] I. Overview This disclosure arises from the following surprising discovery: the solid form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): And its salts, solvates, or eutectic forms. Compound 1 can be in various crystalline forms, including but not limited to forms I, II, III, IV, V, monohydrate, dihydrate, methyl-tetrahydrofuran (MeTHF) solvate, methyl tert-butyl ether (MTBE) solvate 1, MTBE solvate 2, 2-butanol solvate, tert-butanol solvate, p-dioxane solvate, cyclopentylmethyl ether (CPME) solvate, dimethylacetamide (DMAc) solvate, hydrochloride form I, hydrochloride form II, hemisulfate form I, sulfate form I, methanesulfonate form I, ethanesulfonate form I, benzenesulfonate form I, benzenesulfonate form II, toluenesulfonate form I, naphthalenesulfonate 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 a single crystalline form substantially free of other crystalline forms.

[0139] The solid-state X-ray powder diffraction (XRPD) pattern of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-inden-2-carbonyl)indoline-6-sulfonamide (compound 1) provided in this paper was obtained using Cu K α Radiation collected (1.5419 Å).

[0140] II. Definition It should be understood in the following description that this disclosure is considered illustrative of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience and should not be construed as limiting the claims in any way. Embodiments exemplified under any heading may be combined with embodiments exemplified under any other heading.

[0141] 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. It must be noted that, as used herein and in the appended claims, the singular forms “an,” “a,” and “the” include plural references unless the context clearly specifies otherwise. Thus, for example, reference to “compound” includes a plurality of such compounds, and reference to “determination” includes reference to one or more determinations and their equivalents known to one of ordinary skill in the art, and so on.

[0142] As used in this specification, the following terms and phrases are generally intended to have the meanings described below, unless the context in which they are used indicates otherwise.

[0143] The term "about" as used herein includes (and describes) embodiments relating to that value or parameter itself. In some embodiments, the term "about" includes an indicated amount ±10%. In other embodiments, the term "about" includes an indicated amount ±5%. In some other embodiments, the term "about" includes an indicated amount ±1%. Furthermore, the term "about X" includes a description of "X". Moreover, unless the context clearly specifies otherwise, the singular forms "a" and "the" include plural references. Thus, for example, reference to "compound" includes a variety of such compounds, and reference to "assay" includes reference to one or more assays and their equivalents known to those skilled in the art.

[0144] Throughout this specification, values ​​are disclosed in the form of groups or ranges. It is expressly intended that this specification include all individual sub-combinations of the members of such groups and ranges, as well as any combination of the endpoints of such groups or ranges. For example, integers in the range 0 to 40 are expressly intended to be disclosed individually as 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 integers in the range 1 to 20 are expressly intended to be disclosed individually as 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 embodiments or exemplary language (e.g., "such as", "including", or "for example") herein is intended only to better illustrate the teachings of the invention and does not constitute a limitation on the scope of the invention as otherwise claimed.

[0146] A "crystalline form" is a solid material in which its constituent parts are arranged in a highly ordered microstructure, forming a lattice extending in all directions. Crystalline forms can include anhydrous crystalline forms, solvated crystalline forms, and / or hydrated crystalline forms. Salts of compounds can also exist in crystalline forms.

[0147] "Polymorphism" refers to the fact that a solid material can exist in more than one crystalline form.

[0148] As used herein, the term "amorphous" refers to a solid material in which there is no long-range order in the positions of its molecules. An amorphous solid is a substance in which molecules are arranged in a random manner, such that there is no definite arrangement, e.g., molecular packing, and no long-range order. Amorphous solids are typically isotropic, meaning they exhibit similar properties in all directions and do not have a definite melting point. For example, an amorphous material is a solid material in which there are no sharp characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., it is not crystalline, as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of amorphous solids.

[0149] "Hydrate" refers to a complex formed by mixing compound 1 with water. This term includes stoichiometric hydrates (such as monohydrates and dihydrates) as well as non-stoichiometric hydrates. As used herein, the term "hydrate" refers to the solid form (i.e., compound 1) in aqueous solution, although it can be hydrated, but not as a hydrate as used herein. Hydrates can be crystalline, in which both the compound and water form part of a crystal lattice.

[0150] A "solvent" is a complex formed by mixing compound 1 with a solvent. For example, methanol or ethanol can form an "alcohol," which can be stoichiometric or non-stoichiometric. As used herein, the term "solvent" refers to a solid form (i.e., compound 1) in the form of a solvent solution, although it can be solvated, but is not a solvate as used herein. Solvents can be crystalline, in which both the compound and the solvent form part of a crystal lattice.

[0151] "Desolvation" refers to a form of Compound 1 that is a solvate as described herein and from which solvent molecules have been partially or completely removed. Desolvation techniques for preparing a desolvated form include, but are not limited to, exposing the form of Compound 1 (the solvate) to a vacuum, subjecting the solvate to high temperatures, exposing the solvate to a gas stream (such as air or nitrogen), or any combination thereof. Thus, a desolvated form of Compound 1 can be completely free of solvent molecules or partially solvated, wherein solvent molecules are present in stoichiometric or non-stoichiometric amounts.

[0152] "Anhydrous" means that the solid form of the compound contains no water incorporated into its structure. For example, the anhydrous crystalline form contains no water forming part of its crystalline structure. Those skilled in the art will know techniques that can be used to quantify the amount of water associated with the solid. For example, the water content can be determined by Karl Fischer titration or thermogravimetric analysis (TGA). Suitably, the anhydrous solid form of the compound contains less than about 2% by weight, such as less than about 1.5% by weight, less than about 1% by weight, such as less than about 0.5% by weight, about 0.4% by weight, about 0.3% by weight, about 0.2% by weight, about 0.1% by weight, about 0.05% by weight, or about 0.01% by weight of water.

[0153] "Unsolvated" or "non-solvated" means that the solid form of the compound has no solvent incorporated into its structure. For example, the unsolvated crystalline form has no solvent forming part of its crystal structure. Those skilled in the art will know techniques to quantify the amount of solvent associated with the solid. For example, the solvent content can be determined by gas chromatography (GC). Suitably, the unsolvated or non-solvated solid form of the compound contains less than about 2% by weight, such as less than about 1.5% by weight, less than about 1% by weight, such as less than about 0.5% by weight, about 0.4% by weight, about 0.3% by weight, about 0.2% by weight, about 0.1% by weight, about 0.05% by weight, or about 0.01% by weight of solvent.

[0154] The "intermediate phase" or "mesocrystalline phase" is a phase of matter that lies between a solid and a liquid.

[0155] "Alcohol" refers to a solvent containing a hydroxyl group. Representative alcohols may have any suitable number of carbon atoms, such as C1-C6, and any suitable number of hydroxyl groups, such as 1-3. Exemplary alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, etc.

[0156] "Substantially free from other crystalline forms of compound 1" means that the crystalline form of compound 1 contains less than 10% of other crystalline forms of compound 1. For example, substantially free from could mean that the crystalline form of compound 1 contains less than 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of other crystalline forms of compound 1. Preferably, substantially free from means that the crystalline form of compound 1 contains less than 5% of other crystalline forms of compound 1. More preferably, substantially free from means that the crystalline form of compound 1 contains less than 1% of other crystalline forms of compound 1.

[0157] The disclosure described illustratively herein may be practiced appropriately in the absence of any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be understood broadly and without limitation. Furthermore, the terminology and expressions used herein have been used descriptively rather than restrictively, and are not intended to exclude any equivalents or portions thereof of the features shown and described, but it should be recognized that various modifications are possible within the scope of this claimed disclosure.

[0158] Furthermore, this disclosure provides pharmaceutical compositions comprising a crystalline form of compound 1 of this disclosure as an active ingredient and a pharmaceutically acceptable carrier.

[0159] "Pharmaceutical composition" means one or more active ingredients, one or more inert ingredients constituting a carrier, and any product obtained directly or indirectly from the combination, complexation, or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical compositions disclosed herein may cover any composition prepared by mixing at least one compound of this disclosure with a pharmaceutically acceptable carrier.

[0160] As used herein, “pharmaceutically acceptable carriers” include excipients or reagents that are harmless to the disclosed compound or its intended use, such as solvents, diluents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic and absorption-retarding agents, etc. Compositions for preparing pharmaceutically active substances using such carriers and reagents are well known in the art (see, for example, “Remington’s Pharmaceutical Sciences,” Mace Publishing Co., Philadelphia, PA, 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (edited by GSBanker and CTRhodes).

[0161] "Treatment / treating" is a method used to achieve beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes include one or more of the following: a) suppressing a disease or symptom (e.g., reducing one or more symptoms caused by the disease or symptom, and / or attenuating the severity of the disease or symptom); b) slowing or halting the development of one or more clinical symptoms associated with the disease or symptom (e.g., stabilizing the disease or symptom, delaying the worsening or progression of the disease or symptom, and / or delaying its spread (e.g., metastasis of the disease or symptom); and / or c) alleviating the disease, i.e., leading to the resolution of clinical symptoms (e.g., improving the disease state, providing partial or overall relief of the disease or symptom, enhancing the effect of another medication, delaying the progression of the disease, increasing quality of life, and / or prolonging survival). In some embodiments, the term “treatment” means applying the crystalline form of compound 1 of this disclosure for the purpose of: (i) delaying the onset of disease, i.e., preventing or delaying the development of clinical symptoms of the disease; (ii) inhibiting the disease, i.e. preventing the development of clinical symptoms; and / or (iii) alleviating the disease, i.e. causing the reduction of clinical symptoms or their severity.

[0162] "Prevention" means any treatment that prevents the development of any clinical symptoms of a disease or condition. In some implementations, the compound may be administered to subjects (including humans) who are at risk or have 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 humans), which has been or will be the subject of treatment, observation, or experimentation. The methods described herein can be used for human therapeutics and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. Ideally, the mammal treated in the methods of this disclosure is a mammal for which HSV infection is desired to be treated.

[0164] The term "therapeutic effective amount" or "effective amount" in the crystalline form of Compound 1 described herein means an amount sufficient to provide therapeutic benefit (such as improvement of symptoms or slowing of disease progression) when administered to a subject. For example, a therapeutic effective amount may be an amount sufficient to alleviate symptoms of a disease or symptom in response to a herpesvirus helicase-primase inhibitor. The therapeutic effective amount may vary depending on the subject, the disease or symptom being treated, the subject's weight and age, the severity of the disease or symptom, and the method of administration, which can be readily determined by those skilled in the art.

[0165] In this document, when a composition is referred to as "consisting substantially of a particular component," the composition suitably comprises at least 70% by weight of the component, suitably at least 80% by weight of the component, suitably at least 90% by weight of the component, suitably at least 95% by weight of the component, and most preferably at least 99% by weight of the component. Suitably, a composition referred to as "consisting substantially of a particular component" consists of the component, in addition to one or more trace components.

[0166] The phrase “basically as shown” means that 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 the features of the X-ray powder diffraction pattern or DSC thermogram appear in the figure.

[0167] The term "relative volume" refers to the volume (in mL) of liquid used relative to the mass (in grams) of compound 1. For example, 10 relative volumes of solvent are equivalent to 10 mL per gram of compound 1.

[0168] The phrase "FIG." is an abbreviation for "Figure."

[0169] III. Solid form of compound 1 This disclosure provides (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1; see Example 35 of PCT application PCT / US2023 / 022679, and the published reference WO2023 / 225162 A1) in solid form, including crystalline and mesophase forms, as well as salt, solvate, and hydrate forms. In some embodiments, this disclosure provides a crystalline form of Compound 1 having the following structure: And its salts, solvates or hydrates.

[0170] Compound 1 can be in various crystalline forms, including but not limited to forms I, II, III, IV, V, monohydrate, dihydrate, methyl-tetrahydrofuran (MeTHF) solvate, methyl tert-butyl ether (MTBE) solvate 1, MTBE solvate 2, 2-butanol solvate, tert-butanol solvate, p-dioxane solvate, cyclopentylmethyl ether (CPME) solvate, dimethylacetamide (DMAc) solvate, hydrochloride form I, hydrochloride form II, hemisulfate form I, sulfate form I, methanesulfonate form I, ethanesulfonate form I, benzenesulfonate form I, benzenesulfonate form II, toluenesulfonate form I, naphthalenesulfonate 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 a single crystalline form that is substantially free of other crystalline forms.

[0171] In some embodiments, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Or a pharmaceutically acceptable salt or cocrystal thereof. The crystalline form of compound 1 may be anhydrous, a salt, a solvate, a hydrate, or a cocrystal. In some embodiments, the crystalline form of compound 1 may be a salt or a cocrystal. In some embodiments, the crystalline form of compound 1 may be anhydrous or solvated. In some embodiments, the crystalline form of compound 1 may be hydrated.

[0172] In some embodiments, this disclosure provides the crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): The crystalline forms are: 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-tert-butyl ether Solvate 1, Compound 1 Methyl-tert-butyl ether Solvate 2, Compound 1 2-Butanol Solvate, Compound 1 Tert-Butanol Solvate, Compound 1 p-Dioxane Solvate, Compound 1 Cyclopentylmethyl Ether Solvate, Compound 1 Dimethylacetamide Solvate, Compound 1 Hydrochloride Form I, Compound 1 Hydrochloride Form II, Compound 1 Hemisulfate Form I, Compound 1 Sulfate Form I, Compound 1 Methanesulfonate Form I, Compound 1 Ethylsulfonate Form I, Compound 1 Benzenesulfonate Form I, Compound 1 Benzenesulfonate Form II, Compound 1 Toluenesulfonate Form I, Compound 1 Naphthalenesulfonate 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, this disclosure provides crystalline forms of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is compound form I, compound form II, compound form III, compound form IV or compound form V.

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

[0175] In some embodiments, this disclosure provides crystalline forms of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is a solvate of compound 1 methyl-tetrahydrofuran (MeTHF), a solvate of compound 1 methyl tert-butyl ether, a solvate of compound 1 methyl tert-butyl ether, a solvate of compound 1 2-butanol, a solvate of compound 1 tert-butanol, a solvate of compound 1 p-dioxane, a solvate of compound 1 cyclopentylmethyl ether, or a solvate of compound 1 dimethylacetamide.

[0176] In some embodiments, this disclosure provides crystalline forms of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-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 methanesulfonate form I, compound 1 ethanesulfonate form I, compound 1 benzenesulfonate form I, compound 1 benzenesulfonate form II, compound 1 toluenesulfonate form I, compound 1 naphthalenesulfonate 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.

[0177] In some embodiments, this disclosure provides crystalline forms of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form 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 methanesulfonate form I, or compound 1 maleate form I.

[0178] In a preferred embodiment, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-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 pharmaceutical products.

[0179] In a preferred embodiment, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is compound 1 methanesulfonate form I. Advantageously, compound 1 methanesulfonate form I is chemically and physically stable when stored under a variety of stability and forced degradation conditions, and has pharmacokinetic properties suitable for pharmaceutical products.

[0180] Many analytical methods exist that can be used by those skilled in the art of solid-state chemistry to characterize solid forms. As used herein, the term "characterization" means obtaining information about the solid structure of a solid form. For example, powder X-ray diffraction (PXRD / XRPD) is a suitable technique for distinguishing amorphous solid forms from crystalline solid forms, as well as for characterizing and identifying specific crystalline solid forms of compounds.

[0181] Due to variations in X-ray diffraction instruments, samples, and sample preparation, peak values ​​are often reported with the modifiers "±0.2°2θ" or "±0.1°2θ". This is common practice in solid-state chemistry due to the inherent variability in peak values. The variability in peak intensity is a result of how the individual crystals are oriented relative to the external X-ray source within the sample container (referred to as "preferred orientation"). This orientation effect does not provide information about the crystal's structure.

[0182] When the modifiers “±0.2 °2θ” and “±0.1 °2θ” are used at the end of the X-ray diffraction peak list, it should be understood that the modifier applies to each peak specified in the list.

[0183] X-ray powder diffraction is just one of several analytical techniques that can be used to characterize and / or identify crystalline solid forms. Differential scanning calorimetry (DSC) can also be used to characterize and / or identify crystalline solid forms. The typical variability of values ​​related to the onset temperature of differential scanning calorimetry is about ±2 °C.

[0184] It should be noted that, unless otherwise specified, the thermal data (DSC and TGA) presented herein were obtained using a heating rate of 10 °C / min. Furthermore, DSC data were obtained using a zero-aluminum disk.

[0185] Compound 1, Form I In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein this crystalline form is form I (specified herein and characterized as compound 1, form I). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5. o 2θ (±0.2) o An X-ray powder diffraction (XRPD) pattern with five or more peaks at 2θ, in form I.

[0186] In some embodiments, this disclosure provides compound 1 form I, characterized by comprising 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, and 26.5 o 2θ (±0.2) oXRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in form I, characterized by including 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in form I, characterized by including 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0187] In some embodiments, this disclosure provides compound 1 form I, characterized by comprising 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5 o 2θ (±0.1) o An XRPD pattern with five or more peaks at 2θ). In some embodiments, this disclosure provides compound 1, form I, characterized by including peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, and 26.5. o 2θ (±0.1) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in form I, characterized by including 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. o 2θ (±0.1) oXRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in form I, characterized by including 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. o 2θ (±0.1) o XRPD pattern of the peak at 2θ).

[0188] In some embodiments, this disclosure provides compound 1 form I, characterized by comprising 18.0, 21.2, and 23.2 o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 form I, characterized by including peaks at 18.0, 21.2, and 23.2. o 2θ (±0.2) o The peak at 2θ) and also includes at least one, two, or three peaks selected from 12.5, 18.5, and 22.8. o 2θ (±0.2) o XRPD pattern of a specific peak at 2θ).

[0189] In some embodiments, this disclosure provides compound 1 form I, characterized by comprising 18.0, 21.2, and 23.2 o 2θ (±0.1) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 form I, characterized by including peaks at 18.0, 21.2, and 23.2. o 2θ (±0.1) o The peak at 2θ) and also includes at least one, two, or three peaks selected from 12.5, 18.5, and 22.8. o 2θ (±0.1) o XRPD pattern of a specific peak at 2θ).

[0190] In some embodiments, this disclosure provides compound 1 form I, characterized by comprising 18.0, 18.5, 21.2, 22.8, and 23.2 o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 form I, characterized by including peaks at 18.0, 18.5, 21.2, 22.8, and 23.2. o 2θ (±0.1)o XRPD pattern of the peak at 2θ).

[0191] In some embodiments, this disclosure provides compound 1 form I, characterized by comprising 18.0, 21.2, and 23.2 o 2θ (±0.2) o The peak at 2θ) and also includes at least two, five, ten, fifteen, or twenty peaks selected from 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. o 2θ (±0.2) o XRPD pattern of a specific peak at 2θ).

[0192] In some embodiments, this disclosure provides compound 1 form I, characterized by comprising 18.0, 18.5, 21.2, 22.8, and 23.2 o 2θ (±0.2) o The peak at 2θ) and also includes at least two, five, ten, fifteen, or twenty peaks selected from 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. o 2θ (±0.2) o XRPD pattern of a specific peak at 2θ).

[0193] In some embodiments, this disclosure provides compound 1 form I, characterized substantially as follows: Figure 1 The XRPD pattern shown.

[0194] In some embodiments, this disclosure provides compound 1 form I, characterized by a unit cell having the following dimensions as determined by single-crystal X-ray diffraction crystallography: a = 19.6326(18) Å; b = 7.6161(7) Å; c = 14.8409(14) Å; α = 90°; β = 104.029(8)°; and γ = 90°.

[0195] In some embodiments, this disclosure provides compound 1 form I, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 230°C. In some embodiments, this disclosure provides compound 1 form I, characterized by having no thermal events between 25°C and 200°C and having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 230°C. In some embodiments, this disclosure provides compound 1 form I, characterized by being substantially as... Figure 2 The DSC thermogram shown is shown.

[0196] In some embodiments, this disclosure provides compound 1 form I, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 225°C. In some embodiments, this disclosure provides compound 1 form I, characterized by having no thermal events between 25°C and 200°C and having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 225°C. In some embodiments, this disclosure provides compound 1 form I, characterized by being substantially as... Figure 84 The DSC thermogram shown is shown.

[0197] In some embodiments, this disclosure provides compound 1 form I, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 225°C to about 230°C.

[0198] In some embodiments, this disclosure provides compound 1 form I, characterized by comprising 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5 o 2θ (±0.2) o An XRPD pattern with five or more peaks at 2θ) and a DSC thermogram having an endothermic onset temperature of about 225°C to about 230°C. In some embodiments, this disclosure provides compound 1 in form I, characterized by including 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5. o 2θ (±0.2) o An XRPD pattern with five or more peaks at 2θ) and a DSC thermogram with an endothermic onset temperature of about 225 °C. In some embodiments, this disclosure provides compound 1 in form I, characterized by including 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5. o 2θ (±0.2) o XRPD pattern with five or more peaks at 2θ) and DSC thermogram with an endothermic onset temperature of about 230 °C.

[0199] In some embodiments, this disclosure provides compound 1 form I, characterized by comprising 18.0, 21.2, and 23.2 o 2θ (±0.2) o The XRPD pattern of the peak at 2θ) and the DSC thermogram with an endothermic onset temperature of about 225°C to about 230°C. In some embodiments, this disclosure provides compound 1 in form I, characterized by including 18.0, 21.2, and 23.2 o 2θ (±0.2) o The peak at 2θ) and also includes at least one, two, or three peaks selected from 12.5, 18.5, and 22.8. o 2θ (±0.2) o XRPD pattern of a specific peak at 2θ) and DSC thermogram with an endothermic onset temperature of about 225°C to about 230°C.

[0200] In some embodiments, this disclosure provides compound 1 form I, characterized by comprising 18.0, 21.2, and 23.2 o 2θ (±0.1) o The XRPD pattern of the peak at 2θ) and the DSC thermogram with an endothermic onset temperature of about 225°C to about 230°C. In some embodiments, this disclosure provides compound 1 in form I, characterized by including 18.0, 21.2, and 23.2 o 2θ (±0.1) o The peak at 2θ) and also includes at least one, two, or three peaks selected from 12.5, 18.5, and 22.8. o 2θ (±0.1) o XRPD pattern of a specific peak at 2θ) and DSC thermogram with an endothermic onset temperature of about 225°C to about 230°C.

[0201] In some embodiments, this disclosure provides compound 1 form I, characterized by comprising 18.0, 18.5, 21.2, 22.8, and 23.2 o 2θ (±0.2) o The XRPD pattern of the peak at 2θ) and the DSC thermogram having an endothermic onset temperature of about 225°C to about 230°C. In some embodiments, this disclosure provides compound 1 in form I, characterized by including peaks at 18.0, 18.5, 21.2, 22.8, and 23.2. o 2θ (±0.1) o XRPD pattern of the peak at 2θ) and DSC thermogram with an endothermic onset temperature of about 225°C to about 230°C.

[0202] In some embodiments, this disclosure provides compound 1 form I, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 0.4%. In some embodiments, this disclosure provides compound 1 form I, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 0.4% between 40°C and 200°C. In some embodiments, this disclosure provides compound 1 form I, characterized by substantially as... Figure 3 The TGA shown.

[0203] In some embodiments, this disclosure provides compound 1 form I, characterized by dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 0.1%. In some embodiments, this disclosure provides compound 1 form I, characterized by dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 0.1% between about 0% and 90% RH. In some embodiments, this disclosure provides compound 1 form V, characterized by substantially as… Figure 4 The DVS analysis shown.

[0204] Suitablely, compound 1, form I, is unsolventized and anhydrous. Suitablely, compound 1, form I, contains less than about 2% by weight, such as less than about 1.5% by weight, less than about 1% by weight, or less than about 0.5% by weight, of solvent and / or water. Those skilled in the art will know suitable analytical techniques that can quantify the amount of solvent / water associated with the solid. For example, the water content can be determined by Karl Fischer titration. Residual solvent can be determined by gas chromatography. Thermogravimetric analysis (TGA) can also quantify the amount of volatile substances (i.e., solvent and water) associated with the solid (surface-bound or incorporated into the crystal structure).

[0205] In some embodiments, this disclosure provides compound 1 form I, characterized by comprising 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5 o 2θ (±0.2) o An XRPD pattern of five or more peaks at 2θ) and wherein compound 1, form I, contains less than about 2% by weight of solvent and / or water.

[0206] Compound 1 Form II In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein this crystalline form is form II (specified herein and characterized as form II of compound 1). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 12.6, 13.9, 15.3, 18.5, 19.2, 19.7, 22.3, 23.4, or 24.3. o 2θ (±0.2) o An X-ray powder diffraction (XRPD) pattern with five or more peaks at 2θ, form II.

[0207] In some embodiments, this disclosure provides compound 1 form II, characterized by comprising 12.6, 13.9, 15.3, 18.5, 19.2, 19.7, 22.3, 23.4, and 24.3. o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 form II, characterized by including the 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0208] In some embodiments, this disclosure provides compound 1 form II, characterized substantially as follows: Figure 5 The XRPD pattern shown.

[0209] In some embodiments, this disclosure provides compound 1 form II, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 223°C and 245°C. In some embodiments, this disclosure provides compound 1 form II, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 223°C. In some embodiments, this disclosure provides compound 1 form II, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 245°C. In some embodiments, this disclosure provides compound 1 form II, characterized by being substantially as... Figure 6 The DSC thermogram shown is shown.

[0210] In some embodiments, this disclosure provides compound 1 form II, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 0.6%. In some embodiments, this disclosure provides compound 1 form II, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 0.6% between 25°C and 150°C. In some embodiments, this disclosure provides compound 1 form II, characterized by substantially as... Figure 7 The TGA shown.

[0211] In some embodiments, this disclosure provides compound 1 form II, characterized by a dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 0.6%. In some embodiments, this disclosure provides compound 1 form II, characterized by a dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 0.6% between about 0% and about 90% RH. In some embodiments, this disclosure provides compound 1 form II, characterized by substantially as... Figure 8 The DVS analysis shown.

[0212] Compound 1 Form III In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is form III (specified herein and characterized as form III of compound 1). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 10.0, 12.2, 17.3, 18.3, 20.1, 22.0, 23.7, 25.3, or 25.9. o2θ (±0.2) o An X-ray powder diffraction (XRPD) pattern with five or more peaks at 2θ, type III.

[0213] In some embodiments, this disclosure provides compound 1 form III, characterized by comprising 10.0, 12.2, 17.3, 18.3, 20.1, 22.0, 23.7, 25.3, and 25.9. o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 form III, characterized by comprising 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0214] In some embodiments, this disclosure provides compound 1 form III, characterized substantially as follows: Figure 9 The XRPD pattern shown.

[0215] In some embodiments, this disclosure provides compound 1 form III, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 246°C. In some embodiments, this disclosure provides compound 1 form III, characterized substantially as... Figure 10 The DSC thermogram shown is shown.

[0216] In some embodiments, this disclosure provides compound 1 form III, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 3.5%. In some embodiments, this disclosure provides compound 1 form III, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 3.5% between 25°C and 60°C. In some embodiments, this disclosure provides compound 1 form III, characterized by substantially as... Figure 11 The TGA shown.

[0217] In some embodiments, this disclosure provides compound 1 form III, characterized by a dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 4.6%. In some embodiments, this disclosure provides compound 1 form III, characterized by a dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 4.6% between about 0% and about 90% RH. In some embodiments, this disclosure provides compound 1 form III, characterized by substantially as... Figure 12 The DVS analysis shown.

[0218] Compound 1 form IV In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is form IV (specified herein and characterized as form IV of compound 1). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 5.7, 11.2, 16.8, 17.1, 18.7, 21.4, 22.4, 23.3, or 23.8. o 2θ (±0.2) o An X-ray powder diffraction (XRPD) pattern with five or more peaks at 2θ, in form IV.

[0219] In some embodiments, this disclosure provides compound 1 in form IV, characterized by comprising 5.7, 11.2, 16.8, 17.1, 18.7, 21.4, 22.4, 23.3, and 23.8. o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in form IV, characterized by including the 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in form IV, characterized substantially as Figure 13 The XRPD pattern shown.

[0220] In some embodiments, this disclosure provides compound 1 in form IV, characterized by a unit cell having the following dimensions as determined by single-crystal X-ray diffraction crystallography: a = 6.09120(10) Å; b = 11.01750(10) Å; c = 31.8714(4) Å; α = 90°; β = 90°; and γ = 90°.

[0221] In some embodiments, this disclosure provides compound 1 form IV, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 242°C. In some embodiments, this disclosure provides compound 1 form IV, characterized substantially as... Figure 14 The DSC thermogram shown is shown.

[0222] In some embodiments, this disclosure provides compound 1 form IV, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 0.7%. In some embodiments, this disclosure provides compound 1 form IV, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 0.7% between 25°C and 75°C. In some embodiments, this disclosure provides compound 1 form IV, characterized by substantially as... Figure 15 The TGA shown.

[0223] In some embodiments, this disclosure provides compound 1 form IV, characterized by a dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 0.8%. In some embodiments, this disclosure provides compound 1 form IV, characterized by a dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 0.8% between about 0% and 90% RH. In some embodiments, this disclosure provides compound 1 form IV, characterized by substantially as... Figure 16 The DVS analysis shown.

[0224] Compound 1 form V In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is form V (specified herein and characterized as form V of compound 1). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes values ​​of 10.0, 11.8, 13.9, 17.6, 18.1, 18.5, 18.9, 19.6, or 26.0. o 2θ (±0.2) o An X-ray powder diffraction (XRPD) pattern with five or more peaks at 2θ, in form V.

[0225] In some embodiments, this disclosure provides compound 1 form V, characterized by comprising 10.0, 11.8, 13.9, 17.6, 18.1, 18.5, 18.9, 19.6, and 26.0. o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in form V, characterized by including 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0226] In some embodiments, this disclosure provides compound 1 in form V, characterized substantially as follows: Figure 17 The XRPD pattern shown.

[0227] In some embodiments, this disclosure provides compound 1 in form V, characterized substantially as follows: Figure 18 The DSC thermogram shown is shown.

[0228] In some embodiments, this disclosure provides compound 1 form V, characterized by thermogravimetric analysis (TGA) with a weight loss of about 2%. In some embodiments, this disclosure provides compound 1 form V, characterized by thermogravimetric analysis (TGA) with a weight loss of about 2% between 25°C and 100°C. In some embodiments, this disclosure provides compound 1 form V, characterized by substantially as... Figure 19 The TGA shown.

[0229] Compound 1 monohydrate In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is a monohydrate (specified herein and characterized as compound 1 monohydrate). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes values ​​of 12.2, 14.9, 17.5, 20.0, 20.6, 21.8, 23.6, 25.4, or 26.0. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, monohydrate.

[0230] In some embodiments, this disclosure provides a compound 1 monohydrate, characterized by comprising 12.2, 14.9, 17.5, 20.0, 20.6, 21.8, 23.6, 25.4, and 26.0 mg / L. o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides a compound 1 monohydrate, characterized by including 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0231] In some embodiments, this disclosure provides a compound 1 monohydrate, characterized in that it is substantially as follows: Figure 20 The XRPD pattern shown.

[0232] In some embodiments, this disclosure provides a compound 1 monohydrate characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 33°C and about 246°C. In some embodiments, this disclosure provides a compound 1 monohydrate characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 33°C. In some embodiments, this disclosure provides a compound 1 monohydrate characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 246°C. In some embodiments, this disclosure provides a compound 1 monohydrate characterized by being substantially as described above. Figure 21 The DSC thermogram shown is shown.

[0233] In some embodiments, this disclosure provides a compound 1 monohydrate characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 3.7%. In some embodiments, this disclosure provides a compound 1 monohydrate characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 3.7% between 25°C and 100°C. In some embodiments, this disclosure provides a compound 1 monohydrate characterized by substantially as... Figure 22 The TGA shown.

[0234] Compound 1 dihydrate In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is a dihydrate (specified herein and characterized as compound 1 dihydrate). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 8.1, 9.6, 11.7, 16.3, 18.8, 24.5, 25.7, 25.9, or 27.9. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, dihydrate.

[0235] In some embodiments, this disclosure provides a compound 1 dihydrate, characterized by comprising 8.1, 9.6, 11.7, 16.3, 18.8, 24.5, 25.7, 25.9, and 27.9. o 2θ (±0.2) oXRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 dihydrate, characterized by including 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. o 2θ (±0.2) o XRPD pattern of a specific peak at 2θ).

[0236] In some embodiments, this disclosure provides a compound 1 dihydrate, characterized in that it is substantially as follows: Figure 23 The XRPD pattern shown.

[0237] In some embodiments, this disclosure provides a compound 1 dihydrate, characterized in that it is substantially as follows: Figure 24 The differential scanning calorimetry (DSC) thermogram shown is shown.

[0238] In some embodiments, this disclosure provides a compound 1 dihydrate characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 7.4%. In some embodiments, this disclosure provides a compound 1 dihydrate characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 7.4% between 25°C and 100°C. In some embodiments, this disclosure provides a compound 1 dihydrate characterized by substantially as... Figure 25 The TGA shown.

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

[0240] In some embodiments, this disclosure provides a MeTHF solvate of compound 1, characterized substantially as follows: Figure 26 The XRPD pattern shown.

[0241] In some embodiments, this disclosure provides a MeTHF solvate of compound 1, characterized substantially as follows: Figure 27 The differential scanning calorimetry (DSC) thermogram shown is shown.

[0242] In some embodiments, this disclosure provides a MeTHF solvate of compound 1, characterized substantially as follows: Figure 28 The TGA shown.

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

[0244] In some embodiments, this disclosure provides compound 1, MTBE solvate 1, characterized in that it is substantially as follows: Figure 29 The XRPD pattern shown.

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

[0246] In some embodiments, this disclosure provides compound 1 MTBE solvate 2, characterized in that it is substantially as follows: Figure 30 The XRPD pattern shown.

[0247] In some embodiments, this disclosure provides compound 1 MTBE solvate 2, characterized in that it is substantially as follows: Figure 31 The differential scanning calorimetry (DSC) thermogram shown is shown.

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

[0249] In some embodiments, this disclosure provides a solvate of compound 1 2-BuOH, characterized in that it is substantially as follows: Figure 33 The XRPD pattern shown.

[0250] In some embodiments, this disclosure provides a solvate of compound 1 2-BuOH, characterized in that it is substantially as follows: Figure 34 The differential scanning calorimetry (DSC) thermogram shown is shown.

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

[0252] In some embodiments, this disclosure provides a solvate of compound 1 t-BuOH, characterized in that it is substantially as follows: Figure 35 The XRPD pattern shown.

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

[0254] In some embodiments, this disclosure provides compound 1 as a dioxane solvate, characterized in that it is substantially as follows: Figure 36 The XRPD pattern shown.

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

[0256] In some embodiments, this disclosure provides a CPME solvate of compound 1, characterized in that it is substantially as follows: Figure 37 The XRPD pattern shown.

[0257] In some embodiments, this disclosure provides a CPME solvate of compound 1, characterized in that it is substantially as follows: Figure 38 The differential scanning calorimetry (DSC) thermogram shown is shown.

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

[0259] In some embodiments, this disclosure provides a DMAc solvate of compound 1, characterized substantially as follows: Figure 39 The XRPD pattern shown.

[0260] In some embodiments, this disclosure provides a DMAc solvate of compound 1, characterized substantially as follows: Figure 40 The differential scanning calorimetry (DSC) thermogram shown is shown.

[0261] In some embodiments, this disclosure provides a DMAc solvate of compound 1, characterized substantially as follows: Figure 41 The TGA shown.

[0262] Interphase of Compound 1 In some embodiments, this disclosure provides (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide in solid form, wherein the solid form is an intermediate phase (specified herein and characterized as the intermediate phase of compound 1).

[0263] In some embodiments, this disclosure provides an intermediate phase of compound 1, characterized substantially as follows: Figure 42 The XRPD pattern shown.

[0264] Compound 1 hydrochloride form I In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is hydrochloride form I (specified herein and characterized as compound 1 hydrochloride form I). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes values ​​of 8.9, 12.5, 18.9, 19.6, 20.8, 23.8, 24.4, 24.8, or 28.8. o 2θ (±0.2) oX-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, hydrochloride form I.

[0265] In some embodiments, this disclosure provides compound 1 in hydrochloride form I, characterized by comprising 8.9, 12.5, 18.9, 19.6, 20.8, 23.8, 24.4, 24.8, and 28.8 mg / L. o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 hydrochloride form I, characterized by including 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0266] In some embodiments, this disclosure provides compound 1 in hydrochloride form I, characterized substantially as follows: Figure 43 The XRPD pattern shown.

[0267] In some embodiments, this disclosure provides compound 1 in hydrochloride form I, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 221°C. In some embodiments, this disclosure provides compound 1 in hydrochloride form I, characterized by substantially as... Figure 44 The DSC thermogram shown is shown.

[0268] In some embodiments, this disclosure provides compound 1 in hydrochloride form I, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 0.2%. In some embodiments, this disclosure provides compound 1 in hydrochloride form I, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 0.2% between 25°C and 125°C. In some embodiments, this disclosure provides compound 1 in hydrochloride form I, characterized by substantially as... Figure 45 The TGA shown.

[0269] In some embodiments, this disclosure provides compound 1 in hydrochloride form I, characterized by dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 0.4%. In some embodiments, this disclosure provides compound 1 in hydrochloride form I, characterized by dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 0.4% between about 0% and about 90% RH. In some embodiments, this disclosure provides compound 1 in hydrochloride form I, characterized by substantially as... Figure 46 The DVS analysis shown.

[0270] Compound 1 hydrochloride form II In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is hydrochloride form II (specified herein and characterized as compound 1 hydrochloride form II). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 8.3, 12.4, 15.3, 19.2, 22.6, 24.0, 24.8, 26.3, or 28.3. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, hydrochloride form II.

[0271] In some embodiments, this disclosure provides compound 1 in hydrochloride form II, characterized by comprising 8.3, 12.4, 15.3, 19.2, 22.6, 24.0, 24.8, 26.3, and 28.3. o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 hydrochloride form II, characterized by including 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0272] In some embodiments, this disclosure provides compound 1 in hydrochloride form II, characterized substantially as follows: Figure 47 The XRPD pattern shown.

[0273] In some embodiments, this disclosure provides compound 1 in hydrochloride form II, characterized by a unit cell having the following dimensions as determined by single-crystal X-ray diffraction crystallography: a = 10.83810(10) Å; b = 17.4553(2) Å; c = 12.44620(10) Å; α = 90°; β = 93.4720(10)°; and γ = 90°.

[0274] In some embodiments, this disclosure provides compound 1 in hydrochloride form II, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 177°C. In some embodiments, this disclosure provides compound 1 in hydrochloride form II, characterized substantially as... Figure 48 The DSC thermogram shown is shown.

[0275] In some embodiments, this disclosure provides compound 1 in hydrochloride form II, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 3.8%. In some embodiments, this disclosure provides compound 1 in hydrochloride form II, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 3.8% between 40°C and 150°C. In some embodiments, this disclosure provides compound 1 in hydrochloride form II, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 2.1% between 150°C and 200°C. In some embodiments, this disclosure provides compound 1 in hydrochloride form II, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 5.9% between 40°C and 200°C. In some embodiments, this disclosure provides compound 1 in hydrochloride form II, characterized by substantially as... Figure 49 The TGA shown.

[0276] In some embodiments, this disclosure provides compound 1 in hydrochloride form II, characterized by dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 0.7%. In some embodiments, this disclosure provides compound 1 in hydrochloride form II, characterized by dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 0.7% between about 0% and about 90% RH. In some embodiments, this disclosure provides compound 1 in hydrochloride form II, characterized by substantially as... Figure 50 The DVS analysis shown.

[0277] Compound 1 hemisulfate form I In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is hemisulfate form I (specified herein and characterized as hemisulfate form I of compound 1). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes values ​​of 9.6, 11.9, 16.5, 19.4, 20.1, 22.6, 23.8, or 25.8. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, hemisulfate form I.

[0278] In some embodiments, this disclosure provides compound 1 in hemisulfate form I, characterized by comprising 9.6, 11.9, 16.5, 19.4, 20.1, 22.6, 23.8, and 25.8 ppm. o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in hemisulfate form I, characterized by including peaks at 9.6, 11.9, 14.6, 16.5, 19.4, 20.1, 22.6, 23.8, 25.8, and 28.7. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0279] In some embodiments, this disclosure provides compound 1 in hemisulfate form I, characterized in that it is substantially as follows: Figure 51 The XRPD pattern shown.

[0280] In some embodiments, this disclosure provides compound 1 in hemisulfate form I, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 153°C. In some embodiments, this disclosure provides compound 1 in hemisulfate form I, characterized by substantially as... Figure 52 The DSC thermogram shown is shown.

[0281] Compound 1 in sulfate form I In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is sulfate form I (specified herein and characterized as sulfate form I of compound 1). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 9.6, 19.1, 19.4, 20.4, 22.3, 23.6, or 25.5. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, in sulfate form I.

[0282] In some embodiments, this disclosure provides compound 1 in sulfate form I, characterized by comprising 9.6, 19.1, 19.4, 20.4, 22.3, 23.6, and 25.5 mg / L. o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in sulfate form I, characterized by including 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0283] In some embodiments, this disclosure provides compound 1 in sulfate form I, characterized in that it is substantially as follows: Figure 53 The XRPD pattern shown.

[0284] In some embodiments, this disclosure provides compound 1 in sulfate form I, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 165°C. In some embodiments, this disclosure provides compound 1 in sulfate form I, characterized by being substantially as follows: Figure 54 The DSC thermogram shown is shown.

[0285] Compound 1, methanesulfonate form I In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is methanesulfonate form I (specified herein and characterized as compound 1 methanesulfonate form I). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, or 29.6. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, methanesulfonate form I.

[0286] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by comprising 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, and 29.6. o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by including the 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0287] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by comprising 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, or 29.6 o 2θ (±0.1) oAn XRPD pattern with five or more peaks at 2θ). In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by including peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, and 29.6. o 2θ (±0.1) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by including the 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. o 2θ (±0.1) o XRPD pattern of the peak at 2θ).

[0288] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by comprising 7.2, 11.6, 14.3, 17.3, and 18.5 o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by including peaks at 7.2, 11.6, 14.3, 17.3, and 18.5 ppm. o 2θ (±0.1) o XRPD pattern of the peak at 2θ).

[0289] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by comprising 7.2, 11.6, 14.3, 17.3, and 18.5 o 2θ (±0.2) o The peak at 2θ) and also includes at least two, five, ten, fifteen, twenty, or twenty-five 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. o 2θ (±0.2) oXRPD pattern of a specific peak at 2θ).

[0290] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by comprising 7.2, 11.6, 14.3, 17.3, and 18.5 o 2θ (±0.1) o The peak at 2θ) and also includes at least two, five, ten, fifteen, twenty, or twenty-five 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. o 2θ (±0.1) o XRPD pattern of a specific peak at 2θ).

[0291] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized in that it is substantially as follows: Figure 55 The XRPD pattern shown.

[0292] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 250°C. In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by having no thermal events between 25°C and 200°C and having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 250°C. In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by being substantially as... Figure 56 The DSC thermogram shown is shown.

[0293] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 254°C. In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by having no thermal events between 25°C and 200°C and having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 254°C. In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by being substantially as... Figure 85 The DSC thermogram shown is shown.

[0294] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by comprising 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, or 29.6 o 2θ (±0.2) o An XRPD pattern with five or more peaks at 2θ) and an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 250°C. In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by including peaks at 7.2, 11.6, 14.3, 17.3, and 18.5 o 2θ (±0.2) o XRPD pattern of the peak at 2θ) and differential scanning calorimetry (DSC) thermogram with endothermic onset temperature of about 250 °C.

[0295] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by comprising 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, or 29.6 o 2θ (±0.2) o An XRPD pattern with five or more peaks at 2θ) and an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 254 °C. In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by including peaks at 7.2, 11.6, 14.3, 17.3, and 18.5 °C. o 2θ (±0.2) o XRPD pattern of the peak at 2θ) and differential scanning calorimetry (DSC) thermogram with endothermic onset temperature of about 254 °C.

[0296] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 0.1%. In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 0.1% between 25°C and 150°C. In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by substantially as... Figure 57 The TGA shown.

[0297] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 2.3%. In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 2.3% between about 0% and about 90% RH. In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by substantially as... Figure 58 The DVS analysis shown.

[0298] Suitably, Compound 1, in its methanesulfonate form I, is unsolventized and anhydrous. Suitably, Compound 1, in its methanesulfonate form I, contains less than about 2% by weight, such as less than about 1.5% by weight, 1% by weight, 0.5% by weight, 0.2% by weight, or 0.1% by weight, of solvent and / or water. Those skilled in the art will know suitable analytical techniques that can quantify the amount of solvent / water associated with the solid. For example, the water content can be determined by Karl Fischer titration. Residual solvent can be determined by gas chromatography. Thermogravimetric analysis (TGA) can also quantify the amount of volatile substances (i.e., solvent and water) associated with the solid (surface-bound or incorporated into the crystal structure).

[0299] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by comprising 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, or 29.6 o 2θ (±0.2) o An XRPD pattern of five or more peaks at 2θ) and wherein compound 1, in methanesulfonate form I, contains less than about 2% by weight of solvent and / or water.

[0300] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by comprising 7.2, 11.6, 14.3, 17.3, and 18.5 o 2θ (±0.2) o The XRPD pattern of the peak at 2θ) and wherein compound 1, methanesulfonate form I, contains less than about 2% by weight of solvent and / or water.

[0301] Compound 1, ethanesulfonate form I In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is ethanesulfonate form I (specified herein and characterized as compound 1 ethanesulfonate form I). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 7.0, 17.9, 18.4, 20.1, 20.8, 23.0, 23.4, 24.0, or 25.8. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, ethanesulfonate form I.

[0302] In some embodiments, this disclosure provides compound 1 in ethanesulfonate form I, characterized by comprising 7.0, 17.9, 18.4, 20.1, 20.8, 23.0, 23.4, 24.0, and 25.8 mg / L. o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in ethanesulfonate form I, characterized by including 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0303] In some embodiments, this disclosure provides compound 1 in ethanesulfonate form I, characterized substantially as follows: Figure 59 The XRPD pattern shown.

[0304] In some embodiments, this disclosure provides compound 1 in isosulfonate form I, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 258°C. In some embodiments, this disclosure provides compound 1 in isosulfonate form I, characterized by substantially as... Figure 60 The DSC thermogram shown is shown.

[0305] In some embodiments, this disclosure provides compound 1 in ethanesulfonate form I, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 0.1%. In some embodiments, this disclosure provides compound 1 in ethanesulfonate form I, characterized by a thermogravimetric analysis (TGA) showing a weight loss of about 0.1% between 25°C and 150°C. In some embodiments, this disclosure provides compound 1 in ethanesulfonate form I, characterized by substantially as... Figure 61 The TGA shown.

[0306] In some embodiments, this disclosure provides compound 1 in ethanesulfonate form I, characterized by dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 3.3%. In some embodiments, this disclosure provides compound 1 in ethanesulfonate form I, characterized by dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 3.3% between about 0% and about 90% RH. In some embodiments, this disclosure provides compound 1 in ethanesulfonate form I, characterized by substantially as... Figure 62 The DVS analysis shown.

[0307] Compound 1, benzenesulfonate form I In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is benzenesulfonate form I (specified herein and characterized as compound 1 benzenesulfonate form I). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 11.3, 14.9, 16.1, 18.4, 19.8, 21.0, 22.8, or 24.9. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, benzenesulfonate form I.

[0308] In some embodiments, this disclosure provides compound 1 in benzenesulfonate form I, characterized by comprising 11.3, 14.9, 16.1, 18.4, 19.8, 21.0, 22.8, and 24.9 o 2θ (±0.2) oXRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in benzenesulfonate form I, characterized by comprising 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 o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0309] In some embodiments, this disclosure provides compound 1 in benzenesulfonate form I, characterized essentially as follows: Figure 63 The XRPD pattern shown.

[0310] In some embodiments, this disclosure provides compound 1 in benzenesulfonate form I, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 148°C. In some embodiments, this disclosure provides compound 1 in benzenesulfonate form I, characterized by substantially as... Figure 64 The DSC thermogram shown is shown.

[0311] Compound 1, benzenesulfonate form II In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is benzenesulfonate form II (specified herein and characterized as compound 1 benzenesulfonate form II). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features include 12.2, 18.0, 19.3, and 21.7. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of the peak at 2θ, benzenesulfonate form II.

[0312] In some embodiments, this disclosure provides compound 1 in benzenesulfonate form II, characterized by comprising 12.2, 14.4, 16.0, 18.0, 19.3, 21.7, 22.5, 24.9, 27.1, or 28.2. o 2θ (±0.2) oAn XRPD pattern with five or more peaks at 2θ). In some embodiments, this disclosure provides compound 1 in benzenesulfonate form II, characterized by including peaks at 12.2, 14.4, 16.0, 18.0, 19.3, 21.7, 22.5, 24.9, 27.1, and 28.2. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0313] In some embodiments, this disclosure provides compound 1 in benzenesulfonate form II, characterized essentially as follows: Figure 65 The XRPD pattern shown.

[0314] In some embodiments, this disclosure provides compound 1 in benzenesulfonate form II, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 148°C. In some embodiments, this disclosure provides compound 1 in benzenesulfonate form II, characterized substantially as... Figure 66 The DSC thermogram shown is shown.

[0315] Compound 1, toluenesulfonate form I In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is toluenesulfonate form I (specified herein and characterized as compound 1 toluenesulfonate form I). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 4.1, 8.1, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5, or 24.5. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, toluenesulfonate form I.

[0316] In some embodiments, this disclosure provides compound 1 in toluenesulfonate form I, characterized by comprising 4.1, 8.1, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5, and 24.5. o 2θ (±0.2) oXRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in toluenesulfonate form I, characterized by including 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0317] In some embodiments, this disclosure provides compound 1 in toluenesulfonate form I, characterized essentially as follows: Figure 67 The XRPD pattern shown.

[0318] In some embodiments, this disclosure provides compound 1 in toluenesulfonate form I, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 164°C. In some embodiments, this disclosure provides compound 1 in toluenesulfonate form I, characterized by substantially as... Figure 68 The DSC thermogram shown is shown.

[0319] Compound 1 naphthalene sulfonate form I In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is naphthalene sulfonate form I (specified herein and characterized as compound 1 naphthalene sulfonate form I). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 6.6, 12.3, 17.8, 19.0, 21.2, 22.2, 23.9, 25.8, or 26.6. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, naphthalene sulfonate form I.

[0320] In some embodiments, this disclosure provides compound 1-naphthalenesulfonate form I, characterized by comprising 6.6, 12.3, 17.8, 19.0, 21.2, 22.2, 23.9, 25.8, and 26.6 o 2θ (±0.2) oXRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1-naphthalenesulfonate form I, characterized by including 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0321] In some embodiments, this disclosure provides compound 1 naphthalene sulfonate form I, characterized in that it is substantially as follows: Figure 69 The XRPD pattern shown.

[0322] In some embodiments, this disclosure provides compound 1 in naphthalene sulfonate form I, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 215°C. In some embodiments, this disclosure provides compound 1 in naphthalene sulfonate form I, characterized by substantially as... Figure 70 The DSC thermogram shown is shown.

[0323] Compound 1, maleate form I In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is maleate form I (specified herein and characterized as maleate form I of compound 1). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes values ​​of 10.6, 16.9, 18.0, 20.0, 21.7, 22.6, 24.5, 25.5, or 27.3. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, maleate form I.

[0324] In some embodiments, this disclosure provides compound 1 in maleate form I, characterized by comprising 10.6, 16.9, 18.0, 20.0, 21.7, 22.6, 24.5, 25.5, and 27.3 mg / L.o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in maleate form I, characterized by including 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0325] In some embodiments, this disclosure provides compound 1 in maleate form I, characterized essentially as follows: Figure 71 The XRPD pattern shown.

[0326] In some embodiments, this disclosure provides compound 1 in maleate form I, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 198°C. In some embodiments, this disclosure provides compound 1 in maleate form I, characterized by substantially as... Figure 72 The DSC thermogram shown is shown.

[0327] In some embodiments, this disclosure provides compound 1 in maleate form I, characterized by thermogravimetric analysis (TGA) with a weight loss of about 0.04%. In some embodiments, this disclosure provides compound 1 in maleate form I, characterized by thermogravimetric analysis (TGA) with a weight loss of about 0.04% between 25°C and 150°C. In some embodiments, this disclosure provides compound 1 in maleate form I, characterized by substantially as... Figure 73 The TGA shown.

[0328] In some embodiments, this disclosure provides compound 1 in maleate form I, characterized by dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 0.17%. In some embodiments, this disclosure provides compound 1 in maleate form I, characterized by dynamic vapor adsorption (DVS) analysis showing a water absorption rate of about 0.17% between about 0% and about 90% RH. In some embodiments, this disclosure provides compound 1 in maleate form I, characterized by substantially as... Figure 74 The DVS analysis shown.

[0329] Compound 1, L-tartrate form I In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is L-tartrate form I (specified herein and characterized as compound 1 L-tartrate form I). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 9.4, 14.4, 16.2, 17.4, 17.9, 18.9, 20.3, 21.5, or 24.3. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, L-tartrate form I.

[0330] In some embodiments, this disclosure provides compound 1 in L-tartrate form I, characterized by comprising 9.4, 14.4, 16.2, 17.4, 17.9, 18.9, 20.3, 21.5, and 24.3 ppm. o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in L-tartrate form I, characterized by including 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0331] In some embodiments, this disclosure provides compound 1 in L-tartrate form I, characterized in that it is substantially as follows: Figure 75 The XRPD pattern shown.

[0332] In some embodiments, this disclosure provides compound 1 in L-tartrate form I, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 113°C. In some embodiments, this disclosure provides compound 1 in L-tartrate form I, characterized by substantially as... Figure 76 The DSC thermogram shown is shown.

[0333] Compound 1 L-tartrate form II In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is L-tartrate form II (specified herein and characterized as compound 1 L-tartrate form II). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes 11.7, 13.9, 18.6, 21.8, 23.1, 24.5, 26.1, 28.8, or 29.5. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, L-tartrate form II.

[0334] In some embodiments, this disclosure provides compound 1 in L-tartrate form II, characterized by comprising 11.7, 13.9, 18.6, 21.8, 23.1, 24.5, 26.1, 28.8, and 29.5 o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in L-tartrate form II, characterized by including the 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0335] In some embodiments, this disclosure provides compound 1 in L-tartrate form II, characterized essentially as follows: Figure 77 The XRPD pattern shown.

[0336] In some embodiments, this disclosure provides compound 1 in L-tartrate form II, characterized by having endothermic differential scanning calorimetry (DSC) thermograms with onset temperatures of about 26°C, 97°C, and 172°C. In some embodiments, this disclosure provides compound 1 in L-tartrate form II, characterized by substantially as Figure 78 The DSC thermogram shown is shown.

[0337] Compound 1 L-tartrate form III In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is L-tartrate form III (specified herein and characterized as compound 1 L-tartrate form III). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its characteristic is that it includes values ​​of 4.9, 9.8, 17.1, 18.6, 19.6, 20.2, 20.8, 22.0, or 24.6. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, L-tartrate form III.

[0338] In some embodiments, this disclosure provides compound 1 in L-tartrate form III, characterized by comprising 4.9, 9.8, 17.1, 18.6, 19.6, 20.2, 20.8, 22.0, and 24.6 ppm. o 2θ (±0.2) o XRPD pattern of the peak at 2θ). In some embodiments, this disclosure provides compound 1 in L-tartrate form III, characterized by including 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

[0339] In some embodiments, this disclosure provides compound 1 in L-tartrate form III, characterized substantially as follows: Figure 79 The XRPD pattern shown.

[0340] In some embodiments, this disclosure provides compound 1 in L-tartrate form III, characterized by having endothermic differential scanning calorimetry (DSC) thermograms with onset temperatures of about 20°C, 114°C, and 170°C. In some embodiments, this disclosure provides compound 1 in L-tartrate form III, characterized by substantially as Figure 80 The DSC thermogram shown is shown.

[0341] When this specification refers to the crystalline form of compound 1, the crystallinity is conveniently greater than about 60% by weight, more conveniently greater than about 80%, even more conveniently greater than about 90%, and preferably greater than 95%, 98% or 99%.

[0342] In one embodiment, compound 1 form I is pure or substantially pure. As used herein, the term "substantially pure" means that the solid 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 any impurities or other solid forms of compound 1, including alternative crystalline forms, hydrates, solvates, salts, or amorphous forms, as measured, for example, by XRPD. Therefore, substantially pure compound 1 form I as described herein should 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, and greater than 99.5% by weight of compound 1 form I. Suitably, compound 1 form I is provided, wherein when compound 1 form I is analyzed by solid-state techniques, such as X-ray powder diffraction and / or Raman spectroscopy, no other solid forms (amorphous and / or other crystalline forms) are detected. Suitably, a crystalline form of compound 1 consisting essentially of compound 1 form I is provided. Suitably, a crystalline form of compound 1 consisting of compound 1 form I is provided.

[0343] In one embodiment, the methanesulfonate form I of compound 1 is pure or substantially pure. As used herein, the term "substantially pure" means that the solid 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 any impurities or other solid forms of compound 1, including alternative crystalline forms, hydrates, solvates, salts, or amorphous forms, as measured, for example, by XRPD. Therefore, the substantially pure methanesulfonate form I of compound 1 described herein should 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, or greater than 99.5% by weight of the methanesulfonate form I of compound 1. Suitably, a methanesulfonate form I of compound 1 is provided, wherein no other solid forms (amorphous and / or other crystalline forms) are detected when compound 1 methanesulfonate form I is analyzed by solid-state techniques, such as X-ray powder diffraction and / or Raman spectroscopy. Suitably, a crystalline form of compound 1 consisting essentially of compound 1 methanesulfonate form I is provided. Suitably, a crystalline form of compound 1 consisting of compound 1 methanesulfonate form I is provided.

[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 methyl-tetrahydrofuran (MeTHF) solvate, Compound 1 methyl tert-butyl ether solvate 1, Compound 1 methyl tert-butyl ether solvate 2, Compound 1 2-butanol solvate, Compound 1 tert-butanol solvate, Compound 1 p-dioxane solvate, Compound 1 cyclopentylmethyl ether solvate, Compound 1 dimethylacetamide solvate, Compound 1 hydrochloride form I, Compound 1 hydrochloride form II, Compound 1 hemisulfate form I, Compound 1 sulfate form I, Compound 1 ethanesulfonate form I, Compound 1 benzenesulfonate form I, Compound 1 benzenesulfonate form II, Compound 1 toluenesulfonate form I, Compound 1 naphthalenesulfonate 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 are pure or substantially pure. As used herein, the term “substantially pure” means that the solid 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 any impurities or other solid forms of Compound 1, including alternative crystalline forms, hydrates, solvates, salts, or amorphous forms, such as those measured by XRPD.Therefore, the substantially pure forms of Compound 1 (Form II, Form III, Form IV, Form V, Monohydrate, Dihydrate, Methyl-Tetrahydrofuran (MeTHF) solvate, Methyl-tert-butyl ether solvate 1, Methyl-tert-butyl ether solvate 2, 2-Butanol solvate, tert-Butanol solvate, p-Dioxane solvate, Cyclopentylmethyl ether solvate, Dimethylacetamide solvate, Hydrochloride Form I, Hydrochloride Form II, Hemisulfate Form I, Sulfate Form I, Ethylsulfonate Form I, Benzenesulfonate Form I, Benzenesulfonate Form II, Toluenesulfonate Form I, Naphthalenesulfonate Form I, Maleate Form I, L-Tartrate Form I, L-Tartrate Form II, or Compound 1 L-tartrate form III should be understood as containing 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, and greater than 99.5% by weight of compound form II, compound form III, compound form IV, compound form V, compound 1 monohydrate, compound 1 dihydrate, compound 1 methyl-tetrahydrofuran (MeTHF) solvate, compound 1 methyl tert-butyl ether solvate 1, compound 1 methyl tert-butyl ether solvate 2, and compound 1, respectively. 2-Butanol solvate, Compound 1 tert-butanol solvate, Compound 1 p-dioxane solvate, Compound 1 cyclopentylmethyl ether solvate, Compound 1 dimethylacetamide solvate, Compound 1 hydrochloride form I, Compound 1 hydrochloride form II, Compound 1 hemisulfate form I, Compound 1 sulfate form I, Compound 1 ethanesulfonate form I, Compound 1 benzenesulfonate form I, Compound 1 benzenesulfonate form II, Compound 1 toluenesulfonate form I, Compound 1 naphthalenesulfonate 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.Suitablely provided are 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 tert-butyl ether solvate 1, compound 1 methyl tert-butyl ether solvate 2, compound 1 2-butanol solvate, compound 1 tert-butanol solvate, compound 1 p-dioxane solvate, compound 1 cyclopentylmethyl ether solvate, compound 1 dimethylacetamide solvate, compound 1 hydrochloride form I, compound 1 hydrochloride form II, compound 1 hemisulfate form I, compound 1 sulfate form I, compound 1 ethanesulfonate form I, compound 1 benzenesulfonate form I, compound 1 benzenesulfonate form II, compound 1 toluenesulfonate form I, compound 1 naphthalenesulfonate 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 analyzed by solid-state techniques such as X-ray powder diffraction and / or Raman spectroscopy, 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-tert-butyl ether Solvate 1, Compound 1 Methyl-tert-butyl ether Solvate 2, Compound 1 2-Butanol Solvate, Compound 1 Tert-Butanol Solvate, Compound 1 p-Dioxane Solvate, Compound 1 Cyclopentylmethyl Ether Solvate, Compound 1 Dimethylacetamide Solvate, Compound 1 Hydrochloride Form I, Compound 1 Hydrochloride Form II, Compound 1 Hemisulfate Form I, Compound 1 Sulfate Form I, Compound 1 Ethylsulfonate Form I, Compound 1 Benzenesulfonate Form I, Compound 1 Benzenesulfonate Form II, Compound 1 Toluenesulfonate Form I, Compound 1 Naphthalenesulfonate Form I, Compound 1 Maleate Form I, Compound 1 L-Tartrate Form I, Compound 1 No other solid forms (amorphous and / or other crystalline forms) were detected when compound 1 was in L-tartrate form II or L-tartrate form III.Suitablely, crystalline forms of compound 1 are provided, which are essentially composed 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 tert-butyl ether solvate 1, compound 1 methyl tert-butyl ether solvate 2, compound 1 2-butanol solvate, compound 1 tert-butanol solvate, compound 1 p-dioxane solvate, compound 1 cyclopentylmethyl ether solvate, compound 1 dimethylacetamide solvate, compound 1 hydrochloride form I, compound 1 hydrochloride form II, compound 1 hemisulfate form I, compound 1 sulfate form I, compound 1 ethanesulfonate form I, compound 1 benzenesulfonate form I, compound 1 benzenesulfonate form II, compound 1 toluenesulfonate form I, compound 1 naphthalenesulfonate form I, compound 1 maleate form I, compound 1 L-tartrate form I, compound 1 L-tartrate form II, or compound 1 Composition of L-tartrate form III. Suitablely, crystalline forms of compound 1 are provided, which are composed 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 tert-butyl ether solvate 1, compound 1 methyl tert-butyl ether solvate 2, compound 1 2-butanol solvate, compound 1 tert-butanol solvate, compound 1 p-dioxane solvate, compound 1 cyclopentylmethyl ether solvate, compound 1 dimethylacetamide solvate, compound 1 hydrochloride form I, compound 1 hydrochloride form II, compound 1 hemisulfate form I, compound 1 sulfate form I, compound 1 ethanesulfonate form I, compound 1 benzenesulfonate form I, compound 1 benzenesulfonate form II, compound 1 toluenesulfonate form I, compound 1 naphthalenesulfonate form I, compound 1 maleate form I, compound 1 L-tartrate form I, compound 1 L-tartrate form II, or compound 1 Composition of L-tartrate form III.

[0345] Method for preparing compound 1 in solid form The solid form of compound 1 can be prepared by a variety of methods. For example, compound 1 can be dissolved in a single solvent system and crystallized. Alternatively, compound 1 can be crystallized from a two-solvent system by dissolving compound 1 in a solvent (good solvent) and then adding an antisolvent (bad solvent) to the mixture to crystallize compound 1.

[0346] The solvent can be any solvent suitable for forming a solution. Typically, the solvent can be a polar solvent, which in some embodiments is a protic solvent. Other suitable solvents include nonpolar solvents. Suitable solvents include, but are not limited to, water, alkanes (such as heptane, hexane, and cyclohexane), petroleum ethers, C1-C3 alcohols (methanol, ethanol, propanol, isopropanol), ethylene glycol and polyethylene glycol (such as PEG400), alkyl esters (such as ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate), acetonitrile, ketones (such as acetone, butanone, methyl ethyl ketone (MEK), methyl propyl ketone (MPK), and methyl isobutyl ketone (MIBK)), ethers (such as cyclopentylmethyl ether, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane), aromatic compounds (such as benzene and toluene), halogenated solvents (such as dichloromethane, chloroform, and carbon tetrachloride), dimethyl sulfoxide (DMSO), and dimethylformamide (D... Suitable solvents also include, but are not limited to, halogenated C1-C3 alcohols (trifluoromethanol, trifluoroethanol (TFE), hexafluoroisopropanol (HFIPA)). For example, solvents can be polar aprotic solvents such as dichloromethane, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetone, methyl ethyl ketone, dimethylformamide (DMF), acetonitrile (ACN), dimethyl sulfoxide (DMSO), etc. Solvents can also be polar protic solvents such as tert-butanol, n-propanol, isopropanol, ethanol, methanol, acetic acid, water, etc. Solvents can also be nonpolar solvents such as hexane, pentane, petroleum ether, benzene, toluene, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane, chloroform and carbon tetrachloride.

[0347] Two or more solvents may be used in any suitable ratio in the solvent mixture. For example, the ratio of the first solvent to the second solvent may be from 10:1 to about 1:10 (volume / volume or weight / weight), or from about 10:1 to 1:5, or from 10:1 to 1:1, or from 10:1 to 5:1, or from 5:1 to 1:5, or from 5:1 to 1:1, or from 4:1 to 1:1, or from 3:1 to 1:1, or from 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 method for preparing compound 1 in solid form can be carried out under any suitable reaction conditions. For example, the method for preparing compound 1 in crystalline form can be carried out at any suitable temperature (such as, but not limited to, below room temperature, equal to room temperature, or above room temperature). In some embodiments, this 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 temperature of the reaction mixture is about 20°C, or 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, or about 100°C. The temperature of the reaction mixture can also be about 20°C, 15°C, 10°C, 5°C, 0°C, -5°C, -10°C, -20°C, -30°C, -40°C, -50°C, -60°C, -70°C, or about -78°C. In some embodiments, this temperature can be the reflux temperature of the particular solvent used in the method. In other embodiments, the crystalline form of compound 1 may be heated to above about 100°C, causing one crystalline form of compound 1 to form a second crystalline form of compound 1.

[0349] Methods for preparing compound 1 in solid form may include a variety of other steps. For example, solvent evaporation, addition of seed crystals to the mixture, and single or repeated heating and cooling of the mixture are all possible. These methods may include heating the reaction mixture to a temperature of approximately 20°C, or 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, or approximately 100°C. These methods may also include cooling the reaction mixture to a temperature of approximately 20°C, 15°C, 10°C, 5°C, 0°C, -5°C, -10°C, -20°C, -30°C, -40°C, -50°C, -60°C, -70°C, or approximately -78°C. The temperature of the reaction mixture may be varied at any suitable rate. For example, the rate of temperature change may be approximately 0.1°C / min to approximately 10°C / min.

[0350] The method for preparing the crystalline form of compound 1 can be carried out for any suitable time. For example, the time can be several minutes, several hours, or several days. In some embodiments, the time can be several hours, such as overnight. The method for preparing the crystalline form of compound 1 can also be carried out at any suitable pressure. For example, the pressure can be below atmospheric pressure, equal to approximately atmospheric pressure, or above atmospheric pressure.

[0351] Crystallization can be induced by methods known in the art, such as mechanical means, like scraping or rubbing the contact surface of the reaction vessel with, for example, a glass rod. Optionally, a saturated or supersaturated solution can be seeded. Methods for preparing compound 1 in solid form may also include crystallizing the seeds of compound 1.

[0352] Separation of the desired crystalline form can be achieved by removing the solvent and precipitating solvent from the crystals. This is generally done by known methods such as filtration, vacuum filtration, decanting, or centrifugation. Further separation can be achieved by removing any excess solvent from the crystalline form using methods known to those skilled in the art (e.g., applying vacuum and / or by heating).

[0353] In some embodiments, this disclosure provides a method for preparing crystalline compound 1, form I, comprising forming a mixture of compound 1 and a first solvent under conditions suitable for preparing form I, and adding a second solvent to the mixture. In some embodiments, compound 1 is dissolved in the first solvent (a good solvent). In some embodiments, the first solvent may be a polar protic solvent. In some embodiments, the first solvent may be methanol. In some embodiments, the second solvent is an antisolvent. In some embodiments, the second solvent may be water.

[0354] The mixture may contain any suitable ratio of a first solvent and a second solvent. For example, the ratio of the first solvent to the second solvent may be from 10:1 to about 1:10 (volume / volume or weight / weight), or from about 10:1 to 1:5, or from 10:1 to 1:1, or from 10:1 to 5:1, or from 5:1 to 1:5, or from 5:1 to 1:1, or from 4:1 to 1:1, or from 3:1 to 1:1, or from 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 to the second solvent may be about 2:1 (weight / weight). In some embodiments, the ratio of the first solvent to the second solvent may be approximately 1:1 (weight / weight). In some embodiments, the ratio of ethanol to water is approximately 2:1 (weight / weight). In some embodiments, the ratio of ethanol to water is approximately 1:1 (weight / weight).

[0355] The method for preparing crystalline compound 1 may include several additional steps. In some embodiments, the reaction mixture may be heated to a temperature of about 75°C. In some embodiments, the method further includes cooling the reaction mixture to a temperature of about 22°C. In some embodiments, the method for preparing crystalline compound 1 further includes heating the mixture to dissolve compound 1, and then cooling the mixture.

[0356] This method can be carried out under any suitable reaction conditions. For example, the temperature of the reaction mixture can be about 0°C, about -40°C, or about -78°C. In some embodiments, the temperature of the reaction mixture can be about -78°C.

[0357] Method for preparing compound 1 form I In one embodiment of this disclosure, a method for preparing compound 1 in form I is provided.

[0358] In one embodiment, the method for preparing compound 1 form I includes the following steps: a) Provide a solution of compound 1 in the first solvent system; b) Concentrate the solution from step a) and / or add a second solvent system to the solution from step a); c) Mix the mixture obtained from step b); d) Optionally, separate the solid formed in step c); and e) Optionally, dry the solid separated 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, such as at least 20 mg / mL, at room temperature. 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, such as 20 to 40 relative volumes, of the first solvent system. Suitably, compound 1 is dissolved in about 30 relative volumes of acetone.

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

[0362] Suitablely, in step b), the solution from step a) is concentrated to 1 to 10 relative volumes, such as 2.5 to 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, such as less than 5 mg / mL or less than 2 mg / L, at room temperature. Suitably, the second solvent system comprises a proton-polar solvent, and suitably, the second solvent system comprises ethanol and / or isopropanol. Suitably, the second solvent system comprises ethanol. Suitably, 5 to 40 relative volumes, such as 5 to 20 or 10 to 15 relative volumes, of the second solvent system are added to the solution from step a). Suitably, 5 to 40 relative volumes, such as 5 to 20 or 10 to 15 relative volumes, of ethanol are added to the solution from step a). Suitably, in step b), the second solvent is added at a temperature of 25°C to 75°C, such as 40°C to 50°C.

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

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

[0366] Suitablely, the second solvent system is an antisolvent system.

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

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

[0369] Suitably, step c) further includes cooling the mixture. Suitably, the mixture is cooled to below 25°C, such as below 0°C. Suitably, the mixture is cooled to approximately -10°C.

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

[0371] Suitablely, step d) includes separating the solids by filtration.

[0372] Suitablely, step e) includes drying the solid at a temperature above room temperature, such as above 30°C or above 40°C.

[0373] In one aspect of the present invention, a crystalline form of compound 1 form I that can be obtained by the above method is provided.

[0374] Method for preparing compound 1 in methanesulfonate form I In one embodiment of this disclosure, a method for preparing compound 1 in methanesulfonate form I is provided.

[0375] In one embodiment, a method for preparing compound 1 in methanesulfonate form I includes the following steps: a) Provide a solution of compound 1 in the first solvent system; b) Add the methanesulfonic acid in the second solvent system to the solution from step a); c) Optionally, cool the mixture obtained from step b); d) Optionally, separate the solid formed in step c); and e) Optionally, dry the solid separated 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, such as at least 1 mg / mL, 5 mg / mL, 10 mg / mL, or 20 mg / mL, at room temperature. Suitably, the first solvent system comprises a polar solvent. Suitably, the first solvent system comprises aprotic polar solvent. Suitably, the first solvent system comprises acetone, acetonitrile, anisole, butanone, dichloromethane, dimethylacetamide (DMAc), dimethyl sulfoxide, 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 isopropanol. Suitablely, compound 1 is dissolved in a first solvent system of 1 to 50 relative volumes, such as 20 to 40 relative volumes or 25 to 35 relative volumes. Suitablely, compound 1 is dissolved in 25 to 35 relative volumes of acetone.

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

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

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

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

[0381] Suitablely, step a) includes steps a2) and a3).

[0382] Suitablely, step a) includes step a2).

[0383] Suitablely, step a) includes step a3).

[0384] Steps a), a2), and / or a3) can provide a suspension of compound 1 and / or compound 1 methanesulfonate in the first solvent system; therefore, step b) may include adding a second solvent system to the suspension produced by step a), a2), or 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 aprotic polar solvent. Suitably, the second solvent system comprises acetone, acetonitrile, anisole, butanone, dichloromethane, dimethylacetamide (DMAc), dimethyl sulfoxide, 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 isopropanol. Suitably, the second solvent system comprises the same solvent as the first solvent system. Suitably, the second solvent system comprises acetone. Suitably, in step b), a 1.0 to 1.5 molar equivalent, such as a 1.0 to 1.2 molar equivalent, or about 1.0 molar equivalent, of methanesulfonic acid is used. Suitably, the methanesulfonic acid is dissolved in a second solvent system of 1 to 10 relative volumes, such as 1 to 5 or 1 to 3 relative volumes. Suitably, the methanesulfonic acid is dissolved in 1 to 10 relative volumes of acetone, such as 1 to 5 or about 2 relative volumes of acetone.

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

[0387] Suitably, in step b), 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), methanesulfonic acid in the second solvent system is added to the solution from step a) over a period of approximately 2 hours.

[0388] Suitably, step b) includes an additional step (step b2) of adding an additional portion of the second solvent system. Suitably, one to five relative volumes, such as about two relative volumes, of the second solvent system are added.

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

[0390] Suitablely, step b) includes steps b2) and b3).

[0391] Suitablely, step b) includes step b2).

[0392] Suitablely, step b) includes step b3).

[0393] Suitably, in step c), the mixture is cooled to below 45°C. Suitably, in step c), the mixture is cooled to below 30°C. Suitably, the mixture is cooled to about 15°C to 25°C. Suitably, the mixture is cooled over a period of at least 30 minutes, such as at least 1 hour. Suitably, the mixture is cooled over a period of about 2 hours.

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

[0395] Suitablely, step d) includes separating the solids by filtration.

[0396] Suitablely, step e) includes drying the solid at a temperature above room temperature, such as above 30°C or above 40°C.

[0397] In one aspect of the present invention, a crystalline form of compound 1 in the form of methanesulfonate I, which can be obtained by the above method, is provided.

[0398] IV. Compositions and Kits The crystalline form of Compound 1 provided herein is typically administered as a pharmaceutical composition. Therefore, pharmaceutical compositions comprising one or more crystalline forms of Compound 1 provided herein and one or more pharmaceutically acceptable media selected from carriers, adjuvants, and excipients are also provided herein. The crystalline form of Compound 1 provided herein may be the sole active ingredient or one of the active ingredients in a pharmaceutical composition. Suitable pharmaceutically acceptable solvents may include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th edition, (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (edited by GSBanker and CTRhodes).

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

[0400] In one embodiment, this document provides a pharmaceutical composition comprising a pure or substantially pure crystalline form of Compound 1 of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, this document provides 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 is substantially composed of crystalline compound 1 in form I, form II, form III, form IV, form V, monohydrate, dihydrate, methyl tetrahydrofuran (MeTHF) solvate, methyl tert-butyl ether (MTBE) solvate 1, MTBE solvate 2, 2-butanol solvate, tert-butanol solvate, p-dioxane solvate, cyclopentylmethyl ether (CPME) solvate, dimethylacetamide (DMAc) solvate, hydrochloride form I, hydrochloride form II, hemisulfate form I, sulfate form I, methanesulfonate form I, ethanesulfonate form I, benzenesulfonate form I, benzenesulfonate form II, toluenesulfonate form I, naphthalenesulfonate form I, maleate form I, L-tartrate form I, L-tartrate form II, or L-tartrate form III. In one embodiment, this document provides 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 comprises crystalline compound 1 in form I, form II, form III, form IV, form V, monohydrate, dihydrate, methyl tetrahydrofuran (MeTHF) solvate, methyl tert-butyl ether (MTBE) solvate 1, MTBE solvate 2, 2-butanol solvate, tert-butanol solvate, p-dioxane solvate, cyclopentylmethyl ether (CPME) solvate, dimethylacetamide (DMAc) solvate, hydrochloride form I, hydrochloride form II, hemisulfate form I, sulfate form I, methanesulfonate form I, ethanesulfonate form I, benzenesulfonate form I, benzenesulfonate form II, toluenesulfonate form I, naphthalenesulfonate form I, maleate form I, L-tartrate form I, L-tartrate form II, or L-tartrate form III.

[0401] In some embodiments, this document provides 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, a pharmaceutical composition is provided herein comprising a pure or substantially pure form of compound 1 (Form I) and a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, a pharmaceutical composition is provided herein comprising a crystalline form of compound 1 and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the crystalline form of compound 1 consists substantially of crystalline form I of compound 1. In one embodiment, a pharmaceutical composition is provided herein 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 form I of compound 1.

[0403] In some embodiments, this document provides a pharmaceutical composition comprising compound 1 in its 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 in its mesylate form I and a pharmaceutically acceptable carrier, diluent, or excipient.

[0404] In one embodiment, this document provides a pharmaceutical composition comprising pure or substantially pure compound 1 in its mesylate form I and a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, this document provides 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 substantially of crystalline compound 1 in its mesylate form I. In one embodiment, this document provides 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 in its mesylate form I.

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

[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 pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of one or more (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof.In some embodiments, one or 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 inhibitors; HIV gp160 protein inhibitors; HIV gp41 protein inhibitors; HIV-1 reverse transcriptase inhibitors; HLA class I antigen A-2α modulators; HLA Modulators of class I antigen A-24α; Modulators of human cytomegalovirus glycoprotein B; Modulators of human cytomegalovirus glycoprotein H; Modulators of human cytomegalovirus glycoprotein; Modulators of human cytomegalovirus glycoprotein L; Immunoglobulin G agonists; Interferon α2 ligands; Interferon γ receptor antagonists; Modulators of latent membrane protein 1; Modulators of latent membrane protein 2; Modulators of latent membrane protein 2; Progesterone receptor agonists; Modulators of secretory protein BARF1; Modulators of serine-threonine protein kinase UL97; Modulators of T cell surface glycoprotein CD8; Thymidine kinase inhibitors; Modulators of trans-acting transcription protein ICP4; Transferase inhibitors; Unspecified gene inhibitors; Adenosine homocysteine ​​enzyme inhibitors; Basigin inhibitors; Basigin modulators; CCR5 chemokine modulators; CD4 agonists; CD4 modulators; CD89 agonists; CMV 65kDa low-dose matrix phosphoprotein regulators; CRISPR-associated Cas9 regulators; cyclin-dependent kinase inhibitors; cyclin-dependent kinase inhibitors; cyclin-dependent kinase-9 inhibitors; DNA polymerase inhibitors; DNA primase inhibitors; endonuclease regulators; Epstein-Barr nuclear antigen 1 inhibitors; Epstein-Barr nuclear antigen 1 regulators; Epstein-Barr nuclear antigen 1 stimulators; fatty acid synthase inhibitors; herpesvirus envelope glycoprotein B stimulators; herpesvirus envelope glycoprotein D inhibitors; herpesvirus envelope glycoprotein D regulators; HIV gp120 protein inhibitors; HLA class I antigen A-11α regulators; Hsp 90 inhibitors; human cytomegalovirus glycoprotein B inhibitors; human cytomegalovirus glycoprotein B modulators; human cytomegalovirus glycoprotein inhibitors; hyaluronidase inhibitors; immunoglobulin agonists; interferon α1 ligands; interferon α2 ligands; interferon α ligand inhibitors; interferon α ligand modulators; interferon β ligands; large terminal enzyme protein inhibitors; LAT gene inhibitors; NAD-dependent deacetylase sirtuin modulators; nicotinic acetylcholine receptor antagonists; NKG2D ligand modulators; nucleotide transferase inhibitors; protein Jumonji inhibitors; ribonuclease stimulators; serine-threonine protein kinase UL97 inhibitors; synaptic fusion protein-5 inhibitors; TAT protein modulators; T cell surface glycoprotein CD8 stimulators; TLR-4 agonists; and viral ribonucleotide reductase inhibitors.In some implementations, one or more therapeutic agents are selected from famciclovir, acyclovir, and valacyclovir.

[0407] In some embodiments, pharmaceutical compositions are provided herein that comprise a therapeutically effective amount of the crystalline form of compound 1 provided herein, along with a pharmaceutically acceptable carrier.

[0408] The pharmaceutical composition can be administered in single or multiple doses. The pharmaceutical composition can be administered by various methods, including, for example, rectal, buccal, intranasal, and transdermal routes. In some embodiments, the pharmaceutical composition can be administered via intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhaler.

[0409] One method of administration is parenteral, such as by injection. The pharmaceutical composition described herein may be incorporated into forms for injection administration, including, for example, aqueous or oil suspensions or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical solvents. In some embodiments, the crystalline form of compound 1 disclosed herein and the pharmaceutical composition are administered by subcutaneous injection.

[0410] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable formulations, such as sterile injectable aqueous or oily suspensions. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents already mentioned herein, according to known techniques. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents (such as solutions in 1,3-butanediol), or prepared as lyophilized powders. Acceptable solvents and media that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are generally used as solvents or suspension media. For this purpose, any mild non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectable formulations.

[0411] In some embodiments, the sterile injectable formulations disclosed herein can also be sterile injectable solutions or suspensions (such as solutions in 1,3-butanediol) prepared from reconstituted lyophilized powders in non-toxic, parenteral-acceptable diluents or solvents. Acceptable solvents and media that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are generally used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid can also be used in the preparation of injectable formulations.

[0412] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes to make the formulation isotonic with the intended recipient's blood; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners. In some embodiments, the suspension is a microsuspension. In some embodiments, the suspension is a nanosuspension.

[0413] In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) will contain one or more excipients. The excipients should be compatible with the other components of the formulation and physiologically harmless to the recipient. Examples of suitable excipients are well known to those skilled in the art of parenteral formulations and can be found, for example, in the Handbook of Pharmaceutical Excipients (edited by Rowe, Sheskey, and Quinn), 6th edition, 2009. Examples of solubilizing excipients in parenteral formulations (e.g., SC or IM formulations) include, but are not limited to, polysorbates (e.g., polysorbate 20 or 80) and poloxamer (e.g., poloxamer 338, 188, or 207). In some embodiments, the crystalline form of Compound 1 disclosed herein and the pharmaceutical composition are administered together with the implant.

[0414] Oral administration may be another route for administering the crystalline form of Compound 1 provided herein. Administration may be via, for example, capsules or enteric-coated tablets. In preparing pharmaceutical compositions comprising at least one crystalline form of Compound 1 provided herein, the active ingredient (such as the crystalline form of Compound 1 provided herein) is typically diluted with an excipient and / or encapsulated within such a carrier, which may be in the form of capsules, pouches, paper, or other containers. When the excipient is used as a diluent, it may be in the form of a solid, semi-solid, or liquid material, acting as a solvent, carrier, or medium for the active ingredient. Therefore, pharmaceutical compositions may be in the form of tablets, pills, powders, lozenges, pouches, capsules, 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 gelatin capsules and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0415] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose, or any combination thereof. Pharmaceutical compositions may additionally include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and propylparaben; sweeteners; and flavoring agents; or any combination thereof.

[0416] Pharmaceutical compositions comprising at least one crystalline form of Compound 1 described herein can be formulated to provide a rapid, sustained, or delayed release of an active ingredient, such as the crystalline form of Compound 1 provided herein, upon administration to a subject using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems comprising polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are given in U.S. Patents 3,845,770, 4,326,525; 4,902,514; and 5,616,345. Another formulation used in the methods of this disclosure employs a transdermal delivery device (“patch”). Such transdermal patches can be used to provide a controlled amount of continuous or discontinuous infusion of the crystalline form of Compound 1 provided herein. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. ​​Such patches can be configured for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0417] To prepare solid compositions (such as tablets), a major active ingredient may be mixed with a pharmaceutical excipient to form a solid preformed composition containing a homogeneous mixture of the crystalline form of Compound 1 described herein or a mixture thereof. When these preformed compositions are referred to as homogeneous, the active ingredient can be uniformly dispersed throughout the composition, making it easy to subdivide the composition into equivalent unit dosage forms, such as tablets, pills, and capsules.

[0418] The crystalline form of Compound 1 provided herein can be coated or otherwise formulated into tablets or pills to provide a dosage form with the advantage of prolonged action or protection against the acidic conditions of the stomach. For example, the tablets or pills may contain an inner dose component and an outer dose component, the latter being a coating on the former. These two components may be separated by an enteric coating layer, which resists disintegration in the stomach and allows the inner component to enter the duodenum intact or delay release. A variety of materials can be used for such enteric coatings or coatings, including various polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0419] Pharmaceutical compositions for inhalation or inhalation may include solutions and suspensions or mixtures thereof in pharmaceutically acceptable aqueous or organic solvents, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered orally or via nasal inhalation to achieve a local or systemic effect. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized using an inert gas. The nebulized solution may be inhaled directly from a nebulizer, or the nebulizer may be attached to a face mask tent or intermittent positive pressure ventilation machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0420] In one embodiment, this document provides a kit comprising the crystalline form of Compound 1 provided herein and suitable packaging. In some embodiments, the kit also includes instructions for use. In some embodiments, the kit comprises the crystalline form of Compound 1 provided herein, along with a label and / or instructions for use of the crystalline form of Compound 1 for the treatment of indications, including the diseases or conditions described herein.

[0421] In some implementations, the kit also contains one or more (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents or their pharmaceutically acceptable salts.

[0422] In one embodiment, this document provides an article of manufacture containing the crystalline form of compound 1 described herein in a suitable container. In some embodiments, the container may be a vial, a wide-mouth bottle, an ampoule, a pre-filled syringe, or an intravenous bag.

[0423] V. Method The methods provided herein can be applied to cell populations, either in vivo or in vitro. “In vivo” means within a living individual, such as an animal or human. In this context, the methods provided herein can be used for the treatment of an individual. “In vitro” means outside a living individual. Examples of in vitro cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can 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. In this context, this disclosure can be used for a variety of purposes, including therapeutic and experimental purposes. For example, this disclosure can be used in vitro to determine the optimal administration schedule and / or dosage for a given cell type, individual, and other parameters of the crystalline form of Compound 1 disclosed herein. Information gathered from such uses can be used for experimental purposes or clinically for developing in vivo treatment regimens. Other in vitro uses of this disclosure that may be suitable are described below or will become apparent to those skilled in the art. The crystalline form of the selected Compound 1 can be further characterized to examine the safety or tolerability of the dosage in human or non-human subjects. Such properties can be examined using methods commonly known to those skilled in the art.

[0424] In some embodiments, this disclosure provides a method for treating or preventing herpesvirus (conveniently HSV) infection in a patient in need, the method comprising administering to the patient a therapeutically effective amount of the crystalline form of Compound 1 provided herein or a pharmaceutical composition provided herein. In some embodiments, this disclosure provides a method for treating or preventing herpesvirus (conveniently HSV) infection in a patient in need, the method 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, diluent, or excipient. In some embodiments, this disclosure provides a method for treating or preventing herpesvirus (conveniently HSV) infection in a patient in need, the method 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, diluent, or excipient.

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

[0426] In some embodiments, the methods provided herein also include administering a therapeutically effective amount of one, two, three, or four additional therapeutic agents or pharmaceutically acceptable salts thereof. In some embodiments, the methods provided herein involve herpesviruses HSV-1 or HSV-2.

[0427] This disclosure further relates to the use of the crystalline form of Compound 1 disclosed herein for the treatment and / or prevention of diseases and / or symptoms by inhibiting the herpesvirus helicase primase by the crystalline form of Compound 1. Furthermore, this disclosure relates to the use of the crystalline form of Compound 1 for the preparation of a medicament for the treatment and / or prevention of herpesvirus-related diseases and / or symptoms by inhibiting the herpesvirus helicase primase by the crystalline form of Compound 1. In some embodiments, herpesvirus-related diseases or symptoms are alleviated by inhibiting the herpesvirus helicase primase. In some embodiments, this disclosure relates to the use of the crystalline form of Compound 1 disclosed herein for the preparation of a medicament for the treatment and / or prevention of HSV-1 or HSV-2-related diseases and / or symptoms by inhibiting the helicase primase by the 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 methanesulfonate form I.

[0428] The medicament referred to herein can be prepared by conventional methods, including combining the crystalline form of compound 1 according to this disclosure with a pharmaceutically acceptable carrier.

[0429] In some embodiments, this document provides a method for inhibiting the helicase primase of herpesviruses, the method comprising administering to a patient in need (e.g., a patient suffering from a herpesvirus-related disease or symptom) 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 methanesulfonate form I.

[0430] In some embodiments, this document provides a method for inhibiting the helicase primer of HSV-1 or HSV-2, the method comprising administering to a patient in need (e.g., a patient with HSV-1 or HSV-2 related disease or symptoms) a therapeutically effective amount of a crystalline form of Compound 1 or a composition comprising a crystalline form of Compound 1 disclosed herein. In some embodiments, this document provides a method for inhibiting the helicase primer of HSV-1 or HSV-2, the method comprising administering to a patient in need (e.g., a patient with HSV-1 or HSV-2 related disease or symptoms) 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 methanesulfonate form I.

[0431] In one embodiment, a method for inhibiting HSV replication in a subject of need is provided, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of compound 1. In another embodiment, a method for inhibiting HSV replication in a subject of need is provided, 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 methanesulfonate form I.

[0432] In some embodiments, this document provides a method for reducing viral replication, the method comprising contacting the virus with a crystalline form of compound 1 and inhibiting the helicase primase in the virus. In some embodiments, this document provides a method for reducing herpesvirus replication, the method comprising contacting the virus with a crystalline form of compound 1 and inhibiting the helicase primase in the virus. In some embodiments, this document provides a method for reducing HSV-1 or HSV-2 replication, the method comprising contacting the virus with a crystalline form of compound 1 disclosed herein and inhibiting the 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 methanesulfonate form I.

[0433] In some embodiments, this document provides a method for treating a condition induced, aggravated, or accelerated by a herpes virus, the method comprising administering to a patient in need a therapeutically effective amount of a crystalline form of compound 1 or a pharmaceutical composition comprising a crystalline form of compound 1. In some embodiments, this document provides a method for treating a condition induced, aggravated, or accelerated by HSV-1 or HSV-2, the method comprising administering to a patient in need a therapeutically effective amount of a crystalline form of compound 1 or a pharmaceutical composition comprising a crystalline form of compound 1. In some embodiments, the condition is genital herpes, cold sores, HSV keratitis, HSV encephalitis, or disseminated HSV. In some embodiments, the condition 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, a method is provided for reducing the likelihood of HSV infection or the severity of symptoms in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the crystalline form of Compound 1 provided herein. In another embodiment, a method is provided for reducing the likelihood of HSV infection or the severity of symptoms in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the 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, a method is provided for inhibiting the development or progression of a disease or condition caused by or related to HSV infection in a subject of need, the method comprising administering to the subject a therapeutically effective amount of the crystalline form of Compound 1 provided herein. In another embodiment, a method is provided for inhibiting the development or progression of a disease or condition caused by or related to HSV infection in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the 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, a method is provided for treating or preventing a disease or condition caused by or related to HSV infection in a subject of need, the method comprising administering to the subject a therapeutically effective amount of the crystalline form of Compound 1 provided herein. In another embodiment, a method is provided for treating or preventing a disease or condition caused by or related to HSV infection in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the 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 methanesulfonate form I.

[0437] In one particular embodiment, the compound according to this disclosure 1 The crystalline form or pharmaceutical composition according to this disclosure can reduce the time for lesions caused by HSV infection to heal (e.g., the time for complete recovery of lesions) and the duration of symptoms in diseases or conditions such as cold sores or genital herpes. The time for lesion healing can be defined as the complete epithelialization of HSV lesions on the skin and mucous membranes during the treatment period without the appearance of new lesions, for example, as assessed by a physician.

[0438] In one embodiment, the compound according to this disclosure 1 The crystalline form or pharmaceutical composition according to this disclosure can reduce pain or pain intensity (e.g., at the site of lesion) caused by HSV infection in diseases or conditions such as cold sores or genital herpes.

[0439] In some embodiments, this document provides for the use of the crystalline form of compound 1 in the treatment of viral infections. In some embodiments, this document provides for the use of the crystalline form of compound 1 in the treatment of viral infections caused by herpesviruses. In some embodiments, this document provides for the use of the crystalline form of compound 1 in the treatment of viral infections 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 methanesulfonate form I.

[0440] In one embodiment, the use of a crystalline form of compound 1 or a pharmaceutical composition comprising a crystalline form of compound 1 for inhibiting HSV replication in a subject is provided. 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 methanesulfonate form I.

[0441] In one embodiment, the use of a crystalline form of compound 1 or a pharmaceutical composition comprising a crystalline form of compound 1 is provided for reducing the likelihood of HSV infection or the severity of symptoms in a subject of need. 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, the use of a crystalline form of compound 1 or a pharmaceutical composition comprising a crystalline form of compound 1 is provided in inhibiting the development or progression of a disease or condition caused by or related to HSV infection in a subject of need. 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, the use of a crystalline form of compound 1 or a pharmaceutical composition comprising a crystalline form of compound 1 in the treatment or prevention of a disease or condition caused by or related to HSV infection is provided. 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, this document provides the use of the crystalline form of Compound 1 for the preparation of a medicament for the prevention / treatment of viral infections. In some embodiments, this document provides the use of the crystalline form of Compound 1 for the preparation of a medicament for the prevention / treatment of viral infections caused by herpesviruses. In some embodiments, this document provides the use of the crystalline form of Compound 1 for the preparation of a medicament for the prevention / treatment of viral infections 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 methanesulfonate form I.

[0445] In one embodiment, use is provided in the manufacture of a crystalline form of compound 1 or a pharmaceutical composition comprising the crystalline form of compound 1 in the manufacture 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, the use of a crystalline form of compound 1 or a pharmaceutical composition comprising a crystalline form of compound 1 in the manufacture of a medicament for reducing the likelihood of HSV infection or the severity of symptoms in a subject of need is provided. 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, the use of a crystalline form of compound 1 or 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 condition caused by or related to HSV infection in a subject of need is provided. 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, the use of a crystalline form of compound 1 or a pharmaceutical composition comprising a crystalline form of compound 1 in the manufacture of a medicament for treating or preventing a disease or condition caused by or related to HSV infection in a subject of need is provided. 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, this document provides a crystalline form of compound 1, which is used as a drug. In some embodiments, this document provides form I of compound 1, which is used as a drug. In some embodiments, this document provides mesylate form I of compound 1, which is used as a drug.

[0450] In one embodiment, this document provides 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, this document provides a pharmaceutical composition comprising form I of compound 1 and a pharmaceutically acceptable carrier, diluent, or excipient, for use as a medicament. In one embodiment, this document provides a pharmaceutical composition comprising form I of compound 1 mesylate and a pharmaceutically acceptable carrier, diluent, or excipient, for use as a medicament.

[0451] In some embodiments, this document provides a crystalline form of compound 1 for use in a therapeutic manner. In one embodiment, this document provides form I of compound 1 for use in a therapeutic manner. In another embodiment, this document provides methanesulfonate form I of compound 1 for use in a therapeutic manner.

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

[0453] In another aspect, a crystalline form of compound 1 is provided for use in treating herpesvirus (conveniently HSV) infection. In yet another aspect, a pharmaceutical composition comprising a crystalline form of compound 1 and a pharmaceutically acceptable carrier, diluent, or excipient is provided for use in treating herpesvirus (conveniently 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 methanesulfonate form I.

[0454] In some embodiments, this document provides a crystalline form of compound 1 for use in methods of treating viral infections caused by HSV-1 or HSV-2. In some embodiments, this document provides compound 1 in form I for use in methods of treating viral infections caused by HSV-1 or HSV-2. In some embodiments, this document provides compound 1 in mesylate form I for use in methods of treating viral infections caused by HSV-1 or HSV-2.

[0455] In one embodiment, a crystalline form of compound 1 is provided for use in inhibiting HSV replication in a subject. In one embodiment, a pharmaceutical composition comprising a crystalline form of compound 1 and a pharmaceutically acceptable carrier, diluent, or excipient is provided for use in inhibiting 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 methanesulfonate form I.

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

[0457] In one embodiment, a crystalline form of compound 1 is provided for use in inhibiting the development or progression of a disease or condition caused by or related to HSV infection in a subject of need. In one embodiment, a pharmaceutical composition comprising a crystalline form of compound 1 and a pharmaceutically acceptable carrier, diluent, or excipient is provided for use in inhibiting the development or progression of a disease or condition caused by or related to HSV infection in a subject of need. 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 methanesulfonate form I.

[0458] In one embodiment, a crystalline form of compound 1 is provided for use in the treatment or prevention of a disease or condition caused by or related to HSV infection in a subject of need. In one embodiment, a pharmaceutical composition comprising a crystalline form of compound 1 and a pharmaceutically acceptable carrier, diluent, or excipient is provided for use in the treatment or prevention of a disease or condition caused by or related to HSV infection in a subject of need. 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 methanesulfonate form I.

[0459] In some embodiments, the patients being treated are humans. In addition to its use in human treatment, the crystalline form of the invention can also be used in veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, etc. Conveniently, such animals include horses, dogs, and cats.

[0460] In one particular implementation scheme, by HSV Caused by or related to infection HSV Infection-related diseases or conditions include herpes labialis (e.g., oral herpes or whitlow), genital herpes, HSV Related keratitis, HSV Related encephalitis, traumatic herpes, primary encephalitis HSV Gingivostomatitis, Morales meningitis Mollaret's meningitis ) and Bell's paralysis ( Bell's palsy ).

[0461] In one specific implementation, the disease or condition caused by or associated with HSV infection is selected from herpes labialis (e.g., oral herpes labialis or whitlow) or genital herpes. In one implementation, the disease or condition is recurrent herpes labialis or recurrent genital herpes. A history of multiple recurrences of herpes labialis or recurrent genital herpes (e.g., six or more recurrences per year) is considered. HSV Individuals with recurrent disease can be considered to have relapsed disease. HSV .

[0462] In one implementation, the herpes virus being treated is HSV-2. In another implementation, the herpes virus being treated is HSV-2, and the subject requiring treatment has recurrent genital herpes with HSV-2.

[0463] In one implementation, the herpesvirus being treated is HSV-1. In yet another implementation, both HSV-1 and HSV-2 are treated.

[0464] In one implementation, the herpesvirus being treated and prevented is resistant to nucleoside antiviral therapy, such as anti-acyclovir for skin and mucous membranes. HSV Infection. In one implementation, nucleoside antiviral therapy is selected from the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir, and valacyclovir.

[0465] In another implementation, the treated HSV infection is a skin or mucous membrane resistant to antiviral therapy using nucleoside analogues. HSV Infections caused by these nucleoside analogs, such as acyclovir, penciclovir, famciclovir, ganciclovir, or valacyclovir.

[0466] In one particular implementation, the subject requiring the methods disclosed herein is immunocompromised. The subject may be immunocompromised due to conditions including HIV infection, cancer, hematopoietic cell or solid organ transplantation, chronic glucocorticoid use, or genetic immunodeficiency.

[0467] In one particular implementation, the subjects for whom the methods disclosed herein are required are newborns or infants.

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

[0469] In one particular implementation, the subjects requiring the methods disclosed herein have acyclovir-resistant skin and mucous membranes. HSV Infection. The subject may have been diagnosed with the condition based on clinical failure, such as failure to improve after at least 7 days of administration of acyclovir at the approved dose, either orally or intravenously.

[0470] In one particular implementation, the subjects requiring the methods disclosed herein suffer from primary genital disease. HSV Related herpes infections. In one aspect, subjects requiring the methods disclosed herein have severe or progressive genital herpes infections. HSV Related herpes infection.

[0471] VI. Application The crystalline form of Compound 1 disclosed herein (also referred to herein as the active ingredient) can be administered via any route suitable for 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). It should be understood that preferred routes may vary depending on, for example, the recipient's condition. An advantage of the crystalline form of Compound 1 disclosed herein is that it is orally bioavailable and can be administered orally.

[0472] The crystalline form of Compound 1 disclosed herein can be administered to an individual for a desired period of time or duration, depending on an effective dosing regimen, such as at least about 1 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 1 week, at least about 2 weeks, at least about 3 weeks, at least about 1 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 throughout the individual's lifetime.

[0473] In some embodiments, the crystalline form of compound 1 of this disclosure is administered to patients in need once a week, twice a month, once a month, once every two months, once every three months, once every six months, or once a year.

[0474] The specific dose level of the crystalline form of Compound 1 disclosed herein for any particular subject will depend on a variety of factors, including the activity of the specific crystalline form of Compound 1 used, the age, weight, general health condition, sex, diet, time of administration, route of administration and excretion rate, drug combination, and severity of the specific disease. For example, the dose may be expressed as milligrams (mg / kg) of the crystalline form of Compound 1 provided herein per kilogram of subject body weight. A dose between about 0.1 mg / kg and 150 mg / kg may be appropriate. In some embodiments, a dose between about 0.1 mg / kg and 100 mg / kg may be appropriate. In other embodiments, a dose between 0.5 mg / kg and 60 mg / kg may be appropriate. Normalization based on the subject's weight is particularly useful when adjusting for doses among subjects with large differences in size, such as when using the drug in children and adults, or when converting an effective dose for a non-human subject, such as a dog, to a dose suitable for a human subject.

[0475] Dosage can also be described as the total amount of the crystalline form of compound 1 described herein administered per dose. The dosage or frequency of administration of the crystalline form of compound 1 disclosed herein may be adjusted during treatment at the discretion of the administering physician.

[0476] The crystalline form of compound 1 disclosed herein can be administered in a therapeutically effective amount to an individual (e.g., a human). 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 form of Compound 1 provided herein may be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. Therapeutic amounts of the crystalline form of Compound 1 may include from about 0.00001 mg / kg body weight / day to about 10 mg / kg body weight / day, such as from about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or such as from about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day. In some embodiments, therapeutic amounts of the crystalline form of Compound 1 provided herein include from about 30 µg / day to about 300 µg / day, from about 0.3 mg / day to about 30 mg / day, or from about 30 mg / day to about 300 mg / day, or from about 300 mg / day to about 1000 mg / day.

[0478] The crystalline form of Compound 1 of this disclosure may be combined with one or more adjunct therapeutic agents at any dose (e.g., 1 mg to 1000 mg of the crystalline form of Compound 1). One or more adjunct therapeutic agents may be administered before, after, or simultaneously with the administration of the crystalline form of Compound 1 of this disclosure or the pharmaceutical composition of this disclosure. In some embodiments, one or more adjunct therapeutic agents are administered before the crystalline form of Compound 1 or the pharmaceutical composition. In some embodiments, one or more adjunct therapeutic agents are administered after the crystalline form of Compound 1 or the pharmaceutical composition. In some embodiments, one or more adjunct therapeutic agents are administered simultaneously with the crystalline form of Compound 1 or the pharmaceutical composition.

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

[0480] In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is from about 1 mg to about 1000 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is from about 1 mg to about 900 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is from about 1 mg to about 800 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is from about 1 mg to about 700 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is from about 1 mg to about 600 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is from about 1 mg to about 500 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is from about 1 mg to about 400 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is from about 1 mg to about 300 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is from about 1 mg to about 200 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is from about 1 mg to about 100 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is from about 1 mg to about 75 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is from about 1 mg to about 50 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is from about 1 mg to about 25 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is from about 1 mg to about 20 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is from about 1 mg to about 15 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is from about 1 mg to about 10 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is from about 1 mg to about 5 mg.

[0481] In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this 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, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 5 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 100 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 150 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 200 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 250 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 300 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 350 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 400 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 450 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 500 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 550 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 600 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 650 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 700 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 750 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 800 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 850 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 900 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 950 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 1000 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of this disclosure is about 1050 mg.When administered orally, the total weekly dose for human subjects may be from about 1 mg / week to 1,000 mg / week, from about 10 mg / week to 500 mg / week, from about 50 mg / week to 300 mg / week, from about 75 mg / week to 200 mg / week, or from about 100 mg / week to 150 mg / week. In some embodiments, the total weekly dose for human subjects administered as a single dose may be from about 100 mg / week, 200 mg / week, 300 mg / week, 400 mg / week, 500 mg / week, 600 mg / week, 700 mg / week, 800 mg / week, 900 mg / week, or 1000 mg / week. In some embodiments, the total weekly dose for human subjects administered as a single dose of the crystalline form of compound 1 of this disclosure may be from about 100 mg. In some embodiments, the total weekly dose for human subjects administered as a single dose of the crystalline form of compound 1 of this disclosure may be from about 150 mg. In some embodiments, the total weekly dose of the crystalline form of compound 1 of this disclosure administered to a human subject as a single dose may be about 200 mg. In some embodiments, the total weekly dose of the crystalline form of compound 1 of this disclosure administered to a human subject as a single dose may be about 250 mg. In some embodiments, the total weekly dose of the crystalline form of compound 1 of this disclosure administered to a human subject as a single dose may be about 300 mg. In some embodiments, the total weekly dose of the crystalline form of compound 1 of this disclosure administered to a human subject as a single dose may be about 350 mg. In some embodiments, the total weekly dose of the crystalline form of compound 1 of this disclosure administered to a human subject as a single dose may be about 400 mg. In some embodiments, the total weekly dose of the crystalline form of compound 1 of this disclosure administered to a human subject as a single dose may be about 450 mg. In some embodiments, the total weekly dose of the crystalline form of compound 1 of this disclosure administered to a human subject as a single dose may be about 500 mg. In some embodiments, the total weekly dose of the crystalline form of compound 1 of this disclosure administered to a human subject as a single dose may be about 600 mg. In some embodiments, the total weekly dose of the crystalline form of compound 1 of this disclosure administered to a human subject as a single dose may be about 700 mg. In some embodiments, the total weekly dose of the crystalline form of compound 1 of this disclosure administered to a human subject as a single dose may be about 800 mg. In some embodiments, the total weekly dose of the crystalline form of compound 1 of this disclosure administered to a human subject as a single dose may be about 900 mg. In some embodiments, the total weekly dose of the crystalline form of compound 1 of this disclosure administered to a human subject as a single dose may be about 1000 mg.

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

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

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

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

[0486] In some embodiments, the crystalline form of compound 1 provided herein is administered orally once monthly in a single dose of about 500 mg. In some embodiments, the crystalline form of compound 1 provided herein is administered orally once monthly in a single dose of about 550 mg. In some embodiments, the crystalline form of compound 1 provided herein is administered orally once monthly in a single dose of about 600 mg. In some embodiments, the crystalline form of compound 1 provided herein is administered orally once monthly in a single dose of about 650 mg. In some embodiments, the crystalline form of compound 1 provided herein is administered orally once monthly in a single dose of about 700 mg. In some embodiments, the crystalline form of compound 1 provided herein is administered orally once monthly in a single dose of about 750 mg. In some embodiments, the crystalline form of compound 1 provided herein is administered orally once monthly in a single dose of about 800 mg. In some embodiments, the crystalline form of compound 1 provided herein is administered orally once monthly in a single dose of about 850 mg. In some embodiments, the crystalline form of compound 1 provided herein is administered orally once monthly in a single dose of about 900 mg. In some embodiments, the crystalline form of compound 1 provided herein is administered orally once monthly in a single dose of about 950 mg. In some embodiments, the crystalline form of compound 1 provided herein is administered orally once monthly in a single dose of about 1000 mg.

[0487] The frequency of administration of the crystalline form of Compound 1 disclosed herein will be determined by the individual patient's needs and may be, for example, once daily, once weekly, once monthly, once every two months, once every three months, or once every six months. The duration of administration of the crystalline form of Compound 1 is necessary for the continued treatment of herpes virus infections (including HSV-1 and HSV-2 infections) or any other indications described herein. For example, the crystalline form of Compound 1 may be administered to a human suffering from a herpes virus infection (including HSV-1 and HSV-2 infection) during the human's lifetime.

[0488] Administration may be intermittent, with the patient receiving a daily dose of the crystalline form of Compound 1 of this disclosure for periods of several days or more, followed by periods of not receiving the daily dose of the crystalline form of Compound 1 for several days or more. For example, the patient may receive a dose of the crystalline form of Compound 1 every other day or three times a week. Again, by way of example, the patient may receive a daily dose of the crystalline form of Compound 1 for periods of 1 to 14 days, followed by periods of not receiving the crystalline form of Compound 1 for periods of 7 to 21 days, followed by periods of receiving the daily dose of the crystalline form of Compound 1 again. The alternating periods of administration and non-administration of the crystalline form of Compound 1 may be repeated as needed for the clinical treatment of the patient.

[0489] The crystalline form of Compound 1 of this disclosure or the pharmaceutical composition of this disclosure may be administered once, twice, three times, or four times daily in any of the suitable modes described above. Furthermore, administration or treatment with the crystalline form of Compound 1 may continue for multiple days; for example, for a treatment cycle, treatment typically continues for at least 7, 14, or 28 days. Treatment cycles are well known for herpesvirus infections, including HSV-1 and HSV-2 infections. In some embodiments, treatment cycles typically alternate with rest periods of approximately 1 to 28 days, typically approximately 7 or 14 days, between cycles. In other embodiments, treatment cycles may also be continuous.

[0490] The effective dosage of the active ingredient used may vary depending on the specific crystalline form of compound 1 used, the administration method, the condition being treated, and the severity of the condition. Such dosages can be readily determined by those skilled in the art.

[0491] VII. Combination Therapy The crystalline form of Compound 1 provided herein, or the pharmaceutical compositions of the present invention, may be administered alone as the sole therapy, or may be administered in combination with one or more other substances and / or treatments. Such combination therapy may be achieved by administering the individual components of the treatment simultaneously, sequentially, or separately.

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

[0493] In some embodiments, the pharmaceutical composition provided herein has 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 a single 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] This document also considers methods including the administration of a second active agent. For example, in addition to HSV infection, the subject or patient may also suffer from HSV infection-related comorbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or contributed to by HSV infection. This document also considers disclosed pharmaceutical compositions in combination with at least one other agent previously shown to treat these HSV infection-related symptoms. Such combination therapy can be achieved independently (by administering the individual components of treatment simultaneously, sequentially, or separately) and / or by the pharmaceutical compositions of the present invention comprising a second active agent.

[0495] Therefore, this article provides a method for treating or preventing HSV infection in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the 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 methanesulfonate form I.

[0496] Additionally, this document provides a method for treating or preventing HSV infection in a subject of need, 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 methanesulfonate form I.

[0497] In some implementations, one or more adjunctive therapeutic agents include, for example, DNA polymerase inhibitors such as brincidofovir; protein Jumonji inhibitors such as ML-324 and dimethyloxaloylglycine; and interferon α2 ligand modulators such as interferon α-2b and Alpharekin. ® Recombinant human interferon α-2b follow-up biological agents, Herpferon ® Anterferon ® Nicotinic acetylcholine receptor antagonists, such as RPI-MN; virus-specific T-cell therapies, such as readily available single-virus-specific T-cell (VST) therapy, ALVR-108, multi-virus-specific T-cell TI1; other drugs for the treatment of herpesvirus infections, such as BOR-15001L7, lidocaine, lichenstatin-23; or any combination thereof.

[0498] In some implementations, one or more additional therapeutic agents include, for example, antibodies against herpesvirus envelope glycoprotein D, 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 implementations, one or more additional therapeutic agents include, for example, endonuclease modulators, such as macronucleases; interferon α ligand / interferon γ receptor antagonists, such as Anaferon. ® ; or any combination thereof.

[0500] In some embodiments, one or more additional therapeutic agents include, for example, CCR5 chemokine modulators; DNA polymerase inhibitors; DNA primase inhibitors; fatty acid synthase inhibitors; glucocorticoid receptor agonists; helicase inhibitors; herpesvirus envelope glycoprotein D inhibitors; Hsp90 inhibitors; human cytomegalovirus glycoprotein inhibitors; hyaluronidase inhibitors; interferon α1 ligands; interferon α2 ligands; interferon β ligands; T cell surface glycoprotein CD8 stimulators; or cyclin-dependent kinase inhibitors, or any combination thereof.

[0501] In some embodiments, one or more adjunctive therapeutic agents include, for example, DNA primase-helicase inhibitors such as amonexvir, pritelivir, and IM-250; DNA polymerase inhibitors such as famciclovir, penciclovir, valacyclovir, acyclovir, and foscarnet sodium; CCR5 chemokine modulators / human cytomegalovirus glycoprotein inhibitors such as MB-66; Hsp90 inhibitors such as BJ-B11; glucocorticoid receptor agonists such as hydrocortisone; interferon α1 ligand modulators such as interferon α1b and recombinant human interferon α1b; interferon α2 ligand modulators such as recombinant human interferon α-2b and KW-045; and interferon β ligand modulators such as interferon β-1a (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 used to treat herpes simplex virus infection, such as idoxuridine, BTL-TML-HSV, docosyl alcohol, MAR-8644, MAR-8658, NV-HHV-101, PRL-01, HN-0037; or any combination thereof.

[0502] In some implementations, one or more additional therapeutic agents include, for example, hyaluronidase inhibitors such as astodrimer (SPL-7013); live attenuated HSV vaccines such as RVx-101 HSV-1; live attenuated HSV vaccines with deletions in UL20 and UL53 such as VC2; live attenuated HSV vaccines with mutations in the R2 coding region of UL37 such as R2; or HSV-2 subunit trivalent vaccines (containing gC2, gD2, gE2), such as HSV-2 trivalent vaccines; or any combination thereof.

[0503] In some implementations, one or more additional therapeutic agents include, for example, live attenuated recombinant vaccines such as AuroVax; HSV-2 replication-deficient vaccines lacking UL5 and UL29 such as HSV-529; mRNA vaccines targeting HSV-2 disease such as mRNA-1608; or any combination thereof.

[0504] In some implementations, one or more additional therapeutic agents include, for example, CD4 agonists; CD89 agonists; Duffy antigen chemokine receptor modulators; herpesvirus envelope glycoprotein D inhibitors; HIV gp120 protein inhibitors; HIV gp160 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 agonists; or any combination thereof.

[0505] In some implementations, one or more adjunctive therapeutic agents include, for example, nicotinic acetylcholine receptor antagonists such as RPI-78M; anti-herpes simplex virus monoclonal antibodies such as HDIT-101; anti-herpes virus envelope glycoprotein D antibodies such as UB-621; TLR-4 agonists such as the IDC-G103 vaccine; and inactivated HSV-1 and HSV-2 vaccines such as Vitaherpavac. ® Live or 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 vaccines; DNA vaccines, such as pDNA / rVSV vector vaccines; or other drugs used to treat HSV-2, such as EBT-105 and Alloferon. ™ ; or any combination thereof.

[0506] In some implementations, one or more adjunctive therapeutic agents include, for example, HIV gp120 / gp160 / gp41 protein inhibitors, such as griffithsin; hyaluronidase inhibitors, such as Asquim (SPL-7013); CD4 agonists / T-cell surface glycoprotein CD8 vaccines, such as GENO-2; and TAT protein modulators, such as HerpesVaxTat. ® Vaccines; CD89 agonists / Duffy antigen chemokine receptor modulators / immunoglobulin G agonists, such as glycoprotein D+ liposome-encapsulated glycoprotein D booster vaccines; or vaccines such as Profavax-HSV-2 vaccines; HSV-2 mRNA vaccines; glycoprotein D DNA vaccines; or any combination thereof.

[0507] In some implementations, one or more adjunctive therapeutic agents include, for example, DNA vaccines such as the HSV-2 vaccine Admedus; RNA vaccines such as GSK-4108771A; live attenuated virus vaccines such as EXD-12; live attenuated δ-gD2-based viral vaccines; vaccines such as NE-gD2 intranasal nanoemulsion NE-based adjuvanted HSV-2 vaccines; or other drugs for treating HSV-2, such as EBT-105, Alloferon, etc. ™ ; or any combination thereof.

[0508] In some implementations, one or more additional therapeutic agents include, for example, antimicrobial peptides; 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 implementations, one or more adjunctive therapeutic agents include, for example, DNA polymerase inhibitors / thymidine kinase inhibitors, such as acyclovir; CRISPR-associated 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 the treatment of HSV-1, such as ZEP-3Na, MXB-009; CD4 modulator peptide vaccines, such as CEL-1000; and vaccines, such as inactivated HSV-1 and HSV-2 vaccines, such as Vitaherpavac. ® (Herpes vaccine); live or inactivated HSV-1 and HSV-2 vaccines, such as Theravax-HSV-1 vaccine; or viral envelope protein inhibitors, such as MXB-005; or combinations thereof.

[0510] In some implementations, one or more additional therapeutic agents include, for example, TAT protein modulators, such as HerpesVaxTat. ® Vaccine; or a vaccine, such as the Profavax-HSV-1 vaccine; or a combination thereof.

[0511] In some implementations, one or more additional therapeutic agents include, for example, a live attenuated viral vaccine, such as EXD-12; or a live attenuated viral vaccine based on δ-gD2; or a combination thereof.

[0512] In some implementations, one or more additional therapeutic agents include, for example, DNA polymerase inhibitors; herpesvirus envelope glycoprotein D inhibitors; or interferon α2 ligands; or combinations thereof.

[0513] In some implementations, one or more additional therapeutic agents include, for example, DNA polymerase inhibitors such as famciclovir and penciclovir; and interferon α2 ligand modulators such as yallaferon. ® Anti-herpesvirus envelope glycoprotein D antibodies, such as UB-621; or other medications used to treat genital herpes, such as interferon-gamma or alloferon. ™ ZEP-3Na; or combinations thereof.

[0514] In some implementations, one or more additional therapeutic agents include, for example, vaccines, such as NE-gD2 intranasal nanoemulsion-based adjuvant vaccines; or other drugs for the treatment and prevention of genital herpes, such as SQX-77, anti-STI antibodies; or combinations thereof.

[0515] In some implementations, one or more additional therapeutic agents include, for example, a herpes vaccine based on SAPN (self-assembled protein nanoparticles).

[0516] In some embodiments, one or more additional therapeutic agents include, for example, a CMV 65kDa matrix phosphoprotein modulator; a DNA polymerase inhibitor; a G protein-coupled receptor homologue US28 antagonist; a herpesvirus envelope glycoprotein B stimulator; an HLA class I antigen A-11α modulator; an HLA class I antigen A-2α modulator; an HLA class I antigen A-24α modulator; a human cytomegalovirus glycoprotein B inhibitor; a human cytomegalovirus glycoprotein B modulator; a human cytomegalovirus glycoprotein H modulator; a human cytomegalovirus glycoprotein inhibitor; a large terminal enzyme protein inhibitor; a ribonuclease stimulator; a serine-threonine protein kinase UL97 modulator; a synaptic fusion protein-5 inhibitor; a transferase inhibitor; or a viral ribonucleotide reductase inhibitor; or a combination thereof.

[0517] In some embodiments, one or more adjunctive therapeutic agents include, for example, DNA polymerase inhibitors such as ganciclovir, fomivirsen, fomivirsen sodium, and valganciclovir; DNA polymerase inhibitors / serine-threonine protein kinase UL97 modulators such as filociclovir; G protein-coupled receptor homologue US28 antagonists such as SYN-002; large terminal enzyme protein inhibitors such as AIC-387 and 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-11α modulators / HLA class I antigen A-2α modulators / HLA Modulators of class I antigen A-24α, such as allogeneic 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 used to treat 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, and Cytovir. ™ Antiviral cytotoxic T-cell therapy, CMV TCR-transduced T cells, adimlecleucel; or polyclonal antibodies, such as Cytogam ® ; or combinations thereof.

[0518] In some implementations, one or more additional therapeutic agents include, for example, synaptic fusion protein-5 inhibitors, such as Retro-94; large terminal enzyme protein inhibitors, such as letermovir; DNA polymerase inhibitors, such as valganciclovir; and anti-CMV antibodies, such as BT-084 (Cytotect). ® CP); human cytomegalovirus glycoprotein B and glycoprotein H modulatory vaccines, such as mRNA-1647; CMV 65kDa smaller matrix phosphoprotein vaccines, such as IRB-12022; or vaccines, such as mRNA-based vaccines; BD-03 plasmid DNA vaccines; V-212 heat-treated varicella-zoster virus vaccines; protein subunit vaccines, such as VBI-1501A; CMV-MVA pentameric vaccines (RhUL128C-MVA); CMV-MVA trivalent vaccines; VLP-based vaccines SPYVLP-102; or any combination thereof.

[0519] In some embodiments, one or more adjunctive therapeutic agents include, for example, human cytomegalovirus glycoprotein inhibitors, such as CMV-IVIG; adjunctive drugs for the treatment or prevention of CMV, such as artemisinin derivatives, NPC-21; herpesvirus envelope glycoprotein B stimulating vaccines, such as HB-101; CMV 65kDa smaller matrix phosphoprotein modulator vaccines, such as AVX-601; vaccines, such as CMV vaccines; CMV pp65 peptide vaccines; V-160; or multivirus-specific cytotoxic T-cell therapies; or any combination thereof.

[0520] In some implementations, one or more additional therapeutic agents include, for example, DNA polymerase inhibitors such as ganciclovir, fomivir, cidofovir, valganciclovir, or trisodium phosphonate, or any combination thereof.

[0521] In some implementations, one or more additional therapeutic agents include, for example, DNA polymerase inhibitors; helicase inhibitors; immunoglobulin agonists; interferon alpha2 ligands; interferon alpha ligand modulators; interferon beta ligands; or TLR-4 agonists; or any combination thereof.

[0522] In some embodiments, one or more adjunctive therapeutic agents include, for example, DNA polymerase inhibitors such as penciclovir, famciclovir, valacyclovir, acyclovir, and USC-373; DNA primase inhibitors-helicase inhibitors such as amonexvir; and interferon alpha2 ligand modulators such as interferon alpha-2b and yalaferon. ® Pegylated interferon α-1b, INTEFEN ® Interferon α-2a, Anterferon ® Interferon beta ligand modulators, such as RebiSmart ™ Immunoglobulin agonists, such as Varicellan ® , Herpes zoster immunoglobulin-VF; vaccines, such as varicella vaccine (live attenuated); MMRV vaccine; shingles vaccine; recombinant adjuvant shingles vaccine; or medications used to treat varicella-zoster virus infection, such as Herpes Cide. ™ ; or any combination thereof.

[0523] In some implementations, one or more additional therapeutic agents include, for example, vaccines, such as ProQuad. ® Priorix-Tetra ®(MeMuRu-OKA); TLR-4 agonist vaccines, such as CRV-101; vaccines based on the VZV ORF29 mutant; varicella vaccines (live attenuated) such as Sinovac; Varilrix ® Vaccines (VZV-OKA strain); attenuated recombinant subunit vaccines 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 MM-RvaxPRO. ® Adenovirus vector vaccines, such as VTP-400; recombinant varicella-zoster virus vaccines; recombinant shingles vaccines; inactivated varicella-zoster vaccines; live attenuated virus vaccines, such as NBP-608 and Suduvax. ® II. VZV-7D; or anti-varicella-zoster virus antibodies, such as VariZIG ® ; or any combination thereof.

[0524] In some implementations, one or more additional therapeutic agents include, for example, drugs used to treat or prevent varicella-zoster virus infection, such as OV-02; or vaccines, such as EG-HZ; or any combination thereof.

[0525] In some implementations, one or more additional therapeutic agents include, for example, interferon α2 ligands; DNA polymerase inhibitors; transferase inhibitors; CRISPR-associated endonuclease Cas9 modulators; LAT gene inhibitors; or gene inhibitors; or any combination thereof.

[0526] In some implementations, one or more additional therapeutic agents include, for example, DNA polymerase inhibitors such as acyclovir and ganciclovir; and interferon α2 ligand modulators such as interferon α-2b and Anterferon. ® CRISPR-associated endonuclease Cas9 modulators / gene inhibitors, such as HSV-1-targeted CRISPR / Cas9 gene therapy; LAT gene inhibitors, such as IFNγ / LAT siRNA gene therapy (rdHSV1 vector, for herpes simplex keratitis); adjunctive therapies for the treatment of herpes simplex keratitis, such as EKC-Cide. ™ ; or any combination thereof.

[0527] In some embodiments, one or more additional therapeutic agents include, for example, a basigin inhibitor; an envelope glycoprotein GP350 modulator; an Epstein-Barr nuclear antigen 1 inhibitor; an Epstein-Barr nuclear antigen 1 stimulator; an HLA class I antigen A-11α modulator; an HLA class I antigen A-2α modulator; an HLA class I antigen A-24α modulator; a human cytomegalovirus glycoprotein B modulator; a human cytomegalovirus glycoprotein H modulator; a human cytomegalovirus glycoprotein L modulator; a latent membrane protein 1 modulator; a latent membrane protein 2 stimulator; an NKG2D ligand modulator; or a secretory protein BARF1 modulator; or any combination thereof.

[0528] In some embodiments, one or more adjunctive therapeutic agents include, for example, NKG2D ligand modulators such as pamidronate; Epstein-Barr nuclear antigen 1 inhibitors such as VK-2019, anti-Epstein-Barr virus (EBV) peptides; HLA class I antigen A-11α / HLA class I antigen A-2α / HLA class I antigen A-24α modulators such as allogeneic anti-EBV-TCR-T cells, YT-EBV-44; adjunctive drugs for EBV treatment such as ALVR-105, antiviral cytotoxic T-cell therapy; Epstein-Barr nuclear antigen / latent membrane protein 1 and protein 2 / secretory protein BARF1 modulators such as baltaleucel-T (CMD-003); or mRNA vaccines such as mRNA-1195; or any combination thereof.

[0529] In some embodiments, one or more additional therapeutic agents include, for example, basigin modulators, such as EBV gH / gL / gp42 vaccines; or basigin modulators / enveloped glycoprotein GP350 modulators / human cytomegalovirus glycoprotein B modulators / human cytomegalovirus glycoprotein H modulators / human cytomegalovirus glycoprotein L modulators, such as mRNA-1189 vaccines; vaccines, such as EBV gH / gL vaccines; P-989; mRNA vaccines; or EBV cancer vaccines (mRNA, LPP nanoparticles); or any combination thereof.

[0530] In some implementations, one or more additional therapeutic agents include, for example, Epstein-Barr nuclear antigen 1 / latent membrane protein 2 stimulators, such as MVA-based vaccines; multivirus-specific cytotoxic T-cell therapies; or vaccines, such as EBV-VLP vaccines; or any combination thereof.

[0531] In some implementations, one or more additional therapeutic agents include, for example, DNA polymerase inhibitors.

[0532] In some implementations, one or more additional therapeutic agents include, for example, DNA polymerase inhibitors such as bucildofovir; drugs for the treatment of herpesvirus type 6 such as ALVR-105; multivirus-specific cytotoxic T-cell therapy; or HHV-6B glycoprotein complex gH / gL / gQ1 / gQ2 subunit vaccines; or any combination thereof.

[0533] In one implementation, one or more additional therapeutic agents are selected from one or more of the following pharmaceutical agents: i. Nucleoside polymerase inhibitors, such as acyclovir, valacyclovir, famciclovir, penciclovir, and ganciclovir; ii. Pyrophosphate polymerase inhibitors, such as phosphonic acid; iii. Saturated aliphatic alcohols, such as docosanool; iv. Pharmaceuticals such as idoxuridine, trifluuridine, and vidarabine; v. Corticosteroids; and vi. Other helicase-primase inhibitors, such as amonexvir.

[0534] In some cases, the crystalline form of Compound 1 provided herein may be administered as part of a combination therapy in a first amount together with one or more antiviral agents, including nucleoside analogues such as acyclovir, phosphonoformate, ganciclovir, or penciclovir, or corresponding prodrugs (valacyclovir or famciclovir), which 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 constitute a pharmaceutically effective amount. The first, second, or both amounts may be the same, more, or less than the effective amount of each compound administered as a monotherapy. The therapeutically effective amount of the disclosed compound and the antiviral agent may be administered to the subject concurrently, i.e., simultaneously or separately, in any given order and via the same or different routes of administration. In some cases, it may be advantageous to begin administration of the crystalline form of compound 1 first, for example, one or more days or one or more weeks before initiating administration of the antiviral agent. Furthermore, additional medications may be administered in conjunction with the aforementioned combination therapy.

[0536] Suitably, in the combination therapy described above, the crystalline form of compound 1 is compound 1 form I. Suitably, in the combination therapy described above, the crystalline form of compound 1 is compound 1 methanesulfonate form I.

[0537] VIII. Examples The following embodiments are included to demonstrate specific implementations of this disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques that function adequately in the practice of this disclosure and can therefore be considered as specific patterns constituting its practice. However, those skilled in the art should understand that these embodiments are exemplary and not exhaustive. Many changes may be made to the specific implementations of the disclosure without departing from the spirit and scope of this disclosure and still obtaining similar or analogous results.

[0538] The abbreviations used in this article have the following corresponding meanings:

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

[0540] Using a PANalytical X'Pert PRO MPD diffractometer with Cu K α An incident beam of radiation, generated using a long, narrow focusing source and a nickel filter, was used to collect the XRPD pattern. A symmetrical Bragg-Brentano geometry was used to construct the diffractometer. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to verify that the observed position of the Si 111 peak was consistent with the NIST-certified position. The sample was prepared as a circular thin layer centered on a silicon zero-background substrate. An anti-scattering slit (SS) was used to minimize background from air. Soller slits for both the incident and diffracted beams were used to minimize broadening from axial divergence. The diffraction pattern was collected using a scan 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 Instrument 2920 and a Q2000 differential scanning calorimeter. Temperature calibration was performed using NIST-traceable indium. The sample was placed in a zero-aluminum DSC pan, covered with a cap, and rolled up. The weight was then accurately recorded. The weighed aluminum pan, which was to be constructed as the sample pan, was placed on the reference side of the cell. The sample was heated from 20°C to 300°C at a rate of 10°C / min.

[0542] Thermogravimetric analysis (TGA) data were collected using a TA Instruments Discovery thermogravimetric analyzer. Temperature correction was performed using nickel and AlumelÔ. Each sample was placed in an aluminum pan and inserted into the TG furnace. The furnace was heated under nitrogen purging. The samples were heated from ambient temperature to 350°C at a rate of 10°C / min.

[0543] Moisture adsorption / desorption data were collected on a model Q5000 SA (TA Instruments). NaCl and PVP were used as calibration standards. The sample was not dried prior to analysis. Adsorption and desorption data were collected under nitrogen purging in increments of 10% RH, ranging from 5% to 95% RH. The equilibration criterion for analysis was a weight change of less than 0.0100% over 5 minutes, with a maximum equilibration time of 3 hours. The weight percentages reported in the data section are relative to the total sample mass introduced before equilibration at 5% RH, as measured on the instrument.

[0544] A. Compound Examples Example 1. (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-inden-2-carbonyl) Preparation of indoline-6-sulfonamide (compound 1) Compound 1 was prepared according to the procedure described in Example 35 of PCT application PCT / US2023 / 022679 (published reference in WO 2023 / 225162 A1).

[0545] Preparation of intermediate 21 : Preparation of intermediate 21.1: 5-Fluoro-2-methylindoline (40 g, 268 mmol, 1 equivalent) was dissolved in acetic acid (200 mL, 5V). NaBH3CN (50 g, 815 mmol, 3 equivalent) was added in portions while maintaining the temperature below 10 °C. The resulting solution was warmed to room temperature and stirred for 3 hours, during which time the reactants were diluted with ice-cold water (500 mL). The reactants were then extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (750 mL), dried over Na2SO4, and concentrated under vacuum. Crude intermediate 21.1 was separated as a viscous yellow oil and used for the next step without further purification. LC / MS: 151.2 [M+H].

[0546] Preparation of intermediate 21.2: Triethylamine (35 mL, 1 vol) was added to intermediate 21.1 (35 g, 86.6 mmol) in a stirred solution of DCM (300 mL) at 0 °C, followed by the addition of acetyl chloride (35 mL, 1 vol). The reaction mixture was stirred at room temperature for 2 hours. The residue was quenched with cold water (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (750 mL), dried over Na2SO4, and concentrated under vacuum. The crude residue was purified by column chromatography (100–200 silica gel, eluted with 8% EtOAc-hexane) to give intermediate 21.2. LC / MS: 193.2 [M+H].

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

[0548] intermediate (R)- 21 and (S) Preparation of -21: The racemic mixture of intermediate 21.3 (30 g, 110 mmol, 1 equivalent) in 500 mL of 2N sodium hydroxide was heated at 100 °C for 3 h. The reaction mixture was cooled to room temperature and the pH was adjusted to 7 with acetic acid. The precipitate was filtered, washed with water, and dried under vacuum. The resulting deacetylated racemic mixture was then purified by chiral SFC using a ChiralPak IG 240 × 4.6 mm column with a mobile phase of 70:20:10 hexane:methanol:MTBE. The intermediate was collected. (R)- 21 was used as the second eluent (retention time 13.1 min). LC / MS: 230.1 [M+H]. The intermediate was collected. (S) -21 was used as the first eluent (retention time 10.5 min). LC / MS: 230.1 [M+H].

[0549] Preparation of intermediate 19 : Preparation of intermediate 2: 5-(pyridin-2-yl)-2,3-dihydro-1H-inden-2-carboxylic acid Preparation of Intermediate 2.1: Diethyl carbonate (86 mL, 1.5 equivalents) was added to a stirred suspension of 60% NaH (22.72 g, 2 equivalents) in THF (1000 mL) at 0 °C. 5-Bromo-indan-1-one (100 g, 473.1 mmol) was added in portions at this temperature. The reaction mixture was stirred at this temperature until the gas escape subsided. The reaction mixture was slowly heated to 50 °C and stirred for 2 hours. The reaction progress was monitored by TLC, and the reaction mixture was cooled to room temperature after the starting material was consumed. The reactants were diluted with EtOAc (10 V). A 3N HCl aqueous solution was added dropwise. The two layers were separated. The aqueous layer was extracted with EtOAc (2 × 5 V). The combined organic layers were washed with a brine solution (5 V), dried (Na₂SO₄), and evaporated to give a crude product, which was purified by silica gel column chromatography to obtain intermediate 2.1. LCMS: 283.0 [M+H].

[0550] Preparation of intermediate 2.2: Triethylsilane (224 mL) was added dropwise to a solution of intermediate 2.1 (56 g, 197.9 mmol) in 280 mL of TFA at 0 °C, and the reaction mixture was stirred at room temperature for 24 h. The reaction progress was monitored by TLC. After the starting material was consumed, the reaction mixture was evaporated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography 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-tributyltinylpyridine (57.5 g, 1.05 equivalence) in 1,4-dioxane (400 mL) was degassed for 10 min under argon atmosphere. Pd(PPhs)4 (8.6 g, 5 mol%) was then added, followed by another 10 min of degassed solution. The reaction mixture was heated to 90 °C for 16 h. The reaction mixture was filtered through a diatomaceous earth mat, and the mat was washed twice with ethyl acetate. The combined filtrates were evaporated to dryness to give the crude product. The crude product was purified by silica gel column chromatography to give intermediate 2.3. LC / MS: 268.1 [M+H].

[0552] Preparation of Intermediate 2: 2N NaOH aqueous solution (140 mL, 2.2 equivalents) was added to intermediate 2.3 (35 g, 131.1 mmol) in a stirred solution of methanol (350 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was concentrated to 100 mL under reduced pressure. The residue was diluted with water (10 V), and the aqueous layer was washed with ethyl acetate (2 × 2 V). The aqueous phase was neutralized with 2N HCl aqueous solution and extracted with 10% methanol / DCM (3 × 5 V). The organic layer was dried over sodium sulfate and concentrated to give crude product. The crude product was then dissolved in 10% isopropanol / toluene (10 V) solution and treated with activated carbon. The solvent was then removed under reduced pressure. The residue was dissolved in 30% toluene / hexane, stirred for 30 min, filtered, and then dried under vacuum. This process was repeated twice to give intermediate 2. LC / MS: 238.1 [MH].

[0553] Preparation of intermediate 19: (R)-5-(pyridin-2-yl)-2,3-dihydro-1H-inden-2-carboxylic acid Using a Chiralpak AD-H column with 20% methanol as a co-solvent, intermediate 19 was obtained as the first eluent for SFC purification of intermediate 2. LC / MS: 238.1 [MH].

[0554] Preparation of Compound 1 intermediate (R)- 21 was dissolved in THF (10V), and dimethylformamide dimethyl acetal (1.2 equivalents) was immediately added. The solution was stirred at room temperature for 30 minutes, and then the solvent was removed under reduced pressure to obtain a crude residual intermediate. (R)- 21a (LC / MS: 286.1 [M+H]) was used directly in the next step without further purification.

[0555] intermediate (R)- 21a is dissolved in acetonitrile (10V). Intermediate 19 (1 equivalent) is added, followed by TCFH (2 equivalents). The suspension is placed in a room temperature water bath and added dropwise. N- Methylimidazole (5 equivalents). The solution was stirred at room temperature for 1 hour, at which point LC / MS analysis indicated complete conversion to the intermediate. (R)- 21b (LC / MS: 507.2 [M+H]). Hydrazine hydrate (50 equivalents) was then immediately added, and the mixture was stirred at room temperature for 30 minutes, followed by the addition of water (5V). The resulting precipitate was filtered and dried under reduced pressure to give compound 1. 1H NMR (400MHz, DMSO-d6) δ 8.69 (d, J = 4.9Hz, 1H), 8.54 (d, J= 6.6Hz, 1H), 8.10 – 7.84 (m, 4H), 7.58 (s, 2H), 7.51 – 7.24 (m, 3H), 4.90(t, J = 7.5Hz, 1H), 3.77 (p, J = 8.2Hz, 1H), 3.46 (ddt, J = 34.0, 17.5,8.7Hz, 3H), 3.20 (ddd, J = 59.1, 16.3, 8.3Hz, 2H), 2.80 (d, J = 16.9Hz, 1H),1.30 (d, J = 6.2Hz, 3H). LC / MS: 452.1 [M+H].

[0556] Example 2. Compound 1, Form I Will( R , E )- N '-((5-fluoro-2-methylindoline-6-yl)sulfonyl)- N , N - Dimethylformamidin (20.3 g, 71.1 mmol) and ( R 5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid (17.0 g, 71.0 mmol) was dissolved in dichloromethane (170 mL). The mixture was cooled to 10 °C, and a solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphonane-2,4,6-trioxide in dichloromethane (50 wt%, 85.3 mL, 142 mmol) was slowly added to the mixture. The mixture was warmed to 20 °C and stirred for 1 hour, and then triethylamine (80.0 mL, 574 mmol) was slowly added to the mixture. The mixture was stirred at 20 °C. R After the 5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid was completely consumed, the mixture was cooled to 10°C and water (85 mL) was slowly added to the mixture. Stirring was stopped, and the resulting layers were separated. The organic layer was concentrated to a minimum volume by vacuum distillation and then loaded into acetonitrile (170 mL); this process was repeated once. An aqueous solution of ammonium hydroxide (23 wt%, 351 mL, 4.26 mol) was slowly added to the resulting mixture. In the intermediate ( E )- N '-((( R )-5-fluoro-2-methyl-1-(( R)-5-(pyridin-2-yl)-2,3-dihydro-1H-inden-2-carbonyl)indoline-6-yl)sulfonyl)- N , N After complete consumption of dimethylformamide, a slurry was formed. The slurry was filtered, and the solid was washed twice with water (2 × 170 mL). The solid was dried to constant weight (29.1 g, 91% yield). XRPD analysis of the solid showed that it was crystalline (designated as compound 1, form I).

[0557] A representative XRPD pattern of compound 1, form I, is shown in Figure 1 Table 1 shows the peak positions present in the XRPD diffraction pattern obtained from compound 1, form I.

[0558] Table 1. Peak list of compound 1, form I

[0559] DSC thermal spectrum ( Figure 2 The indicated melting point is approximately 230°C.

[0560] The TGA thermogram showed a weight loss of approximately 0.4% from 40°C to 200°C, indicating a non-solventized form. Figure 3 ).

[0561] Figure 4 The DVS analysis is shown, and the DVS analysis indicates that the form is non-hygroscopic, with a water absorption rate of about 0.1% from 0% to 90% RH at 25°C.

[0562] Single crystals of compound 1 form I were prepared by dissolving approximately 40 mg of compound 1 in 1 mL of acetone at approximately 50 °C and then maintaining the solution for 3 days. A slurry was formed, and the sample was analyzed by SCXRD at approximately 100 K. The results (see Table 2) are consistent with those of compound 1 form I with the following parameters.

[0563] Table 2. Lattice parameters of compound 1, form I

[0564] Example 3. Compound 1, Form II At approximately 22°C, about 100 mg of the free base of amorphous compound 1 was stirred together with about 1 mL of toluene in a 4 mL vial equipped with a Teflon-coated magnetic stir bar. After stirring for 3 days, XRPD analysis of the wet solid revealed a new pattern (designated as compound 1 form II). The XRPD pattern remained unchanged after drying under vacuum at 50°C.

[0565] A representative XRPD pattern of Form II is shown in Figure 5Table 3 shows the peak positions present in the XRPD diffraction pattern obtained from form II of compound 1.

[0566] Table 3. Peak list of compound 1, form II

[0567] DSC thermogram of compound 1 form II ( Figure 6 The melt initiation temperature is indicated as approximately 223°C, followed by a melt initiation of approximately 245°C associated with form IV of compound 1.

[0568] The TGA thermogram of compound 1, form II, indicates a weight loss of approximately 0.6% from 25°C to 150°C. Figure 7 ).

[0569] Figure 8 The DVS analysis is shown, and the DVS analysis indicates that the form is slightly hygroscopic, with a water absorption rate of about 0.6% from 0% to 90% RH at 25°C.

[0570] Example 4. Compound 1, Form III Compound 1 form III was obtained by drying the hydrate of compound 1 under vacuum at 50°C.

[0571] A representative XRPD pattern of compound form III is shown in Figure 9 Table 4 shows the peak positions present in the XRPD diffraction pattern obtained from form III of compound 1.

[0572] Table 4. Peak list of compound 1, form III

[0573] DSC thermal spectrum ( Figure 10 This indicates a small endothermic transition below 50°C and an exothermic event with an onset temperature of approximately 206°C. The final endothermic event begins at approximately 246°C.

[0574] The TGA thermogram shows a significant weight loss of approximately 3.5% from 25°C to 60°C, which is attributed to the hygroscopicity of form III. Figure 11 ).

[0575] Figure 12 The DVS analysis is shown, and the DVS analysis indicates that the form is hygroscopic, with a water absorption rate of approximately 4.6% from 0% to 90% RH at 25°C.

[0576] Example 5. Compound 1, Form IV At approximately 22°C, about 150 mg of compound 1, the base form of methanesulfonate I, was stirred with about 1.5 mL of water in a 4-mL vial equipped with a Teflon-coated magnetic stir bar. The sample initially formed a gel-like mesophase over about one hour, and then became a flowable slurry after stirring overnight. It was filtered, and XRPD analysis of the wet solids revealed a new pattern (…). Figure 13 After drying under vacuum at approximately 50°C, its XRPD pattern remained unchanged. Proton NMR analysis showed that the dried solid did not contain detectable methanesulfonic acid. This new form was designated as compound 1, form IV.

[0577] A representative XRPD pattern of Form IV is shown in Figure 13 Table 5 shows the peak positions present in the XRPD diffraction pattern obtained from form IV of compound 1.

[0578] Table 5. Peak list of compound 1 in form IV

[0579] DSC thermal spectrum ( Figure 14 This indicates an endothermic reaction with an initial temperature of approximately 242°C.

[0580] TGA thermal spectrum ( Figure 15 The figure shows that the weight loss from 25°C to 75°C is approximately 0.7%.

[0581] Figure 16 The DVS analysis is shown, and the DVS analysis indicates that the form is slightly hygroscopic, with a water absorption rate of about 0.8% from 0% to 90% RH at 25°C.

[0582] Single crystals of compound 1 form IV were prepared by incubating approximately 50 mg of compound 1 in HCl salt form I at 45 °C in a mixture of 0.5 mL of EtOH and water (1:1 by volume) for several hours. A slurry was formed, and the sample was analyzed by SCXRD at approximately 299 K. When the predicted powder diffraction data were compared with the experimental data, the results were consistent with those of compound 1 form IV, and no solvent was present in the crystal lattice. The lattice parameters are shown in Table 6 below.

[0583] Table 6. Lattice parameters of compound 1, form IV

[0584] Example 6. Compound 1 in form V The sample of compound 1 dihydrate was further dried under vacuum at 50°C for 3 hours, and its XRPD pattern changed. This new form was designated as compound 1 form V.

[0585] A representative XRPD pattern of compound 1, form V, is shown in Figure 17 Table 7 shows the peak positions present in the XRPD diffraction pattern obtained from compound 1 in form V.

[0586] Table 7. Peak list of compound 1, form V

[0587] DSC thermal spectrum ( Figure 18 The DSC thermogram is similar to that of compound 1 dihydrate.

[0588] TGA thermal spectrum ( Figure 19 This indicates a weight loss of approximately 2%.

[0589] Example 7. Compound 1 monohydrate At approximately 22°C, about 50 mg of compound 1, the base form of methanesulfonate, was stirred with about 1 mL of water in a 4-mL vial equipped with a Teflon-coated magnetic stir bar. After two weeks, XRPD analysis of the wet solids revealed a new pattern. Figure 20 (Designated as compound 1 monohydrate). Proton NMR analysis of the dry solid showed no detectable methanesulfonic acid content.

[0590] A representative XRPD pattern of compound 1 monohydrate is shown in Figure 20 Table 8 shows the peak positions present in the XRPD diffraction pattern obtained from compound 1 monohydrate.

[0591] Table 8 Peak list of compound 1 monohydrate

[0592] DSC thermal spectrum ( Figure 21 The data indicates an endothermic transition at an initial temperature of approximately 33°C, attributable to water loss, and an exothermic event at an initial temperature of approximately 203°C. The final endothermic event begins at an initial temperature of approximately 246°C.

[0593] The TGA thermogram showed a significant weight loss of approximately 3.7% from 25°C to 100°C, indicating a monohydrate (theoretical monohydrate water content is 3.8%). Figure 22 ).

[0594] Example 8. Compound 1 dihydrate At approximately 22°C, approximately 120 mg of compound 1, the base form of methanesulfonate, was stirred with approximately 3 mL of water in a 4 mL vial equipped with a Teflon-coated magnetic stir bar. After a total of 4 hours, the sample became a flowable slurry. It was then filtered and dried under vacuum at approximately 22°C for approximately 16 hours.

[0595] A representative XRPD pattern of compound 1 dihydrate is shown in Figure 23Table 9 shows the peak positions present in the XRPD diffraction pattern obtained from compound 1 dihydrate.

[0596] Table 9 Peak list of compound 1 dihydrate

[0597] DSC thermal images are provided Figure 24 It also includes: an endothermic transition below 110°C; an endothermic event with an onset temperature of about 137°C; an exothermic event with an onset temperature of about 170°C; and an endothermic event with an onset temperature of about 247°C.

[0598] The TGA thermogram showed a weight loss of approximately 7.4%, indicating a dihydrate (the theoretical water content of the dihydrate is 7.4%). Figure 25 ).

[0599] Example 9. Compound 1 MeTHF solvate At approximately 22°C, approximately 100 mg of compound form I was stirred with approximately 1 mL of MeTHF in a 4-mL vial equipped with a Teflon-coated magnetic stir bar. After stirring for one day, XRPD analysis of the wet solids revealed a new pattern. Figure 26 (Specified as the MeTHF solvate of compound 1).

[0600] A representative XRPD pattern of the MeTHF solvate of compound 1 is shown in Figure 26 middle.

[0601] DSC thermogram of compound 1 MeTHF solvate after drying under vacuum at 50°C ( Figure 27 This indicates the endothermic transition at approximately 82°C and approximately 228°C.

[0602] The TGA thermogram of the MeTHF solvate (after drying under vacuum at 50 °C) shows a weight loss of approximately 12% from 25 °C to 106 °C, indicating a solvent loss of MeTHF. Figure 28 ).

[0603] Example 10. Compound 1, MTBE solvate 1 At approximately 22°C, about 50 mg of amorphous compound 1 free base was added to about 1 mL of MTBE in a 4 mL vial equipped with a Teflon-coated magnetic stir bar and stirred. After stirring for 3 days, XRPD analysis of the wet solids revealed a new pattern ( Figure 29 (Specified as compound 1 MTBE solvate 1).

[0604] A representative XRPD pattern of compound 1, MTBE solvate 1, is shown in... Figure 29 middle.

[0605] Example 11. Compound 1 MTBE solvate 2 At approximately 22°C, about 50 mg of amorphous compound 1 free base was added to about 1 mL of MTBE in a 4 mL vial equipped with a Teflon-coated magnetic stir bar and stirred. After stirring for 2 weeks, XRPD analysis of the wet solids revealed a new pattern. Figure 30 (Designated as compound 1 MTBE solvate 2). After drying under vacuum at 50°C, its XRPD pattern remains unchanged.

[0606] A representative XRPD pattern of compound 1 MTBE solvate 2 is shown in Figure 30 middle.

[0607] DSC thermogram of compound 1 MTBE solvate 2 after drying under vacuum at 50 °C ( Figure 31 This indicates the endothermic transition at approximately 94°C and the initial temperature of 216°C, the exothermic transition at 225°C, and the final endothermic transition at approximately 243°C.

[0608] Example 12. Compound 1, 2-BuOH solvate At approximately 22°C, about 50 mg of amorphous compound 1 free base was added to about 1 mL of 2-BuOH in a 4 mL vial equipped with a Teflon-coated magnetic stir bar and stirred. After stirring for 3 days, XRPD analysis of the wet solid revealed a new pattern ( Figure 33 (Specified as the solvate of compound 1 2-BuOH).

[0609] A representative XRPD pattern of the 2-BuOH solvate of compound 1 is shown in Figure 33 middle.

[0610] DSC thermogram of compound 1 2-BuOH solvate after drying under vacuum at 50 °C ( Figure 34 The figure indicates an endothermic transition at approximately 88°C, followed by an exothermic transition at approximately 139°C, and an endothermic transition at approximately 243°C.

[0611] Example 13. Compound 1 t-BuOH solvate At approximately 22°C, about 50 mg of amorphous compound 1 free base was added to about 1 mL of t-BuOH in a 4 mL vial equipped with a Teflon-coated magnetic stir bar and stirred. After stirring for 3 days, XRPD analysis of the wet solid revealed a new pattern ( Figure 35 (Specified as the solvate of compound 1 t-BuOH).

[0612] A representative XRPD pattern of the t-BuOH solvate of compound 1 is shown in Figure 35 middle.

[0613] Example 14. Compound 1 p-dioxane solvate At approximately 22°C, approximately 100 mg of amorphous compound 1 free base was added to approximately 0.5 mL of p-dioxane in a 4-mL vial equipped with a Teflon-coated magnetic stir bar and stirred. After stirring for 3 days, XRPD analysis of the wet solids revealed a new pattern ( Figure 36 (Designated as compound 1, p-dioxane solvate).

[0614] A representative XRPD pattern of compound 1 to dioxane solvate is shown in Figure 36 middle.

[0615] Example 15. Compound 1 CPME solvate At approximately 22°C, about 50 mg of amorphous compound 1 free base was added to about 1 mL of CPME in a 4-mL vial equipped with a Teflon-coated magnetic stir bar and stirred. After stirring for 3 days, XRPD analysis of the wet solids revealed a new pattern ( Figure 37 (Designated as compound 1 CPME solvate). Its XRPD pattern remained unchanged after drying under vacuum at 50°C.

[0616] A representative XRPD pattern of the CPME solvate of compound 1 is shown in Figure 37 middle.

[0617] DSC thermogram of compound 1 CPME solvate after drying under vacuum at 50°C ( Figure 38 The DSC thermograms of the CPME solvate of compound 1 after drying under vacuum at 50°C indicate endothermic transitions with onset temperatures of approximately 79°C and 245°C. Figure 38 This indicates endothermic transitions with starting temperatures of approximately 79°C, approximately 223°C, and approximately 245°C.

[0618] Example 16. Compound 1 DMAc solvate At approximately 22°C, about 200 mg of amorphous compound 1 free base was added to a 4-mL vial equipped with a Teflon-coated magnetic stir bar and stirred together with about 0.5 mL of DMAc. After stirring for 17 days, XRPD analysis of the wet solids revealed a new pattern ( Figure 39 (Designated as a solvate of compound 1 DMAc). Its XRPD pattern remained unchanged after drying under vacuum at 50°C.

[0619] A representative XRPD pattern of the DMAc solvate of compound 1 is shown in Figure 39 middle.

[0620] DSC thermogram of compound 1 DMAc solvate after drying under vacuum at 50°C ( Figure 40 This indicates two endothermic transitions with starting temperatures of approximately 125°C and approximately 246°C.

[0621] TGA thermal spectrum ( Figure 41 The results show a significant weight loss of approximately 16.3% from 25°C to 200°C, which is close to the theoretical value of one equivalent of DMAc (16.2%).

[0622] Example 17. Intermediate phase of compound 1 Shortly after stirring compound 1 in water in its methanesulfonate form I, the intermediate phase of compound 1 is obtained. It exhibits a gel-like appearance. XRPD pattern ( Figure 42 The values ​​are shown to be approximately 3.9 and 15.8 ± 0.2. o Two broad peaks at 2θ.

[0623] Example 18. Compound 1 hydrochloride form I Approximately 500 mg of compound 1 in its free base form I was stirred together with 10 mL of acetone solution containing 1.1 equivalents of concentrated HCl in a 20 mL vial equipped with a Teflon-coated magnetic stir bar. A slurry was formed shortly thereafter and filtered, washed with 0.5 mL of acetone, then with 1 mL of heptane, and dried in a vacuum oven at 50 °C for two hours. XRPD analysis revealed a distinctive pattern in the dried solid, which was identified as compound 1 in its hydrochloride form I.

[0624] A representative XRPD pattern of compound 1 hydrochloride form I is shown in Figure 43 Table 10 shows the peak positions present in the XRPD diffraction pattern obtained from compound 1 hydrochloride form I.

[0625] Table 10 Peak list of compound 1 hydrochloride form I

[0626] DSC thermal spectrum ( Figure 44 This indicates an endothermic reaction with an initial temperature of approximately 221°C.

[0627] The TGA thermogram showed a weight loss of approximately 0.2% from 25°C to 125°C, indicating a non-solventized form. Figure 45 ).

[0628] Figure 46 The DVS analysis is shown, and the DVS analysis indicates that the form is slightly hygroscopic, with a water absorption rate of about 0.4% from 0% to 90% RH at 25°C.

[0629] Example 19. Compound 1 hydrochloride form II Compound 1 hydrochloride form II was obtained by stirring Compound 1 hydrochloride form I in water or an EtOH / water mixture with a water content of about 3% or more by volume at about 21°C for 16 hours or longer.

[0630] A representative XRPD pattern of compound 1 hydrochloride form II is shown in Figure 47 Table 11 shows the peak positions present in the XRPD diffraction pattern obtained from compound 1 hydrochloride form II.

[0631] Table 11 Peak list of compound 1 hydrochloride form II

[0632] DSC thermal spectrum ( Figure 48 The reading indicates a melting initiation temperature of approximately 177°C. The DSC thermogram also shows an endothermic event with an initiation temperature of approximately 46°C.

[0633] The TGA thermograms show a weight loss of approximately 3.8% from 40°C to 150°C, and approximately 2.1% from 150°C to 200°C. Figure 49 ).

[0634] Figure 50 The DVS analysis is shown, and the DVS analysis indicates that the form is slightly hygroscopic, with a water absorption rate of about 0.7% from 0% to 90% RH at 25°C.

[0635] Single crystals of compound 1 hydrochloride form II were prepared by dissolving approximately 20 mg of compound 1 in HCl salt form I at approximately 22 °C in a mixture of 0.4 mL EtOH and 0.2 mL water, followed by spontaneous evaporation of the solvent in an open vial. The sample was dried, and some crystals were observed at the bottom of the vial. SCXRD analysis was performed on one crystal at approximately 299 K. The results were consistent with those of compound 1 hydrochloride form II when the predicted powder diffraction data were compared with the experimental data. The lattice parameters are shown in Table 12 below.

[0636] Table 12. Lattice parameters of compound 1 hydrochloride form II

[0637] Example 20. Compound 1 hemisulfate form I A mixture of free base of compound 1, 0.5 equivalents of sulfuric acid, and 0.5 mL of MeCN was stirred at approximately 22 °C for about one day in a 4-mL vial equipped with a Teflon-coated magnetic stir bar. XRPD analysis of the solid dried under vacuum at 50 °C revealed a new pattern, which was designated as hemisulfate form I of compound 1.

[0638] A representative XRPD pattern of compound 1 hemisulfate form I is shown in Figure 51 Table 13 shows the peak positions present in the XRPD diffraction pattern obtained from the hemisulfate form I of compound 1.

[0639] Table 13 Peak list of compound 1 in hemisulfate form I

[0640] DSC thermal spectrum ( Figure 52 This indicates an endothermic event with an initial temperature of approximately 153°C.

[0641] Example 21. Compound 1 in sulfate form I A mixture of free base of compound 1, 1 equivalent of sulfuric acid, and 0.5 mL of MeOH was stirred at approximately 22 °C for about one day in a 4-mL vial equipped with a Teflon-coated magnetic stir bar. XRPD analysis of the solid dried under vacuum at 50 °C revealed a new pattern, which was identified as sulfate form I of compound 1.

[0642] A representative XRPD pattern of compound 1 sulfate form I is shown in Figure 53 Table 14 shows the peak positions present in the XRPD diffraction pattern obtained from the sulfate form I of compound 1.

[0643] Table 14 Peak list of compound 1 in sulfate form I

[0644] DSC thermal spectrum ( Figure 54 This indicates an endothermic event with an initial temperature of approximately 165°C.

[0645] Example 22. Compound 1, methanesulfonate form I At approximately 22°C, about 50 mg of compound 1 in its free base form I was stirred together with 0.5 mL of a 1 equivalent of methanesulfonic acid in a 4 mL vial equipped with a Teflon-coated magnetic stir bar. After stirring for 4 hours, XRPD analysis of the wet solid revealed a new pattern that remained unchanged after drying under vacuum at 50°C. The new salt was designated as compound 1 in its methanesulfonate form I.

[0646] This form can also be obtained from other solvents such as MeCN, EtOH, IPA, acetone, MEK, MIBK, DCM, THF, MeTHF, EtOAc, IPAc, MTBE and toluene.

[0647] A representative XRPD pattern of compound 1 methanesulfonate form I is shown in Figure 55 Table 15 shows the peak positions present in the XRPD diffraction pattern obtained from compound 1 in its methanesulfonate form I.

[0648] Table 15 Peak list of compound 1, mesylate form I.

[0649] DSC thermal spectrum ( Figure 56 The indicated melting point is approximately 250°C.

[0650] The TGA thermogram showed a weight loss of approximately 0.1% from 25°C to 150°C, indicating a non-solventized form. Figure 57 ).

[0651] Figure 58 The DVS analysis is shown, and the DVS analysis indicates that the form is hygroscopic, with a water absorption rate of approximately 2.3% from 0% to 90% RH at 25°C.

[0652] Example 23. Compound 1, ethanesulfonate form I At approximately 22°C, a solution consisting of approximately 50 mg of Compound 1 in 1 mL of acetone was stirred with 1 equivalent of ethanesulfonic acid in a 4 mL vial equipped with a Teflon-coated magnetic stir bar. After stirring for approximately 16 hours, XRPD analysis of the wet solid revealed a new pattern that remained unchanged after drying under vacuum at 50°C. The new salt was designated as Compound 1 ethanesulfonate form I.

[0653] A representative XRPD pattern of compound 1 ethanesulfonate form I is shown in Figure 59 Table 16 shows the peak positions present in the XRPD diffraction pattern obtained from compound 1 in its ethanesulfonate form I.

[0654] Table 16 Peak list of compound 1, ethanesulfonate form I

[0655] DSC thermal spectrum ( Figure 60 The indicated melting point is approximately 258°C.

[0656] The TGA thermogram showed a weight loss of approximately 0.1% from 25°C to 150°C, indicating a non-solventized form. Figure 61 ).

[0657] Figure 62 The DVS analysis is shown, and the DVS analysis indicates that the form is hygroscopic, with a water absorption rate of approximately 3.3% from 0% to 90% RH at 25°C.

[0658] Example 24. Compound 1, benzenesulfonate form I At approximately 22°C, about 50 mg of compound 1 in its free base form I was stirred together with 1 equivalent of benzenesulfonic acid in 0.5 mL of acetone solution in a 4 mL vial equipped with a Teflon-coated magnetic stir bar. After stirring for 1 day, the solution was dried in a vacuum oven at 50°C and dissolved in 0.5 mL of MeOH. After stirring for 2 days, it was allowed to crystallize. Aliquots of the slurry were filtered and dried in a vacuum oven at 50°C. XRPD analysis of the solid dried under vacuum at 50°C revealed a new pattern, which was identified as compound 1 in its benzenesulfonate form I.

[0659] A representative XRPD pattern of compound 1 benzenesulfonate form I is shown in Figure 63 Table 17 shows the peak positions present in the XRPD diffraction pattern obtained from compound 1 benzenesulfonate form I.

[0660] Table 17 Peak list of compound 1 benzenesulfonate form I

[0661] DSC thermal spectrum ( Figure 64 The indicated melting point is approximately 148°C.

[0662] Example 25. Compound 1, benzenesulfonate form II Aliquots of the slurry of compound 1 benzenesulfonate from the previous embodiment in methanol were dried in a vacuum oven at 50°C and then stirred with 0.5 mL of MeCN. After stirring for approximately 16 hours, XRPD analysis of the solid dried under vacuum at 50°C revealed a new pattern, which was designated as form II of compound 1 benzenesulfonate.

[0663] A representative XRPD pattern of compound 1 benzenesulfonate form II is shown in Figure 65 Table 18 shows the peak positions present in the XRPD diffraction pattern obtained from compound 1 in benzenesulfonate form II.

[0664] Table 18 Peak list of compound 1 benzenesulfonate form II

[0665] DSC thermal spectrum ( Figure 66 The indicated melting point is approximately 148°C.

[0666] Example 26. Compound 1, toluenesulfonate form I At approximately 22°C, about 50 mg of compound 1 in its free base form I was stirred together with 1 equivalent of p-toluenesulfonic acid in 0.5 mL of acetone solution in a 4 mL vial equipped with a Teflon-coated magnetic stir bar. After stirring for 1 day, the solution was dried in a vacuum oven at 50°C and dissolved in 0.5 mL of MeOH. After stirring for 2 days, the solution was allowed to crystallize, and the slurry was filtered and dried in a vacuum oven at 50°C. XRPD analysis of the solid dried under vacuum at 50°C revealed a new pattern, which was identified as compound 1 in its toluenesulfonate form I.

[0667] A representative XRPD pattern of compound 1 toluenesulfonate form I is shown in Figure 67 Table 19 shows the peak positions present in the XRPD diffraction pattern obtained from compound 1 in toluenesulfonate form I.

[0668] Table 19 Peak list of compound 1 toluenesulfonate form I

[0669] DSC thermal spectrum ( Figure 68 The indicated melting point is approximately 164°C.

[0670] Example 27. Compound 1, naphthalene sulfonate form I At approximately 22°C, about 50 mg of compound 1 in its free base form I was stirred together with 1 equivalent of naphthalene-2-sulfonic acid in 0.5 mL of acetone solution in a 4 mL vial equipped with a Teflon-coated magnetic stir bar. After stirring for 1 day, the solution was dried in a vacuum oven at 50°C and dissolved in 0.5 mL of MeOH. After stirring for 2 days, it was allowed to crystallize. The slurry was filtered and dried in a vacuum oven at 50°C. XRPD analysis of the dried solid revealed a new pattern, which was identified as compound 1 in its naphthalene sulfonate form I.

[0671] A representative XRPD pattern of compound 1 naphthalene sulfonate form I is shown in Figure 69 Table 20 shows the peak positions present in the XRPD diffraction pattern obtained from compound 1 naphthalene sulfonate form I.

[0672] Table 20 Peak list of compound 1 naphthalene sulfonate form I

[0673] DSC thermal spectrum ( Figure 70 The indicated melting point is approximately 215°C.

[0674] Example 28. Compound 1, maleate form I At approximately 50°C, about 50 mg of Compound 1 in its free base form I was stirred with 0.5 mL of a 1 equivalent of maleic acid in acetone solution for about 30 minutes in a 4-mL vial equipped with a Teflon-coated magnetic stir bar, and then cooled to approximately 21°C. After stirring for about 16 hours, XRPD analysis of the wet solid revealed a new pattern that remained unchanged after drying under vacuum at 50°C. The new salt was designated as Compound 1 maleate form I.

[0675] A representative XRPD pattern of maleate form I of compound 1 is shown in Figure 71 Table 21 shows the peak positions present in the XRPD diffraction pattern obtained from maleate form I of compound 1.

[0676] Table 21 Peak list of compound 1, maleate form I

[0677] DSC thermal spectrum ( Figure 72 This indicates an endothermic reaction with an initial temperature of approximately 198°C.

[0678] The TGA thermogram showed a weight loss of approximately 0.04% from 25°C to 150°C, indicating a non-solventized form. Figure 73 The weight loss at higher temperatures may be due to the loss of maleic acid (theoretically, the maleic acid content is 20.5%).

[0679] Figure 74 The DVS analysis is shown, and the DVS analysis indicates that the form is non-hygroscopic, with a water absorption rate of approximately 0.17% from 0% to 90% RH at 25°C.

[0680] Example 29. Compound 1, L-tartrate form I Compound 1 in 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 (approximately 1.5 equivalents) in 7 mL of acetone. The mixture was stirred in a sealed vial at 70 °C for several minutes, then cooled to approximately 21 °C. After stirring for several hours, the slurry was filtered, and the solid was dried in a vacuum oven at 50 °C. The solid was characterized by XRPD and DSC and designated as compound 1 in L-tartrate form I.

[0681] A representative XRPD pattern of compound 1, L-tartrate form I, is shown in Figure 75 Table 22 shows the peak positions present in the XRPD diffraction pattern obtained from compound 1 in L-tartrate form I.

[0682] Table 22 Peak list of compound 1, L-tartrate form I

[0683] DSC thermal spectrum ( Figure 76 The primary endothermic temperature is indicated as approximately 113°C.

[0684] Example 30. Compound 1, L-tartrate form II 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 a vacuum oven at 50 °C. The solid was characterized by XRPD and DSC and designated as Compound 1 L-tartrate form II. Proton NMR showed approximately 1 equivalent of L-tartaric acid and approximately 0.6 equivalents of MeCN.

[0685] A representative XRPD pattern of compound 1, L-tartrate form II, is shown in Figure 77 Table 23 shows the peak positions present in the XRPD diffraction pattern obtained from compound 1 in L-tartrate form II.

[0686] Table 23 Peak list of compound 1, L-tartrate form II

[0687] DSC thermal spectrum ( Figure 78 The data indicates three major endothermic events with initial temperatures of approximately 26°C, 97°C, and 172°C, respectively.

[0688] Example 31. Compound 1, L-tartrate form III Compound 1 L-tartrate form I was obtained by stirring in MeCN for 3 days, filtering, and drying the solid 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 showed approximately 1 equivalent of L-tartaric acid and approximately 0.1 equivalent of MeCN.

[0689] A representative XRPD pattern of compound 1, L-tartrate form III, is shown in Figure 79 Table 24 shows the peak positions present in the XRPD diffraction pattern obtained from compound 1 in L-tartrate form III.

[0690] Table 24 Peak list of compound 1, L-tartrate form III

[0691] DSC thermal spectrum ( Figure 80 This indicates three major endothermic events with initial temperatures of approximately 20°C, 114°C, and 170°C.

[0692] B. Bioassay Example 32. Bioassay HSV-2 cytomic assays The ability of the compound to inhibit HSV-2 replication was tested by monitoring the expression of the HSV protein gD using a high-throughput immunofluorescence-based assay. Ten serially diluted (3-fold) doses of the compound were prepared in 100% DMSO at starting concentrations of 0.2 mM or 2 mM. Quadruple 250 nL of the compound was spotted onto black collagen-coated 384-well microplates (Greiner catalog number 781956) with clear bottoms using a Labcyte ECHO acoustic dispenser. The final starting concentration for the assay was 1 μM or 10 μM. Each microplate included DMSO (compound-free) and prepirenzevir as negative and positive controls, respectively.

[0693] ARPE-19 cells (ATCC catalog number CRL-2302) were maintained in DMEM / F-12 Glutamax medium (ThermoFisher Scientific catalog number 10565018) supplemented with 10% FBS (Corning catalog number 35-011-CV) and 1% penicillin-streptomycin (catalog number 30-002-CI). Before confluence, cells were transferred to centrifuge tubes and rotated at 1000 rpm for 5 minutes. Cells were resuspended in assay medium (DMEM / F-12 Glutamax, 2% FBS, 1% penicillin-streptomycin) and counted. The cell density was adjusted to 150,000 cells / ml, and cells were infected with HSV-2 virus (MS strain, ATCC catalog number VR-540) at an MOI of 0.06 in 50 ml conical tubes with constant agitation for 1 hour. The cells were then rotated at 1000 rpm for 5 minutes, and the medium was replaced with assay medium (EMD Millipore catalog number S1-100ML) containing 2% FBS or 10% human serum. 50 μL of infection suspension was added to the microplate wells pre-spotted with the compound (7,500 cells / well). The plates were incubated at 37°C for 16 hours.

[0694] Cell culture medium was aspirated using Biomek Fx, and 50 μL of paraformaldehyde solution (Electron Microscopy Sciences, 15712-S) diluted to 4% in DPBS (Corning catalog number 21-031-CM) was added to each well. After incubation at room temperature for 30 minutes, the plate was washed four times with 100 μL / well PBS using a Biomek washer. A 1:500 solution of primary antibody (anti-HSV gD, Virusys catalog number P1103) was prepared in permeabilization buffer (Invitrogen catalog number 00-8333-56), and 50 μL of the solution was added to each well. After incubating at room temperature for 1 hour, 50 μL of a 1:1000 solution of secondary antibody (Alexa Fluor 488 goat anti-mouse, Thermo Fisher Scientific catalog number A11001) and DAPI (Thermo Fisher Scientific catalog number 62248) in permeabilization buffer was added to the wells, and the plate was incubated in the dark at room temperature for 1 hour. The plate was washed four more times, and 50 μL of DPBS was added to all wells. The plate was then sealed with a black adhesive sealant. Fluorescence was measured using a Cellomics plate reader.

[0695] Data analysis was performed using Thermo Scientific HCS Studio software. In short, cells were identified using DAPI nuclear staining, and thresholds were set to filter cells based on shape and size. A second threshold based on green fluorescence intensity (detecting HSV-2 gD) was set to identify HSV-2-infected cells. Data were reported as the mean fluorescence intensity of HSV-2-infected cells. The EC50 value was defined as the compound concentration that causes a 50% reduction in mean fluorescence intensity, and this value was calculated using an S-type dose-response model to generate a curve fit. In this assay, the EC50 for prepirenrovir was 150 nM.

[0696] MT-4 CC50 Measurement Compounds were tested in 384-well plates: 18 compounds were tested in duplicate. Compounds were diluted 7-point, 3-fold with DMSO using Bravo. The assay plate containing 20 µL of the compound-containing medium was seeded at 20 µL / well with 2000 MT-4 cells via multi-drop to begin the assay. The plates were incubated at 37°C for 5 days. On day 6, 40 µL of CellTiterGlo was added to each well. Luminescence was read using Victor II. CC... 50 The value is defined as the concentration of the compound that causes a 50% reduction in the luminescence signal, and this value is calculated using an S-type dose-response model to generate a curve fit.

[0697] HSV qPCR assay HSV replication in the presence or absence of the compound was measured by qPCR using the following procedure: In a clear-bottom 96-well plate, the DMSO stock compound solution (1 mM–10 mM) was serially diluted (2.5-fold) in DMSO. The compound was then diluted 1:20 in assay medium (DMEM / F12 Glutamax + 2% fetal bovine serum + 1% penicillin-streptomycin), and 10 µL of these dilutions were added to each 96-well tissue culture plate, resulting in a final starting concentration of 0.5 µM–5 µM.

[0698] ARPE-19 cells (ATCC catalog number CRL-2302) maintained in growth medium (DMEM / F12 Glutamax + 10% FBS + 1% penicillin-streptomycin) were transferred to centrifuge tubes and rotated at 1000 rpm for 5 minutes. Cells were resuspended in assay medium, counted, and the cell density was adjusted to 2.8E+05 cells / ml with assay medium. Cells were then infected for 1 hour at an MOI of 0.05 with HSV-1 (KOS strain, ATCC catalog number VR-1493) or HSV-2 virus (MS strain, ATCC catalog number VR-540) in 50-mL conical tubes with constant shaking. 90 µL of infection suspension (25,000 cells) was added to the assay plate containing the added compounds. After incubation overnight at 37°C, the cell culture medium was removed, and cell lysis was performed using the prepGEMUniversal kit (MicroGEM catalog number PUN1000). Specifically, 100 µL of the prepGEM master mixture (94.75 µL water, 5 µL buffer, 0.25 µL enzyme stock solution) was added to each well, and the plate was incubated at room temperature for 15 minutes, followed by a 5-minute incubation on a plate shaker. Cell lysates were then transferred to a 96-well PCR-compatible microplate (AppliedBiosystems, catalog number N8010560). The plate was sealed with a heat-resistant plastic sealing film and heated on a thermal cycler under the following conditions: 75 °C for 10 minutes, followed by 95 °C for 5 minutes. Finally, the plate was cooled to room temperature with gentle shaking before qPCR setup.

[0699] qPCR was performed using the QuantiNova Multiplex PCR Kit (Qiagen catalog number 208456) with a total reaction volume of 20 µL. 15 µL of reagent mixture (5 µL 4X QuantiNova Master Mix, 0.1 µL QN Rox reference dye, 1 µL 20X HSV primer / probe mixture, and 8.9 µL PCR-grade water) and 5 µL of cell lysate were added to the wells of a 96-well rapid optical microplate (Applied Biosystems catalog number 4246906). The plate was sealed with clear sealing film, rotated, and qPCR was performed on an Applied Biosystems Quantstudio 7 Flex instrument under the following conditions: 95 °C for 2 min, followed by 40 cycles alternating between 95 °C for 5 sec and 60 °C for 30 sec.

[0700] Analysis was performed using the dCT method, where dCT = CT (test) - CT (DMSO). Using 2^ -dCTThe equation calculates the fold change. This fold change is then converted to a percentage relative to the DMSO control (no drug). EC50 is determined using nonlinear regression analysis with GraphPadPrism software.

[0701] In this assay, the EC50 for both prepirenvir and amonexvir was 14 nM. The EC50 for acyclovir was 1250 nM.

[0702] Biochemical assay of carbonic anhydrase (esterase) The activity of the compound in inhibiting the hydrolysis of 4-nitrophenylacetate (4NPA) mediated by human carbonic anhydrase (hCA) was tested using a high-throughput 384-well assay (Verpoorte et al., JBC, 1967). Ten doses of the compound were prepared in 100% DMSO at an initial concentration of 10 mM, serially diluted 3-fold. Then, 200 nL of the compound was spotted in quadruplicate onto clear 384-well microplates (Perkin Elmer catalog number 6007640) using a Labcyte ECHO acoustic dispenser. The final starting concentration for the assay was 50 μM. Each microplate included DMSO (without the compound) and acetazolamide as negative and positive controls, respectively.

[0703] Prepare a 1.5 μM hCA1 solution (R&D systems catalog number 2180-CA) or a 1 μM hCAII solution (Genscript catalog number U3256FL150-4 / P5GA002) in assay buffer (25 mM Tris (pH 7.5), 100 mM NaCl, 1% DMSO), and add 20 μL of the solution to the compound using a Biotek Micro Flo. After pre-incubating at room temperature for 15 min, add 20 μL of assay buffer solution containing 4 mM 4NPA substrate (Sigma catalog number N8130) to initiate the reaction. Incubate the microplate at room temperature for 60 min, then read the absorbance at 405 nM on an Envision plate reader. Define the IC50 value as the compound concentration that causes a 50% decrease in absorbance, and calculate this value using an S-type dose-response model to generate a curve fit. The IC50 of acetazolamide was 0.04 µM in hCAII assay and 1.1 µM in hCAI assay.

[0704] Plasma stability assay The test compound was incubated at 2 μM in rat or human plasma (BioIVT, Westbury, NY) at 37 °C for up to 4 hours. At specified time points, the incubated aliquots were quenched by adding 9 volumes of 100% acetonitrile containing the internal standard. After the final collection, the samples were centrifuged at 4500 rpm for 10 minutes, and the supernatant was transferred to a new plate containing an equal volume of water for analysis by liquid chromatography combined with triple quadrupole mass spectrometry (LC-MS / MS). The percentage of the test compound remaining in the plasma after incubation (the ratio of the analyte peak area to the internal standard peak area) was plotted against the incubation time, and the plasma half-life (t1 / 2) was calculated based on a linear fit to the natural logarithm of the curve.

[0705] Stability determination of cryopreserved hepatocytes The test compound was administered at 1 μM in 24-well plates (1 × 10⁻⁶) with cryopreserved rat or human hepatocytes (BioIVT, Westbury, NY) at 37 °C. 6 Incubate samples together (cells / mL / well) for up to 6 hours. At specified time points, transfer samples to 96-well plates and quench with 2 volumes of a solution containing 90% acetonitrile, 10% methanol, 0.1% formic acid, and an internal standard. Centrifuge the sample plate at 3200 rpm for 15 minutes and transfer the supernatant to a fresh plate containing half a volume of water. Analyze the resulting solution by LC-MS / MS. Plot the data (ratio of analyte to internal standard peak area) on a semi-logarithmic scale and fit using exponential fitting. Assuming first-order kinetics, determine the half-life (t1 / 2) and metabolic rate. Calculate the predicted hepatic clearance based on the half-life using a well-stirred model.

[0706] C. Large-scale synthesis of compound 1 form I and compound 1 methanesulfonate form I Example 33. Large-scale manufacturing of compound 1, form I Compound 1 (5.61 kg) was dissolved in acetone (30 V) at 45-50 °C. The solution was concentrated to 5 V, and ethanol (12 V) was added at 45 °C over 3 hours. After aging for 2 hours, the slurry was cooled to -10 °C over 3 hours. After aging for 2 hours, the slurry was filtered and washed with ethanol (1.5 V). The product was dried at 50 °C to give 4.95 kg of compound 1 in form I (88% yield, 99.9% area purity).

[0707] Example 34. Large-scale manufacturing of compound 1 in methanesulfonat...

Claims

1. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Or its pharmaceutically acceptable salt or cocrystal.

2. The crystalline form according to claim 1, The crystalline form is: Compound 1, Form I Compound 1, Form II Compound 1, Form III Compound 1, Form IV Compound 1 in form V, Compound 1 monohydrate, Compound 1 dihydrate, Compound 1-methyl-tetrahydrofuran (MeTHF) solvate, Compound 1, methyl tert-butyl ether solvate 1, Compound 1, methyl tert-butyl ether solvate 2, Compound 1, 2-Butanol solvate, Compound 1 tert-butanol solvate, Compound 1 is effective against dioxane solvates, Compound 1 cyclopentylmethyl ether solvate, Compound 1 dimethylacetamide solvate, Compound 1 hydrochloride form I, Compound 1 hydrochloride form II Compound 1 hemisulfate form I, Compound 1 in sulfate form I Compound 1, methanesulfonate form I, Compound 1, ethanesulfonate form I, Compound 1, benzenesulfonate form I, Compound 1, benzenesulfonate form II Compound 1, toluenesulfonate form I, Compound 1, naphthalene sulfonate 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 according to claim 2, wherein the crystalline form is: Compound 1, Form I Compound 1, Form II Compound 1, Form III Compound 1 in form IV, or Compound 1, form V.

4. The crystalline form according to claim 2, wherein the crystalline form is: Compound 1, form I.

5. The crystalline form according to claim 2, wherein the crystalline form is: Compound 1 monohydrate, or Compound 1 dihydrate.

6. The crystalline form according to claim 2, wherein the crystalline form is: Compound 1-methyl-tetrahydrofuran (MeTHF) solvate, Compound 1, methyl tert-butyl ether solvate 1, Compound 1, methyl tert-butyl ether solvate 2, Compound 1, 2-Butanol solvate, Compound 1 tert-butanol solvate, Compound 1 is effective against dioxane solvates, Compound 1 cyclopentylmethyl ether solvate, or Compound 1 is a dimethylacetamide solvate.

7. The crystalline form according to claim 2, wherein the crystalline form is: Compound 1 hydrochloride form I, Compound 1 hydrochloride form II Compound 1 hemisulfate form I, Compound 1 in sulfate form I Compound 1, methanesulfonate form I, Compound 1, ethanesulfonate form I, Compound 1, benzenesulfonate form I, Compound 1, benzenesulfonate form II Compound 1, toluenesulfonate form I, Compound 1, naphthalene sulfonate 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 according to claim 2, wherein the crystalline form is: Compound 1 is in methanesulfonate form I.

9. The crystalline form according to claim 2, wherein the crystalline form 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, methanesulfonate form I, or Compound 1 is in maleate form I.

10. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Includes 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.

5. o 2θ (±0.2) o An X-ray powder diffraction (XRPD) pattern with five or more peaks at 2θ, in form I.

11. The crystalline form according to claim 10, characterized in that... Including 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, and 26.

5. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

12. The crystalline form according to claim 10 or 11, characterized in that... Including the following values: 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

13. The crystalline form according to any one of claims 10 to 12, characterized in that... Basically, it is an XRPD pattern as shown in Figure 1.

14. The crystalline form according to any one of claims 10 to 13, characterized in that... The unit cell, as determined by single-crystal X-ray diffraction crystallography, has the following dimensions: a = 19.6326(18) Å; b = 7.6161(7) Å; c = 14.8409(14) Å; α = 90°; β = 104.029(8)°; and γ = 90°.

15. The crystalline form according to any one of claims 10 to 14, characterized in that... Differential scanning calorimetry (DSC) thermogram with an endothermic start temperature of approximately 230°C.

16. The crystalline form according to any one of claims 10 to 15, characterized in that... Basically, it is the DSC thermogram shown in Figure 2.

17. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Including 12.6, 13.9, 15.3, 18.5, 19.2, 19.7, 22.3, 23.4, or 24.

3. o 2θ (±0.2) o An X-ray powder diffraction (XRPD) pattern with five or more peaks at 2θ, form II.

18. The crystalline form according to claim 17, characterized in that... Including 12.6, 13.9, 15.3, 18.5, 19.2, 19.7, 22.3, 23.4, and 24.

3. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

19. The crystalline form according to claim 17 or 18, characterized in that... This includes values ​​of 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

20. The crystalline form according to any one of claims 17 to 19, characterized in that... Basically, it is an XRPD pattern as shown in Figure 5.

21. The crystalline form according to any one of claims 17 to 20, characterized in that... Differential scanning calorimetry (DSC) thermograms with endothermic onset temperatures of approximately 223°C and 245°C.

22. The crystalline form according to any one of claims 17 to 21, characterized in that... Basically, it is the DSC thermogram shown in Figure 6.

23. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-inden-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Includes 10.0, 12.2, 17.3, 18.3, 20.1, 22.0, 23.7, 25.3, or 25.

9. o 2θ (±0.2) o An X-ray powder diffraction (XRPD) pattern with five or more peaks at 2θ, type III.

24. The crystalline form according to claim 23, characterized in that... Includes 10.0, 12.2, 17.3, 18.3, 20.1, 22.0, 23.7, 25.3, and 25.

9. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

25. The crystalline form according to claim 23 or 24, characterized in that... Includes values ​​in the following ranges: 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

26. The crystalline form according to any one of claims 23 to 25, characterized in that... Basically, it is an XRPD pattern as shown in Figure 9.

27. The crystalline form according to any one of claims 23 to 26, characterized in that... Differential scanning calorimetry (DSC) thermogram with an endothermic onset temperature of approximately 246 °C.

28. The crystalline form according to any one of claims 23 to 27, characterized in that... Basically, it is a DSC thermogram as shown in Figure 10.

29. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Includes 5.7, 11.2, 16.8, 17.1, 18.7, 21.4, 22.4, 23.3, or 23.

8. o 2θ (±0.2) o An X-ray powder diffraction (XRPD) pattern with five or more peaks at 2θ, in form IV.

30. The crystalline form according to claim 29, characterized in that... Including 5.7, 11.2, 16.8, 17.1, 18.7, 21.4, 22.4, 23.3, and 23.

8. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

31. The crystalline form according to claim 29 or 30, characterized in that... Including the following values: 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

32. The crystalline form according to any one of claims 29 to 31, characterized in that... Basically, it is an XRPD pattern as shown in Figure 13.

33. The crystalline form according to any one of claims 29 to 32, characterized in that... The unit cell, as determined by single-crystal X-ray crystal diffraction, has the following dimensions: a = 6.09120(10) Å; b = 11.01750(10) Å; c = 31.8714(4) Å; α = 90°; β = 90°; and γ = 90°.

34. The crystalline form according to any one of claims 29 to 33, characterized in that... Differential scanning calorimetry (DSC) thermogram with an endothermic onset temperature of approximately 242°C.

35. The crystalline form according to any one of claims 29 to 34, characterized in that... Basically, it is a DSC thermogram as shown in Figure 14.

36. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Includes 10.0, 11.8, 13.9, 17.6, 18.1, 18.5, 18.9, 19.6, or 26.

0. o 2θ (±0.2) o An X-ray powder diffraction (XRPD) pattern with five or more peaks at 2θ, in form V.

37. The crystalline form according to claim 36, characterized in that... Includes versions 10.0, 11.8, 13.9, 17.6, 18.1, 18.5, 18.9, 19.6, and 26.

0. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

38. The crystalline form according to claim 36 or 37, characterized in that... Included in 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

39. The crystalline form according to any one of claims 36 to 38, characterized in that... Basically, it is an XRPD pattern as shown in Figure 17.

40. The crystalline form according to any one of claims 36 to 39, characterized in that... Thermogravimetric analysis (TGA) with approximately 2% weight loss.

41. The crystalline form according to any one of claims 36 to 40, characterized in that... Basically, it is a TGA as shown in Figure 19.

42. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Includes 12.2, 14.9, 17.5, 20.0, 20.6, 21.8, 23.6, 25.4, or 26.

0. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, monohydrate.

43. The crystalline form according to claim 42, characterized in that... Including 12.2, 14.9, 17.5, 20.0, 20.6, 21.8, 23.6, 25.4, and 26.

0. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

44. The crystalline form according to claim 42 or 43, characterized in that... Including values ​​of 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

45. The crystalline form according to any one of claims 42 to 44, characterized in that... Basically, it is an XRPD pattern as shown in Figure 20.

46. ​​The crystalline form according to any one of claims 42 to 45, characterized in that... Differential scanning calorimetry (DSC) thermograms with endothermic onset temperatures of approximately 33°C and 246°C.

47. The crystalline form according to any one of claims 42 to 46, characterized in that... Basically, it is a DSC thermogram as shown in Figure 21.

48. The crystalline form according to any one of claims 42 to 47, characterized in that... Thermogravimetric analysis (TGA) showed a weight loss of approximately 3.7%.

49. The crystalline form according to any one of claims 42 to 48, characterized in that... Basically, it is a TGA as shown in Figure 22.

50. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Including 8.1, 9.6, 11.7, 16.3, 18.8, 24.5, 25.7, 25.9, or 27.

9. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, dihydrate.

51. The crystalline form according to claim 50, characterized in that... Including 8.1, 9.6, 11.7, 16.3, 18.8, 24.5, 25.7, 25.9, and 27.

9. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

52. The crystalline form according to claim 50 or 51, characterized in that... Including the following values: 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

53. The crystalline form according to any one of claims 50 to 52, characterized in that... Basically, it is an XRPD pattern as shown in Figure 23.

54. The crystalline form according to any one of claims 50 to 53, characterized in that... Thermogravimetric analysis (TGA) showed a weight loss of approximately 7.4%.

55. The crystalline form according to any one of claims 50 to 54, characterized in that... Basically, it is a TGA as shown in Figure 25.

56. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Including 8.9, 12.5, 18.9, 19.6, 20.8, 23.8, 24.4, 24.8, or 28.

8. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, hydrochloride form I.

57. The crystalline form according to claim 56, characterized in that... Including 8.9, 12.5, 18.9, 19.6, 20.8, 23.8, 24.4, 24.8, and 28.

8. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

58. The crystalline form according to claim 56 or 57, characterized in that... Including the following values: 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

59. The crystalline form according to any one of claims 56 to 58, characterized in that... Basically, it is an XRPD pattern as shown in Figure 43.

60. The crystalline form according to any one of claims 56 to 59, characterized in that... Differential scanning calorimetry (DSC) thermogram with an endothermic start temperature of approximately 221 °C.

61. The crystalline form according to any one of claims 56 to 60, characterized in that... Basically, it is a DSC thermogram as shown in Figure 44.

62. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-inden-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Includes 8.3, 12.4, 15.3, 19.2, 22.6, 24.0, 24.8, 26.3, or 28.

3. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, hydrochloride form II.

63. The crystalline form according to claim 62, characterized in that... Including 8.3, 12.4, 15.3, 19.2, 22.6, 24.0, 24.8, 26.3, and 28.

3. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

64. The crystalline form according to claim 62 or 63, characterized in that... This includes the following values: 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

65. The crystalline form according to any one of claims 62 to 64, characterized in that... Basically, it is an XRPD pattern as shown in Figure 47.

66. The crystalline form according to any one of claims 62 to 65, characterized in that... The unit cell, as determined by single-crystal X-ray crystal diffraction, has the following dimensions: a = 10.83810(10) Å; b = 17.4553(2) Å; c = 12.44620(10) Å; α = 90°; β = 93.4720(10)°; and γ = 90°.

67. The crystalline form according to any one of claims 62 to 66, characterized in that... Differential scanning calorimetry (DSC) thermogram with an endothermic onset temperature of approximately 177°C.

68. The crystalline form according to any one of claims 62 to 67, characterized in that... Basically, it is a DSC thermogram as shown in Figure 48.

69. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-inden-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Including 9.6, 11.9, 16.5, 19.4, 20.1, 22.6, 23.8, or 25.

8. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, hemisulfate form I.

70. The crystalline form according to claim 69, characterized in that... Including 9.6, 11.9, 16.5, 19.4, 20.1, 22.6, 23.8, and 25.

8. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

71. The crystalline form according to claim 69 or 70, characterized in that... Including 9.6, 11.9, 14.6, 16.5, 19.4, 20.1, 22.6, 23.8, 25.8, and 28.

7. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

72. The crystalline form according to any one of claims 69 to 71, characterized in that... Basically, it is an XRPD pattern as shown in Figure 51.

73. The crystalline form according to any one of claims 69 to 72, characterized in that... Differential scanning calorimetry (DSC) thermogram with an endothermic onset temperature of approximately 153°C.

74. The crystalline form according to any one of claims 69 to 73, characterized in that... Basically, it is a DSC thermogram as shown in Figure 52.

75. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Including 9.6, 19.1, 19.4, 20.4, 22.3, 23.6, or 25.

5. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, in sulfate form I.

76. The crystalline form according to claim 75, characterized in that... Including 9.6, 19.1, 19.4, 20.4, 22.3, 23.6, and 25.

5. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

77. The crystalline form according to claim 75 or 76, characterized in that... Including the following values: 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

78. The crystalline form according to any one of claims 75 to 77, characterized in that... Basically, it is an XRPD pattern as shown in Figure 53.

79. The crystalline form according to any one of claims 75 to 78, characterized in that... Differential scanning calorimetry (DSC) thermogram with an endothermic start temperature of approximately 165°C.

80. The crystalline form according to any one of claims 75 to 79, characterized in that... Basically, it is a DSC thermogram as shown in Figure 54.

81. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Includes 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, or 29.

6. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, methanesulfonate form I.

82. The crystalline form according to claim 81, characterized in that... Including 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, and 29.

6. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

83. The crystalline form according to claim 81 or 82, characterized in that... Included in 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

84. The crystalline form according to any one of claims 81 to 83, characterized in that... Basically, it is an XRPD pattern as shown in Figure 55.

85. The crystalline form according to any one of claims 81 to 84, characterized in that... Differential scanning calorimetry (DSC) thermogram with an endothermic start temperature of approximately 250°C.

86. The crystalline form according to any one of claims 81 to 85, characterized in that... Basically, it is a DSC thermogram as shown in Figure 56.

87. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Includes versions 7.0, 17.9, 18.4, 20.1, 20.8, 23.0, 23.4, 24.0, or 25.

8. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, ethanesulfonate form I.

88. The crystalline form according to claim 87, characterized in that... Includes versions 7.0, 17.9, 18.4, 20.1, 20.8, 23.0, 23.4, 24.0, and 25.

8. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

89. The crystalline form according to claim 87 or 88, characterized in that... Included in 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

90. The crystalline form according to any one of claims 87 to 89, characterized in that... Basically, it is an XRPD pattern as shown in Figure 59.

91. The crystalline form according to any one of claims 87 to 90, characterized in that... Differential scanning calorimetry (DSC) thermogram with an endothermic onset temperature of approximately 258°C.

92. The crystalline form according to any one of claims 87 to 91, characterized in that... Basically, it is a DSC thermogram as shown in Figure 60.

93. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Including 11.3, 14.9, 16.1, 18.4, 19.8, 21.0, 22.8, or 24.9 o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, benzenesulfonate form I.

94. The crystalline form according to claim 93, characterized in that... Including 11.3, 14.9, 16.1, 18.4, 19.8, 21.0, 22.8, and 24.

9. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

95. The crystalline form according to claim 93 or 94, characterized in that... Including 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 o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

96. The crystalline form according to any one of claims 93 to 95, characterized in that... Basically, it is an XRPD pattern as shown in Figure 63.

97. The crystalline form according to any one of claims 93 to 96, characterized in that... Differential scanning calorimetry (DSC) thermogram with an endothermic start temperature of approximately 148°C.

98. The crystalline form according to any one of claims 93 to 97, characterized in that... Basically, it is a DSC thermogram as shown in Figure 64.

99. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Includes versions 12.2, 18.0, 19.3, and 21.

7. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of the peak at 2θ, benzenesulfonate form II.

100. The crystalline form according to claim 99, characterized in that... Includes 12.2, 14.4, 16.0, 18.0, 19.3, 21.7, 22.5, 24.9, 27.1, or 28.

2. o 2θ (±0.2) o XRPD pattern of five or more peaks at 2θ).

101. The crystalline form according to claim 99 or 100, characterized in that... Including 12.2, 14.4, 16.0, 18.0, 19.3, 21.7, 22.5, 24.9, 27.1, and 28.

2. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

102. The crystalline form according to any one of claims 99 to 101, characterized in that... Basically, it is an XRPD pattern as shown in Figure 65.

103. The crystalline form according to any one of claims 99 to 102, characterized in that... Differential scanning calorimetry (DSC) thermogram with an endothermic start temperature of approximately 148°C.

104. The crystalline form according to any one of claims 99 to 103, characterized in that... Basically, it is a DSC thermogram as shown in Figure 66.

105. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Includes 4.1, 8.1, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5, or 24.

5. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, toluenesulfonate form I.

106. The crystalline form according to claim 105, characterized in that... Includes 4.1, 8.1, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5, and 24.

5. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

107. The crystalline form according to claim 105 or 106, characterized in that... Includes 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

108. The crystalline form according to any one of claims 105 to 107, characterized in that... Basically, it is an XRPD pattern as shown in Figure 67.

109. The crystalline form according to any one of claims 105 to 108, characterized in that... Differential scanning calorimetry (DSC) thermogram with an endothermic start temperature of approximately 164°C.

110. The crystalline form according to any one of claims 105 to 109, characterized in that... Basically, it is a DSC thermogram as shown in Figure 68.

111. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Including 6.6, 12.3, 17.8, 19.0, 21.2, 22.2, 23.9, 25.8, or 26.

6. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, naphthalene sulfonate form I.

112. The crystalline form according to claim 111, characterized in that... Including 6.6, 12.3, 17.8, 19.0, 21.2, 22.2, 23.9, 25.8, and 26.

6. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

113. The crystalline form according to claim 111 or 112, characterized in that... Including the following values: 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

114. The crystalline form according to any one of claims 111 to 113, characterized in that... Basically, it is an XRPD pattern as shown in Figure 69.

115. The crystalline form according to any one of claims 111 to 114, characterized in that... Differential scanning calorimetry (DSC) thermogram with an endothermic start temperature of approximately 215°C.

116. The crystalline form according to any one of claims 111 to 115, characterized in that... Basically, it is a DSC thermogram as shown in Figure 70.

117. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Including 10.6, 16.9, 18.0, 20.0, 21.7, 22.6, 24.5, 25.5, or 27.

3. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, maleate form I.

118. The crystalline form according to claim 117, characterized in that... Including 10.6, 16.9, 18.0, 20.0, 21.7, 22.6, 24.5, 25.5, and 27.

3. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

119. The crystalline form according to claim 117 or 118, characterized in that... This includes values ​​in 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

120. The crystalline form according to any one of claims 117 to 119, characterized in that... Basically, it is an XRPD pattern as shown in Figure 71.

121. The crystalline form according to any one of claims 117 to 120, characterized in that... Differential scanning calorimetry (DSC) thermogram with an endothermic start temperature of approximately 198°C.

122. The crystalline form according to any one of claims 117 to 121, characterized in that... Basically, it is a DSC thermogram as shown in Figure 72.

123. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-inden-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Includes 9.4, 14.4, 16.2, 17.4, 17.9, 18.9, 20.3, 21.5, or 24.

3. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, L-tartrate form I.

124. The crystalline form according to claim 123, characterized in that... This includes values ​​of 9.4, 14.4, 16.2, 17.4, 17.9, 18.9, 20.3, 21.5, and 24.

3. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

125. The crystalline form according to claim 123 or 124, characterized in that... Included in 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

126. The crystalline form according to any one of claims 123 to 125, characterized in that... Basically, it is an XRPD pattern as shown in Figure 75.

127. The crystalline form according to any one of claims 123 to 126, characterized in that... Differential scanning calorimetry (DSC) thermogram with an endothermic onset temperature of approximately 113°C.

128. The crystalline form according to any one of claims 123 to 127, characterized in that... Basically, it is a DSC thermogram as shown in Figure 76.

129. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Including 11.7, 13.9, 18.6, 21.8, 23.1, 24.5, 26.1, 28.8, or 29.5 o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, L-tartrate form II.

130. The crystalline form according to claim 129, characterized in that... Including 11.7, 13.9, 18.6, 21.8, 23.1, 24.5, 26.1, 28.8, and 29.

5. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

131. The crystalline form according to claim 129 or 130, characterized in that... Includes 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

132. The crystalline form according to any one of claims 129 to 131, characterized in that... Basically, it is an XRPD pattern as shown in Figure 77.

133. The crystalline form according to any one of claims 129 to 132, characterized in that... Differential scanning calorimetry (DSC) thermograms with endothermic onset temperatures of approximately 26°C, 97°C, and 172°C.

134. The crystalline form according to any one of claims 129 to 133, characterized in that... Basically, it is a DSC thermogram as shown in Figure 78.

135. A crystalline form of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-inden-2-carbonyl)indoline-6-sulfonamide (compound 1): Its features Includes 4.9, 9.8, 17.1, 18.6, 19.6, 20.2, 20.8, 22.0, or 24.

6. o 2θ (±0.2) o X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ, L-tartrate form III.

136. The crystalline form according to claim 135, characterized in that... Including 4.9, 9.8, 17.1, 18.6, 19.6, 20.2, 20.8, 22.0, and 24.

6. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

137. The crystalline form according to claim 135 or 136, characterized in that... Including the following values: 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. o 2θ (±0.2) o XRPD pattern of the peak at 2θ).

138. The crystalline form according to any one of claims 135 to 137, characterized in that... Basically, it is an XRPD pattern as shown in Figure 79.

139. The crystalline form according to any one of claims 135 to 138, characterized in that... Differential scanning calorimetry (DSC) thermograms with endothermic onset temperatures of approximately 20°C, 114°C, and 170°C.

140. The crystalline form according to any one of claims 135 to 139, characterized in that... Basically, it is a DSC thermogram as shown in Figure 80.

141. A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 140 and at least one pharmaceutically acceptable carrier.

142. The pharmaceutical composition of claim 141, wherein the pharmaceutical composition further comprises one, two, three or four additional therapeutic agents.

143. The pharmaceutical composition of claim 142, wherein the additional therapeutic agent is selected from famciclovir, acyclovir, and valacyclovir.

144. A method of treating herpes virus infection, the method comprising administering to a patient in need a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 140 or according to any one of claims 141 to 143.

145. The method of claim 144, wherein the method comprises administering, in combination with one, two, three or four additional therapeutic agents, the crystalline form of any one of claims 1 to 140 or the pharmaceutical composition of any one of claims 141 to 143.

146. The method of claim 144 or 145, wherein the herpesvirus is HSV-1 or HSV-2.

147. A method of treating a condition induced, aggravated, or accelerated by a herpes virus, the method comprising administering to a patient in need a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 140 or according to any one of claims 141 to 143.

148. The method of claim 147, wherein the condition is genital herpes, cold sores, HSV keratitis, HSV encephalitis, or disseminated HSV.

149. The method of claim 147 or 148, wherein the method comprises administering, in combination with one, two, three or four additional therapeutic agents, the crystalline form of any one of claims 1 to 140 or the pharmaceutical composition of any one of claims 141 to 143.

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 the crystalline form according to any one of claims 1 to 140 or the pharmaceutical composition according to any one of claims 141 to 143 in the manufacture of a medicament for treating HSV infection.

152. Use of the crystalline form according to any one of claims 1 to 140 or the pharmaceutical composition according to any one of claims 141 to 143 in the treatment of viral infections.

153. Use of the crystalline form according to any one of claims 1 to 140 or the pharmaceutical composition according to any one of claims 141 to 143 in the treatment of viral infections caused by herpesviruses.

154. Use of the crystalline form according to any one of claims 1 to 140 or the pharmaceutical composition according to any one of claims 141 to 143 in the treatment of viral infections caused by HSV-1 or HSV-2.

155. Use of the crystalline form according to any one of claims 1 to 140 or the pharmaceutical composition according to any one of claims 141 to 143 for the preparation of a medicament for treating viral infections.

156. Use of the crystalline form according to any one of claims 1 to 140 or the pharmaceutical composition according to any one of claims 141 to 143 for the preparation of a medicament for treating viral infections caused by herpesviruses.

157. Use of the crystalline form according to any one of claims 1 to 140 or the pharmaceutical composition according to any one of claims 141 to 143 for the preparation of a medicament for treating viral infections caused by HSV-1 or HSV-2.

158. The crystalline form according to any one of claims 1 to 140 or the pharmaceutical composition according to any one of claims 141 to 143, wherein the crystalline form or the pharmaceutical composition is used in a method of treating viral infections caused by HSV-1 or HSV-2.

159. The crystalline form or pharmaceutical composition used according to claim 158, wherein the viral infection is genital herpes, cold sores, HSV keratitis, HSV encephalitis, or disseminated HSV.

160. The crystalline form or pharmaceutical composition used according to claim 158 or 159, wherein the compound is administered in combination with an additional therapeutic agent.

161. The crystalline form according to any one of claims 1 to 140 or the pharmaceutical composition according to any one of claims 141 to 143, wherein the crystalline form or the pharmaceutical composition is used in a therapeutic manner.

162. A method for preparing compound 1 in form I, the method comprising the following steps: a) Provide a solution of compound 1 in the first solvent system; b) Concentrate the solution from step a) and / or add a second solvent system to the solution from step a); c) Mix the mixture obtained from step b); d) Optionally, separate the solid formed in step c); and e) Optionally, dry the solid separated from step d).

163. A method for preparing compound 1 in methanesulfonate form I, the method comprising the following steps: a) Provide a solution of compound 1 in the first solvent system; b) Add the methanesulfonic acid in the second solvent system to the solution from step a); c) Optionally, cool the mixture obtained from step b); d) Optionally, separate the solid formed in step c); and e) Optionally, dry the solid separated from step d).

Images