Solid forms of a hsv helicase primase inhibitor

Abstract

The present disclosure provides crystalline forms, solvates, and hydrates of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2, 3-dihydro-1H-indene-2-carbonyl) indoline-6-sulfonamide, as well as methods of making the same.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480073183.1 (22) Application Date 2024.11.15 (30) Priority Data 63 / 600,285 2023.11.17 US (85) PCT International Application Entering National Phase Date 2026.05.18 (86) PCT International Application Application Data PCT / IB2024 / 061402 2024.11.15 (87) PCT International Application Publication Data WO2025 / 104687 EN 2025.05.22 (71) Applicant Gilead Sciences, Inc. Address California, USA (72) Inventors E. Narayanan A. Parsons Shi Bing T.P. Stratton D.H. Yin Xujie (74) Patent Agency King & Wood Mallesons, Beijing 11256 Patent Attorney Ma Hui (51) Int.Cl. C07D 401 / 10 (2006.01) A61K 31 / 4439 (2006.01) A61P 31 / 12 (2006.01) (54) Invention Title Solid Form of HSV Helicase Primer Inhibitor (57) Abstract This disclosure provides the crystalline form, solvate and hydrate of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, as well as a method of preparation. Claims 16 pages, Description 98 pages, Drawings 52 pages, CN 122270446 A 2026.06.23 CN 1 22 27 04 46 A 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 a pharmaceutically acceptable salt or cocrystal thereof. 2. The crystalline form according to claim 1, wherein the crystalline form is: Compound 1 form I, Compound 1 form II, Compound 1 form III, Compound 1 form IV, Compound 1 form V, Compound 1 monohydrate, Compound 1 dihydrate, Compound 1 methyl-tetrahydrofuran (MeTHF) solvate, Compound 1 methyl 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 in ethanesulfonate form I, compound 1 in benzenesulfonate form I, compound 1 in benzenesulfonate form II, compound 1 in toluenesulfonate form I, compound 1 in naphthalenesulfonate form I, compound 1 in maleate form I, compound 1 in L-tartrate form I, compound 1 in L-tartrate form II, or compound 1 in L-tartrate form III as described on page 1 / 16 of claim 2 (CN 122270446 A). 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 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: methyl-tetrahydrofuran (MeTHF) solvate of compound 1, methyl tert-butyl ether solvate 1 of compound 1, methyl tert-butyl ether solvate 2 of compound 1, 2-butanol solvate of compound 1, tert-butanol solvate of compound 1, p-dioxane solvate of compound 1, cyclopentylmethyl ether solvate of compound 1, or dimethylacetamide solvate of compound 1. 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 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. 8. The crystalline form according to claim 2, wherein the crystalline form is: Compound 1 methanesulfonate form I. 9. The crystalline form according to claim 2, wherein the crystalline form is: (Claims 2 / 16, page 3, CN 122270446 A) 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. 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):The crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5°2θ (±0.2°2θ), in form I. 11. The crystalline form according to claim 10, characterized by an XRPD pattern comprising peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, and 26.5°2θ (±0.2°2θ). 12. The crystalline form according to claim 10 or 11, characterized by an XRPD pattern comprising peaks at 12.3, 12.5, 13.3, 14.4, 16.6, 17.3, 18.0, 18.5, 19.8, 20.3, 21.2, 22.8, 23.2, 24.0, 24.6, 25.0, 25.3, 26.5, 27.6, 28.1, 28.7, 29.5, 30.9, 31.5, 32.2, 36.4, and 37.1°2θ (±0.2°2θ). 13. The crystalline form according to any one of claims 10 to 12, characterized by an XRPD pattern substantially as shown in FIG. 1. 14. The crystalline form according to any one of claims 10 to 13, characterized in that the unit cell has 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°. 15. The crystalline form according to any one of claims 10 to 14, characterized in that it has an endothermic differential scanning calorimetry (DSC) thermogram with an initial temperature of about 230 °C. 16. The crystalline form according to any one of claims 10 to 15, characterized in that it has a DSC thermogram substantially as shown in FIG2. 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): Claims 3 / 16, page 4, CN 122270446 A, characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 12.6, 13.9, 15.3, 18.5, 19.2, 19.7, 22.3, 23.4 or 24.3°2θ (±0.2°2θ), form II. 18. The crystalline form according to claim 17, characterized by an XRPD pattern comprising peaks at 12.6, 13.9, 15.3, 18.5, 19.2, 19.7, 22.3, 23.4 and 24.3°2θ (±0.2°2θ).19. The crystalline form according to claim 17 or 18, characterized by an XRPD pattern comprising peaks at 9.4, 12.6, 13.9, 15.3, 16.7, 17.3, 18.5, 19.2, 19.7, 22.3, 23.4, 24.3, 25.1, 25.7, 26.4, 28.0, 29.0, 29.7, 31.5, 33.7, and 35.3°2θ (±0.2°2θ). 20. The crystalline form according to any one of claims 17 to 19, characterized by an XRPD pattern substantially as shown in FIG. 5. 21. The crystalline form according to any one of claims 17 to 20, characterized by an endothermic differential scanning calorimetry (DSC) thermogram with onset temperatures of about 223 °C and 245 °C. 22. The crystalline form according to any one of claims 17 to 21, characterized by a DSC thermogram substantially as shown in FIG. 6. 23. 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), characterized in that it comprises an X-ray powder diffraction (XRPD) pattern of five or more peaks at 10.0, 12.2, 17.3, 18.3, 20.1, 22.0, 23.7, 25.3 or 25.9°2θ (±0.2°2θ), form III. 24. The crystalline form according to claim 23, characterized in that it comprises an XRPD pattern of peaks at 10.0, 12.2, 17.3, 18.3, 20.1, 22.0, 23.7, 25.3 and 25.9°2θ (±0.2°2θ). 25. The crystalline form according to claim 23 or 24, characterized by an XRPD pattern comprising peaks at 10.0, 12.2, 12.7, 13.3, 14.7, 15.0, 15.8, 17.3, 18.3, 19.1, 20.1, 20.3, 20.8, 22.0, 23.0, 23.7, 24.4, 25.3, 25.9, 27.0, 28.0, 28.5, 28.9, and 30.3°2θ (±0.2°2θ). 26. The crystalline form according to any one of claims 23 to 25, characterized by an XRPD pattern substantially as shown in FIG. 9. 27. The crystalline form according to any one of claims 23 to 26, characterized by an endothermic differential scanning calorimetry (DSC) thermogram with an initial temperature of about 246 °C. 28. The crystalline form according to any one of claims 23 to 27, characterized by a DSC thermogram substantially as shown in FIG10. 29. A (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-Crystalline form of 6-sulfonamide (compound 1): Claims 4 / 16, page 5, CN 122270446 A. Characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 5.7, 11.2, 16.8, 17.1, 18.7, 21.4, 22.4, 23.3, or 23.8°2θ (±0.2°2θ), form IV. 30. The crystalline form according to claim 29, characterized by an XRPD pattern comprising peaks at 5.7, 11.2, 16.8, 17.1, 18.7, 21.4, 22.4, 23.3, and 23.8°2θ (±0.2°2θ). 31. The crystalline form according to claim 29 or 30, characterized by an XRPD pattern comprising peaks at 5.7, 8.6, 11.2, 11.7, 13.8, 16.2, 16.8, 17.1, 17.6, 18.2, 18.7, 19.7, 20.4, 21.4, 21.8, 22.4, 23.3, 23.8, 24.5, 25.7, 26.5, 27.7, 29.2, 30.0, 31.4, 32.7, 33.2, 33.7, 34.8, 35.3, and 38.3°2θ (±0.2°2θ). 32. The crystalline form according to any one of claims 29 to 31, characterized by an XRPD pattern substantially as shown in FIG. 13. 33. The crystalline form according to any one of claims 29 to 32, characterized in that the unit cell has the following dimensions as determined by single-crystal X-ray diffraction: 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 it has an endothermic differential scanning calorimetry (DSC) thermogram with an initial temperature of about 242 °C. 35. The crystalline form according to any one of claims 29 to 34, characterized in that it has a DSC thermogram substantially as shown in FIG. 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), characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 10.0, 11.8, 13.9, 17.6, 18.1, 18.5, 18.9, 19.6, or 26.0°2θ (±0.2°2θ), in form V. 37. The crystalline form according to claim 36, characterized by comprising peaks at 10.0, 11.8, 13.9, 17.6, 18.1, 18.5, 18.9, 19.6, or 26.0°2θ (±0.2°2θ).38. The crystalline form according to claim 36 or 37, characterized by an XRPD pattern comprising peaks at 9.2, 10.0, 11.8, 12.5, 13.9, 15.3, 15.8, 16.8, 17.3, 17.6, 18.1, 18.5, 18.9, 19.6, 20.4, 21.2, 21.7, 22.4, 23.8, 25.0, 26.0, 27.0, and 28.4°2θ (±0.2°2θ). 39. The crystalline form according to any one of claims 36 to 38, characterized by an XRPD pattern substantially as shown in FIG. 17. Claims 5 / 16, page 6, CN 122270446 A 40. The crystalline form according to any one of claims 36 to 39, characterized by thermogravimetric analysis (TGA) with a weight loss of about 2%. 41. The crystalline form according to any one of claims 36 to 40, characterized by a TGA substantially as shown in FIG19. 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): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 12.2, 14.9, 17.5, 20.0, 20.6, 21.8, 23.6, 25.4 or 26.0°2θ (±0.2°2θ), a monohydrate. 43. The crystalline form according to claim 42, characterized by an XRPD pattern comprising peaks at 12.2, 14.9, 17.5, 20.0, 20.6, 21.8, 23.6, 25.4 and 26.0°2θ (±0.2°2θ). 44. The crystalline form according to claim 42 or 43, characterized by an XRPD pattern comprising peaks at 10.0, 12.2, 12.5, 13.2, 14.9, 16.3, 17.5, 18.7, 19.0, 19.4, 20.0, 20.6, 21.1, 21.8, 23.0, 23.6, 24.5, 25.4, 26.0, 27.8, 28.3, 28.6, 30.1, 31.4, 32.1, 32.8, 34.3, 35.9, 36.9, 38.3, and 39.0°2θ (±0.2°2θ). 45. The crystalline form according to any one of claims 42 to 44, characterized by an XRPD pattern substantially as shown in FIG. 20. 46. ​​The crystalline form according to any one of claims 42 to 45, characterized in that it has an endothermic differential scanning calorimetry (DSC) thermogram with an initial temperature of about 33 °C and 246 °C.47. The crystalline form according to any one of claims 42 to 46, characterized by a DSC thermogram substantially as shown in FIG21. 48. The crystalline form according to any one of claims 42 to 47, characterized by a thermogravimetric analysis (TGA) with a weight loss of about 3.7%. 49. The crystalline form according to any one of claims 42 to 48, characterized by a TGA substantially as shown in FIG22. 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): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 8.1, 9.6, 11.7, 16.3, 18.8, 24.5, 25.7, 25.9 or 27.9°2θ (±0.2°2θ), dihydrate. Claims 6 / 16, page 7, CN 122270446 A 51. The crystalline form according to claim 50, characterized by an XRPD pattern comprising peaks at 8.1, 9.6, 11.7, 16.3, 18.8, 24.5, 25.7, 25.9 and 27.9°2θ (±0.2°2θ). 52. The crystalline form according to claim 50 or 51, characterized by an XRPD pattern comprising peaks at 8.1, 9.6, 10.5, 11.7, 12.2, 15.1, 16.3, 17.6, 18.1, 18.8, 19.2, 20.9, 21.7, 22.4, 22.8, 23.4, 23.8, 24.5, 25.0, 25.7, 25.9, 26.4, 26.6, 27.2, 27.9, 29.1, 29.6, and 34.5°2θ (±0.2°2θ). 53. The crystalline form according to any one of claims 50 to 52, characterized by an XRPD pattern substantially as shown in FIG. 23. 54. The crystalline form according to any one of claims 50 to 53, characterized by thermogravimetric analysis (TGA) with a weight loss of approximately 7.4%. 55. The crystalline form according to any one of claims 50 to 54, characterized in that it is substantially the TGA shown in FIG25. 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), characterized in that it comprises an X-ray powder diffraction (XRPD) pattern of five or more peaks at 8.9, 12.5, 18.9, 19.6, 20.8, 23.8, 24.4, 24.8 or 28.8°2θ (±0.2°2θ), hydrochloride form I.57. The crystalline form according to claim 56, characterized in that it comprises an XRPD pattern including peaks at 8.9, 12.5, 18.9, 19.6, 20.8, 23.8, 24.4, 24.8, and 28.8°2θ (±0.2°2θ). 58. The crystalline form according to claim 56 or 57, characterized in that it comprises an XRPD pattern including peaks at 8.9, 12.5, 15.2, 15.9, 18.9, 19.2, 19.6, 20.8, 21.5, 23.8, 24.4, 24.8, 25.9, 26.2, 26.9, 27.7, 28.8, 30.4, 31.2, 32.5, 33.8, and 38.9°2θ (±0.2°2θ). 59. The crystalline form according to any one of claims 56 to 58, characterized in that it has essentially the XRPD pattern shown in FIG43. 60. The crystalline form according to any one of claims 56 to 59, characterized in that it has an endothermic differential scanning calorimetry (DSC) thermogram with an initial temperature of about 221 °C. 61. The crystalline form according to any one of claims 56 to 60, characterized in that it has essentially the DSC thermogram shown in FIG44. 62. 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): Claims 7 / 16, page 8, CN 122270446 A, characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 8.3, 12.4, 15.3, 19.2, 22.6, 24.0, 24.8, 26.3 or 28.3°2θ (±0.2°2θ), hydrochloride form II. 63. The crystalline form according to claim 62, characterized by an XRPD pattern comprising peaks at 8.3, 12.4, 15.3, 19.2, 22.6, 24.0, 24.8, 26.3 and 28.3°2θ (±0.2°2θ). 64. The crystalline form according to claim 62 or 63, characterized by an XRPD pattern comprising peaks at 8.3, 9.8, 11.8, 12.4, 15.3, 17.0, 17.8, 18.4, 19.2, 19.5, 20.5, 21.1, 21.6, 22.6, 23.2, 23.4, 24.0, 24.8, 25.1, 25.4, 26.3, 26.8, 27.4, 28.3, 29.5, 29.9, 30.6, 32.4, and 33.4°2θ (±0.2°2θ). 65. The crystalline form according to any one of claims 62 to 64, characterized by an XRPD pattern substantially as shown in FIG. 47. 66.The crystalline form according to any one of claims 62 to 65 is characterized by a unit cell having the following dimensions as determined by single-crystal X-ray diffraction: 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 is characterized by an endothermic differential scanning calorimetry (DSC) thermogram with an initial temperature of about 177 °C. 68. The crystalline form according to any one of claims 62 to 67 is characterized by a DSC thermogram substantially as shown in FIG48. 69. 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), characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 9.6, 11.9, 16.5, 19.4, 20.1, 22.6, 23.8 or 25.8°2θ (±0.2°2θ), in hemisulfate form I. 70. The crystalline form according to claim 69, characterized by an XRPD pattern comprising peaks at 9.6, 11.9, 16.5, 19.4, 20.1, 22.6, 23.8 and 25.8°2θ (±0.2°2θ). 71. The crystalline form according to claim 69 or 70, characterized by an XRPD pattern comprising peaks at 9.6, 11.9, 14.6, 16.5, 19.4, 20.1, 22.6, 23.8, 25.8, and 28.7°2θ (±0.2°2θ). 72. The crystalline form according to any one of claims 69 to 71, characterized by an XRPD pattern substantially as shown in FIG. 51. 73. The crystalline form according to any one of claims 69 to 72, characterized by an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 153 °C. 74. The crystalline form according to any one of claims 69 to 73, characterized by a DSC thermogram substantially as shown in FIG. 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): Claims 8 / 16, page 9, CN 122270446 A, characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 9.6, 19.1, 19.4, 20.4, 22.3, 23.6 or 25.5°2θ (±0.2°2θ), in sulfate form I.76. The crystalline form according to claim 75, characterized by an XRPD pattern comprising peaks at 9.6, 19.1, 19.4, 20.4, 22.3, 23.6, and 25.5°2θ (±0.2°2θ). 77. The crystalline form according to claim 75 or 76, characterized by an XRPD pattern comprising peaks at 9.6, 12.7, 14.1, 15.5, 16.6, 18.4, 19.1, 19.4, 20.4, 22.0, 22.3, 22.9, 23.6, 24.3, 25.5, 26.8, and 27.6°2θ (±0.2°2θ). 78. The crystalline form according to any one of claims 75 to 77, characterized by an XRPD pattern substantially as shown in FIG. 53. 79. The crystalline form according to any one of claims 75 to 78, characterized in that it has an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 165 °C. 80. The crystalline form according to any one of claims 75 to 79, characterized in that it has a DSC thermogram substantially as shown in FIG. 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): characterized in that it comprises an X-ray powder diffraction (XRPD) pattern of five or more peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8 or 29.6 °2θ (±0.2 °2θ), methanesulfonate form I. 82. The crystalline form according to claim 81, characterized by an XRPD pattern comprising peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8 and 29.6°2θ (±0.2°2θ). 83. The crystalline form according to claim 81 or 82, characterized by an XRPD pattern comprising peaks at 7.2, 8.9, 11.6, 12.8, 14.3, 16.1, 16.4, 17.3, 18.1, 18.5, 19.1, 19.5, 20.2, 20.6, 20.9, 20.9, 21.4, 22.2, 22.5, 23.2, 24.0, 24.7, 25.4, 25.7, 26.1, 26.8, 27.7, 29.6, 31.0, 31.5, 32.4, 34.0, 35.4, 35.9, 36.3, 37.2, and 37.9°2θ (±0.2°2θ). 84. The crystalline form according to any one of claims 81 to 83, characterized by an XRPD pattern substantially as shown in FIG55. 85. The crystalline form according to any one of claims 81 to 84, characterized by having an initial temperature of about 250°C.86. The crystalline form according to any one of claims 81 to 85, characterized in that it is substantially as shown in the DSC thermogram of claim 9 / 16, page 10, CN 122270446 A. 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): characterized in that it comprises an X-ray powder diffraction (XRPD) pattern of five or more peaks at 7.0, 17.9, 18.4, 20.1, 20.8, 23.0, 23.4, 24.0 or 25.8°2θ (±0.2°2θ), ethanesulfonate form I. 88. The crystalline form according to claim 87, characterized by an XRPD pattern comprising peaks at 7.0, 17.9, 18.4, 20.1, 20.8, 23.0, 23.4, 24.0 and 25.8°2θ (±0.2°2θ). 89. The crystalline form according to claim 87 or 88, characterized by an XRPD pattern comprising peaks at 7.0, 8.7, 11.6, 12.3, 13.9, 14.5, 16.3, 17.0, 17.9, 18.4, 18.9, 19.5, 20.1, 20.6, 20.8, 21.9, 22.2, 23.0, 23.4, 24.0, 24.6, 25.2, 25.8, 27.1, 27.8, 28.4, 29.8, 30.6, 31.1, 32.3, 34.7, 35.5, and 36.2°2θ (± 0.2°2θ). 90. The crystalline form according to any one of claims 87 to 89, characterized by an XRPD pattern substantially as shown in FIG. 59. 91. The crystalline form according to any one of claims 87 to 90, characterized in that it has an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 258 °C. 92. The crystalline form according to any one of claims 87 to 91, characterized in that it has a DSC thermogram substantially as shown in FIG60. 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): characterized in that it comprises an X-ray powder diffraction (XRPD) pattern of five or more peaks at 11.3, 14.9, 16.1, 18.4, 19.8, 21.0, 22.8 or 24.9 °2θ (±0.2 °2θ), benzenesulfonate form I. 94. The crystalline form according to claim 93, characterized in that it comprises 11.3, 14.9, 16.1, 18.4, 19.8,95. The crystalline form according to claim 93 or 94, characterized by XRPD patterns including peaks at 10.0, 10.5, 11.3, 14.4, 14.9, 16.1, 17.1, 18.4, 19.8, 21.0, 22.8, 24.9, 25.8, 27.0, and 31.5 o2θ (±0.2 o2θ). 96. The crystalline form according to any one of claims 93 to 95, characterized by an XRPD pattern substantially as shown in FIG. 63. Claims 10 / 16 pages 11 CN 122270446 A 97. The crystalline form according to any one of claims 93 to 96, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram with an initial temperature of about 148 °C. 98. The crystalline form according to any one of claims 93 to 97, characterized by a DSC thermogram substantially as shown in FIG64. 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), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.2, 18.0, 19.3, and 21.7°2θ (±0.2°2θ), benzenesulfonate form II. 100. The crystalline form according to claim 99, characterized in that it comprises an XRPD pattern of five or more peaks at 12.2, 14.4, 16.0, 18.0, 19.3, 21.7, 22.5, 24.9, 27.1, or 28.2°2θ (±0.2°2θ). 101. The crystalline form according to claim 99 or 100, characterized in that it comprises an XRPD pattern of peaks at 12.2, 14.4, 16.0, 18.0, 19.3, 21.7, 22.5, 24.9, 27.1, and 28.2°2θ (±0.2°2θ). 102. The crystalline form according to any one of claims 99 to 101, characterized in that it comprises an XRPD pattern substantially as shown in FIG. 65. 103. The crystalline form according to any one of claims 99 to 102, characterized in that it has an endothermic differential scanning calorimetry (DSC) thermogram with an initial temperature of about 148°C. 104. The crystalline form according to any one of claims 99 to 103, characterized in that it has a DSC thermogram substantially as shown in FIG. 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):The toluenesulfonate form is characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 4.1, 8.1, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5, or 24.5°2θ (±0.2°2θ). 106. The crystalline form according to claim 105, characterized by an XRPD pattern comprising peaks at 4.1, 8.1, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5, and 24.5°2θ (±0.2°2θ). 107. The crystalline form according to claim 105 or 106, characterized by an XRPD pattern comprising peaks at 4.1, 5.0, 6.7, 8.1, 9.3, 9.9, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5, 20.4, 22.2, and 24.5°2θ (±0.2°2θ). 108. The crystalline form according to any one of claims 105 to 107, characterized by an XRPD pattern substantially as shown in FIG. 67, page 11 / 16 of claim 12, CN 122270446 A. 109. The crystalline form according to any one of claims 105 to 108, characterized by an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 164°C. 110. The crystalline form according to any one of claims 105 to 109, characterized by a DSC thermogram substantially as shown in FIG. 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), characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 6.6, 12.3, 17.8, 19.0, 21.2, 22.2, 23.9, 25.8 or 26.6°2θ (±0.2°2θ), in naphthalene sulfonate form I. 112. The crystalline form according to claim 111, characterized by an XRPD pattern comprising peaks at 6.6, 12.3, 17.8, 19.0, 21.2, 22.2, 23.9, 25.8 and 26.6°2θ (±0.2°2θ). 113. The crystalline form according to claim 111 or 112, characterized by comprising 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,XRPD patterns of peaks at 25.8, 26.6, 27.2, 27.7, 28.3, 29.1, 29.9, 30.8, 32.1, 32.7, and 33.3°2θ (±0.2°2θ). 114. The crystalline form according to any one of claims 111 to 113, characterized by an XRPD pattern substantially as shown in FIG. 69. 115. The crystalline form according to any one of claims 111 to 114, characterized by an endothermic differential scanning calorimetry (DSC) thermogram with an initial temperature of about 215°C. 116. The crystalline form according to any one of claims 111 to 115, characterized by a DSC thermogram substantially as shown in FIG. 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), characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 10.6, 16.9, 18.0, 20.0, 21.7, 22.6, 24.5, 25.5, or 27.3°2θ (±0.2°2θ), maleate form I. 118. The crystalline form according to claim 117, characterized by an XRPD pattern comprising peaks at 10.6, 16.9, 18.0, 20.0, 21.7, 22.6, 24.5, 25.5, and 27.3°2θ (±0.2°2θ). 119. The crystalline form according to claim 117 or 118, characterized by an XRPD pattern comprising peaks at 9.1, 10.0, 10.6, 12.9, 13.7, 15.0, 15.5, 16.1, 16.9, 17.2, 18.0, 18.4, 19.2, 20.0, 21.7, 22.6, 24.5, 24.8, 25.5, 25.9, 26.1, 27.3, 30.0, 30.6, 31.8, 33.1, and 38.3°2θ (±0.2°2θ). 120. The crystalline form according to any one of claims 117 to 119, characterized by an XRPD pattern substantially as shown in FIG. 71. 121. The crystalline form according to any one of claims 117 to 120, characterized in that it has an endothermic differential scanning calorimetry (DSC) thermogram with an initial temperature of about 198°C. 122. The crystalline form according to any one of claims 117 to 121, characterized in that it has a DSC thermogram substantially as shown in FIG. 72. 123. An (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoleThe crystalline form of lino-6-sulfonamide (compound 1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 9.4, 14.4, 16.2, 17.4, 17.9, 18.9, 20.3, 21.5, or 24.3°2θ (±0.2°2θ), L-tartrate form I. 124. The crystalline form according to claim 123, characterized by an XRPD pattern comprising peaks at 9.4, 14.4, 16.2, 17.4, 17.9, 18.9, 20.3, 21.5, and 24.3°2θ (±0.2°2θ). 125. The crystalline form according to claim 123 or 124, characterized by an XRPD pattern comprising peaks at 8.2, 8.7, 9.4, 12.7, 13.5, 14.4, 14.7, 15.2, 16.2, 17.4, 17.9, 18.9, 19.2, 19.7, 20.3, 21.5, 21.9, 23.0, 23.8, 24.3, 24.8, 25.4, 26.5, 27.5, 29.0, 29.7, and 33.4°2θ (±0.2°2θ). 126. The crystalline form according to any one of claims 123 to 125, characterized by an XRPD pattern substantially as shown in FIG. 75. 127. The crystalline form according to any one of claims 123 to 126, characterized by an endothermic differential scanning calorimetry (DSC) thermogram with an initial temperature of about 113°C. 128. The crystalline form according to any one of claims 123 to 127, characterized by a DSC thermogram substantially as shown in FIG76. 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), characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 11.7, 13.9, 18.6, 21.8, 23.1, 24.5, 26.1, 28.8 or 29.5°2θ (±0.2°2θ), L-tartrate form II. 130. The crystalline form according to claim 129, characterized by an XRPD pattern comprising peaks at 11.7, 13.9, 18.6, 21.8, 23.1, 24.5, 26.1, 28.8, and 29.5°2θ (±0.2°2θ). 131. The crystalline form according to claim 129 or 130, characterized by comprising peaks at 7.7, 8.0, 8.3, 11.3, ...XRPD patterns of peaks at 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°2θ (±0.2°2θ). 132. The crystalline form according to any one of claims 129 to 131, characterized by an XRPD pattern substantially as shown in FIG77. 133. The crystalline form according to any one of claims 129 to 132, characterized in that it has an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 26°C, 97°C, and 172°C. 134. The crystalline form according to any one of claims 129 to 133, characterized in that it has a DSC thermogram substantially as shown in FIG. 78. 135. 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): characterized in that it comprises an X-ray powder diffraction (XRPD) pattern of five or more peaks at 4.9, 9.8, 17.1, 18.6, 19.6, 20.2, 20.8, 22.0, or 24.6°2θ (±0.2°2θ), L-tartrate form III. 136. The crystalline form according to claim 135, characterized in that it comprises an XRPD pattern including peaks at 4.9, 9.8, 17.1, 18.6, 19.6, 20.2, 20.8, 22.0, and 24.6°2θ (±0.2°2θ). 137. The crystalline form according to claim 135 or 136, characterized in that it comprises an XRPD pattern including peaks at 4.9, 9.8, 12.2, 13.7, 15.4, 17.1, 17.9, 18.6, 19.6, 20.2, 20.8, 22.0, 23.4, 24.6, 25.2, 26.5, 28.2, 29.2, 29.9, 30.6, 32.1, 33.9, 36.3, and 38.5°2θ (±0.2°2θ). 138. The crystalline form according to any one of claims 135 to 137, characterized in that it substantially has the XRPD pattern shown in FIG. 79. 139. The crystalline form according to any one of claims 135 to 138, characterized in that it has an endothermic differential scanning calorimetry (DSC) thermogram with starting temperatures of about 20°C, 114°C, and 170°C. 140. The crystalline form according to any one of claims 135 to 139, characterized in that it substantially has the pattern shown in FIG. 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 according to claim 141, further comprising one, two, three, or four additional therapeutic agents. 143. The pharmaceutical composition according to claim 142, wherein the additional therapeutic agent is selected from famciclovir, acyclovir, and valacyclovir. 144. A method for treating herpesvirus infection, the method comprising administering to a patient in need a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 140 or according to any one of claims 141 to 143. 145. The method according to claim 144, wherein the method comprises administering the pharmaceutical composition according to any one of claims 1 to 140 or according to any one of claims 141 to 143 in combination with one, two, three, or four additional therapeutic agents. 146. The method of claim 144 or 145, wherein the herpesvirus is HSV-1 or HSV-2. 147. A method of treating a condition induced, aggravated, or accelerated by a herpesvirus, the method comprising administering to a patient in need a therapeutically effective amount of the crystalline form of any one of claims 1 to 140 or the pharmaceutical composition of 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 the crystalline form of any one of claims 1 to 140 or the pharmaceutical composition of any one of claims 141 to 143 in combination with one, two, three, or four additional therapeutic agents. 150. The method of claim 149, wherein the one or more additional therapeutic agents are administered simultaneously with the crystalline form or the pharmaceutical composition. 151. Use of the crystalline form of any one of claims 1 to 140 or the pharmaceutical composition of 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 in 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 in the preparation of a medicament for treating viral infections caused by herpesvirus. 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 in the preparation of a medicament for treating viral infections caused by HSV-1 or HSV-2. 158. 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, 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: (Claims 15 / 16 pages 16 CN 122270446 A) a) providing a solution of compound 1 in a first solvent system; b) concentrating the solution from step a) and / or adding a second solvent system to the solution from step a); c) mixing the mixture obtained from step b); d) optionally separating the solid formed in step c); and e) optionally drying the solid separated from step d). 163. A method for preparing compound 1 in methanesulfonate form I, the method comprising the steps of: a) providing a solution of compound 1 in a first solvent system; b) adding methanesulfonic acid in a second solvent system to the solution from step a); c) optionally cooling the mixture obtained from step b); d) optionally separating the solid formed in step c); and e) optionally drying the solid separated from step d). (Claims 16 / 16)17 CN 122270446 A Cross-Reference to Related Applications Regarding Solid Forms of HSV Helicase Primase Inhibitors

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

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

[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 to cause oral herpes, while HSV-2 is a sexually transmitted infection that causes 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 treatments for these infections are primarily based on nucleoside analogs 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 dissociates 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 salt, solvate, or hydrate.

[0007] In another 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 (compound 1): Specification 1 / 98 pages 18 CN 122270446 AThe 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 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): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0 or 26.5° 2θ (± 0.2° 2θ), form I.

[0009] In another 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 (compound 1): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 12.6, 13.9, 15.3, 18.5, 19.2, 19.7, 22.3, 23.4 or 24.3° 2θ (± 0.2° 2θ), form II.

[0010] In another 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 (compound 1): Specification 2 / 98 pages 19 CN 122270446 A Characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 10.0, 12.2, 17.3, 18.3, 20.1, 22.0, 23.7, 25.3 or 25.9° 2θ (± 0.2° 2θ), form III.

[0011] In another 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 (compound 1): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 5.7, 11.2, 16.8, 17.1, 18.7, 21.4, 22.4, 23.3 or 23.8° 2θ (± 0.2° 2θ), form IV.

[0012] In another 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 (compound 1): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 10.0, 11.8, 13.9, 17.6, 18.1, 18.5, 18.9, 19.6 or 26.0° 2θ (± 0.2° 2θ), in form V.

[0013] In another 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 (compound 1): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 12.2, 14.9, 17.5, 20.0, 20.6, 21.8, 23.6, 25.4 or 26.0° 2θ (± 0.2° 2θ), a monohydrate.

[0014] In another 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 (compound 1): Specification 3 / 98 pages 20 CN 122270446 A, characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 8.1, 9.6, 11.7, 16.3, 18.8, 24.5, 25.7, 25.9 or 27.9° 2θ (±0.2° 2θ), dihydrate.

[0015] In another embodiment, this disclosure provides a MeTHF solvate of compound 1, characterized by an XRPD pattern substantially as shown in FIG. 26.

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

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

[0018] In another embodiment, this disclosure provides a 2-BuOH solvate of compound 1, characterized by an XRPD pattern substantially as shown in FIG. 33.

[0019] In another embodiment, this disclosure provides a t-BuOH solvate of compound 1, characterized by an XRPD pattern substantially as shown in FIG. 35.

[0020] In another embodiment, this disclosure provides a p-dioxane solvate of compound 1, characterized by an XRPD pattern substantially as shown in FIG. 36.

[0021] In another embodiment, this disclosure provides a CPME solvate of compound 1, characterized by an XRPD pattern substantially as shown in FIG. 37.

[0022] In another embodiment, this disclosure provides a DMAc solvate of compound 1, characterized by an XRPD pattern substantially as shown in FIG. 39.

[0023] In another embodiment, this disclosure provides an intermediate phase of compound 1, characterized by an XRPD pattern substantially as shown in FIG. 42.

[0024] In another 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 (compound 1): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 8.9, 12.5, 18.9, 19.6, 20.8, 23.8, 24.4, 24.8 or 28.8° 2θ (± 0.2° 2θ), in hydrochloride form I.

[0025] In another 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 (compound 1): Specification 4 / 98 pages 21 CN 122270446 A Characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 8.3, 12.4, 15.3, 19.2, 22.6, 24.0, 24.8, 26.3 or 28.3° 2θ (± 0.2° 2θ), hydrochloride form II.

[0026] In another 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 (compound 1): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 9.6, 11.9, 16.5, 19.4, 20.1, 22.6, 23.8 or 25.8° 2θ (±0.2° 2θ), in hemisulfate form I.

[0027] In another 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 (compound 1): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 9.6, 19.1, 19.4, 20.4, 22.3, 23.6 or 25.5° 2θ (±0.2° 2θ), in sulfate form I.

[0028] In another 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 (compound 1): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8 or 29.6° 2θ (± 0.2° 2θ), methanesulfonate form I.

[0029] In another 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 (compound 1): Specification 5 / 98 page 22 CN 122270446 A Characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 7.0, 17.9, 18.4, 20.1, 20.8, 23.0, 23.4, 24.0 or 25.8° 2θ (± 0.2° 2θ), ethanesulfonate form I.

[0030] In another 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 (compound 1): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 11.3, 14.9, 16.1, 18.4, 19.8, 21.0, 22.8 or 24.9° 2θ (±0.2° 2θ), in benzenesulfonate form I.

[0031] In another 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 (compound 1): characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.2, 18.0, 19.3, and 21.7° 2θ (±0.2° 2θ), benzenesulfonate form II.

[0032] In another 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 (compound 1): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 4.1, 8.1, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5 or 24.5° 2θ (±0.2° 2θ), in toluenesulfonate form I.

[0033] In another 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 (compound 1): Specification 6 / 98 page 23 CN 122270446 A Characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 6.6, 12.3, 17.8, 19.0, 21.2, 22.2, 23.9, 25.8 or 26.6° 2θ (± 0.2° 2θ), naphthalene sulfonate form I.

[0034] In another 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 (compound 1): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 10.6, 16.9, 18.0, 20.0, 21.7, 22.6, 24.5, 25.5 or 27.3° 2θ (± 0.2° 2θ), maleate form I.

[0035] In another 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 (compound 1): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 9.4, 14.4, 16.2, 17.4, 17.9, 18.9, 20.3, 21.5 or 24.3° 2θ (± 0.2° 2θ), L-tartrate form I.

[0036] In another 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 (compound 1): characterized by comprising 11.7, 13.9, 18.6, 21.8, 23.1, 24.5, 26.1, 28.8 or 29.5° 2θ (± 0.2°)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): Specification 7 / 98 pages 24 CN 122270446 A Characterized by including an X-ray powder diffraction (XRPD) pattern of five or more peaks at 4.9, 9.8, 17.1, 18.6, 19.6, 20.2, 20.8, 22.0 or 24.6° 2θ (±0.2° 2θ), L-tartrate form III.

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

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

[0040] In some embodiments, a method of treating a condition induced, exacerbated, or accelerated by a herpesvirus is provided herein, comprising administering to a patient in need a therapeutically effective amount of a crystalline form of compound 1 of the present disclosure or a pharmaceutical composition thereof.

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

[0042] In some embodiments, the use of a crystalline form of compound 1 of the present disclosure or a pharmaceutical composition thereof is provided herein in the treatment of viral infections.

[0043] In some embodiments, the use of a crystalline form of compound 1 of the present disclosure or a pharmaceutical composition thereof is provided herein in the treatment of viral infections caused by herpesviruses.

[0044] In some embodiments, 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 is provided herein.

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

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

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

[0048] In some embodiments, the crystalline form of Compound 1 provided herein or the pharmaceutical composition provided herein is provided 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 form I is provided.

[0050] In one embodiment, Compound 1 form I is provided that can be obtained by the methods described herein.

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

[0052] In one embodiment, Compound 1 methanesulfonate form I is provided that can be obtained by the methods described herein. Brief Description of the Drawings

[0053] Figure 1 shows an XRPD pattern of Compound 1 form I.

[0054] Figure 2 shows a DSC thermogram of Compound 1 form I. Specification 8 / 98 pages 25 CN 122270446 A

[0055] Figure 3 shows a TGA thermogram of Compound 1 form I.

[0056] Figure 4 shows the DVS analysis of compound 1 form I.

[0057] Figure 5 shows the XRPD pattern of compound 1 form II.

[0058] Figure 6 shows the DSC thermogram of compound 1 form II.

[0059] Figure 7 shows the TGA thermogram of compound 1 form II.

[0060] Figure 8 shows the DVS analysis of compound 1 form II.

[0061] Figure 9 shows the XRPD pattern of compound 1 form III.

[0062] Figure 10 shows the DSC thermogram of compound 1 form III.

[0063] Figure 11 shows the TGA thermogram of compound 1 form III.

[0064] Figure 12 shows the DVS analysis of compound 1 form III.

[0065] Figure 13 shows the XRPD pattern of compound 1 form IV.

[0066] Figure 14 shows the DSC thermogram of compound 1 form IV.

[0067] Figure 15 shows the TGA thermogram of compound 1 form IV.

[0068] Figure 16 shows the DVS analysis of compound 1 form IV.

[0069] Figure 17 shows the XRPD pattern of compound 1 form V.

[0070] Figure 18 shows the DSC thermogram of compound 1 form V.

[0071] Figure 19 shows the TGA thermogram of compound 1 form V.

[0072] Figure 20 shows the XRPD pattern of compound 1 monohydrate.

[0073] Figure 21 shows the DSC thermogram of compound 1 monohydrate.

[0074] Figure 22 shows the TGA thermogram of compound 1 monohydrate.

[0075] Figure 23 shows the XRPD pattern of compound 1 dihydrate.

[0076] Figure 24 shows the DSC thermogram of compound 1 dihydrate.

[0077] Figure 25 shows the TGA thermogram of compound 1 dihydrate.

[0078] Figure 26 shows the XRPD pattern of compound 1 MeTHF solvate.

[0079] Figure 27 shows the DSC thermogram of compound 1 MeTHF solvate.

[0080] Figure 28 shows the TGA thermogram of compound 1 MeTHF solvate.

[0081] Figure 29 shows the XRPD pattern of compound 1 MTBE solvate 1.

[0082] Figure 30 shows the XRPD pattern of compound 1 MTBE solvate 2.

[0083] Figure 31 shows the DSC thermogram of compound 1 MTBE solvate 2.

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

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

[0086] Figure 34 shows the DSC thermogram of the compound 1 2-BuOH solvate.

[0087] Figure 35 shows the XRPD pattern of the compound 1 t-BuOH solvate.

[0088] Figure 36 shows the XRPD pattern of the compound 1 p-dioxane solvate.

[0089] Figure 37 shows the XRPD pattern of the compound 1 CPME solvate.

[0090] Figure 38 shows the DSC thermogram of the compound 1 CPME solvate.

[0091] Figure 39 shows the XRPD pattern of the compound 1 DMAc solvate.

[0092] Figure 40 shows the DSC thermogram of the DMAc solvate of compound 1. Specification 9 / 98 pages 26 CN 122270446 A

[0093] Figure 41 shows the TGA thermogram of the DMAc solvate of compound 1.

[0094] Figure 42 shows the XRPD pattern of the mesophase of compound 1.

[0095] Figure 43 shows the XRPD pattern of hydrochloride form I of compound 1.

[0096] Figure 44 shows the DSC thermogram of hydrochloride form I of compound 1.

[0097] Figure 45 shows the TGA thermogram of hydrochloride form I of compound 1.

[0098] Figure 46 shows the DVS analysis of hydrochloride form I of compound 1.

[0099] Figure 47 shows the XRPD pattern of hydrochloride form II of compound 1.

[0100] Figure 48 shows the DSC thermogram of hydrochloride form II of compound 1.

[0101] Figure 49 shows the TGA thermogram of hydrochloride form II of compound 1.

[0102] Figure 50 shows the DVS analysis of compound 1 hydrochloride form II.

[0103] Figure 51 shows the XRPD pattern of compound 1 in hemisulfate form I.

[0104] Figure 52 shows the DSC thermogram of compound 1 in hemisulfate form I.

[0105] Figure 53 shows the XRPD pattern of compound 1 in sulfate form I.

[0106] Figure 54 shows the DSC thermogram of compound 1 in sulfate form I.

[0107] Figure 55 shows the XRPD pattern of compound 1 in methanesulfonate form I.

[0108] Figure 56 shows the DSC thermogram of compound 1 in methanesulfonate form I.

[0109] Figure 57 shows the TGA thermogram of compound 1 in methanesulfonate form I.

[0110] Figure 58 shows the DVS analysis of compound 1 in methanesulfonate form I.

[0111] Figure 59 shows the XRPD pattern of compound 1 in ethanesulfonate form I.

[0112] Figure 60 shows the DSC thermogram of compound 1 in ethanesulfonate form I.

[0113] Figure 61 shows the TGA thermogram of compound 1 in ethanesulfonate form I.

[0114] Figure 62 shows the DVS analysis of compound 1 in ethanesulfonate form I.

[0115] Figure 63 shows the XRPD pattern of compound 1 in benzenesulfonate form I.

[0116] Figure 64 shows the DSC thermogram of compound 1 in benzenesulfonate form I.

[0117] Figure 65 shows the XRPD pattern of compound 1 in benzenesulfonate form II.

[0118] Figure 66 shows the DSC thermogram of compound 1 in benzenesulfonate form II.

[0119] Figure 67 shows the XRPD pattern of compound 1 in toluenesulfonate form I.

[0120] Figure 68 shows the DSC thermogram of compound 1 in toluenesulfonate form I.

[0121] Figure 69 shows the XRPD pattern of compound 1 in naphthalenesulfonate form I.

[0122] Figure 70 shows the DSC thermogram of compound 1 in naphthalenesulfonate form I.

[0123] Figure 71 shows the XRPD pattern of maleate form I of compound 1.

[0124] Figure 72 shows the DSC thermogram of maleate form I of compound 1.

[0125] Figure 73 shows the TGA thermogram of maleate form I of compound 1.

[0126] Figure 74 shows the DVS analysis of maleate form I of compound 1.

[0127] Figure 75 shows the XRPD pattern of L-tartrate form I of compound 1.

[0128] Figure 76 shows the DSC thermogram of L-tartrate form I of compound 1.

[0129] Figure 77 shows the XRPD pattern of L-tartrate form II of compound 1.

[0130] Figure 78 shows the DSC thermogram of L-tartrate form II of compound 1.

[0131] Figure 79 shows the XRPD pattern of L-tartrate form III of compound 1. Specification 10 / 98 pages 27 CN122270446 A

[0132] Figure 80 shows the DSC thermogram of compound 1 L-tartrate form III.

[0133] Figure 81 shows the XRPD overlay of the stability study sample of compound 1 form I.

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

[0135] Figure 83 shows the PK curves of compound 1 form I (free base) and compound 1 methanesulfonate form I (MSA salt) pretreated with pentagastrin in capsule powder.

[0136] Figure 84 shows the DCS thermogram of compound 1 form I.

[0137] Figure 85 shows the DCS thermogram of compound 1 methanesulfonate form I. Detailed Description

[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 cocrystals. 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-indene-2-carbonyl)indoline-6-sulfonamide (compound 1) provided herein was collected using Cu Kα radiation (1.5419 Å).

[0140] II. Definitions It should be understood 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 illustrated under any heading may be combined with embodiments illustrated 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 referents unless the context clearly specifies otherwise. Thus, for example, reference to “compound” includes a variety of such compounds, and reference to “determination” includes reference to one or more determinations and their equivalents known to one of those skilled in the art, and so on.

[0142] As used herein, 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 “about” value or parameter referred to 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.” Furthermore, 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 members of such groups and ranges, as well as any combination of the various endpoints of such groups or ranges. For example, integers in the range of 0 to 40 are explicitly 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 of 1 to 20 are explicitly 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 otherwise claimed invention.

[0146] A “crystalline form” is a solid material in which the components of the solid material are arranged in a highly ordered microstructure, thereby forming a lattice extending in all directions. Crystalline forms may include anhydrous crystalline forms, solvated crystalline forms, and / or hydrated crystalline forms. Salts of compounds may also exist in crystalline forms.

[0147] “Polymorphic” means 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 the molecules are arranged in a random manner, such that there is no definite arrangement, such as molecular packing, and no long-range order. Amorphous solids are generally isotropic, i.e., 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. The term includes stoichiometric hydrates (such as monohydrates and dihydrates) as well as non-stoichiometric hydrates. As used herein, the term “hydrate” refers to a solid form in the form of an aqueous solution (i.e., compound 1), which, although it can be hydrated, is not a hydrate as used herein. A hydrate may be crystalline, wherein both the compound and water form part of a crystal lattice.

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

[0151] “Desolventization” 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. Desolventization techniques for preparing a desolventized form include, but are not limited to, exposing the form of compound 1 (solvent) 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. Therefore, the 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 does not contain water incorporated into its structure. For example, the anhydrous crystalline form does not contain water as part of the crystal structure. Those skilled in the art will know techniques that can be used to quantify the amount of water associated with a 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, etc.For example, less than about 0.5 wt%, about 0.4 wt%, about 0.3 wt%, about 0.2 wt%, about 0.1 wt%, about 0.05 wt%, or about 0.01 wt% 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 the crystal structure. Those skilled in the art will know techniques that can 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 wt%, such as less than about 1.5 wt%, less than about 1 wt%, such as less than about 0.5 wt%, about 0.4 wt%, about 0.3 wt%, about 0.2 wt%, about 0.1 wt%, about 0.05 wt%, or about 0.01 wt% of solvent.

[0154] "Mesophase" or "mesocrystalline" phase is a phase of matter between a solid and a liquid.

[0155] "Alcohol" refers to a solvent having 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 may 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. 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 without the presence of any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as "comprising," "including," "containing," etc., should be understood broadly and without limitation. Furthermore, the terms and expressions used herein are used as descriptive terms and not as limiting terms, 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 the claimed disclosure.

[0158] In addition, this disclosure provides pharmaceutical compositions comprising the 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 and one or more inert ingredients constituting a carrier, and is formed by a combination, complexation or aggregation of any two or more ingredients or by the dissociation of one or more ingredients, or by one or more of the ingredients.Any product obtained directly or indirectly from other types of reactions or interactions of multiple components. Therefore, the pharmaceutical compositions of this disclosure 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 carrier" includes excipients or agents that are harmless to the disclosed compound or its use, such as solvents, diluents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic and absorption delay 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 GS Banker and CTRhodes).

[0161] "Treatment" is a method for obtaining a beneficial or desired outcome, including clinical results. A beneficial or desired clinical outcome includes one or more of the following: a) suppression of disease or symptom (e.g., reduction of symptoms caused by disease). [Instructions for Use 13 / 98 pages 30 CN 122270446 A] (i) to treat a disease or condition, i.e., to reduce the severity of the disease or condition; b) to slow or prevent the development of one or more clinical symptoms associated with the disease or condition (e.g., to stabilize the disease or condition, delay the worsening or progression of the disease or condition, and / or delay its spread (e.g., metastasis of the disease or condition); and / or c) to alleviate the disease, i.e., to result in the resolution of clinical symptoms (e.g., to improve the disease state, to provide partial or overall relief of the disease or condition, to enhance the effect of another drug, to delay the progression of the disease, to increase quality of life and / or to prolong survival). In some embodiments, the term “treatment” means to administer the crystalline form of compound 1 of this disclosure for the purpose of: (i) delaying the onset of the 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., resulting in the resolution of clinical symptoms or their severity.

[0162] “Prevention” means any treatment of a disease or condition that results in the non-development of clinical symptoms of the disease or condition. In some embodiments, 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 in human therapies and / or human treatments.Or veterinary application. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. The mammal treated in the methods of this disclosure is ideally a mammal for which HSV infection is desired.

[0164] The term “therapeutic effective amount” or “effective amount” in the crystalline form of Compound 1 described herein means an amount sufficient to achieve treatment to provide a 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 manner of administration, which may be readily determined by those skilled in the art.

[0165] In this document, when referring to a composition 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 “substantially composed of a particular component” consists of said component, except for one or more trace components.

[0166] The phrase “substantially 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 an 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 g) of compound 1. For example, 10 relative volumes of solvent correspond 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, WO 2023 / 225162 A1) in solid form, including crystalline and mesophase forms, as well as salt, solvate and hydrate forms. In some embodiments, this disclosure provides crystalline forms of Compound 1 having the following structure: Specification 14 / 98 pages 31 CN 122270446 A and its salts, solvates or hydrates.

[0170] Compound 1 may be in various crystalline forms, including but not limited to form I, form II, form III, form IV, formFormula 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.

[0171] 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): 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 crystalline forms of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (compound 1): These 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 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.

[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 1 form I, compound 1 form II, compound 1 form III, compound 1 form IV or compound 1 form V.

[0174] 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 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 many 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 in the sample container (referred to as “preferred orientation”). This orientation effect does not provide structural information about the crystals.

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

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

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

[0185] Compound 1 Form I In some embodiments, this disclosure provides (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,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 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): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0 or 26.5° 2θ (± 0.2° 2θ), form I.

[0186] In some embodiments, this disclosure provides compound 1 form I, characterized by an XRPD pattern comprising peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0 and 26.5° 2θ (±0.2° 2θ). In some embodiments, this disclosure provides compound 1 form I, characterized by an XRPD pattern comprising peaks at 12.3, 12.5, 13.3, 14.4, 16.6, 17.3, 18.0, 18.5, 19.8, 20.3, 21.2, 22.8, 23.2, 24.0, 24.6, 25.0, 25.3, 26.5, 27.6, 28.1, 28.7, 29.5, 30.9, 31.5, 32.2, 36.4, and 37.1° 2θ (±0.2° 2θ). In some embodiments, this disclosure provides compound 1 form I, characterized by an XRPD pattern comprising peaks at 12.3, 12.5, 13.3, 14.4, 16.6, 17.3, 18.0, 18.5, 19.8, 20.3, 21.2, 22.8, 23.2, 24.0, 24.6, 25.0, 25.3, 26.5, 27.6, 28.1, 28.7, 29.5, 30.9, 31.5, 32.2, 36.4, and 37.1° 2θ (±0.2° 2θ).

[0187] In some embodiments, this disclosure provides compound 1 in form I, characterized by an XRPD pattern comprising five or more peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5° 2θ (±0.1° 2θ). In some embodiments, this disclosure provides compound 1 in form I, characterized by an XRPD pattern comprising peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, and 26.5° 2θ (±0.1° 2θ). In some embodimentsIn this disclosure, compound 1 in form I is characterized by an XRPD pattern comprising peaks at 12.3, 12.5, 13.3, 14.4, 16.6, 17.3, 18.0, 18.5, 19.8, 20.3, 21.2, 22.8, 23.2, 24.0, 24.6, 25.0, 25.3, 26.5, 27.6, 28.1, 28.7, 29.5, 30.9, 31.5, 32.2, 36.4 and 37.1° 2θ (±0.1° 2θ). In some embodiments, this disclosure provides compound 1 in form I, characterized by an XRPD pattern comprising peaks at 12.3, 12.5, 13.3, 14.4, 16.6, 17.3, 18.0, 18.5, 19.8, 20.3, 21.2, 22.8, 23.2, 24.0, 24.6, 25.0, 25.3, 26.5, 27.6, 28.1, 28.7, 29.5, 30.9, 31.5, 32.2, 36.4, and 37.1° 2θ (±0.1° 2θ).

[0188] In some embodiments, this disclosure provides compound 1 in form I, characterized by an XRPD pattern comprising peaks at 18.0, 21.2, and 23.2° 2θ (±0.2° 2θ). In some embodiments, this disclosure provides compound 1 form I, characterized by including peaks at 18.0, 21.2, and 23.2° 2θ (±0.2° 2θ) and further including at least one, two, or three XRPD patterns of specific peaks selected from those at 12.5, 18.5, and 22.8° 2θ (±0.2° 2θ).

[0189] In some embodiments, this disclosure provides compound 1 form I, characterized by including XRPD patterns of peaks at 18.0, 21.2, and 23.2° 2θ (±0.1° 2θ). In some embodiments, this disclosure provides compound 1 form I, specification 17 / 98 pages 34 CN 122270446 A, characterized by including peaks at 18.0, 21.2, and 23.2° 2θ (±0.1° 2θ) and further including at least one, two, or three XRPD patterns of specific peaks selected from those at 12.5, 18.5, and 22.8° 2θ (±0.1° 2θ).

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

[0191] In some embodiments, this disclosure provides compound 1 form I, characterized by including peaks at 18.0, 21.2 and 23.2° 2θ (±0.2° 2θ) and further including at least two, five, ten, fifteen or twenty XRPD patterns of specific peaks selected from the peaks at 12.3, 12.5, 13.3, 14.4, 16.6, 17.3, 18.5, 19.8, 20.3, 22.8, 24.0, 24.6, 25.0, 25.3, 26.5, 27.6, 28.1, 28.7, 29.5, 30.9, 31.5, 32.2, 36.4 and 37.1° 2θ (±0.2° 2θ).

[0192] 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° 2θ (±0.2° 2θ) and further including at least two, five, ten, fifteen, or twenty XRPD patterns of specific peaks selected from those at 12.3, 12.5, 13.3, 14.4, 16.6, 17.3, 19.8, 20.3, 24.0, 24.6, 25.0, 25.3, 26.5, 27.6, 28.1, 28.7, 29.5, 30.9, 31.5, 32.2, 36.4, and 37.1° 2θ (±0.2° 2θ).

[0193] In some embodiments, this disclosure provides compound 1 in form I, characterized by an XRPD pattern substantially as shown in FIG. 1.

[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 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 no thermal events between 25°C and 200°C and 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 a DSC thermogram substantially as shown in FIG2.

[0196] In some embodiments, this disclosure provides compound 1 in 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 in form I.Formula I, characterized by no thermal events between 25°C and 200°C and an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 225°C. In some embodiments, this disclosure provides compound I form I, characterized by a DSC thermogram substantially as shown in FIG84.

[0197] In some embodiments, this disclosure provides compound I form I, characterized by 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 I form I, characterized by an XRPD pattern comprising five or more peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0 or 26.5° 2θ (±0.2° 2θ) and a DSC thermogram with an endothermic onset temperature of about 225°C to about 230°C. In some embodiments, this disclosure provides compound 1, form I, characterized by an XRPD pattern comprising five or more peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5° 2θ (±0.2° 2θ) and a DSC thermogram having an endothermic onset temperature of about 225°C. In some embodiments, this disclosure provides compound 1, form I, characterized by an XRPD pattern comprising five or more peaks at 12.3, 12.5, 17.3, 18.0, 18.5, 21.2, 23.2, 24.0, or 26.5° 2θ (±0.2° 2θ) and a DSC thermogram having an endothermic onset temperature of about 230°C.

[0199] In some embodiments, this disclosure provides compound 1 form I, characterized by an XRPD pattern comprising peaks at 18.0, 21.2, and 23.2° 2θ (±0.2° 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 form I, characterized by an XRPD pattern comprising peaks at 18.0, 21.2, and 23.2° 2θ (±0.2° 2θ) and further comprising at least one, two, or three specific peaks selected from peaks at 12.5, 18.5, and 22.8° 2θ (±0.2° 2θ) and a DSC thermogram having 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 an XRPD pattern comprising peaks at 18.0, 21.2, and 23.2° 2θ (±0.1° 2θ) and a DSC thermal index having an endothermic onset temperature of about 225°C to about 230°C.Spectrum. In some embodiments, this disclosure provides compound 1 form I, characterized by including peaks at 18.0, 21.2, and 23.2° 2θ (±0.1° 2θ) and further including at least one, two, or three specific peaks selected from those at 12.5, 18.5, and 22.8° 2θ (±0.1° 2θ) and a DSC thermogram having 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 including XRPD patterns of peaks at 18.0, 18.5, 21.2, 22.8, and 23.2° 2θ (±0.2° 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 form I, characterized by an XRPD pattern including peaks at 18.0, 18.5, 21.2, 22.8, and 23.2° 2θ (±0.1° 2θ) and a DSC thermogram having 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 thermogravimetric analysis (TGA) with a weight loss of about 0.4%. In some embodiments, this disclosure provides compound 1 form I, characterized by thermogravimetric analysis (TGA) with 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 a TGA substantially as shown in FIG3.

[0203] In some embodiments, this disclosure provides compound 1 form I, characterized by dynamic vapor adsorption (DVS) analysis with a water absorption rate of about 0.1%. In some embodiments, this disclosure provides compound 1 form I, characterized by a dynamic vapor adsorption (DVS) analysis of 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 a DVS analysis substantially as shown in FIG4.

[0204] Suitably, compound 1 form I is unsolvated and anhydrous. Suitably, compound 1 form I contains less than about 2% by weight, such as less than about 1.5% by weight, less than about 1% 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 a solid. For example, the water content can be determined by Karl Fischer titration. The 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 a solid (surface-bound or incorporated into a crystal structure).

[0205] In some embodiments, this disclosure provides compound 1 form I, characterized by including 12.3, 12.5,An XRPD pattern of five or more peaks at 17.3, 18.0, 18.5, 21.2, 23.2, 24.0 or 26.5° 2θ (±0.2° 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 the crystalline form is Form II (specified herein and characterized as Compound 1 Form II). In some embodiments, this disclosure provides a crystalline form of (R)-5-fluoro-2-methyl-1-indoline-6-sulfonamide (compound 1) characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 12.6, 13.9, 15.3, 18.5, 19.2, 19.7, 22.3, 23.4 or 24.3° 2θ (± 0.2° 2θ), form II.

[0207] In some embodiments, this disclosure provides compound 1 form II, characterized by an XRPD pattern comprising peaks at 12.6, 13.9, 15.3, 18.5, 19.2, 19.7, 22.3, 23.4, and 24.3° 2θ (±0.2° 2θ). In some embodiments, this disclosure provides compound 1 form II, characterized by an XRPD pattern comprising peaks at 9.4, 12.6, 13.9, 15.3, 16.7, 17.3, 18.5, 19.2, 19.7, 22.3, 23.4, 24.3, 25.1, 25.7, 26.4, 28.0, 29.0, 29.7, 31.5, 33.7, and 35.3° 2θ (±0.2° 2θ).

[0208] In some embodiments, this disclosure provides compound 1 form II, characterized by an XRPD pattern substantially as shown in FIG. 5.

[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, wherein...The characteristic is that it is essentially a DSC thermogram as shown in FIG6.

[0210] In some embodiments, the present disclosure provides compound 1 form II, characterized by thermogravimetric analysis (TGA) with a weight loss of about 0.6%. In some embodiments, the present disclosure provides compound 1 form II, characterized by thermogravimetric analysis (TGA) with a weight loss of about 0.6% between 25 °C and 150 °C. In some embodiments, the present disclosure provides compound 1 form II, characterized by a TGA essentially as shown in FIG7.

[0211] In some embodiments, the present disclosure provides compound 1 form II, characterized by dynamic vapor adsorption (DVS) analysis with a water absorption rate of about 0.6%. In some embodiments, the present disclosure provides compound 1 form II, characterized by dynamic vapor adsorption (DVS) analysis with a water absorption rate of about 0.6% between about 0% and about 90% RH. In some embodiments, the present disclosure provides compound 1 form II, characterized by a DVS analysis essentially as shown in FIG8.

[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 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 (compound 1): Specification 20 / 98 page 37 CN 122270446 A Characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 10.0, 12.2, 17.3, 18.3, 20.1, 22.0, 23.7, 25.3 or 25.9° 2θ (± 0.2° 2θ), form III.

[0213] In some embodiments, this disclosure provides compound 1 form III, characterized by comprising an XRPD pattern of peaks at 10.0, 12.2, 17.3, 18.3, 20.1, 22.0, 23.7, 25.3, and 25.9° 2θ (±0.2° 2θ). In some embodiments, this disclosure provides compound 1 form III, characterized by comprising an XRPD pattern of peaks at 10.0, 12.2, 12.7, 13.3, 14.7, 15.0, 15.8, 17.3, 18.3, 19.1, 20.1, 20.3, 20.8, 22.0, 23.0, 23.7, 24.4, 25.3, 25.9, 27.0, 28.0, 28.5, 28.9, and 30.3° 2θ (±0.2° 2θ).XRPD pattern of the peak at 2θ).

[0214] In some embodiments, this disclosure provides compound 1 form III, characterized by an XRPD pattern substantially as shown in FIG9.

[0215] In some embodiments, this disclosure provides compound 1 form III, characterized by 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 by a DSC thermogram substantially as shown in FIG10.

[0216] In some embodiments, this disclosure provides compound 1 form III, characterized by thermogravimetric analysis (TGA) with a weight loss of about 3.5%. In some embodiments, this disclosure provides compound 1 form III, characterized by thermogravimetric analysis (TGA) with 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 a TGA substantially as shown in FIG11.

[0217] In some embodiments, this disclosure provides compound 1 form III, characterized by dynamic vapor adsorption (DVS) analysis with 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 of about 4.6% water absorption between about 0% and about 90% RH. In some embodiments, this disclosure provides compound 1 form III, characterized by a DVS analysis substantially as shown in FIG12.

[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 (designated and characterized herein as 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 (compound 1): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 5.7, 11.2, 16.8, 17.1, 18.7, 21.4, 22.4, 23.3 or 23.8° 2θ (± 0.2° 2θ), form IV.

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

[0220] In some embodiments, this disclosure provides compound 1 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 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 by a DSC thermogram substantially as shown in FIG. 14.

[0222] In some embodiments, this disclosure provides compound 1 form IV, characterized by a thermogravimetric analysis (TGA) with a weight loss of about 0.7%. In some embodiments, this disclosure provides compound 1 form IV, characterized by thermogravimetric analysis (TGA) with 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 a TGA substantially as shown in FIG15.

[0223] In some embodiments, this disclosure provides compound 1 form IV, characterized by dynamic vapor adsorption (DVS) analysis with a water absorption rate of about 0.8%. In some embodiments, this disclosure provides compound 1 form IV, characterized by dynamic vapor adsorption (DVS) analysis with 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 a DVS analysis substantially as shown in FIG16.

[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 (in this document).Designated and characterized as 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 (compound 1): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 10.0, 11.8, 13.9, 17.6, 18.1, 18.5, 18.9, 19.6 or 26.0° 2θ (± 0.2° 2θ), form V.

[0225] In some embodiments, this disclosure provides compound 1 form V, characterized by an XRPD pattern comprising peaks at 10.0, 11.8, 13.9, 17.6, 18.1, 18.5, 18.9, 19.6, and 26.0° 2θ (±0.2° 2θ). In some embodiments, this disclosure provides compound 1 form V, characterized by an XRPD pattern comprising peaks at 9.2, 10.0, 11.8, 12.5, 13.9, 15.3, 15.8, 16.8, 17.3, 17.6, 18.1, 18.5, 18.9, 19.6, 20.4, 21.2, 21.7, 22.4, 23.8, 25.0, 26.0, 27.0, and 28.4° 2θ (±0.2° 2θ).

[0226] In some embodiments, this disclosure provides compound 1 form V, characterized by an XRPD pattern substantially as shown in FIG. 17. Specification 22 / 98 pages 39 CN 122270446 A

[0227] In some embodiments, this disclosure provides compound 1 form V, characterized by a DSC thermogram substantially as shown in FIG. 18.

[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 a TGA substantially as shown in FIG. 19.

[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):The hydrate is characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 12.2, 14.9, 17.5, 20.0, 20.6, 21.8, 23.6, 25.4, or 26.0° 2θ (± 0.2° 2θ).

[0230] In some embodiments, this disclosure provides a hydrate of compound 1, characterized by an XRPD pattern comprising peaks at 12.2, 14.9, 17.5, 20.0, 20.6, 21.8, 23.6, 25.4, and 26.0° 2θ (± 0.2° 2θ). In some embodiments, this disclosure provides a compound 1 monohydrate characterized by an XRPD pattern comprising peaks at 10.0, 12.2, 12.5, 13.2, 14.9, 16.3, 17.5, 18.7, 19.0, 19.4, 20.0, 20.6, 21.1, 21.8, 23.0, 23.6, 24.5, 25.4, 26.0, 27.8, 28.3, 28.6, 30.1, 31.4, 32.1, 32.8, 34.3, 35.9, 36.9, 38.3, and 39.0° 2θ (±0.2° 2θ).

[0231] In some embodiments, this disclosure provides a compound 1 monohydrate characterized by an XRPD pattern substantially as shown in FIG20.

[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 having a DSC thermogram substantially as shown in FIG21.

[0233] In some embodiments, this disclosure provides a compound 1 monohydrate characterized by having a thermogravimetric analysis (TGA) with a weight loss of about 3.7%. In some embodiments, this disclosure provides a compound 1 monohydrate characterized by having a thermogravimetric analysis (TGA) with a weight loss of about 3.7% between 25°C and 100°C. In some embodiments, this disclosure provides compound 1 monohydrate, characterized essentially as shown in FIG22, TGA.

[0234] Compound 1 dihydrate In some embodiments, this disclosure provides (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2, Specification 23 / 98 pages 40 CN 122270446 AA 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): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 8.1, 9.6, 11.7, 16.3, 18.8, 24.5, 25.7, 25.9 or 27.9° 2θ (±0.2° 2θ), the dihydrate.

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

[0236] In some embodiments, this disclosure provides a compound 1 dihydrate characterized by an XRPD pattern substantially as shown in FIG. 23.

[0237] In some embodiments, this disclosure provides a compound 1 dihydrate characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG24.

[0238] In some embodiments, this disclosure provides a compound 1 dihydrate characterized by a thermogravimetric analysis (TGA) with a weight loss of about 7.4%. In some embodiments, this disclosure provides a compound 1 dihydrate characterized by a thermogravimetric analysis (TGA) with 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 a TGA substantially as shown in FIG25.

[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 by an XRPD pattern substantially as shown in FIG26.

[0241] In some embodiments, this disclosure provides a MeTHF solvate of compound 1, characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG27.

[0242] In some embodiments, this disclosure provides a MeTHF solvate of compound 1, characterized by a TGA substantially as shown in FIG28.

[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 (designated and characterized herein as compound 1 MTBE solvate 1). Specification 24 / 98 pages 41 CN 122270446 A

[0244] In some embodiments, this disclosure provides compound 1 MTBE solvate 1, characterized by an XRPD pattern substantially as shown in FIG29.

[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 by an XRPD pattern substantially as shown in FIG30.

[0247] In some embodiments, this disclosure provides compound 1 MTBE solvate 2, characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG31.

[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 compound 1 2-BuOH solvate characterized by an XRPD pattern substantially as shown in FIG. 33.

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

[0251] 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 the t-BuOH solvate (specified herein and characterized as compound 1 t-BuOH solvate).

[0252] In some embodiments, this disclosure provides a compound 1 t-BuOH solvate characterized by a substantially XRPD pattern as shown in FIG35.

[0253] Compound 1 p-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 p-dioxane solvate, characterized by a substantially XRPD pattern as shown in FIG36.

[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 (designated and characterized herein as Compound 1 CPME solvate).

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

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

[0258] Compound 1 DMAc solvate specification 25 / 98 pages 42 CN 122270446 A 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 and characterized herein as compound 1 DMAc solvate).

[0259] In some embodiments, this disclosure provides compound 1 DMAc solvate, characterized by an XRPD pattern substantially as shown in FIG39.

[0260] In some embodiments, this disclosure provides compound 1 DMAc solvate, characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG40.

[0261] In some embodiments, this disclosure provides a DMAc solvate of compound 1, characterized substantially by the TGA pattern shown in FIG41.

[0262] Intermediate phase of compound 1 In some embodiments, this disclosure provides a solid 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 solid form is an intermediate phase (designated and characterized herein as the intermediate phase of compound 1).

[0263] In some embodiments, this disclosure provides an intermediate phase of compound 1, characterized substantially by the XRPD pattern shown in FIG42.

[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): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 8.9, 12.5, 18.9, 19.6, 20.8, 23.8, 24.4, 24.8 or 28.8° 2θ (± 0.2° 2θ), hydrochloride form I.

[0265] In some embodiments, this disclosure provides compound 1 hydrochloride form I, characterized by an XRPD pattern comprising peaks at 8.9, 12.5, 18.9, 19.6, 20.8, 23.8, 24.4, 24.8 and 28.8° 2θ (± 0.2° 2θ). In some embodiments, this disclosure provides compound 1 hydrochloride form I, characterized by an XRPD pattern comprising peaks at 8.9, 12.5, 15.2, 15.9, 18.9, 19.2, 19.6, 20.8, 21.5, 23.8, 24.4, 24.8, 25.9, 26.2, 26.9, 27.7, 28.8, 30.4, 31.2, 32.5, 33.8, and 38.9° 2θ (±0.2° 2θ).

[0266] In some embodiments, this disclosure provides compound 1 hydrochloride form I, characterized by an XRPD pattern substantially as shown in FIG43.

[0267] In some embodiments, this disclosure provides compound 1 hydrochloride form I, characterized by an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 221°C. In some embodiments, this disclosure provides chemicalCompound 1 in hydrochloride form I is characterized by a DSC thermogram substantially as shown in FIG44.

[0268] In some embodiments, this disclosure provides compound 1 in hydrochloride form I, characterized by thermogravimetric analysis (TGA) with a weight loss of about 0.2%. In some embodiments, this disclosure provides compound 1 in hydrochloride form I, characterized by thermogravimetric analysis (TGA) with 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 a TGA substantially as shown in FIG45.

[0269] In some embodiments, this disclosure provides compound 1 in hydrochloride form I, characterized by dynamic vapor adsorption (DVS) analysis with 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 with 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 a DVS analysis substantially as shown in FIG46.

[0270] Compound 1 in 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 in 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): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 8.3, 12.4, 15.3, 19.2, 22.6, 24.0, 24.8, 26.3 or 28.3° 2θ (± 0.2° 2θ), hydrochloride form II.

[0271] In some embodiments, this disclosure provides compound 1 hydrochloride form II, characterized by an XRPD pattern comprising peaks at 8.3, 12.4, 15.3, 19.2, 22.6, 24.0, 24.8, 26.3 and 28.3° 2θ (± 0.2° 2θ). In some embodiments, this disclosure provides compound 1 in hydrochloride form II, characterized by comprising 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,XRPD patterns of peaks at 25.4, 26.3, 26.8, 27.4, 28.3, 29.5, 29.9, 30.6, 32.4 and 33.4° 2θ (±0.2° 2θ).

[0272] In some embodiments, this disclosure provides compound 1 hydrochloride form II, characterized by an XRPD pattern substantially as shown in FIG47.

[0273] In some embodiments, this disclosure provides compound 1 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 hydrochloride form II, characterized by an endothermic differential scanning calorimetry (DSC) thermogram with an onset temperature of about 177°C. In some embodiments, this disclosure provides compound 1 hydrochloride form II, characterized by a DSC thermogram substantially as shown in FIG48.

[0275] In some embodiments, this disclosure provides compound 1 hydrochloride form II, characterized by a thermogravimetric analysis (TGA) with a weight loss of about 3.8%. In some embodiments, this disclosure provides compound 1 hydrochloride form II, characterized by a thermogravimetric analysis (TGA) with a weight loss of about 3.8% between 40°C and 150°C. In some embodiments, this disclosure provides compound 1 hydrochloride form II, characterized by a thermogravimetric analysis (TGA) with 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 thermogravimetric analysis (TGA) with 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 a TGA substantially as shown in FIG49.

[0276] In some embodiments, this disclosure provides compound 1 in hydrochloride form II, characterized by dynamic vapor adsorption (DVS) analysis with 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 with 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 a DVS analysis substantially as shown in FIG50.

[0277] Compound 1 in hemisulfate form IIn 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): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 9.6, 11.9, 16.5, 19.4, 20.1, 22.6, 23.8 or 25.8° 2θ (±0.2° 2θ), hemisulfate form I.

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

[0279] In some embodiments, this disclosure provides a hemisulfate form I of compound 1, characterized by an XRPD pattern substantially as shown in FIG. 51.

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

[0281] Compound 1 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 compound 1 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 (compound 1): Specification 28 / 98 pages 45 CN 122270446 A Characterized by including 9.6, 19.1, 19.4, 20.4, 22.3, 23.6 or 25.5°X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ (±0.2° 2θ), sulfate form I.

[0282] In some embodiments, this disclosure provides compound 1 in sulfate form I, characterized by an XRPD pattern including peaks at 9.6, 19.1, 19.4, 20.4, 22.3, 23.6 and 25.5° 2θ (±0.2° 2θ). In some embodiments, this disclosure provides compound 1 in sulfate form I, characterized by an XRPD pattern including peaks at 9.6, 12.7, 14.1, 15.5, 16.6, 18.4, 19.1, 19.4, 20.4, 22.0, 22.3, 22.9, 23.6, 24.3, 25.5, 26.8 and 27.6° 2θ (±0.2° 2θ).

[0283] In some embodiments, this disclosure provides compound 1 in sulfate form I, characterized by an XRPD pattern substantially as shown in FIG. 53.

[0284] In some embodiments, this disclosure provides compound 1 in sulfate form I, characterized by 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 a DSC thermogram substantially as shown in FIG. 54.

[0285] Compound 1 in 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 in 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): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8 or 29.6° 2θ (± 0.2° 2θ), methanesulfonate form I.

[0286] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by an XRPD pattern comprising peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, and 29.6° 2θ (±0.2° 2θ). In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by an XRPD pattern comprising peaks at 7.2, 8.9, 11.6, and 29.6° 2θ (±0.2° 2θ).XRPD patterns of peaks at 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° 2θ (±0.2° 2θ).

[0287] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by an XRPD pattern comprising five or more peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, or 29.6° 2θ (±0.1° 2θ). (Page 29 / 98 of specification, CN 122270446 A) In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by an XRPD pattern comprising peaks at 7.2, 8.9, 11.6, 12.8, 14.3, 16.1, 16.4, 17.3, 18.1, 18.5, 19.1, 19.5, 20.2, 20.6, 20.9, 20.9, 21.4, 22.2, 22.5, 23.2, 24.0, 24.7, 25.4, 25.7, 26.1, 26.8, 27.7, 29.6, 31.0, 31.5, 32.4, 34.0, 35.4, 35.9, 36.3, 37.2, and 37.9° 2θ (±0.1° 2θ).

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

[0289] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by peaks at 7.2, 11.6, 14.3, 17.3, and 18.5° 2θ (±0.2° 2θ) and further comprising at least two, five, ten, or fifteen peaks.One, twenty, or twenty-five XRPD patterns selected from specific peaks at 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° 2θ (±0.2° 2θ).

[0290] 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° 2θ (±0.1° 2θ) and further including 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°. XRPD pattern of a specific peak at 2θ (±0.1° 2θ).

[0291] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by an XRPD pattern substantially as shown in FIG55.

[0292] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by 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 no thermal events between 25°C and 200°C 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 a DSC thermogram substantially as shown in FIG56.

[0293] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by 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 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 a DSC thermogram substantially as shown in FIG85.

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

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

[0296] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by thermogravimetric analysis (TGA) with a weight loss of about 0.1%. In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by thermogravimetric analysis (TGA) with 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 a TGA substantially as shown in FIG. 57.

[0297] In some embodiments, this disclosure provides compound 1 in methanesulfonate form I, characterized by dynamic vapor adsorption (DVS) analysis with 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 with 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 a DVS analysis substantially as shown in FIG. 58.

[0298] Suitably, compound 1 in methanesulfonate form I is unsolvated and anhydrous. Suitable, compound 1 methanesulfonic acidSalt 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 an XRPD pattern of five or more peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, or 29.6° 2θ (±0.2° 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 an XRPD pattern comprising peaks at 7.2, 11.6, 14.3, 17.3, and 18.5° 2θ (±0.2° 2θ) and wherein compound 1 in methanesulfonate form I comprises less than about 2% by weight of solvent and / or water.

[0301] Compound 1 in 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 in ethanesulfonate form I (specified herein and characterized as compound 1 in 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): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 7.0, 17.9, 18.4, 20.1, 20.8, 23.0, 23.4, 24.0 or 25.8° 2θ (± 0.2° 2θ), in ethanesulfonate form I. Specification 31 / 98 pages 48 CN 122270446 A

[0302] In some embodiments, this disclosure provides compound 1 in ethanesulfonate form I, characterized by an XRPD pattern comprising peaks at 7.0, 17.9, 18.4, 20.1, 20.8, 23.0, 23.4, 24.0, and 25.8° 2θ (±0.2° 2θ). In some embodiments, this disclosure provides compound 1 in ethanesulfonate form I, characterized by peaks at 7.0, 8.7, 11.6, and 25.8° 2θ (±0.2° 2θ).XRPD patterns of peaks at 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° 2θ (±0.2° 2θ).

[0303] In some embodiments, this disclosure provides compound 1 in ethanesulfonate form I, characterized by an XRPD pattern substantially as shown in FIG59.

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

[0305] In some embodiments, this disclosure provides compound 1 in ethanesulfonate form I, characterized by a thermogravimetric analysis (TGA) with 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) with 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 a TGA substantially as shown in FIG. 61.

[0306] In some embodiments, this disclosure provides compound 1 in ethanesulfonate form I, characterized by dynamic vapor adsorption (DVS) analysis with a water absorption rate of about 3.3%. In some embodiments, this disclosure provides compound 1 in ethanesulfonate form I, characterized by a dynamic vapor adsorption (DVS) analysis of about 3.3% water absorption between about 0% and about 90% RH. In some embodiments, this disclosure provides compound 1 in ethanesulfonate form I, characterized by a DVS analysis substantially as shown in FIG62.

[0307] Compound 1 in 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 in 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): characterized by comprising 11.3, 14.9, 16.1, 18.4, 19.8, 21.0, 22.8, or 24.9°.X-ray powder diffraction (XRPD) pattern of five or more peaks at 2θ (±0.2° 2θ), benzenesulfonate form I.

[0308] In some embodiments, this disclosure provides compound 1 benzenesulfonate form I, characterized by an XRPD pattern including peaks at 11.3, 14.9, 16.1, 18.4, 19.8, 21.0, 22.8 and 24.9° 2θ (±0.2° 2θ). In some embodiments, this disclosure provides compound 1 benzenesulfonate form I, characterized by an XRPD pattern including peaks at 10.0, 10.5, 11.3, 14.4, 14.9, 16.1, 17.1, 18.4, 19.8, 21.0, 22.8, 24.9, 25.8, 27.0 and 31.5° 2θ (±0.2° 2θ).

[0309] In some embodiments, this disclosure provides compound 1 in benzenesulfonate form I, characterized by an XRPD pattern substantially as shown in Figure 63 of document 49, page 32 / 98, CN 122270446 A.

[0310] In some embodiments, this disclosure provides compound 1 in benzenesulfonate form I, characterized by 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 a DSC thermogram substantially as shown in Figure 64.

[0311] Compound 1 in 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 in 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): characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.2, 18.0, 19.3, and 21.7° 2θ (±0.2° 2θ), benzenesulfonate form II.

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

[0313] In some embodiments, this disclosure provides compound 1 in benzenesulfonate form II, characterized by an XRPD pattern substantially as shown in FIG. 65.

[0314] In some embodiments, this disclosure provides compound 1 in benzenesulfonate form II, characterized by 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 by a DSC thermogram substantially as shown in FIG. 66.

[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): Specification 33 / 98 pages 50 CN 122270446 A Characteristically characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 4.1, 8.1, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5 or 24.5° 2θ (±0.2° 2θ), toluenesulfonate form I.

[0316] In some embodiments, this disclosure provides compound 1 in toluenesulfonate form I, characterized by an XRPD pattern comprising peaks at 4.1, 8.1, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5, and 24.5° 2θ (±0.2° 2θ). In some embodiments, this disclosure provides compound 1 in toluenesulfonate form I, characterized by an XRPD pattern comprising peaks at 4.1, 5.0, 6.7, 8.1, 9.3, 9.9, 12.4, 12.9, 15.8, 16.2, 18.3, 19.5, 20.4, 22.2, and 24.5° 2θ (±0.2° 2θ).

[0317] In some embodiments, this disclosure provides compound 1 in toluenesulfonate form I, characterized by an XRPD pattern substantially as shown in FIG. 67.

[0318] In some embodiments, this disclosure provides compound 1 in toluenesulfonate form I, characterized by having the following properties:An endothermic differential scanning calorimetry (DSC) thermogram with an initial temperature of about 164 °C. In some embodiments, this disclosure provides compound 1 in toluenesulfonate form I, characterized by a DSC thermogram substantially as shown in FIG68.

[0319] Compound 1 in naphthalenesulfonate 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 naphthalenesulfonate form I (specified herein and characterized as compound 1 in naphthalenesulfonate 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): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 6.6, 12.3, 17.8, 19.0, 21.2, 22.2, 23.9, 25.8 or 26.6° 2θ (± 0.2° 2θ), naphthalene sulfonate form I.

[0320] In some embodiments, this disclosure provides compound 1 naphthalene sulfonate form I, characterized by an XRPD pattern comprising peaks at 6.6, 12.3, 17.8, 19.0, 21.2, 22.2, 23.9, 25.8 and 26.6° 2θ (±0.2° 2θ). In some embodiments, this disclosure provides compound 1 naphthalene sulfonate form I, characterized by an XRPD pattern comprising peaks at 6.6, 8.9, 12.3, 13.2, 14.5, 16.3, 16.8, 17.8, 18.4, 19.0, 19.9, 20.4, 20.7, 21.2, 21.4, 22.2, 22.9, 23.9, 25.0, 25.8, 26.6, 27.2, 27.7, 28.3, 29.1, 29.9, 30.8, 32.1, 32.7, and 33.3° 2θ (±0.2° 2θ).

[0321] In some embodiments, this disclosure provides compound 1 naphthalene sulfonate form I, characterized by an XRPD pattern substantially as shown in FIG. 69.

[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 a DSC thermogram substantially as shown in FIG70.

[0323] Compound 1 in maleate form I In some embodiments, this disclosure provides (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,A crystalline form of 3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, wherein the crystalline form is maleate form I (specified and characterized herein 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): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 10.6, 16.9, 18.0, 20.0, 21.7, 22.6, 24.5, 25.5, or 27.3° 2θ (± 0.2° 2θ), maleate form I.

[0324] In some embodiments, this disclosure provides compound 1 in maleate form I, characterized by an XRPD pattern comprising peaks at 10.6, 16.9, 18.0, 20.0, 21.7, 22.6, 24.5, 25.5 and 27.3° 2θ (±0.2° 2θ). In some embodiments, this disclosure provides compound 1 in maleate form I, characterized by an XRPD pattern comprising peaks at 9.1, 10.0, 10.6, 12.9, 13.7, 15.0, 15.5, 16.1, 16.9, 17.2, 18.0, 18.4, 19.2, 20.0, 21.7, 22.6, 24.5, 24.8, 25.5, 25.9, 26.1, 27.3, 30.0, 30.6, 31.8, 33.1, and 38.3° 2θ (±0.2° 2θ).

[0325] In some embodiments, this disclosure provides compound 1 in maleate form I, characterized by an XRPD pattern substantially as shown in FIG71.

[0326] In some embodiments, this disclosure provides compound 1 in maleate form I, characterized by 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 a DSC thermogram substantially as shown in FIG. 72.

[0327] In some embodiments, this disclosure provides compound 1 in maleate form I, characterized by a 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 a 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 a TGA substantially as shown in FIG. 73.

[0328] In some embodiments, this disclosure provides compound 1 in maleate form I, characterized by dynamic vapor adsorption (DVS) analysis having 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 having 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 DVS analysis substantially as shown in FIG74.

[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 (designated and characterized herein 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): Specification 35 / 98 pages 52 CN 122270446 A Characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 9.4, 14.4, 16.2, 17.4, 17.9, 18.9, 20.3, 21.5 or 24.3° 2θ (± 0.2° 2θ), L-tartrate form I.

[0330] In some embodiments, this disclosure provides compound 1 L-tartrate form I, characterized by an XRPD pattern comprising peaks at 9.4, 14.4, 16.2, 17.4, 17.9, 18.9, 20.3, 21.5 and 24.3° 2θ (±0.2° 2θ). In some embodiments, this disclosure provides compound 1 in L-tartrate form I, characterized by an XRPD pattern comprising peaks at 8.2, 8.7, 9.4, 12.7, 13.5, 14.4, 14.7, 15.2, 16.2, 17.4, 17.9, 18.9, 19.2, 19.7, 20.3, 21.5, 21.9, 23.0, 23.8, 24.3, 24.8, 25.4, 26.5, 27.5, 29.0, 29.7, and 33.4° 2θ (±0.2° 2θ).

[0331] In some embodiments, this disclosure provides compound 1 in L-tartrate form I, characterized by an XRPD pattern substantially as shown in FIG. 75.

[0332] In some embodiments, this disclosure provides compound 1 in L-tartrate form I, characterized by having an XRPD pattern comprising peaks at 8.2, 8.7, 9.4, 12.7, 13.5, 14.4, 14.7, 15.2, 16.2, 17.4, 17.9, 18.9, 19.2, 19.7, 20.3, 21.5, 21.9, 23.0, 23.8, 24.3, 24.8, 25.4, 26.5, 27.5, 29.0, 29.7, and 33.4° 2θ (±0.2° 2θ).An endothermic differential scanning calorimetry (DSC) thermogram with an initial temperature of about 113°C. In some embodiments, this disclosure provides compound 1 in L-tartrate form I, characterized by a DSC thermogram substantially as shown in FIG76.

[0333] Compound 1 in 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 in 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): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 11.7, 13.9, 18.6, 21.8, 23.1, 24.5, 26.1, 28.8 or 29.5° 2θ (± 0.2° 2θ), L-tartrate form II.

[0334] In some embodiments, this disclosure provides compound 1 L-tartrate form II, characterized by an XRPD pattern comprising peaks at 11.7, 13.9, 18.6, 21.8, 23.1, 24.5, 26.1, 28.8 and 29.5° 2θ (±0.2° 2θ). In some embodiments, this disclosure provides compound 1 in L-tartrate form II, characterized by an XRPD pattern comprising peaks at 7.7, 8.0, 8.3, 11.3, 11.7, 13.9, 14.3, 15.6, 16.6, 16.9, 18.0, 18.6, 18.9, 20.2, 20.5, 21.8, 22.2, 22.6, 23.1, 23.6, 24.5, 25.2, 26.1, 26.7, 27.6, 28.8, 29.5, 30.0, 30.9, 31.4, 32.0, 33.5, 34.8, 36.3, 37.5, and 38.0° 2θ (±0.2° 2θ).

[0335] In some embodiments, this disclosure provides compound 1 in L-tartrate form II, characterized by the XRPD pattern shown in FIG. 77 on page 36 / 98 of the basic specification, 53 CN 122270446 A.

[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 1L-tartrate form II, characterized by a DSC thermogram substantially as shown in FIG78.

[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): characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more peaks at 4.9, 9.8, 17.1, 18.6, 19.6, 20.2, 20.8, 22.0 or 24.6° 2θ (±0.2° 2θ), L-tartrate form III.

[0338] In some embodiments, this disclosure provides compound 1 L-tartrate form III, characterized by an XRPD pattern comprising peaks at 4.9, 9.8, 17.1, 18.6, 19.6, 20.2, 20.8, 22.0 and 24.6° 2θ (±0.2° 2θ). In some embodiments, this disclosure provides compound 1 in L-tartrate form III, characterized by an XRPD pattern comprising peaks at 4.9, 9.8, 12.2, 13.7, 15.4, 17.1, 17.9, 18.6, 19.6, 20.2, 20.8, 22.0, 23.4, 24.6, 25.2, 26.5, 28.2, 29.2, 29.9, 30.6, 32.1, 33.9, 36.3, and 38.5° 2θ (±0.2° 2θ).

[0339] In some embodiments, this disclosure provides compound 1 in L-tartrate form III, characterized by an XRPD pattern substantially as shown in FIG79.

[0340] In some embodiments, this disclosure provides compound 1 in L-tartrate form III, characterized by having an endothermic differential scanning calorimetry (DSC) thermogram 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 a DSC thermogram substantially as shown in FIG80.

[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 more than about 80% by weight, more than 85% by weight, more than 90% by weight, more than 95% by weight, more than 98% by weight, more than 99% by weight, or more 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 by 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 substantially 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, compound 1 methanesulfonate 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, the substantially pure form I of Compound 1 methanesulfonate 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 methanesulfonate form I. Suitably, compound 1 is provided in methanesulfonate form I, wherein no other solid forms (amorphous and / or other crystalline forms) are detected when compound 1 in 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 in methanesulfonate form I is provided. Suitably, a crystalline form of compound 1 consisting of compound 1 in 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, as measured by XRPD, for example. 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 to contain greater than approximately 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 95% by weight, greater than 98% by weight, and greater than [missing information].Compound 1 in 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, hemisulfonate form I, sulfate form I, ethanesulfonate form I, benzenesulfonate form I, benzenesulfonate form II, toluenesulfonate form I, naphthalenesulfonate form I, maleate form I, and so on, in 99% by weight and greater than 99.5% by weight. 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) Solvent, Compound 1 Methyl-tert-butyl ether Solvent 1, Compound 1 Methyl-tert-butyl ether Solvent 2, Compound 1 2-Butanol Solvent, Compound 1 Tert-Butanol Solvent, Compound 1 p-Dioxane Solvent, Compound 1 Cyclopentylmethyl ether Solvent, Compound 1 Dimethylacetamide Solvent, Compound 1 Hydrochloride Form I, ...When Compound 1 is in hydrochloride form II, hemisulfate form I, sulfate 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, no other solid forms (amorphous and / or other crystalline forms) were detected. 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, comprising: 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 cyclopentyl methyl ether, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, 1,2-dimethoxyethane, and 1 Suitable solvents include, but are not limited to, 4-dioxane, aromatic compounds (such as benzene and toluene), halogenated solvents (such as dichloromethane, chloroform, and carbon tetrachloride), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF). Suitable solvents also include, but are not limited to, halogenated C1-C3 alcohols (trifluoromethanol, trifluoroethanol (TFE), hexafluoroisopropanol (HFIPA)). For example, 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, methyl tetrahydrofuran, 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 the solid form of compound 1 can be carried out under any suitable reaction conditions. For example, the method for preparing the crystalline form of compound 1 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, the temperature can be about -78°C to about 100°C, or about 0°C to about 50°C, or 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 may 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 may be the reflux temperature of a particular solvent used in the method. In other embodiments, the crystalline form of compound 1 may be heated to above about 100°C, such that one crystalline form of compound 1 forms a second crystalline form of compound 1.

[0349] Methods for preparing the solid form of compound 1 may include a variety of other steps. For example, the solvent may be evaporated, seed crystals may be added to the mixture, and the mixture may be heated and cooled once or repeatedly. For example, these methods may include heating the reaction mixture to a temperature of 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. 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 may be carried out for any suitable time. For example, the time may be several minutes, several hours, or several days. In some embodiments, the time may be several hours, such as overnight. The method for preparing the crystalline form of compound 1 may also be carried out at any suitable pressure. For example, the pressure may be below atmospheric pressure, equal to approximately atmospheric pressure, or above atmospheric pressure.

[0351] Crystallization may be induced by methods known in the art, for example by mechanical means, such as scraping or rubbing the contact surfaces of the reaction vessel with, for example, a glass rod. Optionally, a saturated or supersaturated solution can be seeded. The method 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. Generally, this is 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 by 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 of this disclosure, the method comprising forming a mixture of compound 1 of this disclosure with 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 proportions of the first solvent and the second solvent. For example, the ratio of the first solvent to the second solvent can be from 10:1 to about 1:10 (volume / volume or weight / weight), or from about 10:1 to 1:5, or 10:1 to 1:1, or 10:1 to 5:1, or 5:1 to 1:5, or 5:1 to 1:1, or 4:1 to 1:1, or 3:1 to 1:1, or 2:1 to 1:1. Other solvent ratios include about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or about 1:10 (volume / volume or weight / weight). In some embodiments, the ratio of the first solvent to the second solvent can be about 2:1 (weight / weight). In some embodiments, the ratio of the first solvent to the second solvent can be about 1:1 (weight / weight). In some embodiments, the ratio of ethanol to water is about 2:1 (weight / weight). In some embodiments, the ratio of ethanol to water is about 1:1 (weight / weight).

[0355] The method for preparing crystalline compound 1 may include several other 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 cooling the mixture.

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

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

[0358] In one embodiment, a method for preparing compound 1 in form I comprises the following steps: a) providing a solution of compound 1 in a first solvent system; b) concentrating the solution from step a) and / or adding a second solvent system to the solution from step a); c) mixing the mixture obtained from step b); d) optionally separating the solid formed in step c); and e) optionally drying 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 a first solvent system of 1 to 40 relative volumes, such as 20 to 40 relative volumes. Suitably, compound 1 is dissolved in about 30 relative volumes of acetone.

[0360] Suitably, step a) is performed at 25°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] Suitably, 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 comprises acetone and the second solvent system comprises ethanol.

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

[0367] Suitably, step b) includes concentrating the solution from step a) and adding the second solvent system to the solution from step a). Suitably, step b) includes concentrating the solution from step a) and adding the 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 minutes 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) also includes cooling the mixture. Suitably, the mixture is cooled to below 25°C, such as below 0°C. Suitably, the mixture is cooled to about -10°C.

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

[0371] Suitably, step d) includes separating the solid by filtration.

[0372] Suitably, 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 invention, a crystalline form of compound 1 in form I that can be obtained by the above method is provided.

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

[0375] In one embodiment, a method for preparing compound 1 in methanesulfonate form I comprises the following steps: a) providing a solution of compound 1 in a first solvent system; b) adding methanesulfonic acid in a second solvent system to the solution from step a); c) optionally cooling the mixture obtained from step b); d) optionally separating the solid formed in step c); and e) optionally drying 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 an 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 proton polar solvent. Suitably, the first solvent system comprises ethanol and / or isopropanol. Suitably, compound 1 is dissolved in 1 to 50 relative volumes, such as 20 to 40 relative volumes or 25 to 35 relative volumes, of the first solvent system. Suitably, compound 1 is dissolved in 25 to 35 relative volumes of acetone.

[0377] Suitably, 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 the form of methanesulfonate 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 minutes to 120 minutes, such as about 30 minutes. Suitably, step a3) is performed at the same temperature as step a), such as between 25°C and 75°C, or more preferably between 40°C and 60°C or between 45°C and 55°C.

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

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

[0383] Suitably, 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 steps a), a2), or a3).

[0385] Suitably, the second solvent system contains a solvent in which methanesulfonate is soluble at ambient temperature. Suitably, the second solvent system contains a polar solvent. Suitably, the second solvent system contains an 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, etc.THF and / or toluene. Suitably, the second solvent system comprises acetone. Suitably, the second solvent system comprises a proton-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), 1.0 to 1.5 molar equivalents, such as 1.0 to 1.2 molar equivalents, or about 1.0 molar equivalents of methanesulfonic acid are used. Suitably, the methanesulfonic acid is dissolved in 1 to 10 relative volumes, such as 1 to 5 or 1 to 3 relative volumes of the second solvent system. 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 performed 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 about 2 hours.

[0388] Suitably, step b) includes an additional step (step b2) of adding an additional portion of the second solvent system. Suitably, 1 to 5 relative volumes, such as about 2 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] Suitably, step b) includes steps b2) and b3).

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

[0392] Suitably, 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 approximately 2 hours.

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

[0395] Suitably, step d) includes separating the solid by filtration.

[0396] Suitably, 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 invention, a crystalline form of compound 1 mesylate 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 generally administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions are also provided herein that comprise one or more crystalline forms of compound 1 provided herein and one or more pharmaceutically acceptable media selected from carriers, adjuvants and excipients. The crystalline form of compound 1 provided herein may be the sole active ingredient or one of the active ingredients of 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, a pharmaceutical composition comprising a pure or substantially pure crystalline form of compound 1 of the present disclosure and a pharmaceutically acceptable carrier, diluent, or excipient is provided herein. 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 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, and p-dioxane solvate. (Instructions for Use, Page 44 / 98, 61 CN 122270446 A)It consists of compounds, cyclopentylmethyl ether (CPME) solvates, dimethylacetamide (DMAc) solvates, 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, a pharmaceutical composition is provided herein 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 pure or substantially pure 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 compound 1 form I. 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 compound 1 form I.

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

[0404] In one embodiment, a pharmaceutical composition is provided herein comprising pure or substantially pure compound 1 in its mesylate 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 compound 1 in its mesylate form I. 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 compound 1 in its mesylate form I.

[0405] When the pharmaceutical composition is described herein in relation to the crystalline form of compound 1, the 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 class I antigen A-24α modulators; human cytomegalovirus glycoprotein B modulators; human cytomegalovirus glycoprotein H modulators; human cytomegalovirus glycoprotein inhibitors; human cytomegalovirus glycoprotein L modulators; immunoglobulin G agonists; interferon α2 ligands; interferon γ receptor antagonists; latent membrane protein 1 modulators; latent membrane protein 2 modulators; latent membrane protein 2 stimulators. Progesterone receptor agonists; BARF1 secretory protein regulators; UL97 serine-threonine protein kinase regulators; CD8 stimulators on T cell surface glycoproteins; thymidine kinase inhibitors; ICP4 trans-acting transcription protein regulators; transferase inhibitors; unspecified gene inhibitors; adenosine homocysteine ​​kinase inhibitors; basilin inhibitors; basilin regulators; CCR5 chemokine regulators; CD4 agonists; CD4 regulators; CD89 agonists; CMV65kDa 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 embodiments, one or more therapeutic agents are selected from famciclovir, acyclovir, and valacyclovir.

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

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

[0409] One mode of administration is parenteral, for example, by injection. Forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions or emulsions, with sesame oil, 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 compositions 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 oil suspensions.Suspension. The suspension can be formulated using suitable dispersants or wetting agents and suspending agents mentioned herein according to known techniques. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic, parenteral acceptable diluent or solvent (such as a solution in 1,3-butanediol), or prepared as a lyophilized powder. Acceptable solvents and media that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, 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. In addition, fatty acids such as oleic acid can also be used to prepare injectables.

[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 a non-toxic, parenteral acceptable diluent or solvent. Acceptable solvents and media that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, 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. Furthermore, 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 blood of the intended recipient; 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 the preparation of a pharmaceutical composition comprising at least one crystalline form of compound 1 provided herein...When composing pharmaceutical compositions, the active ingredient (such as the crystalline form of Compound 1 provided herein) is typically diluted with an excipient and / or encapsulated within 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 can 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 the 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 containing 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 the crystalline form of Compound 1 provided herein for continuous or discontinuous infusion. 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 constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0417] To prepare solid compositions (such as tablets), the 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 mixtures thereof. When these preformed compositions are referred to as homogeneous, as described on pages 47 / 98 of this specification (CN 122270446 A), 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] Tablets or pills in the crystalline form of Compound 1 provided herein may be coated or otherwise formulated to provide a dosage form with the advantage of prolonged action or protection against the acidic conditions of the stomach. For example, 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 is used to resist disintegration in the stomach and allow the inner component to enter the duodenum intact or delay release. A variety of materials may be used for such enteric coatings or coatings, including a variety of 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 via oral or nasal inhalation routes to achieve local or systemic effects. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized using an inert gas. The nebulized solution can be inhaled directly from a nebulizer, or the nebulizer can be attached to a mask tent or intermittent positive pressure ventilation machine. The solution, suspension, or powder composition can be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0420] In one embodiment, a kit comprising the crystalline form of Compound 1 provided herein and suitable packaging is provided herein. 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 to treat an indication, including the disease or condition described herein.

[0421] In some embodiments, the kit also comprises 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.

[0422] In one embodiment, an article comprising the crystalline form of Compound 1 described herein in a suitable container is provided herein. In some embodiments, the container may be a vial, wide-mouth bottle, ampoule, pre-filled syringe, or intravenous bag.

[0423] V. Methods The methods provided herein can be applied to cell populations in vivo or in vitro. “In vivo” means within a living individual, such as in 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, includingTherapeutic 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 selected crystalline form of Compound 1 may 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 generally known to those skilled in the art.

[0424] In some embodiments, this disclosure provides a method of 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 of 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 the crystalline form of compound 1 provided herein or a pharmaceutical composition comprising compound 1, the crystalline form of compound 1, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0425] In some embodiments, this disclosure provides a method for treating 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 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, the crystalline form of compound 1, or a pharmaceutical composition comprising compound 1, the crystalline form of compound 1, 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 a pharmaceutical composition comprising Compound 1 mesylate form I and a pharmaceutically acceptable carrier, diluent, or excipient.

[0426] In some embodiments, the method provided herein further comprises administering a therapeutically effective amount of one, two, three, or four additional therapeutic agents or pharmaceutically acceptable salts thereof. In some embodiments, the method provided herein includes a herpesvirus that is 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 medicaments referred to herein can be prepared by conventional methods, including combining a 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 a herpesvirus helicase primer enzyme, the method comprising administering to a patient in need (e.g., a patient with a herpesvirus-related disease or condition) a therapeutically effective amount of a crystalline form of compound 1 or a composition comprising a crystalline form of compound 1. In one embodiment, the crystalline form of compound 1 is compound 1 form I. In another embodiment, the crystalline form of compound 1 is compound 1 mesylate form I.

[0430] In some embodiments, this document provides a method for inhibiting a helicase primer enzyme of HSV-1 or HSV-2, the method comprising administering to a patient in need (e.g., a patient with an HSV-1 or HSV-2-related disease or condition) a therapeutically effective amount of a crystalline form of compound 1 or a composition comprising a crystalline form of compound 1. In some embodiments, 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 an HSV-1 or HSV-2 related disease or symptom) a therapeutically effective amount of the crystalline form of Compound 1 disclosed herein or a composition comprising the crystalline form of Compound 1 disclosed herein. In one embodiment, the crystalline form of Compound 1 is Compound 1 form I. In another embodiment, the crystalline form of Compound 1 is Compound 1 mesylate form I.

[0431] In one embodiment, a method for inhibiting HSV replication in a subject in need is provided, the specification page 49 / 98 66 CN 122270446 AThe method includes administering a therapeutically effective amount of the crystalline form of compound 1 to a subject. In one embodiment, a method for inhibiting HSV replication in a subject of need is provided, the method comprising administering a therapeutically effective amount of a pharmaceutical composition to the subject, the pharmaceutical composition comprising the crystalline form of compound 1 and a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, the crystalline form of compound 1 is compound 1 form I. In another embodiment, the crystalline form of compound 1 is compound 1 mesylate form I.

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

[0433] In some embodiments, 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 the crystalline form of compound 1 or a pharmaceutical composition comprising the 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 the crystalline form of compound 1 or a pharmaceutical composition comprising the 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 for reducing the likelihood of HSV infection or the severity of symptoms in a subject in need is provided, the method comprising administering to the subject a therapeutically effective amount of the crystalline form of compound 1 provided herein. 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 a pharmaceutical composition comprising the crystalline form of compound 1 provided herein and a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment...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.

[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 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 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.

[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 one embodiment, a method is provided for treating or preventing a disease or condition caused by or associated with 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.

[0437] In a particular embodiment, the crystalline form of Compound 1 according to this disclosure or the pharmaceutical composition according to this disclosure may reduce the time for healing of lesions caused by HSV infection in a disease or condition (such as cold sores or genital herpes) (e.g., the time for complete recovery of the lesions) and the duration of symptoms. The time for lesion healing may be defined as the complete epithelialization of HSV lesions of 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 crystalline form of compound 1 according to this disclosure or the pharmaceutical composition according to this disclosure can reduce pain or pain intensity (e.g., at the site of lesions) caused by HSV infection in a disease or condition (such as cold sores or genital herpes).

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

[0440] 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 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.

[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 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.

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

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

[0444] In some embodiments, use is provided herein of the crystalline form of compound 1 for the preparation of a medicament for the prevention / treatment of viral infections. In some embodiments, use herein 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 in 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 mesylate form I.

[0445] In one embodiment, the use of the crystalline form of Compound 1 or a pharmaceutical composition comprising the crystalline form of Compound 1 is provided in the manufacture of a medicament for inhibiting HSV replication in a subject. In one embodiment, the crystalline form of Compound 1...The crystalline form is compound 1 form I. In another embodiment, the crystalline form of compound 1 is compound 1 mesylate form I. Specification 51 / 98 pages 68 CN 122270446 A

[0446] In one embodiment, use of the crystalline form of compound 1 or a pharmaceutical composition comprising the crystalline form of compound 1 is provided in the manufacture of a medicament for reducing the likelihood or severity of 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.

[0447] In one embodiment, use of the crystalline form of compound 1 or a pharmaceutical composition comprising the crystalline form of compound 1 is provided in the manufacture of a medicament for inhibiting the development or progression of 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.

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

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

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

[0452] In one embodiment, a crystalline form comprising the compound 1 provided herein and pharmaceutically feasible is provided herein.Pharmaceutical compositions comprising a carrier, diluent, or excipient accepted for use in therapy. In one embodiment, a pharmaceutical composition comprising Compound 1 Form I provided herein and a pharmaceutically acceptable carrier, diluent, or excipient is provided for use in therapy. In one embodiment, a pharmaceutical composition comprising Compound 1 Mesylate Form I and a pharmaceutically acceptable carrier, diluent, or excipient is provided for use in therapy.

[0453] In another aspect, a crystalline form of Compound 1 is provided for use in the treatment of herpesvirus (conveniently HSV) infection. In 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 the treatment of 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 Mesylate Form I.

[0454] In some embodiments, a crystalline form of Compound 1 is provided herein 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 in form I. In one embodiment, the crystalline form of compound 1 is compound 1 in mesylate 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 likelihood of HSV infection or the severity of symptoms in a subject in need.Used in the treatment or prevention of disease or condition caused or associated with HSV infection 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 the development or progression of disease or condition caused or associated with 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.

[0458] In one embodiment, a crystalline form of compound 1 is provided for use in the treatment or prevention of disease or condition caused or associated with 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 disease or condition caused or associated with 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.

[0459] In some embodiments, the patient being treated is a human. 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 embodiment, the disease or condition caused by or associated with HSV infection is selected from herpes labialis (e.g., oral herpes labialis or whitlow), genital herpes, HSV-associated keratitis, HSV-associated encephalitis, traumatic herpes, primary HSV gingivostomatitis, Mollaret's meningitis, and Bell's palsy.

[0461] In one particular embodiment, 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 embodiment, the disease or condition is recurrent herpes labialis or recurrent genital herpes. Individuals with a history of multiple recurrent cold sores or recurrent genital herpes (e.g., HSV recurring six or more times per year) may be considered to have recurrent HSV.

[0462] In one embodiment, the herpesvirus treated is HSV-2. In another embodiment, the herpesvirus treated is HSV-2, and the subject requiring treatment has HSV-2 recurrent genital herpes.

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

[0464] In one embodiment, the herpesvirus being treated and prevented is resistant to nucleoside antiviral therapy, such as acyclovir-resistant mucocutaneous HSV infection. In one embodiment, the nucleoside antiviral therapy is selected from the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir, and valacyclovir.

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

[0466] In one particular embodiment, the subject for whom the methods disclosed herein are required is immunocompromised. Subjects may be immunocompromised due to conditions including HIV infection, cancer, hematopoietic cell or solid organ transplantation and chronic glucocorticoid use or genetic immunodeficiency.

[0467] In one particular embodiment, the subject for whom the methods disclosed herein are required is a newborn or infant.

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

[0469] In one particular embodiment, the subject requiring the method disclosed herein has an acyclovir-resistant mucocutaneous HSV infection. The subject may have been diagnosed with the condition based on clinical failure, for example, failure to improve after at least 7 days of administration of an oral or intravenous dose of acyclovir at an approved dose.

[0470] In one particular embodiment, the subject requiring the method disclosed herein has a primary genital HSV-associated herpes infection. In one aspect, the subject requiring the method disclosed herein has a severe or progressive genital HSV-associated herpes infection.

[0471] VI. The crystalline form of compound 1 of this disclosure (also referred to herein as the active ingredient) may 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. The 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 duration or period of time desired, 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 life.

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

[0474] The specific dose level of the crystalline form of compound 1 of this disclosure 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 the subject's 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 the dosage between subjects with large size differences (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] The dosage may 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 of this disclosure may be adjusted during treatment at the discretion of the administering physician. Specification 54 / 98 pages 71 CN 122270446 A

[0476] The crystalline form of Compound 1 of this disclosure may 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 every three months. In some embodiments, the crystalline form of compound 1 is administered 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. A therapeutically effective amount of the crystalline form of compound 1 may include about 0.00001 mg / kg.From body weight / day to about 10 mg / kg body weight / day, such as about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or such as about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 provided herein includes about 30 µg / day to about 300 µg / day, about 0.3 mg / day to about 30 mg / day, or about 30 mg / day to about 300 mg / day, or 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 additional therapeutic agents at any dose of the crystalline form of compound 1 of this disclosure (e.g., 1 mg to 1000 mg of the crystalline form of compound 1). One or more adjunctive therapeutic agents may be administered before, after, or simultaneously with the application of the crystalline form of Compound 1 of this disclosure or the pharmaceutical composition of this disclosure. In some embodiments, one or more adjunctive therapeutic agents are administered before the crystalline form of Compound 1 or the pharmaceutical composition. In some embodiments, one or more adjunctive therapeutic agents are administered after the crystalline form of Compound 1 or the pharmaceutical composition. In some embodiments, one or more adjunctive therapeutic agents are administered simultaneously with the crystalline form of Compound 1 or the pharmaceutical composition.

[0479] Therapeutic effective doses may include about 0.1 mg / dose to about 1000 mg / dose, such as about 50 mg / dose to about 500 mg / dose, or such as about 100 mg / dose to about 400 mg / dose, or such as about 150 mg / dose to about 350 mg / dose, or such as about 200 mg / dose to about 300 mg / dose, or such as about 0.01 mg / dose to about 1000 mg / dose, or such as about 0.01 mg / dose to about 100 mg / dose, or such as about 0.1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 1000 mg / dose. Other therapeutically effective amounts of the crystalline form of compound 1 of this disclosure 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 of this disclosure 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, and 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 the present disclosure is about 1 mg to about 1000 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of the present disclosure is about 1 mg to about 900 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of the present disclosure is about 1 mg to about 800 mg. In some embodiments, the therapeutically effective amount of the crystalline form of compound 1 of the present disclosure is about 1 mg to about 700 mg. In some embodiments, 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 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 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 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 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...The therapeutic amounts of the crystalline form of compound 1 of this disclosure are approximately 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 275 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, or 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 1000 mg / week.The total weekly dose of compound 1 of the present disclosure, administered as a single dose, may be approximately 10 mg / week to 500 mg / week, approximately 50 mg / week to 300 mg / week, approximately 75 mg / week to 200 mg / week, or approximately 100 mg / week to 150 mg / week. In some embodiments, the total weekly dose of compound 1 of the present disclosure, administered as a single dose, may be approximately 100 mg. In some embodiments, the total weekly dose of compound 1 of the present disclosure, administered as a single dose, may be approximately 150 mg. In some embodiments, the total weekly dose of compound 1 of the present disclosure, administered as a single dose, may be approximately 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 the present disclosure administered to a human subject in a single dose may be about 700 mg. In some embodiments, the total weekly dose of the crystalline form of compound 1 of the present disclosure administered to a human subject in a single dose may be about 800 mg. In some embodiments, the total weekly dose of the crystalline form of compound 1 of the present disclosure administered to a human subject in a single dose may be about 900 mg. In some embodiments, the total weekly dose of the crystalline form of compound 1 of the present disclosure administered to a human subject in a single dose may be about 1000 mg.

[0482] When administered orally, the total monthly dose of the crystalline form of compound 1 of the present disclosure to a human subject may be about 500 mg / month to 1000 mg / month, about 600 mg / month to 900 mg / month, or about 700 mg / month to 800 mg / month. In some embodimentsIn this embodiment, the total weekly dose of the crystalline form of Compound 1 of this disclosure administered to a human subject in a single dose may be 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 administered to a human subject in a single dose may be about 500 mg. In some embodiments, the total monthly dose of the crystalline form of Compound 1 of this disclosure administered to a human subject in a single dose may be about 550 mg. In some embodiments, the total monthly dose of the crystalline form of Compound 1 of this disclosure administered to a human subject in a single dose may be 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 in 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 in a single dose may be about 700 mg. In some embodiments, the total monthly dose of the crystalline form of Compound 1 of the present disclosure administered to a human subject by a single dose may be about 750 mg. In some embodiments, the total monthly dose of the crystalline form of Compound 1 of the present disclosure administered to a human subject by a single dose may be about 800 mg. In some embodiments, the total monthly dose of the crystalline form of Compound 1 of the present disclosure administered to a human subject by a single dose may be about 850 mg. In some embodiments, the total monthly dose of the crystalline form of Compound 1 of the present disclosure administered to a human subject by a single dose may be about 900 mg. In some embodiments, the total monthly dose of the crystalline form of Compound 1 of the present disclosure administered to a human subject by a single dose may be about 950 mg. In some embodiments, the total monthly dose of the crystalline form of Compound 1 of the present disclosure administered to a human subject by a single dose may be about 1000 mg.

[0483] The single dose may be administered hourly, daily, weekly, or monthly. For example, the 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 be administered once every 1, 2, 3, 4, 5, or 6 days, or once every 7 days. A single dose may also be administered once every 1, 2, or 3 weeks, or once every 4 weeks. In some embodiments, a single dose may be administered once weekly. A single dose may also be administered once 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 administered once daily in the methods disclosed herein. In some embodiments, the crystalline form of compound 1 provided herein is administered weekly in the methods disclosed herein.Once. In some embodiments, the crystalline form of compound 1 provided herein is administered once a month in the method disclosed herein. In some embodiments, the crystalline form of compound 1 provided herein is administered once every two months in the method disclosed herein. In some embodiments, the crystalline form of compound 1 provided herein is administered once every three months in the method disclosed herein. In some embodiments, the crystalline form of compound 1 provided herein is administered 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 a week in a single dose of about 100 mg. In some embodiments, the crystalline form of compound 1 provided herein is administered orally once a week in a single dose of about 150 mg. In some embodiments, the crystalline form of compound 1 provided herein is administered orally once a week in a single dose of about 200 mg. In some embodiments, the crystalline form of compound 1 provided herein is administered orally once a week in a single dose of about 250 mg. In some embodiments, the crystalline form of compound 1 provided herein is administered orally once a week 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 about 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 in a single dose of about 850 mg.A single dose is administered orally once monthly. 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 of this disclosure will be determined by the needs of the individual patient 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 administration of the crystalline form of compound 1 is necessary for the duration of treatment of herpesvirus infection (including HSV-1 and HSV-2 infection) or any other indication described herein. For example, the crystalline form of compound 1 may be administered to a human suffering from herpesvirus 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 several days or more without receiving the daily dose of the crystalline form of compound 1. 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 7 to 21 days without receiving the crystalline form of compound 1, followed by periods of a daily dose of the crystalline form of compound 1 again (e.g., 1 to 14 days). Depending on the clinical needs of the patient, alternating periods of administration of the crystalline form of compound 1 followed by periods of non-administration of the crystalline form of compound 1 may be repeated.

[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 using any suitable pattern of the specification 58 / 98 pages 75 CN 122270446 A. Moreover, application or treatment with the crystalline form of compound 1 can continue for several 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 dose 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 being treated. Such doses can be readily determined by those skilled in the art.

[0491] VII. Combination TherapyThe crystalline form of Compound 1 provided herein or the pharmaceutical composition of the present invention may be administered alone as the sole therapy or may be administered together 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 disease or condition 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 the crystalline form of Compound 1 and one or more adjunctive therapeutic agents. 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, one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, one or more additional therapeutic agents are four additional therapeutic agents.

[0494] This document also contemplates methods including the administration of a second active agent. For example, in addition to HSV infection, a 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 contemplates disclosed pharmaceutical compositions in combination with at least one other agent previously shown to treat these HSV infection-related symptoms. Such combination therapy may be achieved independently (by administering the individual components of treatment simultaneously, sequentially, or separately) and / or by the pharmaceutical composition of the present invention comprising a second active agent.

[0495] Therefore, this document provides a method for treating or preventing 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, 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 in need, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of compound 1 and a pharmaceutically acceptable carrier, diluent, or excipient, and co-administering to the subject a therapeutically effective amount of an additional therapeutic agent.Preferably, the crystalline form of compound 1 is compound 1 form I. Also preferably, the crystalline form of compound 1 is compound 1 methanesulfonate form I.

[0497] In some embodiments, one or more additional therapeutic agents include, for example, DNA polymerase inhibitors, such as brincidofovir; protein Jumonji inhibitors, such as ML-324, dimethyloxaloylglycine; interferon α2 ligand modulators, such as interferon α-2b, Alpharekin®, recombinant human interferon α-2b follow-up biologics, 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, multivirus-specific T-cell TI1; other drugs for treating herpesvirus infections, such as BOR-15001L7, lidocaine, lichenstatin-23; or any combination thereof.

[0498] In some embodiments, one or more adjunctive 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 embodiments, one or more adjunctive therapeutic agents include, for example, endonuclease modulators, such as broad-spectrum nucleases; 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 additional therapeutic agents include, for example, DNA primase-helicase inhibitors, such as amonexvir, pritelivir, IM-250; DNA polymerase inhibitors, such as famciclovir, penciclovir, valacyclovir, acyclovir, foscarnet sodium; CCR5 chemokine regulators / 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, recombinant human interferon α1b; interferon α2 ligand modulators, such as recombinant human interferon α-2b, KW-045; 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, docosanol, MAR-8644, MAR-8658, NV-HHV-101, PRL-01, HN-0037; or any combination thereof.

[0502] In some embodiments, one or more adjunctive 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 of 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 embodiments, one or more adjunctive 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 embodiments, 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 embodiments, 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 IDC-G103 vaccine; and inactivated HSV-1 and HSV-2 vaccines, such as those described in the specification, page 60 / 98, 77 CN 122270446 A.Vitaherpavac®; live and 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 for the treatment of HSV-2, such as EBT-105, Alloferon™; or any combination thereof.

[0506] In some embodiments, one or more additional 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; TAT protein modulators, such as HerpesVaxTat® vaccine; 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 vaccine; HSV-2 mRNA vaccine; glycoprotein D DNA vaccine; or any combination thereof.

[0507] In some embodiments, 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 viral 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 medicines for treating HSV-2, such as EBT-105, Alloferon™; or any combination thereof.

[0508] In some embodiments, one or more adjunctive 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 embodiments, one or more adjunctive therapeutic agents include, for example, DNA polymerase inhibitors / thymidine kinase inhibitors, such as acyclovir; CRISPR-associated endonuclease Cas9 modulators, such as EBT-104; nicotinic acetylcholine receptor antagonists, such as RPI-78M; cyclin-dependent kinase-9 inhibitors, such as FIT-039; other drugs for the treatment of HSV-1, such as ZEP-3Na, MXB-009; CD4 modulator peptide vaccines, such as CEL-1000; vaccines, such as inactivated HSV-1 vaccines.HSV-1 and HSV-2 vaccines, such as Vitaherpavac® (anti-herpes vaccine); live and 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 embodiments, one or more adjunctive therapeutic agents include, for example, TAT protein modulators, such as HerpesVaxTat® vaccine; or vaccines, such as Profavax-HSV-1 vaccine; or combinations thereof.

[0511] In some embodiments, one or more adjunctive therapeutic agents include, for example, live attenuated viral vaccines, such as EXD-12; or live attenuated δ-gD2-based viral vaccines; or combinations thereof.

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

[0513] In some embodiments, one or more adjunctive therapeutic agents include, for example, DNA polymerase inhibitors such as famciclovir, penciclovir; interferon α2 ligand modulators such as Yallaferon®; anti-herpesvirus envelope glycoprotein D antibodies such as UB-621; or other drugs for the treatment of genital herpes, such as interferon γ, Alloferon™, ZEP-3Na; or combinations thereof.

[0514] In some embodiments, one or more adjunctive therapeutic agents include, for example, vaccines such as NE-gD2 intranasal nanoemulsion NE-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 embodiments, one or more adjunctive therapeutic agents include, for example, herpes vaccines 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 regulator; 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 regulator; an HLA class I antigen A-2α regulator; an HLA class I antigen A-24α regulator; a human cytomegalovirus glycoprotein B inhibitor; a human cytomegalovirus glycoprotein B regulator; a human cytomegalovirus glycoprotein H regulator; a human cytomegalovirus glycoprotein inhibitor; a large terminal enzyme protein inhibitor; a ribonuclease stimulator; a serine-threonine protein kinase UL97 regulator; 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 for the treatment of CMV, such as USC-505, USC-596, CMV pp65 and ppM83 derived peptides, artemifone (BAY-44-9585), PG-36, CMX-16669, HN-0141, ALVR-105, NPP-669, CMV pH4 human immunoglobulin, Cytovir™, antiviral cytotoxic T cell therapy, CMV TCR-transduced T cells, adimlecleucel; or polyclonal antibodies, such as Cytogam®; or combinations thereof.

[0518] In some embodiments, 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; anti-CMV antibodies, such as BT-084 (Cytotect® CP); human cytomegalovirus glycoprotein B and glycoprotein H modulator 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 therapy; or any combination thereof.

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

[0521] In some embodiments, one or more additional therapeutic agents include, for example, DNA polymerase inhibitors; helicase inhibitors; immunoglobulin agonists; interferon α2 ligands; interferon α ligand modulators; interferon β ligands; or TLR-4 agonists; or any combination thereof.

[0522] In some embodiments, one or more additional therapeutic agents include, for example, DNA polymerase inhibitors such as penciclovir, famciclovir, valacyclovir, acyclovir, USC-373; DNA primase inhibitors-helicase inhibitors such as amonexvir; interferon α2 ligand modulators such as interferon α-2b, Yallaferon®, pegylated interferon α-1b, INTEFEN®, interferon α-2a, Anterferon®; interferon β ligand modulators such as RebiSmart™; immunoglobulin activators such as Varicellon®, shingles immunoglobulin-VF; vaccines such as varicella vaccine (live attenuated); MMRV vaccine; shingles vaccine; recombinant adjuvant shingles vaccine; or medicines for treating varicella-zoster virus infection such as HerpeCide™; or any combination thereof.

[0523] In some embodiments, one or more adjunctive therapeutic agents include, for example, vaccines such as ProQuad®; Priorix-Tetra® (MeMuRu-OKA); protein subunit TLR-4 agonist vaccines such as CRV-101; vaccines based on the VZV ORF29 mutant; varicella vaccines (live attenuated) such as Sinovac; Varilrix® vaccine (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 M-M-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, Suduvax® II, VZV-7D; or anti-varicella-zoster virus antibodies, such as VariZIG®; or any combination thereof.

[0524] In some embodiments, one or more adjunctive therapeutic agents include, for example, drugs for treating or preventing varicella-zoster virus infection, such as OV-02; or vaccines, such as EG-HZ; or any combination thereof.

[0525] In some embodiments, one or more adjunctive 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 embodiments, one or more additional therapeutic agents include, for example, DNA polymerase inhibitors such as acyclovir, ganciclovir; interferon α2 ligand modulators such as interferon α-2b, 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, herpes simplex keratitis); additional medicines for the treatment of herpes 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 therapies 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 adjunctive 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 embodiments, one or more adjunctive 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 therapy; or vaccines, such as EBV-VLP vaccines; or any combination thereof.

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

[0532] In some embodiments, one or more adjunctive 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 embodiment, one or more adjunctive therapeutic agents are selected from one or more of the following agents: i. nucleoside polymerase inhibitors, such as acyclovir, valacyclovir, famciclovir, penciclovir, and ganciclovir; ii. pyrophosphate polymerase inhibitors, such as phosphonoformic acid; iii. saturated aliphatic alcohols, such as docosanol; iv. agents 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 analogs such as acyclovir, phosphonoformic acid, ganciclovir, or penciclovir or corresponding prodrugs (vacyclovir or famciclovir), which may beThe second amount is administered. 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.

[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 amounts of the disclosed compounds and the antiviral agent may be administered to the subject together, 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 the start of administration of the antiviral agent. In addition, additional medications may be given together with the combination therapy described above.

[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 include the following examples to demonstrate specific embodiments of the present disclosure. Those skilled in the art will understand that the techniques disclosed in the following examples represent techniques that are fully functional in the practice of the present disclosure and can therefore be considered as specific patterns constituting its practice. However, those skilled in the art will understand that these examples are exemplary and not exhaustive in accordance with the present disclosure. Many changes may be made to the specific embodiments of the disclosure without departing from the spirit and scope of the present disclosure and similar or analogous results may still be obtained.

[0538] The abbreviations used herein have the following corresponding meanings: Specification 64 / 98 pages 81 CN 122270446 A Specification 65 / 98 pages 82 CN 122270446 A Specification 66 / 98 pages 83 CN 122270446 A

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

[0540] The XRPD pattern was collected using a PANalytical X'Pert PRO MPD diffractometer with an incident beam of Cu Kα radiation generated using a long, narrow focusing source and a nickel filter. 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. A Soller slit was used for both the incident and diffracted beams to minimize broadening from axial divergence. The sample was then analyzed using sample and data collector software v. 2.2b.Diffraction patterns were collected using a scanning position sensitive detector (X'Celerator) at 240 mm.

[0541] Differential scanning calorimetry (DSC) data were collected using a TA Instruments 2920 and Q2000 differential scanning calorimeter. Temperature calibration was performed using NIST traceable indium. 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 10°C / min.

[0542] Thermogravimetric analysis (TGA) data were collected using a TA Instruments Discovery thermogravimetric analyzer. Temperature calibration was performed using nickel and aluminum. Each sample was placed in an aluminum pan and inserted into a TG furnace. The furnace was heated under nitrogen purging. The sample was heated from ambient temperature to 350°C at 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 10% RH increments within the range of 5% to 95% RH. The equilibration standard for analysis was a weight change of less than 0.0100% over 5 minutes, with a maximum equilibration time of 3 hours (see manual page 67 / 98, 84 CN 122270446 A). 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. Preparation of (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)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 keeping 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. The crude intermediate 21.1 was separated into 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. When the reaction was complete, 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] Preparation of intermediates (R)-21 and (S)-21: A 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 hours. The reactants were 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. Intermediate (R)-21 was collected as the second eluent (retention time 13.1 min). LC / MS: 230.1 [M+H]. Intermediate (S)-21 was collected as the first eluent (retention time 10.5 min). LC / MS: 230.1 [M+H].

[0549] Preparation of intermediate 19: Preparation of intermediate 2: Preparation of 5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid 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-indene-1-one (100 g, 1.5 equivalents) was added in portions at this temperature.473.1 mmol). The reaction mixture was stirred at this temperature until the gas escaped and disappeared. 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). 3 N 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 brine (5 V), dried (Na2SO4) and evaporated to give a crude product, which was purified by silica gel column chromatography to give 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 TFA (280 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 24 hours. The reaction progress was monitored by TLC. After the starting materials were consumed, the reaction mixture was evaporated to dryness under reduced pressure to obtain a 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: The stirred solution of intermediate 2.2 (40 g, 148.7 mmol) and 2-tributyltinylpyridine (57.5 g, 1.05 equivalent) in 1,4-dioxane (400 mL) was degassed for 10 min using argon, at which point Pd(PPhs)4 (8.6 g, 5 mol%) was added and degassed again for 10 min. The reaction mixture was heated to 90 °C and maintained for 16 h. The reaction mixture was filtered through a diatomaceous earth pad and the diatomaceous earth pad was washed twice with ethyl acetate. The combined filtrates were evaporated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 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 obtain a 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 minutes, filtered, and then dried under vacuum. This process was repeated twice to obtain intermediate 2. LC / MS: 238.1 [M-H].

[0553] Preparation of Intermediate 19: (R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid, specification 69 / 98 pages, 86 CN 122270446 A. 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 [M-H].

[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 crude residual intermediate (R)-21a (LC / MS: 286.1 [M+H]), which was used directly in the next step without further purification.

[0555] Intermediate (R)-21a was dissolved in acetonitrile (10V). Intermediate 19 (1 equivalent) was added, followed by TCFH (2 equivalents). The suspension was placed in a room temperature water bath, and N-methylimidazole (5 equivalents) was added dropwise. The solution was stirred at room temperature for 1 hour, at which point LC / MS analysis indicated complete conversion to intermediate (R)-21b (LC / MS: 507.2 [M+H]). Then, hydrazine hydrate (50 equivalents) was immediately added, and the mixture was stirred at room temperature for 30 minutes, followed by the addition of water (5V). The precipitate was filtered and dried under reduced pressure to give compound 1. ¹H NMR (400 MHz, DMSO-d⁶) δ 8.69 (d, J = 4.9 Hz, 1H), 8.54 (d, J = 6.6 Hz, 1H), 8.10 – 7.84 (m, 4H), 7.58 (s, 2H), 7.51 – 7.24 (m, 3H), 4.90 (t, J = 7.5 Hz, 1H), 3.77 (p, J = 8.2 Hz, 1H), 3.46 (ddt, J = 34.0, 17.5, 8.7 Hz, 3H), 3.20 (ddd, J = 59.1, 16.3, 8.3Hz, 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 (R,E)-N'-((5-fluoro-2-methylindoline-6-yl)sulfonyl)-N,N-dimethylformamidin (20.3g,(71.1 mmol) and (R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid (17.0 g, 71.0 mmol) were 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. After (R)-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. Stop stirring and separate the resulting layers. Concentrate the organic layer to a minimum volume by vacuum distillation and then charge it into acetonitrile (170 mL); repeat the process once more. Slowly add an aqueous solution of ammonium hydroxide (23 wt%, 351 mL, 4.26 mol) to the resulting mixture (page 70 / 98, CN 122270446 A). After the intermediate (E)-N'-(((R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indoline-6-yl)sulfonyl)-N,N-dimethylformamidinium is completely consumed, a slurry is formed. Filter the slurry and wash the solid twice with water (2 × 170 mL). Dry the solid 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 presents the peak positions present in the XRPD diffraction patterns obtained from compound 1 form I.

[0558] Table 1: Peak list of compound 1 form I

[0559] The DSC thermogram (Figure 2) indicates a melting initiation temperature of approximately 230 °C.

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

[0561] Figure 4 shows the DVS analysis, which indicates that the form is non-hygroscopic, with a water absorption rate of approximately 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 subjected to SCXRD analysis at approximately 100 K. The results (see Table 2) are consistent with those of compound 1, form I, which has the following parameters. Specification 71 / 98 pages 88 CN 122270446 A

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

[0564] Example 3. Compound 1 form II At about 22°C, about 100 mg of amorphous compound 1 free base was stirred 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 showed a new pattern (designated as compound 1 form II). After drying under vacuum at 50°C, its XRPD pattern remained unchanged.

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

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

[0567] The DSC thermogram of compound 1 form II (Figure 6) indicates a melting initiation temperature of about 223°C, followed by a melting initiation of about 245°C associated with form IV of compound specification 72 / 98 pages 89 CN 122270446 A 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] The DVS analysis is shown in Figure 8, and this DVS analysis indicates that the form is slightly hygroscopic, with a water absorption rate of approximately 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 1 form III is shown in Figure 9. Table 4 presents the peak positions present in the XRPD diffraction pattern obtained from compound 1 form III.

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

[0573] The DSC thermogram (Figure 10) indicates a small endothermic transition below 50°C and an exothermic event with an onset temperature of approximately 206°C. The onset temperature of the final endothermic event is approximately 246°C.

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

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

[0576] Example 5. Compound 1 Form IV At about 22°C, about 150 mg of compound form I (page 73 / 98, CN 122270446 A 1 methanesulfonate base) was stirred with about 1.5 mL of water in a 4-mL vial equipped with a Teflon-coated magnetic stir bar. The sample first became a gel-like mesophase after about one hour, and then became a flowable slurry after stirring overnight. It was filtered, and XRPD analysis of the wet solids showed 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 have detectable methanesulfonic acid content. 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 presents the peak positions present in the XRPD diffraction patterns obtained from compound 1 form IV.

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

[0579] The DSC thermogram (Figure 14) indicates an endothermic onset temperature of approximately 242°C.

[0580] The TGA thermogram (Figure 15) shows a weight loss of approximately 0.7% from 25°C to 75°C.

[0581] Figure 16 shows the DVS analysis, which indicates that the form is slightly hygroscopic, with a water absorption rate of approximately 0.8% from 0% to 90% RH at 25°C. Instructions 74 / 98 pages 91 CN 122270446 A

[0582] Single crystals of compound 1 form IV were prepared by holding approximately 50 mg of compound 1 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 subjected to SCXRD analysis 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 there was no solvent in the 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 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 presents the peak positions present in the XRPD diffraction pattern obtained from compound 1 form V.

[0586] Table 7 Peak list of compound 1 form V Specification 75 / 98 pages 92 CN 122270446 A

[0587] The DSC thermogram (Fig. 18) is similar to the DSC thermogram of compound 1 dihydrate.

[0588] The TGA thermogram (Fig. 19) shows an approximately 2% weight loss.

[0589] Example 7. Compound 1 monohydrate At approximately 22°C, approximately 50 mg of compound 1 methanesulfonate base form I was stirred with approximately 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 solid showed a new pattern (Fig. 20, designated as compound 1 monohydrate). Proton NMR analysis of the dry solid showed that it did not have a detectable methanesulfonic acid content.

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

[0591] Table 8 Peak list of compound 1 monohydrate Specification 76 / 98 pages 93 CN 122270446 A

[0592] The DSC thermogram (Figure 21) indicates an endothermic transition at an initial temperature of about 33°C at which water loss is attributed, and an exothermic event at an initial temperature of about 203°C. The initial temperature of the final endothermic event is about 246°C.

[0593] The TGA thermogram shows a significant weight loss of about 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 about 22°C, about 120 mg of compound 1 methanesulfonate base form I was stirred with about 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 filtered and dried under vacuum at about 22°C for about 16 hours.

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

[0596] Table 9 Peak list of compound 1 dihydrate, page 77 / 98, CN 122270446 A

[0597] The DSC thermogram is provided in Figure 24 and 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 shows a weight loss of about 7.4%, indicating the dihydrate (the theoretical water content of the dihydrate is 7.4%) (Figure 25).

[0599] Example 9. Compound 1 MeTHF solvate was stirred at about 22°C with about 1 mL of MeTHF in a 4-mL vial equipped with a Teflon-coated magnetic stir bar. After one day of stirring, XRPD analysis of the wet solids showed a new pattern (Fig. 26, designated as compound 1 MeTHF solvate).

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

[0601] The DSC thermogram of compound 1 MeTHF solvate after drying under vacuum at 50°C (Fig. 27) indicates an endothermic transition at about 82°C and about 228°C.

[0602] The TGA thermogram of compound 1 MeTHF solvate (after drying under vacuum at 50°C) shows a weight loss of about 12% from 25°C to 106°C, indicating solvent loss of MeTHF (Fig. 28). Specification page 78 / 98, 95 CN 122270446 A

[0603] Example 10. Compound 1MTBE solvate 1: At approximately 22°C, approximately 50 mg of amorphous compound 1 free base was stirred together with approximately 1 mL of MTBE in a 4-mL vial equipped with a Teflon-coated magnetic stir bar. After stirring for 3 days, XRPD analysis of the wet solid showed a new pattern (Fig. 29, designated as compound 1 MTBE solvate 1).

[0604] A represen...

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).

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