Crystalline form of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide

Abstract

The present disclosure provides crystalline forms of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide, N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrochloride, and N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrobromide, pharmaceutical compositions comprising these crystalline forms, methods of making these crystalline forms, and methods of treating a disease, condition, or disorder in a subject comprising administering these crystalline forms to the subject.

Description

[Technical field]

[0001] 2. Background of the Invention FIELD OF THEINVENTION The present disclosure relates to crystalline forms of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide ("Compound 1"), N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrochloride ("Compound 1 HCl"), and N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrobromide ("Compound 1 HBr"); pharmaceutical compositions comprising crystalline forms of Compound 1, Compound 1 HCl, and Compound 1 HBr; and methods of treating a disease, condition, or disorder in a subject comprising administering to the subject crystalline forms of Compound 1, Compound 1 HCl, and Compound 1 HBr. [Background technology]

[0002] background N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide ("Compound 1") is a small molecule inhibitor of the enzymatic activity of histone methyltransferase (HMT) Su(var)3-9, Enhancer-of-zeste, Trithorax domain-containing 2 (SETD2), also known as KMT3A. This compound and methods for its synthesis are disclosed in WO2020 / 037079. There is a need for solid forms of Compound 1 for use in treating cancer, as well as other diseases, disorders, and conditions in subjects. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2020 / 037079 Summary of the Invention [Means for solving the problem]

[0004] Summary of the Invention In one aspect, the disclosure provides a crystalline form of Compound 1, a crystalline form of Compound 1 HCl, and a crystalline form of Compound 1 HBr.

[0005] In another aspect, the disclosure provides a pharmaceutical composition comprising a crystalline form of Compound 1, a crystalline form of Compound 1 HCl, or a crystalline form of Compound 1 HBr, and one or more pharma- ceutically acceptable excipients.

[0006] In another aspect, the disclosure provides a method of making a crystalline form of Compound 1, a crystalline form of Compound 1 HCl, or a crystalline form of Compound 1 HBr.

[0007] In another aspect, the disclosure provides a method of treating a disease, disorder, or condition, e.g., cancer, in a subject in need of such treatment by administering a crystalline form of Compound 1, a crystalline form of Compound 1 HCl, or a crystalline form of Compound 1 HBr.

[0008] In another aspect, the disclosure provides a crystalline form of Compound 1, a crystalline form of Compound 1 HCl, or a crystalline form of Compound 1 HBr, or a composition thereof, for use in treating a disease, disorder, or condition, e.g., cancer, in a subject.

[0009] In another aspect, the disclosure provides a crystalline form of Compound 1, a crystalline form of Compound 1 HCl, or a crystalline form of Compound 1 HBr for use in the manufacture of a medicament for treating a disease, disorder, or condition, e.g., cancer, in a subject.

[0010] In another aspect, the disclosure provides a kit comprising a crystalline form of Compound 1, a crystalline form of Compound 1 HCl, or a crystalline form of Compound 1 HBr.

[0011] In another aspect, the disclosure provides a method of making a pharmaceutical composition comprising a crystalline form of Compound 1, a crystalline form of Compound 1 HCl, or a crystalline form of Compound 1 HBr and one or more pharma- ceutically acceptable excipients. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 is an XRPD diffractogram of free base Form I.

[0013] [Diagram 2] FIG. 2 is an XRPD diffractogram of free base Form II.

[0014] [Diagram 3] FIG. 3 is an FTIR spectrum of free base Form II.

[0015] [Figure 4] FIG. 4 is a DSC and TGA thermogram of free base Form II.

[0016] [Diagram 5] FIG. 5 is an XRPD diffractogram of free base Form III.

[0017] [Figure 6] FIG. 6 is a DSC and TGA thermogram of free base Form III.

[0018] [Figure 7] FIG. 7 is an XRPD diffractogram of free base Form IV.

[0019] [Figure 8] FIG. 8 is a DSC and TGA thermogram of free base Form IV.

[0020] [Figure 9] FIG. 9 is an XRPD diffractogram of HCl Form I.

[0021] [Figure 10] FIG. 10 is a DSC and TGA thermogram of HCl Form I.

[0022] [Figure 11] FIG. 11 is an XRPD diffractogram of HCl Form II.

[0023] [Figure 12] FIG. 12 is the DSC and TGA thermograms of HCl Form II.

[0024] [Figure 13] FIG. 13 is an XRPD diffractogram of HBr Form I.

[0025] [Figure 14] FIG. 14 is a DSC and TGA thermogram of HBr Form I.

[0026] [Figure 15] 15 is a line graph showing the mean plasma concentration versus time profiles of Compound 1 in male beagle dogs following a single oral dose of free base Form I and free base Form II. Data are presented as mean ± SD, with n=3 for each group.

[0027] [Figure 16] FIG. 16 is a process flow diagram for preparing tablets containing free base Form II. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] Detailed Description of the Invention I. Crystalline Forms of the Present Disclosure In one embodiment, the disclosure provides crystalline forms of Compound 1. These are referred to as "free base" forms. Free Base Form I

[0029] In another embodiment, the crystalline form of Compound 1 is characterized as having a powder X-ray diffraction pattern with peaks at 7.0, 9.8, 14.1, 14.9, 15.2, 17.5, 18.1, 19.2, 20.0, 20.7, 22.5, and 23.9 degrees 2Θ using CuKα radiation, where the 2Θ values ​​are ±0.2 degrees 2Θ. This crystalline form is referred to as "free base form I". Free base form I is a mixture of free base form II and free base form IV. See below.

[0030] In another embodiment, free base Form I is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 7.0, 14.0, 18.0, 20.0, and 20.7 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0031] In another embodiment, free base Form I is characterized as having an XRPD diffractogram essentially the same as that depicted in FIG. 1, using CuKα radiation.

[0032] In another embodiment, the free base Form I is characterized as having thermal events having an onset temperature of about 41.9° C. and a peak temperature of about 62.6° C., an onset temperature of about 70.5° C. and a peak temperature of about 80.0° C., an onset temperature of about 132.9° C. and a peak temperature of about 144.1° C., and an onset temperature of about 214.5° C. and a peak temperature of about 220.0° C. based on differential scanning calorimetry (DSC). Free Base Form II

[0033] In another embodiment, the crystalline form of Compound 1 is characterized as having a powder X-ray diffraction pattern with the peaks listed in Table A using CuKα radiation, where the 2Θ values ​​are ±0.2 degrees 2Θ. This crystalline form is referred to as "Free Base Form II." Free Base Form II is anhydrous.

[0034] In another embodiment, the free base Form II is characterized as having an X-ray powder diffraction pattern using CuKα radiation with the d-spacings listed in Table A.

[0035] In another embodiment, the free base Form II is characterized as having an X-ray powder diffraction pattern using CuKα radiation with peaks at 7.0, 9.8, 11.1, 14.0, 15.2, 15.5, 16.8, 17.5, 18.0, 19.6, 20.2, 20.8, 21.1, 22.1, 22.5, 23.9, 24.4, 24.8, 25.1, 26.0, 28.3, 29.4, and 30.0 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0036] In another embodiment, the free base Form II is 7.0, 9.8, 10.0, 11.0, 11.2, 14.0, 14.3, 15.1, 15.5, 15.9, 16.2, 16.8, 17.5, 18.0, 19.4, 19.6, 20.2, 20.8, 21.1, 22.1, 22.4, 23.8, 24.4, 24.8, 25.1, 25.7, 25.9, 26.2, 27.2, 27.9, 28.0, 29.1, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 39.0, 40.0, 41.0, 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 49.0, 50.0, 51.0, 52.0, 53.0, 54.0, 55.0, 56.0, 57.0, 58.0, 59.0, 60.0, 61.0, 62.0, 63.0, 64.0, 65.0, 66.0, 67.0, 68.0, 69.0, 70.0, 71.0, 72.0, 73.0, 74.0, 75.0, 76.0, 77.0, 78.0, 79.0, 80.0, 81.0 and / or 39.4 degrees 2Θ, wherein the 2Θ values ​​are ±0.2 degrees 2Θ.

[0037] In another embodiment, the free base Form II is characterized as having an X-ray powder diffraction pattern using CuKα radiation with at least three peaks at 7.0, 9.8, 11.1, 14.0, 15.2, 15.5, 16.8, 17.5, 18.0, 19.6, 20.2, 20.8, 21.1, 22.1, 22.5, 23.9, 24.4, 24.8, 25.1, 26.0, 28.3, 29.4, and / or 30.0 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0038] In another embodiment, the free base Form II is 7.0, 9.8, 10.0, 11.0, 11.2, 14.0, 14.3, 15.1, 15.5, 15.9, 16.2, 16.8, 17.5, 18.0, 19.4, 19.6, 20.2, 20.8, 21.1, 22.1, 22.4, 23.8, 24.4, 24.8, 25.1, 25.7, 25.9, 26.2, 27.2, 27.9, 28.0, 29.1, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 39.0, 40.0, 41.0, 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 49.0, 50.0, 51.0, 52.0, 53.0, 54.0, 55.0, 56.0, 57.0, 58.0, 59.0, 60.0, 61.0, 62.0, 63.0, 64.0, 65.0, 66.0, 67.0, 68.0, 69.0, 70.0, 71.0, 72.0, 73.0, 74.0, 75.0, 76.0, 77.0, 78.0, 79.0, 80.0, 81.0 and / or 39.4 degrees 2Θ, wherein the 2Θ values ​​are ±0.2 degrees 2Θ.

[0039] In another embodiment, the free base Form II is characterized as having an X-ray powder diffraction pattern using CuKα radiation with at least four peaks at 7.0, 9.8, 11.1, 14.0, 15.2, 15.5, 16.8, 17.5, 18.0, 19.6, 20.2, 20.8, 21.1, 22.1, 22.5, 23.9, 24.4, 24.8, 25.1, 26.0, 28.3, 29.4, and / or 30.0 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0040] In another embodiment, the free base Form II is 7.0, 9.8, 10.0, 11.0, 11.2, 14.0, 14.3, 15.1, 15.5, 15.9, 16.2, 16.8, 17.5, 18.0, 19.4, 19.6, 20.2, 20.8, 21.1, 22.1, 22.4, 23.8, 24.4, 24.8, 25.1, 25.7, 25.9, 26.2, 27.2, 27.9, 28.0, 29.1, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 39.0, 40.0, 41.0, 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 49.0, 50.0, 51.0, 52.0, 53.0, 54.0, 55.0, 56.0, 57.0, 58.0, 59.0, 60.0, 61.0, 62.0, 63.0, 64.0, 65.0, 66.0, 67.0, 68.0, 69.0, 70.0, 71.0, 72.0, 73.0, 74.0, 75.0, 76.0, 77.0, 78.0, 79.0, 80.0, 81.0 and / or 39.4 degrees 2Θ, wherein the 2Θ values ​​are ±0.2 degrees 2Θ.

[0041] In another embodiment, the free base Form II is characterized as having an X-ray powder diffraction pattern using CuKα radiation with at least five peaks at 7.0, 9.8, 11.1, 14.0, 15.2, 15.5, 16.8, 17.5, 18.0, 19.6, 20.2, 20.8, 21.1, 22.1, 22.5, 23.9, 24.4, 24.8, 25.1, 26.0, 28.3, 29.4, and / or 30.0 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0042] In another embodiment, free base Form II is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 7.0, 14.0, 18.0, and 20.2 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0043] In another embodiment, free base Form II is characterized as having an XRPD diffractogram essentially the same as that depicted in FIG. 2, using CuKα radiation.

[0044] In another embodiment, the free base Form II has the following amino acids: 3292, 2934, 2860, 1628, 1528, 1508, 1449, 1248, 791, 777, and 745 cm-1 and is characterized as having an infrared (IR) spectrum with stretches at -1 Values ​​are ±4cm -1 It is.

[0045] In another embodiment, free base Form II is characterized as having an IR spectrum essentially the same as that depicted in FIG.

[0046] In another embodiment, free base Form II is characterized as having a melting point with an onset temperature of about 224.3° C. and a peak temperature of about 225.7° C. based on differential scanning calorimetry (DSC).

[0047] In another embodiment, free base Form II is characterized as having a DSC thermogram essentially the same as that depicted in FIG. Free Base Form III

[0048] In another embodiment, the crystalline form of Compound 1 is characterized as having a powder X-ray diffraction pattern with the peaks listed in Table B using CuKα radiation, where the 2Θ values ​​are ±0.2 degrees 2Θ. This crystalline form is referred to as "Free Base Form III." Free Base Form III is a dehydrated form of Free Base Form IV. See below.

[0049] In another embodiment, the free base Form III is characterized as having an X-ray powder diffraction pattern using CuKα radiation with d-spacings listed in Table B.

[0050] In another embodiment, the free base Form III is characterized as having an X-ray powder diffraction pattern using CuKα radiation with peaks at 7.6, 9.3, 14.8, 15.4, 15.5, 17.1, 17.5, 18.0, 19.8, 22.1, 22.7, 26.0, 27.7, and 29.8 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ. In another embodiment, the free base Form III is characterized as having an X-ray powder diffraction pattern using CuKα radiation with at least three peaks at 7.6, 9.3, 14.8, 15.4, 15.5, 17.1, 17.5, 18.0, 19.8, 22.1, 22.7, 26.0, 27.7, and / or 29.8 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0051] In another embodiment, the free base Form III is characterized as having an X-ray powder diffraction pattern using CuKα radiation with at least three peaks at 7.6, 9.3, 14.8, 15.4, 15.5, 17.1, 17.5, 18.0, 19.8, 22.1, 22.7, 26.0, 27.7, and / or 29.8 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0052] In another embodiment, the free base Form III is characterized as having an X-ray powder diffraction pattern using CuKα radiation having at least four peaks at 7.6, 9.3, 14.8, 15.4, 15.5, 17.1, 17.5, 18.0, 19.8, 22.1, 22.7, 26.0, 27.7, and / or 29.8 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0053] In another embodiment, the free base Form III is characterized as having an X-ray powder diffraction pattern using CuKα radiation with at least five peaks at 7.6, 9.3, 14.8, 15.4, 15.5, 17.1, 17.5, 18.0, 19.8, 22.1, 22.7, 26.0, 27.7, and / or 29.8 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0054] In another embodiment, the free base Form III is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 7.6, 14.8, 18.0, and 19.8 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0055] In another embodiment, the free base Form III is characterized as having an XRPD diffractogram essentially the same as that depicted in FIG. 5, using CuKα radiation.

[0056] In another embodiment, the free base Form III is characterized as having thermal events having peak temperatures of about 139.0° C., 176.1° C., and 223.2° C. based on differential scanning calorimetry (DSC).

[0057] In another embodiment, the free base Form III is characterized as having a DSC thermogram essentially the same as that depicted in FIG. Free Base Form IV

[0058] In another embodiment, the crystalline form of Compound 1 is characterized as having a powder X-ray diffraction pattern with the peaks listed in Table C using CuKα radiation, where the 2Θ values ​​are ±0.2 degrees 2Θ. This crystalline form is referred to as "free base form IV." Free base form IV is a hydrate represented by the formula: Compound 1·xH2O, where x is about 3.

[0059] In another embodiment, the free base Form IV is characterized as having an X-ray powder diffraction pattern using CuKα radiation with d-spacings listed in Table C.

[0060] In another embodiment, the free base Form IV is characterized as having an X-ray powder diffraction pattern using CuKα radiation with peaks at 6.2, 7.0, 9.0, 9.8, 13.8, 14.5, 14.8, 15.9, 16.4, 18.1, 18.7, 19.1, 19.9, 20.5, 21.7, 22.4, 22.9, 23.6, 24.5, 25.5, 26.2, 26.6, 28.8, 29.8, and 30.9 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ. In another embodiment, the free base Form IV is characterized as having an X-ray powder diffraction pattern using CuKα radiation with at least three peaks at 6.2, 7.0, 9.0, 9.8, 13.8, 14.5, 14.8, 15.9, 16.4, 18.1, 18.7, 19.1, 19.9, 20.5, 21.7, 22.4, 22.9, 23.6, 24.5, 25.5, 26.2, 26.6, 28.8, 29.8, and / or 30.9 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0061] In another embodiment, the free base Form IV is characterized as having an X-ray powder diffraction pattern using CuKα radiation with at least four peaks at 6.2, 7.0, 9.0, 9.8, 13.8, 14.5, 14.8, 15.9, 16.4, 18.1, 18.7, 19.1, 19.9, 20.5, 21.7, 22.4, 22.9, 23.6, 24.5, 25.5, 26.2, 26.6, 28.8, 29.8, and / or 30.9 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0062] In another embodiment, the free base Form IV is characterized as having an X-ray powder diffraction pattern using CuKα radiation with at least five peaks at 6.2, 7.0, 9.0, 9.8, 13.8, 14.5, 14.8, 15.9, 16.4, 18.1, 18.7, 19.1, 19.9, 20.5, 21.7, 22.4, 22.9, 23.6, 24.5, 25.5, 26.2, 26.6, 28.8, 29.8, and / or 30.9 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0063] In another embodiment, the free base form IV is characterized as having a powder X-ray diffraction pattern with peaks at 14.8, 18.1, 19.1, 19.9, and 20.5 degrees 2Θ using CuKα radiation, where the 2Θ values ​​are ±0.2 degrees 2Θ and the 2Θ values ​​are ±0.2 degrees 2Θ using CuKα radiation.

[0064] In another embodiment, free base Form IV is characterized as having an XRPD diffractogram essentially the same as that depicted in FIG. 7, using CuKα radiation.

[0065] In another embodiment, free base Form IV is characterized as having thermal events having peak temperatures of about 94.7°C, 139.2°C, 166.2°C, and 222.8°C based on differential scanning calorimetry (DSC).

[0066] In another embodiment, the free base Form III is characterized as having a DSC thermogram essentially the same as that depicted in FIG.

[0067] In another embodiment, the disclosure provides a crystalline form of Compound 1 HCl. HCl Form I

[0068] In another embodiment, the crystalline form of Compound 1 is characterized as having a powder X-ray diffraction pattern with the peaks listed in Table D using CuKα radiation, where the 2Θ values ​​are ±0.2 degrees 2Θ. This crystalline form is referred to as "HCl Form I." HCl Form I is a hydrate represented by the formula: Compound 1 HCl·xH2O, where x is about 1.

[0069] In another embodiment, HCl Form I is characterized as having an X-ray powder diffraction pattern using CuKα radiation with d-spacings listed in Table D.

[0070] In another embodiment, HCl Form I is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 13.6, 14.6, 14.8, 16.8, 17.6, 18.6, 20.3, 21.1, 21.6, 22.6, 24.1, 25.1, 25.4, 25.8, 26.4, 27.6, and 30.3 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ. In another embodiment, HCl Form I is characterized as having an X-ray powder diffraction pattern using CuKα radiation having at least three peaks at 13.6, 14.6, 14.8, 16.8, 17.6, 18.6, 20.3, 21.1, 21.6, 22.6, 24.1, 25.1, 25.4, 25.8, 26.4, 27.6, and / or 30.3 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0071] In another embodiment, HCl Form I is characterized as having an X-ray powder diffraction pattern using CuKα radiation having at least four peaks at 13.6, 14.6, 14.8, 16.8, 17.6, 18.6, 20.3, 21.1, 21.6, 22.6, 24.1, 25.1, 25.4, 25.8, 26.4, 27.6, and / or 30.3 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0072] In another embodiment, HCl Form I is characterized as having a powder X-ray diffraction pattern with five three peaks at 13.6, 14.6, 14.8, 16.8, 17.6, 18.6, 20.3, 21.1, 21.6, 22.6, 24.1, 25.1, 25.4, 25.8, 26.4, 27.6, and / or 30.3 degrees 2Θ using CuKα radiation, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0073] In another embodiment, HCl Form I is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 13.6, 14.6, 22.6, 24.1, 25.0, and 26.4 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0074] In another embodiment, HCl Form I is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 14.6 and 25.0 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0075] In another embodiment, HCl Form I is characterized as having an XRPD diffractogram essentially the same as that depicted in FIG. 9, using CuKα radiation.

[0076] In another embodiment, HCl Form I is characterized as having a melting point with an onset temperature of 96.1° C. and a peak temperature of 151.4° C. based on differential scanning calorimetry (DSC).

[0077] In another embodiment, HCl Form I is characterized as having a DSC thermogram essentially the same as that depicted in FIG. HCl Form II

[0078] In another embodiment, the crystalline form of Compound 1 is characterized as having a powder X-ray diffraction pattern with the peaks listed in Table E using CuKα radiation, where the 2Θ values ​​are ±0.2 degrees 2Θ. This crystalline form is referred to as "HCl Form II." HCl Form II is anhydrous.

[0079] In another embodiment, HCl Form II is characterized as having an X-ray powder diffraction pattern using CuKα radiation with d-spacings listed in Table E.

[0080] In another embodiment, HCl Form II is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 7.7, 9.3, 10.9, 13.0, 14.2, 15.2, 16.0, 16.8, 17.7, 18.7, 19.9, 21.5, 21.7, 22.6, 26.1, 27.4, 27.9, 28.6, 30.0, and 33.7 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ. In another embodiment, HCl Form II is characterized as having an X-ray powder diffraction pattern using CuKα radiation having at least three peaks at 7.7, 9.3, 10.9, 13.0, 14.2, 15.2, 16.0, 16.8, 17.7, 18.7, 19.9, 21.5, 21.7, 22.6, 26.1, 27.4, 27.9, 28.6, 30.0, and / or 33.7 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0081] In another embodiment, HCl Form II is characterized as having an X-ray powder diffraction pattern using CuKα radiation having at least four peaks at 7.7, 9.3, 10.9, 13.0, 14.2, 15.2, 16.0, 16.8, 17.7, 18.7, 19.9, 21.5, 21.7, 22.6, 26.1, 27.4, 27.9, 28.6, 30.0, and / or 33.7 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0082] In another embodiment, HCl Form II is characterized as having an X-ray powder diffraction pattern using CuKα radiation having at least five peaks at 7.7, 9.3, 10.9, 13.0, 14.2, 15.2, 16.0, 16.8, 17.7, 18.7, 19.9, 21.5, 21.7, 22.6, 26.1, 27.4, 27.9, 28.6, 30.0, and / or 33.7 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0083] In another embodiment, HCl Form II is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 15.2, 16.0, 17.7, and 22.6 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0084] In another embodiment, HCl Form II is characterized as having an XRPD diffractogram essentially the same as that depicted in FIG. 11, using CuKα radiation.

[0085] In another embodiment, HCl Form II is characterized as having a melting point with an onset temperature of 296.4° C. and a peak temperature of 308.3° C. based on differential scanning calorimetry (DSC).

[0086] In another embodiment, HCl Form II is characterized as having a DSC thermogram essentially the same as that depicted in FIG.

[0087] In another embodiment, the disclosure provides a crystalline form of Compound 1HBr. HBr form I

[0088] In another embodiment, the crystalline form of Compound 1 is characterized as having a powder X-ray diffraction pattern with the peaks listed in Table F using CuKα radiation, where the 2Θ values ​​are ±0.2 degrees 2Θ. This crystalline form is referred to as "HBr Form I." HBr Form I is a hydrate represented by the formula: Compound 1 HBr·xH2O, where x is about 1.

[0089] In another embodiment, HBr Form I is characterized as having a powder X-ray diffraction pattern using CuKα radiation with d-spacings listed in Table F.

[0090] In another embodiment, HBr Form I is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 7.6, 12.3, 12.8, 13.6, 14.1, 14.5, 15.0, 15.5, 16.7, 17.7, 18.8, 19.5, 20.4, 21.2, 22.6, 24.2, 25.1, 26.0, 26.5, 27.1, 28.4, 29.3, 30.6, 31.2, 33.4, and 36.0 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0091] In another embodiment, HBr Form I is characterized as having an X-ray powder diffraction pattern using CuKα radiation having at least three peaks at 7.6, 12.3, 12.8, 13.6, 14.1, 14.5, 15.0, 15.5, 16.7, 17.7, 18.8, 19.5, 20.4, 21.2, 22.6, 24.2, 25.1, 26.0, 26.5, 27.1, 28.4, 29.3, 30.6, 31.2, 33.4, and / or 36.0 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0092] In another embodiment, HBr Form I is characterized as having an X-ray powder diffraction pattern using CuKα radiation having at least four peaks at 7.6, 12.3, 12.8, 13.6, 14.1, 14.5, 15.0, 15.5, 16.7, 17.7, 18.8, 19.5, 20.4, 21.2, 22.6, 24.2, 25.1, 26.0, 26.5, 27.1, 28.4, 29.3, 30.6, 31.2, 33.4, and / or 36.0 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0093] In another embodiment, HBr Form I is characterized as having an X-ray powder diffraction pattern using CuKα radiation having at least five peaks at 7.6, 12.3, 12.8, 13.6, 14.1, 14.5, 15.0, 15.5, 16.7, 17.7, 18.8, 19.5, 20.4, 21.2, 22.6, 24.2, 25.1, 26.0, 26.5, 27.1, 28.4, 29.3, 30.6, 31.2, 33.4, and / or 36.0 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0094] In another embodiment, HBr Form I is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 18.8, 21.2, 22.6, 25.0, 26.5 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0095] In another embodiment, HBr Form I is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 18.8, 25.0, and 26.5 degrees 2Θ, where the 2Θ values ​​are ±0.2 degrees 2Θ.

[0096] In another embodiment, HBr Form I is characterized as having an XRPD diffractogram essentially the same as that depicted in FIG. 13, using CuKα radiation.

[0097] In another embodiment, HBr Form I is characterized as having a thermal event with an onset temperature of 66.4° C. and a peak temperature of 122.8° C.; and an onset temperature of 177.7° C. and a peak temperature of 189.0° C., based on differential scanning calorimetry (DSC).

[0098] In another embodiment, HBr Form I is characterized as having a DSC thermogram essentially the same as that depicted in FIG.

[0099] The crystalline forms of Compound 1, the crystalline form of Compound 1 HCl, and the crystalline form of Compound 1 HBr described in this section are collectively referred to as the "crystalline forms of the disclosure" (each individually referred to as a "crystalline form of the disclosure").

[0100] In another embodiment, the crystalline forms of the present disclosure are characterized as comprising about 10% to about 20% by weight, e.g., about 10%, about 11%, about 12%, about 13%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%, of another physical form, e.g., a crystalline or amorphous form, of Compound 1, Compound 1 HCl, or Compound 1 HBr.

[0101] In another embodiment, the crystalline form of the present disclosure is characterized as containing about 1% to about 10% by weight of another physical form of Compound 1, Compound 1 HCl, or Compound 1 HBr, e.g., about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1%.

[0102] In another embodiment, the crystalline form of the present disclosure is characterized as containing about 0.1% to about 1% by weight of another physical form of Compound 1, Compound 1 HCl, or Compound 1 HBr, e.g., about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1%.

[0103] In another embodiment, the crystalline forms of the present disclosure are characterized as not containing any other physical form of Compound 1, Compound 1 HCl, or Compound 1 HBr detectable by XRPD.

[0104] In another embodiment, the crystalline form of the present disclosure has an average particle size distribution of about 0.1 μm to about 500 μm.

[0105] In another embodiment, the crystalline form of the present disclosure has an average particle size distribution of from about 1 μm to about 100 μm.

[0106] In another embodiment, the crystalline form of the present disclosure has an average particle size distribution of from about 5 μm to about 25 μm.

[0107] In another embodiment, the crystalline form of the present disclosure has an average particle size distribution of about 100 μm, about 90 μm, about 80 μm, about 70 μm, about 60 μm, about 50 μm, about 40 μm, about 35 μm, about 30 μm, about 25 μm, about 20 μm, about 15 μm, about 10 μm, about 5 μm, or about 1 μm. II. Compositions of the Disclosure

[0108] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a crystalline form of the present disclosure and one or more pharma- ceutically acceptable excipients.

[0109] In another embodiment, the one or more pharma- ceutical acceptable excipients include a ductile diluent, e.g., microcrystalline cellulose, partially pregelatinized maize starch; a brittle diluent, e.g., anhydrous lactose, mannitol, anhydrous dibasic calcium phosphate; a disintegrant, e.g., croscarmellose sodium, sodium starch glycolate, crospovidone; a binder, e.g., hydroxypropyl cellulose, a glidant, e.g., colloidal silicon dioxide; or a lubricant, e.g., magnesium stearate, stearic acid; or combinations thereof.

[0110] In another embodiment, the pharmaceutical composition comprises: (a) from about 20% w / w to about 30% w / w of the crystalline form; (b) from about 60% w / w to about 80% w / w of one or more ductile or brittle diluents; (c) from about 1% w / w to about 5% w / w of one or more disintegrants; and (d) from about 0.5% w / w to about 3% w / w of one or more lubricants.

[0111] In another embodiment, the one or more pharma- ceutically acceptable excipients comprise microcrystalline cellulose, partially pregelatinized maize starch, anhydrous lactose, mannitol, anhydrous dibasic calcium phosphate, croscarmellose sodium, sodium starch glycolate, crospovidone, hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate, or stearic acid, or a combination thereof.

[0112] In another embodiment, the pharmaceutical composition comprises: (a) about 25% w / w crystalline form; (b) about 35% w / w microcrystalline cellulose; (c) about 35% w / w anhydrous lactose; (d) about 3% w / w croscarmellose sodium; and (e) about 1.5% w / w magnesium stearate.

[0113] In another embodiment, the pharmaceutical composition is a dry granule.

[0114] In another embodiment, the pharmaceutical composition is formulated as a tablet.

[0115] In another embodiment, the pharmaceutical composition is formulated as a film-coated tablet.

[0116] In another embodiment, the film coating comprises hydroxypropyl methylcellulose (HPMC) 2910 / hypromellose, titanium dioxide, and macrogol / PEG.

[0117] The pharmaceutical compositions and formulations described in this section are collectively referred to as the "compositions of the disclosure" (each individually referred to as a "composition of the disclosure"). III. Methods of Making the Compositions of the Present Disclosure

[0118] In another embodiment, the present disclosure provides a method of making a composition of the present disclosure, said method comprising blending a crystalline form of the present disclosure with one or more pharma- ceutically acceptable excipients.

[0119] In another embodiment, the method of making the composition of the present disclosure comprises sieving one or more pharma- ceutically acceptable excipients, for example, through a 40 mesh or 50 mesh sieve depending on the excipient, to remove possible agglomerations.

[0120] In another embodiment, a method of making a composition of the present disclosure includes blending one or more excipients for 10-30 minutes at a blending speed of, for example, 20 rpm to obtain a uniform blend.

[0121] In another embodiment, a method of making a composition of the present disclosure includes lubricating the blend with, for example, magnesium stearate or stearic acid at a blending speed of, for example, 20 rpm for 5-10 minutes to obtain a lubricated blend.

[0122] In another embodiment, the method of making the disclosed composition includes passing the lubricated blend through a roller compactor to produce a dry granule. In another embodiment, the dry granule is lubricated with, for example, magnesium stearate or stearic acid at a blending speed of, for example, 20 rpm for 5-10 minutes to obtain a lubricated granule.

[0123] In another embodiment, the disclosure provides a method of making a composition of the disclosure, said method comprising compressing a lubricated granulation to obtain a tablet.

[0124] In another embodiment, the tablet is coated with a film coating composition. Suitable film coatings are described in Table 1 and in WO 2013 / 045961. [Table 1]

[0125] In another embodiment, the film coating composition comprises HPMC2910 / hypromellose, titanium dioxide, and macrogol / PEG. IV. Methods of Treating a Disease, Disorder, or Condition

[0126] In another embodiment, the present disclosure provides a method of treating a disease, disorder, or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of the present disclosure, or a therapeutic amount of a composition of the present disclosure.

[0127] In another embodiment, the disease, disorder, or condition is cancer.

[0128] In another embodiment, the cancer is any one or more of the cancers in Table 2. [Table 2-1] [Table 2-2] [Table 2-3]

[0129] In another embodiment, the cancer is a hematological cancer. Exemplary hematological cancers include, but are not limited to, those listed in Table 3. [Table 3]

[0130] In another embodiment, the cancer is diffuse large B-cell lymphoma.

[0131] In another embodiment, the cancer is mantle cell lymphoma.

[0132] In another embodiment, the cancer is multiple myeloma.

[0133] In another embodiment, the multiple myeloma is characterized as having a chromosomal translocation involving the immunoglobulin heavy chain locus at 14q32. In another embodiment, the chromosomal translocation is a t(4;14) translocation, i.e., the multiple myeloma is a t(4;14) multiple myeloma.

[0134] In another embodiment, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of the present disclosure, or a therapeutic amount of a composition of the present disclosure, in combination with a therapeutically effective amount of an anti-cancer agent.

[0135] In another embodiment, the anti-cancer agents comprise one or more glucocorticoid receptor agonists, one or more immunomodulatory agents, one or more proteasome inhibitors, one or more Bcl-2 inhibitors, one or more pleiotropic pathway modulators, one or more XPO1 inhibitors, one or more histone deacetylase inhibitors, one or more EZH2 inhibitors, one or more BTK inhibitors, one or more anti-CD20 monoclonal antibodies, one or more alkylating agents, one or more topoisomerase II inhibitors, one or more vinca alkaloids, one or more platinum-based agents, one or more nucleoside anti-cancer agents, one or more PI3K inhibitors, one or more CDK4 / 6 inhibitors, or one or more CARM1 inhibitors, or a combination thereof.

[0136] In another embodiment, the anti-cancer agent comprises a glucocorticoid receptor agonist, hi another embodiment, the glucocorticoid receptor agonist is dexamethasone.

[0137] In another embodiment, the anticancer agent comprises an immunomodulatory agent, hi another embodiment, the immunomodulatory agent is pomalidomide or lenalidomide.

[0138] In another embodiment, the anticancer agent comprises a proteasome inhibitor, hi another embodiment, the proteasome inhibitor is bortezomib.

[0139] In another embodiment, the anticancer agent comprises a Bcl-2 inhibitor, hi another embodiment, the Bcl-2 inhibitor is venetoclax.

[0140] In another embodiment, the anti-cancer agent comprises a pleiotropic pathway modulator, hi another embodiment, the pleiotropic pathway modulator is CC-122.

[0141] In another embodiment, the anticancer agent comprises an XPO1 inhibitor. In another embodiment, the XPO1 inhibitor is selinexor.

[0142] In another embodiment, the anticancer agent comprises a histone deacetylase inhibitor, hi another embodiment, the histone deacetylase inhibitor is panobinostat.

[0143] In another embodiment, the anticancer agent is an EZH2 inhibitor. In another embodiment, the EZH2 inhibitor is tazemetostat.

[0144] In another embodiment, the anticancer agent comprises a BTK inhibitor. In another embodiment, the BTK inhibitor is ibrutinib, acalabrutinib, or zanubrutinib.

[0145] In another embodiment, the anti-cancer agent comprises an anti-CD20 monoclonal antibody, hi another embodiment, the anti-CD20 monoclonal antibody is rituximab.

[0146] In another embodiment, the anticancer agent comprises a PI3K inhibitor, hi another embodiment, the PI3K inhibitor is copanlisib.

[0147] In another embodiment, the anticancer agent comprises a CDK4 / 6 inhibitor, hi another embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0148] In another embodiment, the anticancer agent comprises a CARM1 inhibitor, hi another embodiment, the CARM1 inhibitor is EZM2302.

[0149] In another embodiment, the anticancer agent comprises an alkylating agent, hi another embodiment, the alkylating agent is mafosfamide.

[0150] In another embodiment, the anticancer agent comprises a topoisomerase II inhibitor, hi another embodiment, the topoisomerase II inhibitor is doxorubicin and etoposide.

[0151] In another embodiment, the anticancer agent comprises a vinca alkaloid, hi another embodiment, the vinca alkaloid is vincristine.

[0152] In another embodiment, the anticancer agent comprises a platinum-based drug, hi another embodiment, the platinum-based drug is carboplatin or oxaliplatin.

[0153] In another embodiment, the anti-cancer agent comprises a nucleoside anti-cancer agent, hi another embodiment, the nucleoside anti-cancer agent is gemcitabine. V.Kit

[0154] In another embodiment, the present disclosure provides a kit comprising a crystalline form of the present disclosure or a composition of the present disclosure packaged in a manner facilitating its use to practice the methods of the present disclosure.

[0155] In another embodiment, the kit comprises a crystalline form of the present disclosure or a composition of the present disclosure packaged in a container such as a sealed bottle, with a label affixed to the container and an insert included in the kit describing the use of the crystalline form of the present disclosure or the composition of the present disclosure to practice a method of the present disclosure for treating a disease, disorder, or condition, e.g., cancer, in a subject. In another embodiment, the crystalline form of the present disclosure or the composition of the present disclosure is packaged in unit dosage form, e.g., as a tablet, e.g., as a film-coated tablet.

[0156] In another embodiment, the kit further comprises an insert, e.g., instructions for administering the disclosed crystalline form or the disclosed composition to a subject having a disease, disorder, or condition, hi another embodiment, the disease, disorder, or condition is cancer. VI. Methods of Making the Crystalline Forms of the Present Disclosure

[0157] In another embodiment, the present disclosure provides a method of making a crystalline form of the present disclosure.

[0158] In another embodiment, the disclosure provides a method of making free base Form II.

[0159] In another embodiment, the present disclosure provides a method of making free base Form II, the method comprising:

[0160] (i) heating a mixture of Compound 1, ethanol, and water until Compound 1 is dissolved;

[0161] (ii) cooling the solution to about 50° C.;

[0162] (iii) optionally seeding the solution with free base Form II;

[0163] (iv) cooling the solution to about 0° C.;

[0164] (v) isolating the free base form II thus formed; The present invention provides a method comprising:

[0165] In another embodiment, the free base Form II is isolated by filtration.

[0166] In another embodiment, the method further comprises washing the free base Form II with a mixture of water and ethanol.

[0167] In another embodiment, the method further comprises drying the free base Form II under reduced pressure. VII.Definition N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide or “Compound 1” has the structure [ka] It refers to a compound having the formula:

[0168] N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrochloride or "Compound 1 HCl" refers to the hydrochloride salt of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide.

[0169] N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrobromide or "Compound 1 HBr" refers to the hydrobromide salt of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide.

[0170] As used herein, the term "substantially pure" with respect to the crystalline forms of the present disclosure means that the crystalline material contains about 10% or less by weight, e.g., about 1% to about 10%, e.g., about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1%, of any other crystalline or amorphous form(s) of Compound 1, Compound 1 HCl, or Compound 1 HBr. In another embodiment, the crystalline form of the present disclosure is substantially pure free base Form II.

[0171] As used herein, the term "pure" with respect to the crystalline forms of the present disclosure means that the crystalline material contains about 1% or less by weight, e.g., about 0.1% to about 1%, e.g., about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1%, or less, of any other crystalline or amorphous form(s) of Compound 1, Compound 1 HCl, or Compound 1 HBr. In one embodiment, the crystalline forms of the present disclosure do not contain XRPD detectable amounts of any other crystalline or amorphous form(s) of Compound 1, Compound 1 HCl, or Compound 1 HBr.

[0172] As used herein, the term "amorphous" refers to a solid form of Compound 1, Compound 1 HCl, or Compound 1 HBr that lacks the long-range order characteristic of a crystal, i.e., the solid is non-crystalline.

[0173] As used herein, the term "essentially the same" with respect to XRPD peak positions and / or relative intensities means that variations in peak positions and / or intensities are taken into account when comparing XRPD diffractograms. Similarly, the term "essentially the same" with respect to Raman or IR peak positions means that variations in peak positions are taken into account when comparing Raman or IR spectra. For example, XRPD peak positions may exhibit, for example, instrument-to-instrument variations of 0.2° 2Θ, i.e., ±0.2 degrees 2Θ, and Raman and IR peak positions may exhibit, for example, instrument-to-instrument variations of 4 cm. -1 , i.e. ±4cm -1 For example, relative peak intensities in XRPD diffractograms can also show instrumental variations due to crystallinity, orientation, sample surface preparation, and other factors known to those skilled in the art, and should be used only as a qualitative measure.

[0174] As used herein, the term "micronization" refers to a process or method in which a population of particles is reduced in size, typically to the micron scale.

[0175] As used herein, the term "micron" or "μm" means 1×10 -6 It refers to the unit "micrometer."

[0176] As used herein, the term "therapeutically effective amount" refers to an amount of Compound 1 sufficient to treat one or more symptoms of a disease, condition, injury, or disorder, or to arrest the progression of a disease, condition, injury, or disorder, or to bring about regression of a disease, condition, injury, or disorder.

[0177] In one embodiment, the crystalline form of the present disclosure or the composition of the present disclosure is administered to a subject in an amount effective to achieve its intended therapeutic purpose.While individual needs may vary, it is within the skill of the art to determine the optimal range of effective amounts of each compound.Typically, the crystalline form of the present disclosure is orally administered to a mammal, for example, a human, at a dosage of about 0.0025 to about 1500 mg per kg of mammalian body weight per day, or an equivalent amount of a pharmacologic acceptable salt or solvate thereof, to treat a particular disorder.The useful oral dosage of the crystalline form of the present disclosure administered to a mammal is about 0.1 mg to about 10 mg per kg of mammalian body weight, or an equivalent amount of a pharmacologic acceptable salt or solvate thereof.

[0178] In one embodiment, the crystalline form of the present disclosure or the composition of the present disclosure is administered to a subject at a total daily dosage of about 50 mg to about 2000 mg. In another embodiment, the crystalline form of the present disclosure or the composition of the present disclosure is administered to a subject at a total daily dosage of about 100 mg to about 1000 mg. In another embodiment, the crystalline form of the present disclosure or the composition of the present disclosure is administered to a subject at a total daily dosage of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg.

[0179] A unit oral dose may comprise from about 1 mg to about 1000 mg of the crystalline form of the present disclosure, e.g., from about 1 mg to about 500 mg, from about 10 mg to about 250 mg, from about 25 mg to about 200 mg of the crystalline form. The unit dose may be administered one or more times daily as one or more tablets or capsules, each containing, e.g., from about 10 mg to about 250 mg of the compound, or an equivalent amount of a pharma- ceutically acceptable salt or solvate thereof. In one embodiment, a unit oral dose, e.g., a tablet, comprises about 25 mg of the crystalline form of the present disclosure. In another embodiment, a unit oral dose, e.g., a tablet, comprises about 100 mg of the crystalline form of the present disclosure. In another embodiment, a unit oral dose, e.g., a tablet, comprises about 200 mg of the crystalline form of the present disclosure. In another embodiment, a unit oral dose of from about 10 mg to about 250 mg of the crystalline form of the present disclosure is administered to a subject once daily. In another embodiment, a unit oral dosage of about 10 mg to about 250 mg of the crystalline form of the present disclosure is administered to a subject twice daily.In another embodiment, a unit oral dosage of about 10 mg to about 250 mg of the crystalline form of the present disclosure is administered to a subject three times daily.

[0180] As used herein, terms such as "chemically stable" with respect to the crystalline forms of the present disclosure mean that the crystalline solid exhibits less than 0.5% chemical decomposition, e.g., less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1%, or less than 0.05% chemical decomposition after storage at a temperature of about 25° C. and a relative humidity of about 60% for at least 3 months. In determining the amount of decomposition, methods such as HPLC known in the art can be used to measure the appearance of one or more chemical impurities and / or the disappearance of Compound 1.

[0181] The terms "a" and "an" refer to one or to more than one.

[0182] As used herein, the term "about" includes the recited number plus or minus 10%. Thus, "about 10" means 9 to 11.

[0183] As used herein, "average particle size distribution" or "D 50 " is the diameter at which 50% by weight of the particles have a larger equivalent diameter and the remaining 50% by weight have a smaller equivalent diameter as determined by laser diffraction, for example in a Malvern Master Sizer Microplus instrument or equivalent.

[0184] As used herein, the term "excipient" refers to any ingredient present or added to the crystalline form of the present disclosure to obtain a pharmaceutical formulation suitable for administration to a subject, e.g., a tablet for oral administration. Excipients are typically inert substances, e.g., microcrystalline cellulose, added to a composition to facilitate processing, handling, dissolution, administration, etc., of the crystalline form of the present disclosure. Useful excipients include, but are not limited to, adjuvants, antiadherents, binders, carriers, disintegrants, fillers, flavorings, dyes, diluents, lubricants, glidants, preservatives, sorbents, solvents, surfactants, and sweeteners.

[0185] Conventional pharmaceutical excipients are well known to those skilled in the art.For example, a wide variety of pharmaceutical excipients can be used in combination with the crystalline form of the present disclosure, including microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, and others listed in Handbook of Pharmaceutical Excipients, Pharmaceutical Press 4th Ed. (2003) and Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st Ed. (2005).In one embodiment, the composition comprises free base Form II that is formulated as a tablet.

[0186] As used herein, the term "subject" refers to an animal, e.g., a human, or a livestock animal, e.g., a cow, sheep, pig, horse, dog, or cat. In one embodiment, the subject is a human.

[0187] As used herein, the term "container" refers to any receptacle and lid, and therefore, any receptacle and lid suitable for storing, transporting, dispensing, and / or handling a pharmaceutical product or excipient.

[0188] The term "insert" means the information that accompanies a pharmaceutical product that provides instructions on how to administer the product, along with safety and effectiveness data necessary to enable physicians, pharmacists, and patients to make informed decisions regarding the use of the product. Package inserts are commonly recognized as the "label" for pharmaceutical products. VIII. Specific Embodiments

[0189] The present disclosure provides the following specific embodiments.

[0190] Embodiment 1.

[0191] (a) N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide having free base form II, free base form III, or free base form IV, or a mixture thereof; or

[0192] (b) N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrochloride having HCl form I, or HCl form II, or a mixture thereof; or

[0193] (c) N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrobromide with HBr form I

[0194] A crystalline polymorph of

[0195] (i) the free base Form II is characterized as having a powder X-ray diffraction pattern using CuKα radiation having peaks at 7.0, 14.0, 18.0, and 20.2 degrees 2Θ, wherein said 2Θ values ​​are ±0.2 degrees 2Θ;

[0196] (ii) the free base Form III is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 7.6, 14.8, 18.0, and 19.8 degrees 2Θ, wherein said 2Θ values ​​are ±0.2 degrees 2Θ;

[0197] (iii) free base Form IV is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 14.8, 18.1, 19.1, 19.9, and 20.5 degrees 2Θ, wherein said 2Θ values ​​are ±0.2 degrees 2Θ;

[0198] (iv) HCl Form I is characterized as having a powder X-ray diffraction pattern using CuKα radiation having peaks at 14.6 and 25.0 degrees 2Θ, wherein said 2Θ values ​​are ±0.2 degrees 2Θ;

[0199] (v) HCl Form II is characterized as having a powder X-ray diffraction pattern using CuKα radiation having peaks at 15.2, 16.0, 17.7, and 22.6 degrees 2Θ, wherein said 2Θ values ​​are ±0.2 degrees 2Θ;

[0200] (vi) HBr Form I is characterized as having a powder X-ray diffraction pattern using CuKα radiation having peaks at 18.8, 25.1, and 26.5 degrees 2Θ, wherein said 2Θ values ​​are ±0.2 degrees 2Θ. Crystal polymorphism.

[0201] Embodiment 2. The crystalline polymorph of embodiment 1 which is N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide having the free base Form II.

[0202] Embodiment 3. The crystalline polymorph of embodiment 1 which is N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide having the free base Form III.

[0203] Embodiment 4. The crystalline polymorph of embodiment 1 which is N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide having the free base Form IV.

[0204] Embodiment 5. The crystalline polymorph of any one of embodiments 2 to 4, comprising about 5% or less of any other physical form of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide.

[0205] Embodiment 6. The crystalline polymorph of embodiment 1 which is N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrochloride having HCl Form I.

[0206] Embodiment 7. The crystalline polymorph of embodiment 1 which is N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrochloride having HCl Form II.

[0207] Embodiment 8. The crystalline polymorph of embodiment 6 or 7, comprising about 5% or less of any other physical form of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrochloride.

[0208] Embodiment 9. The crystalline polymorph of embodiment 1 which is N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrochloride having HBr Form I.

[0209] Embodiment 10. The crystalline polymorph of embodiment 9, comprising about 5% or less of any other physical form of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrobromide.

[0210] Embodiment 11. A pharmaceutical composition comprising the crystalline polymorph of any one of embodiments 1 to 10 and one or more pharma- ceutically acceptable excipients.

[0211] Embodiment 12. The pharmaceutical composition of embodiment 11, wherein the one or more pharma- ceutical acceptable excipients comprise a ductile diluent, a brittle diluent, a disintegrant, a binder, a glidant, or a lubricant, or a combination thereof.

[0212] Embodiment 13. The pharmaceutical composition of embodiment 11, wherein the one or more pharma-ceutically acceptable excipients comprise microcrystalline cellulose, partially pregelatinized maize starch, anhydrous lactose, mannitol, anhydrous dibasic calcium phosphate, croscarmellose sodium, sodium starch glycolate, crospovidone, hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate, or stearic acid, or a combination thereof.

[0213] Embodiment 14.

[0214] (a) about 25% w / w crystalline polymorphism;

[0215] (b) about 35% w / w microcrystalline cellulose;

[0216] (c) about 35% w / w anhydrous lactose;

[0217] (d) about 3% w / w of croscarmellose sodium;

[0218] (e) about 1.5% w / w magnesium stearate; 14. The pharmaceutical composition of embodiment 13, comprising:

[0219] Embodiment 15. The pharmaceutical composition of embodiment 14, further comprising a film coating.

[0220] Embodiment 16. The pharmaceutical composition of embodiment 15, wherein the film coating composition comprises HPMC2910 / hypromellose, titanium dioxide, and macrogol / PEG.

[0221] Embodiment 17. The pharmaceutical composition of any one of embodiments 11 to 16, which is formulated as a film-coated tablet.

[0222] Embodiment 18. A method of making the pharmaceutical composition of any one of embodiments 11 to 17, said method comprising blending the crystalline polymorph with one or more pharma- ceutically acceptable excipients.

[0223] Embodiment 19. A method of treating cancer in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of the crystalline polymorph of any one of embodiments 1 to 10, or a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 11 to 17.

[0224] Embodiment 20. The crystalline polymorph of any one of embodiments 1 to 10, or the pharmaceutical composition of any one of embodiments 11 to 17, for use in treating cancer in a subject.

[0225] Embodiment 21. Use of the crystalline polymorph of any one of embodiments 1 to 10, or the pharmaceutical composition of any one of embodiments 11 to 17, in the manufacture of a medicament for treating cancer in a subject.

[0226] Embodiment 22. The method of embodiment 19, the crystalline polymorph or pharmaceutical composition of claim 20, or the use of claim 21, wherein the cancer is any one or more of the cancers in Table 2.

[0227] Embodiment 23. The method of embodiment 21, the crystalline polymorph or the pharmaceutical composition of claim 20, or the use of claim 21, wherein the cancer is a hematological cancer.

[0228] Embodiment 24. The method, crystalline polymorph, pharmaceutical composition, or use of embodiment 23, wherein the hematological cancer is any one or more of the cancers in Table 3.

[0229] Embodiment 25. The method, crystalline polymorph, pharmaceutical composition, or use of embodiment 24, wherein the hematological cancer is diffuse large B-cell lymphoma.

[0230] Embodiment 26. The method, crystalline polymorph, pharmaceutical composition, or use of embodiment 24, wherein the hematological cancer is mantle cell lymphoma.

[0231] Embodiment 27. The method, crystalline polymorph, pharmaceutical composition, or use of embodiment 24, wherein the hematological cancer is multiple myeloma.

[0232] Embodiment 28. The method, crystalline polymorph, pharmaceutical composition, or use of embodiment 27, wherein the hematological cancer is t(4;14) multiple myeloma.

[0233] Embodiment 29. The method, crystalline polymorph, pharmaceutical composition, or use of any one of embodiments 19 to 28, further comprising administering to the subject a therapeutically effective amount of an anti-cancer agent.

[0234] Embodiment 30. The method, crystalline polymorph, pharmaceutical composition, or use of embodiment 29, wherein the anti-cancer agent comprises one or more glucocorticoid receptor agonists, one or more immunomodulatory agents, one or more proteasome inhibitors, one or more Bcl-2 inhibitors, one or more pleiotropic pathway regulators, one or more XPO1 inhibitors, one or more histone deacetylase inhibitors, one or more EZH2 inhibitors, one or more BTK inhibitors, one or more anti-CD20 monoclonal antibodies, one or more alkylating agents, one or more topoisomerase II inhibitors, one or more vinca alkaloids, one or more platinum-based drugs, one or more nucleoside anti-cancer agents, one or more PI3K inhibitors, one or more CDK4 / 6 inhibitors, or one or more CARM1 inhibitors, or combinations thereof.

[0235] Embodiment 31. The method, crystalline polymorph, pharmaceutical composition, or use of embodiment 29 or 30, wherein the anticancer agent comprises a glucocorticoid receptor agonist.

[0236] Embodiment 32. The method, crystalline polymorph, pharmaceutical composition, or use of embodiment 31, wherein the glucocorticoid receptor agonist is dexamethasone.

[0237] Embodiment 33. The method, crystalline polymorph, pharmaceutical composition, or use of any one of embodiments 29 to 32, wherein the anticancer agent comprises an immunomodulatory agent.

[0238] Embodiment 34. The method, crystalline polymorph, pharmaceutical composition, or use of embodiment 33, wherein the immunomodulatory agent is pomalidomide or lenalidomide.

[0239] Embodiment 35. The method, crystalline polymorph, pharmaceutical composition, or use of any one of embodiments 29 to 34, wherein the anticancer agent comprises a proteasome inhibitor.

[0240] Embodiment 36. The method, crystalline polymorph, pharmaceutical composition, or use of embodiment 35, wherein the proteasome inhibitor is bortezomib.

[0241] Embodiment 37. The method, crystalline polymorph, pharmaceutical composition, or use of any one of embodiments 29 to 36, wherein the anticancer agent comprises a Bcl-2 inhibitor.

[0242] Embodiment 38. The method of embodiment 37, wherein the Bcl-2 inhibitor is venetoclax.

[0243] Embodiment 39. The method of any one of embodiments 29 to 38, wherein the anticancer agent comprises a pleiotropic pathway modulator.

[0244] Embodiment 40. The method of embodiment 39, wherein the pleiotropic pathway modulator is CC-122.

[0245] Embodiment 41. The method of any one of embodiments 29 to 40, wherein the anticancer agent comprises an XPO1 inhibitor.

[0246] Embodiment 42. The method of embodiment 41, wherein the XPO1 inhibitor is selinexor.

[0247] Embodiment 43. The method of any one of embodiments 29 to 42, wherein the anticancer agent comprises a histone deacetylase inhibitor.

[0248] Embodiment 44. The method of embodiment 43, wherein the histone deacetylase inhibitor is panobinostat.

[0249] Embodiment 45. The method of any one of embodiments 29 to 44, wherein the anticancer agent is an EZH2 inhibitor.

[0250] Embodiment 46. The method of embodiment 45, wherein the EZH2 inhibitor is tazemetostat.

[0251] Embodiment 47. The method of any one of embodiments 29 to 46, wherein the anticancer agent comprises a BTK inhibitor.

[0252] Embodiment 48. The method of embodiment 47, wherein the BTK inhibitor is ibrutinib, acalabrutinib, or zanubrutinib.

[0253] Embodiment 49. The method of any one of embodiments 29 to 48, wherein the anti-cancer agent comprises an anti-CD20 monoclonal antibody.

[0254] Embodiment 50. The method of embodiment 49, wherein the anti-CD20 monoclonal antibody is rituximab.

[0255] Embodiment 51. The method of any one of embodiments 29 to 50, wherein the anticancer agent comprises a PI3K inhibitor.

[0256] Embodiment 52. The method of embodiment 51, wherein the PI3K inhibitor is copanlisib.

[0257] Embodiment 53. The method of any one of embodiments 29 to 52, wherein the anticancer agent comprises a CDK4 / 6 inhibitor.

[0258] Embodiment 54. The method of embodiment 53, wherein the CDK4 / 6 inhibitor is palbociclib.

[0259] Embodiment 55. The method of any one of embodiments 29 to 54, wherein the anticancer agent comprises a CARM1 inhibitor.

[0260] Embodiment 56. The method of embodiment 55, wherein the CARM1 inhibitor is EZM2302.

[0261] Embodiment 57. The method of any one of embodiments 29 to 56, wherein the anticancer agent comprises an alkylating agent.

[0262] Embodiment 58. The method of embodiment 57, wherein the alkylating agent is mafosfamide.

[0263] Embodiment 59. The method of any one of embodiments 29 to 58, wherein the anticancer agent comprises a topoisomerase II inhibitor.

[0264] Embodiment 60. The method of embodiment 58, wherein the topoisomerase II inhibitors are doxorubicin and etoposide.

[0265] Embodiment 61. The method of any one of embodiments 29 to 60, wherein the anticancer agent comprises a vinca alkaloid.

[0266] Embodiment 62. The method of embodiment 61, wherein the vinca alkaloid is vincristine.

[0267] Embodiment 63. The method of any one of embodiments 29 to 62, wherein the anticancer agent comprises a platinum-based agent.

[0268] Embodiment 64. The method of embodiment 63, wherein the platinum-based drug is carboplatin or oxaliplatin.

[0269] Embodiment 65. The method of any one of embodiments 29 to 64, wherein the anticancer agent comprises a nucleoside anticancer agent.

[0270] Embodiment 66. The method of embodiment 65, wherein the nucleoside anticancer agent is gemcitabine.

[0271] Embodiment 67. A kit comprising the crystalline polymorph of any one of embodiments 1 to 10 or the pharmaceutical composition of any one of embodiments 11 to 17, and instructions for administering the pharmaceutical composition to a subject in need thereof.

[0272] Embodiment 68. The kit of embodiment 67, further comprising an anticancer drug.

[0273] Embodiment 69. A kit for carrying out the method of any one of embodiments 19 or 22 to 28, said kit comprising (a) the crystalline polymorph or pharmaceutical composition, and (b) instructions for administering the crystalline polymorph or pharmaceutical composition to a subject.

[0274] Embodiment 70. A kit for carrying out the method of any one of embodiments 29 to 66, said kit comprising: (a) a crystalline polymorph or a pharmaceutical composition, (b) instructions for administering the crystalline polymorph or pharmaceutical composition to a subject, (c) an anti-cancer agent, and (d) instructions for administering the anti-cancer agent to a subject.

[0275] Embodiment 71. A method for preparing the free base Form II of embodiment 1, said method comprising:

[0276] (i) heating N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide in ethanol and water to obtain a solution;

[0277] (ii) cooling the solution to about 0° C.;

[0278] (iii) optionally seeding the solution;

[0279] (iv) isolating the free base Form II; A method comprising: EXAMPLES

[0280] Instrumentation X-ray Powder Diffraction (PXRD or XRPD) XRPD patterns were determined using an X-ray diffractometer, e.g., a Bruker D8 advance or D2 Phaser equipped with a LynxEye detector. Samples were scanned from 3 to 40°2θ with a step size of 0.02°2θ. Tube voltage and current were 40 KV and 40 mA, respectively. Differential Scanning Calorimetry (DSC)

[0281] DSC was performed using a Discovery DSC250 (TA Instruments, US). Samples were placed in aluminum pinhole hermetic pans and the weight was accurately recorded. Samples were heated from 25° C. to the final temperature at a rate of 10° C. / min. Fourier transform infrared spectroscopy (FT-IR)

[0282] FTIR was obtained using a Shimadzu IR Tracer 100. Samples were prepared by the KBr pellet method, and the 4000–400 cm -1 The IR spectra were recorded during Thermogravimetric analysis (TGA)

[0283] TGA was performed on a Discovery TGA55 (TA Instruments, US). Samples were placed in tared aluminum pans without lids, automatically weighed, and inserted into the TGA furnace. Samples were heated from ambient temperature to the final temperature at a rate of 10° C. / min. Example 1 Synthesis and Characterization of Polymorphs of the Present Disclosure Free Base Form I

[0284] The racemic mixture of the free base of Compound 1 was separated by chiral supercritical fluid chromatography (SFC) and the fractions containing Compound 1 were pooled and concentrated under reduced pressure. The material was then dried under reduced pressure (approximately 15 Torr) to give the free base Form I. Free Base Form II

[0285] The synthesis of the TFA salt of compound 1 is described in Example 1 of WO2020 / 037079. The free base of compound 1 is heated in a solution of EtOH and water to dissolve the compound. The solution is slowly cooled to 50±5°C and seed crystals are added. The mixture is further cooled to approximately 2.5±2.5°C. The crystalline product is filtered, washed with a mixture of purified water and ethanol, and then dried under reduced pressure to obtain free base form II. A list of XRPD peaks (±0.2 degrees 2Θ) of free base form II is provided in Table A. [Table A-1] [Table A-2] Free Base Form III

[0286] Free base Form III was obtained by drying Form IV under reduced pressure at 50° C. A list of XRPD peaks (±0.2 degrees 2Θ) for free base Form III is provided in Table B. [Table B] Free Base Form IV

[0287] Free base Form IV was obtained by slurrying Compound 1 in water at room temperature. A list of XRPD peaks (±0.2 degrees 2Θ) for free base Form IV is provided in Table C. [Table C] HCl Form I

[0288] HCl Form I was obtained by dissolving Compound 1 in acetonitrile and water containing 3M HCl, stirring at room temperature for 2 days with slow evaporation, and drying the crystals thus obtained under reduced pressure at 50° C. for about 4 hours. A list of XRPD peaks (±0.2 degrees 2Θ) of HCl Form I is provided in Table D. [Table D] HCl Form II

[0289] HCl Form I was obtained by dissolving HCl Form I in an aqueous solution of acetone and 1.1 equivalents of HCl at 50° C., cooling to 40° C. at 0.1° C. / min, seeding the solution and holding for 2 hours. The resulting suspension was cooled to 20° C. at 0.1° C. / min and then stirred overnight / weekend. After filtration, the solid thus obtained was HCl Form II. A list of XRPD peaks (±0.2 degrees 2Θ) of HCl Form II is provided in Table E. [Table E] HBr form I

[0290] For HBr Form I, compound 1 was obtained in an aqueous solution of acetonitrile and 1.1 equivalents of HBr. The solution was stirred overnight at room temperature to precipitate a solid. The solid was filtered and dried under reduced pressure at 50° C. to obtain HBr Form I. A list of XRPD peaks (±0.2 degrees 2Θ) for HBr Form I is provided in Table F. [Table F] Example 2 Preparation of film-coated tablets

[0291] Table 2A shows the ingredients for a film-coated tablet containing 25 mg of free base Form II. A process flow diagram is provided in Figure 16. [Table 2A] Sifting

[0292] Lactose Anhydrous DT HV was passed through a 40 mesh (450 μm) sieve. Free base Form II was poured from the bag onto a 50 mesh (355 μm) sieve. The bag of free base Form II was washed with Microcrystalline Cellulose PH102 and both free base Form II and Microcrystalline Cellulose PH102 were sieved through a 50 mesh sieve.

[0293] Croscarmellose sodium was passed through the same 50 mesh sieve into the same bag.

[0294] Magnesium stearate (intragranular and extragranular) was passed through a 30 mesh (600 μm) sieve into a separate bag. Blending and Lubrication (Blending)

[0295] Free base Form II and excipients, except for intragranular and extragranular magnesium stearate, were placed in a 5 L blending box and blended for 20 minutes at 20 rpm.

[0296] At selected time points, six samples were taken from different blending points and tested for blend uniformity. The blend uniformity results are shown in Table 3A. [Table 3A]

[0297] After blending, 0.5% sieved intragranular magnesium stearate was added to the blending box and blending was carried out for 5 minutes at a speed of 20 rpm. Roller Compaction and Grinding

[0298] The lubricated blend was passed through a roller compactor at different feed rates to produce dry granules.

[0299] The sieve analysis results for the dried granules after roller compaction are shown in Table 4. Other granule properties are shown in Table 5. [Table 4] [Table 5] Lubricating (granules)

[0300] 1% extragranular magnesium stearate was blended with the granules for 5 minutes. Six samples were taken from different blending points and tested for blend uniformity. The blend uniformity results are shown in Table 6. [Table 6] compression

[0301] The lubricated granules were compressed into tablets using a rotary press. During compression, tablets were sampled at different stages and tested for tablet weight, hardness, and content uniformity. coating

[0302] The tablet cores were coated using Opadry® Complete Film Coating System 03B180001 white. A coating suspension with 12% solids was prepared. The coating weight gain was in the range of 3.0±0.5%.

[0303] The dissolution results for the resulting coated tablets are shown in Table 7. [Table 7]

[0304] The effectiveness of the coating process was further confirmed in a tablet assay by testing the content uniformity of the coated tablets, and the results are shown in Table 8. [Table 8]

[0305] The process parameters are summarized in Table 9. [Table 9] Example 3 Pharmacokinetics of free base forms I and II

[0306] In this study, free base Form I and free base Form II were administered at 25 mg / kg and 100 mg / kg (0.5% carboxymethylcellulose (CMC) and 0.1% Tween in water at pH 7) to male beagle dogs. The dogs were fasted overnight and then fed one hour prior to oral administration of the forms. Blood samples were collected at predefined time points up to 48 hours. Plasma concentrations of Compound 1 were determined by a liquid chromatography with tandem mass spectrometry (LC-MS / MS) method. The concentration-time profiles are shown in Figure 15 and relevant PK parameters are summarized in Table 10. [Table 10]

[0307] The above results demonstrate that free base Form II unexpectedly provides greater exposure in dogs than free base Form I. This difference was dose-dependent. At a dose of 25 mg / kg, the C max , and the area under the plasma concentration-time curve extrapolated from time 0 to infinity (AUC0-inf) were approximately 40% and 20% greater than those of free base form I, respectively. The difference in exposure to compound 1 was magnified at the 100 mg / kg dose, with the C max and AUC 0-inf were 1.8-fold and 3.1-fold greater, respectively, than those of free base form I. The above results suggest that free base form II was absorbed more extensively than free base form I, especially at the 100 mg / kg dose. Without wishing to be bound by any particular theory, the more extensive absorption of free base form II may be due to differences in the solubility or dissolution process of these forms in the intestinal lumen of dogs.

[0308] It should be understood that the foregoing described embodiments and examples are not intended to be limiting in any way to the scope of the present disclosure, and that the claims set forth herein are intended to encompass all embodiments and examples, whether or not expressly set forth herein.

[0309] All patents and publications mentioned herein are fully incorporated by reference in their entirety.

Claims

1. (a) N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide having free base form II, free base form III, or free base form IV, or a mixture thereof; or (b) N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrochloride having HCl Form I, or HCl Form II, or a mixture thereof; or (c) N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrobromide having HBr Form I A crystalline form of (i) free base Form II is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 7.0, 14.0, 18.0, and 20.2 degrees 2Θ, wherein said 2Θ values ​​are ±0.2 degrees 2Θ; (ii) free base Form III is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 7.6, 14.8, 18.0, and 19.8 degrees 2Θ, wherein said 2Θ values ​​are ±0.2 degrees 2Θ; (iii) free base Form IV is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 14.8, 18.1, 19.1, 19.9, and 20.5 degrees 2Θ, wherein said 2Θ values ​​are ±0.2 degrees 2Θ; (iv) HCl Form I is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 14.6 and 25.0 degrees 2Θ, wherein said 2Θ values ​​are ±0.2 degrees 2Θ; (v) HCl Form II is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 15.2, 16.0, 17.7, and 22.6 degrees 2Θ, wherein said 2Θ values ​​are ±0.2 degrees 2Θ; (vi) HBr Form I is characterized as having a powder X-ray diffraction pattern using CuKα radiation with peaks at 18.8, 25.1, and 26.5 degrees 2Θ, wherein said 2Θ values ​​are ±0.2 degrees 2Θ. Crystalline form.

2. 2. The crystalline form of claim 1, which is N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide having the free base Form II.

3. 2. The crystalline form of claim 1, which is N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide having the free base Form III.

4. 2. The crystalline form of claim 1, which is N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide having free base Form IV.

5. 5. The crystalline form of any one of claims 2 to 4, containing about 5% or less of any other physical form of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide.

6. 2. The crystalline form of claim 1, which is N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrochloride having HCl Form I.

7. 10. The crystalline form of claim 1, which is N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrochloride having HCl Form II.

8. 8. The crystalline form of claim 6 or 7, containing about 5% or less of any other physical form of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrochloride.

9. 2. The crystalline form of claim 1, which is N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrochloride having HBr Form I.

10. 10. The crystalline form of claim 9, containing about 5% or less of any other physical form of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide hydrobromide.

11. 11. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 10 and one or more pharmaceutically acceptable excipients.

12. 12. The pharmaceutical composition of claim 11, wherein the one or more pharmaceutically acceptable excipients comprise a ductile diluent, a brittle diluent, a disintegrant, a binder, a glidant, or a lubricant, or a combination thereof.

13. 12. The pharmaceutical composition of claim 11, wherein the one or more pharmaceutically acceptable excipients comprise microcrystalline cellulose, partially pregelatinized maize starch, anhydrous lactose, mannitol, anhydrous dibasic calcium phosphate, croscarmellose sodium, sodium starch glycolate, crospovidone, hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate, or stearic acid, or a combination thereof.

14. (a) about 25% w / w of said crystalline form; (b) about 35% w / w microcrystalline cellulose; (c) about 35% w / w anhydrous lactose; (d) about 3% w / w croscarmellose sodium; (e) about 1.5% w / w magnesium stearate; 14. The pharmaceutical composition of claim 13, comprising:

15. 15. The pharmaceutical composition of claim 14, further comprising a film coating.

16. 16. The pharmaceutical composition of claim 15, wherein the film coating composition comprises HPMC2910 / hypromellose, titanium dioxide, and macrogol / PEG.

17. 17. The pharmaceutical composition of any one of claims 11 to 16, formulated as a film-coated tablet.

18. 18. A method of making the pharmaceutical composition of any one of claims 11 to 17, said method comprising blending said crystalline form with said one or more pharmaceutically acceptable excipients.

19. 18. A composition comprising the crystalline form of any one of claims 1 to 10, or the pharmaceutical composition of any one of claims 11 to 17, for use in a method of treating cancer in a subject in need thereof.

20. 20. The composition or pharmaceutical composition of claim 19, wherein the cancer is any one or more of the cancers in Table 2.

21. 20. The composition or pharmaceutical composition of claim 19, wherein the cancer is a hematological cancer.

22. 22. The composition or pharmaceutical composition of claim 21, wherein the hematological cancer is any one or more of the cancers in Table 3.

23. 23. The composition or pharmaceutical composition of claim 22, wherein the hematological cancer is diffuse large B-cell lymphoma, mantle cell lymphoma, or multiple myeloma.

24. 24. The composition or pharmaceutical composition of claim 23, wherein the hematological cancer is t(4;14) multiple myeloma.

25. A composition or pharmaceutical composition described in any one of claims 19 to 24, wherein the method further comprises administering a therapeutically effective amount of an anticancer agent to the subject.

26. 26. The composition or pharmaceutical composition of claim 25, wherein the anti-cancer agents comprise one or more glucocorticoid receptor agonists, one or more immunomodulatory agents, one or more proteasome inhibitors, one or more Bcl-2 inhibitors, one or more pleiotropic pathway modulators, one or more XPO1 inhibitors, one or more histone deacetylase inhibitors, one or more EZH2 inhibitors, one or more BTK inhibitors, one or more anti-CD20 monoclonal antibodies, one or more alkylating agents, one or more topoisomerase II inhibitors, one or more vinca alkaloids, one or more platinum-based agents, one or more nucleoside anti-cancer agents, one or more PI3K inhibitors, one or more CDK4 / 6 inhibitors, or one or more CARM1 inhibitors, or a combination thereof.

27. 18. A kit comprising the crystalline form of any one of claims 1 to 10 or the pharmaceutical composition of any one of claims 11 to 17 and instructions for administering said crystalline form or said pharmaceutical composition to a subject in need thereof.

28. 25. A kit for carrying out the method of any one of claims 19 to 24, the kit comprising: (a) the crystalline form or the pharmaceutical composition; and (b) instructions for administering the crystalline form or the pharmaceutical composition to the subject.

29. 27. A kit for carrying out the method of any one of claims 25-26, the kit comprising: (a) the crystalline form or the pharmaceutical composition; (b) instructions for administering the crystalline form or the pharmaceutical composition to the subject; (c) the anti-cancer agent; and (d) instructions for administering the anti-cancer agent to the subject.

30. 10. A method for preparing the free base Form II of claim 1, said method comprising: (i) heating N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide in ethanol and water to obtain a solution; (ii) cooling the solution to about 0°C; (iii) optionally adding seed crystals to the solution; (iv) isolating said free base Form II; A method comprising:

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