Macrocyclic azolopyridines

Abstract

The present disclosure relates, in part, to (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, a crystalline form of the free base, and a crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 170,212, filed April 2, 2021, which is incorporated by reference in its entirety into this specification. [Background technology]

[0002] background Polycomb repressive complex 2 (PRC2) is a multi-subunit chromatin regulatory complex that functions in the repression of gene expression and is dysregulated in many human diseases. PRC2 contains SUZ12 (suppressor of zeste 12), EED (embryonic ectoderm development) and a catalytic subunit, EZH2 (enhancer of zeste homolog 2), and represses genes by methylating histone H3 on lysine 27 (H3K27me3) at and around the promoter regions of genes. EED mediates the repression of gene activity by binding to the H3K27me3 mark, where it allosterically activates the methyltransferase activity of PRC2 (e.g., trimethylation of lysine 27 on histone H3 (H3K27me3). This key element of chromatin regulation is involved in the regulation of gene transcription and plays a key role in development, differentiation, and regeneration.

[0003] EED regulates PRC2 in silencing the expression of genes and genes involved in development, such as fetal orthologs (e.g., gamma globin), Hox genes, and X-chromosome inactivation. Abnormal expression of PRC2 has also been observed in various human cancers, such as hepatocellular carcinoma, breast cancer, and prostate cancer. Thus, EED and / or PRC2 provide pharmacological targets for the treatment of diseases or disorders, such as cancer and blood disorders, for example, to affect the transcription of specific target genes in blood and other tissues.

[0004]

[0004] Polymorphism is the ability of a substance to crystallize in more than one crystal lattice arrangement. Crystallization, or polymorphism, can affect many aspects of the solid state properties of a drug substance. A crystalline substance can be significantly different from the amorphous form, and different crystalline forms of a substance can be significantly different from each other in many ways, including solubility, dissolution rate, and / or bioavailability. In general, it is difficult to predict which crystalline solid forms a given compound will form. It is even more difficult to predict the physical properties of these crystalline solid forms. Furthermore, it can be advantageous to have a crystalline form of a therapeutic agent for a particular formulation and / or manufacturing process. Summary of the Invention [Means for solving the problem]

[0005] overview

[0005] The present disclosure relates, at least in part, to a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base.

[0006]

[0006] For example, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.6 2θ°, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.6, 11.9, and 15.3 2θ°, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.6, 11.9, 14.5, 15.3, 20.7, and 22.6 ...16.1, Disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, anhydrous free base, characterized by an X-ray powder diffraction pattern with characteristic peaks at 17.2, 17.3, 20.7, 22.6, 23.3, 26.2, and 24.5 degrees 2θ.

[0007] Also disclosed herein is a crystalline salt form of pharma- ceutically acceptable (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine.For example, the disclosed crystalline salt form can be selected from the group consisting of benzenesulfonate, citrate, fumarate, hydrochloride, maleate, L-malate, methanesulfonate, phosphate, pyruvate, sulfate, L-tartrate, and toluenesulfonate, and their crystalline hydrates and solvates.

[0008] (S)-12-Fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine is, for example, a modulator of EED and / or a modulator of PRC2; [ka] It is represented by:

[0009]

[0009] Further contemplated herein are pharmaceutical compositions comprising the disclosed crystalline free base form, or the disclosed crystalline salt form, of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine and a pharma- ceutical acceptable excipient, for example compositions formulated for oral, subcutaneous or intravenous administration. Further contemplated herein is a drug substance comprising at least a detectable amount of the disclosed crystalline free base form or the disclosed crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine. For example, disclosed herein is a drug substance comprising a substantially pure crystalline free base form or a crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine.

[0010]

[0010] Also provided in the present specification is a method for treating a blood disorder (e.g., sickle cell disease or β-thalassemia) in a patient in need thereof, comprising administering to the patient an effective amount of the disclosed crystalline free base form or the disclosed crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine. For example, provided herein is a method of treating a blood disorder (e.g., sickle cell disease or β-thalassemia) in a patient in need thereof comprising administering to the patient an effective amount of a pharmaceutical composition comprising the disclosed crystalline free base form, or a pharmaceutical composition comprising the disclosed crystalline salt form, of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine.

[0011]

[0011] Further provided in the present specification is a method for treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of the disclosed crystalline free base form or the disclosed crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine. For example, provided herein is a method of treating cancer in a patient in need thereof comprising administering to the patient an effective amount of a pharmaceutical composition comprising the disclosed crystalline free base form, or a pharmaceutical composition comprising the disclosed crystalline salt form, of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine. [Brief description of the drawings]

[0012] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]

[0012] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, anhydrous free base, form P. [Diagram 2]

[0013] 1 shows characterization of Form P by differential scanning calorimetry (DSC). [Diagram 3]

[0014] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form A. [Figure 4]

[0015] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form B. [Diagram 5]

[0016] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form C. [Figure 6]

[0017] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form D. [Figure 7]

[0018] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate form E. [Figure 8]

[0019] 1 shows characterization of Form E by differential scanning calorimetry (DSC). [Figure 9]

[0020] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form F. [Figure 10]

[0021] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate form H. [Figure 11]

[0022] 1 shows characterization of Form H by differential scanning calorimetry (DSC). [Figure 12]

[0023] FIG. 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, Form I. [Figure 13]

[0024] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form J. [Figure 14]

[0025] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form K. [Figure 15]

[0026] 1 shows characterization of Form K by differential scanning calorimetry (DSC). [Figure 16]

[0027] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base form L. [Figure 17]

[0028] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form M. [Figure 18]

[0029] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form N. [Figure 19]

[0030] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form O. [Figure 20]

[0031] 1 shows characterization of form O by differential scanning calorimetry (DSC). [Figure 21]

[0032] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base form Q. [Figure 22]

[0033] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form R. [Figure 23]

[0034] 1 shows characterization of Form R by differential scanning calorimetry (DSC). [Figure 24]

[0035] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form S. [Diagram 25]

[0036] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base form T. [Figure 26]

[0037] 1 shows characterization of Form T by differential scanning calorimetry (DSC). [Figure 27]

[0038] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form U. [Figure 28]

[0039] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, form V of the free base. [Figure 29]

[0040] FIG. 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form W. [Diagram 30]

[0041] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, benzenesulfonate salt, form 1-A. [Diagram 31]

[0042] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, benzenesulfonate salt form 1-B. [Diagram 32]

[0043] 1 shows characterization of Form 1-B by differential scanning calorimetry (DSC). [Diagram 33]

[0044] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, citrate salt form 2-A. [Diagram 34]

[0045] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, citrate salt form 2-B. [Diagram 35]

[0046] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, citrate salt form 2-C. [Diagram 36]

[0047] 1 shows characterization of Form 2-C by Differential Scanning Calorimetry (DSC). [Figure 37]

[0048] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, fumarate salt form 3-A. [Figure 38]

[0049] 1 shows characterization of Form 3-A by differential scanning calorimetry (DSC). [Figure 39]

[0050] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride salt form 5-A. [Diagram 40]

[0051] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride salt form 5-B. [Diagram 41]

[0052] 1 shows characterization of Form 5-B by Differential Scanning Calorimetry (DSC). [Diagram 42]

[0053] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride salt form 5-C. [Diagram 43]

[0054] 1 shows the characterization of Form 5-C by Differential Scanning Calorimetry (DSC). [Diagram 44]

[0055] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride salt form 5-D. [Diagram 45]

[0056] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, maleate salt form 7-A. [Figure 46]

[0057] 1 shows characterization of Form 7-A by differential scanning calorimetry (DSC). [Figure 47]

[0058] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-malate form 8-A. [Figure 48]

[0059] 1 shows characterization of Form 8-A by differential scanning calorimetry (DSC). [Figure 49]

[0060] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-malate form 8-B. [Figure 50]

[0061] 1 shows characterization of Form 8-B by Differential Scanning Calorimetry (DSC). [Figure 51]

[0062] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, methanesulfonate salt form 9-A. [Figure 52]

[0063] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, methanesulfonate salt form 9-B. [Diagram 53]

[0064] 1 shows characterization of Form 9-B by Differential Scanning Calorimetry (DSC). [Figure 54]

[0065] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, methanesulfonate salt form 9-C. [Figure 55]

[0066] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, phosphate salt, form 10-A. [Figure 56]

[0067] 1 shows characterization of Form 10-A by differential scanning calorimetry (DSC). [Figure 57]

[0068] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, pyruvate salt, form 11-A. [Figure 58]

[0069] 1 shows characterization of Form 11-A by differential scanning calorimetry (DSC). [Figure 59]

[0070] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, sulfate salt, form 12-A. [Figure 60]

[0071] 1 shows characterization of Form 12-A by Differential Scanning Calorimetry (DSC). [Figure 61]

[0072] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-tartrate salt form 13-A. [Figure 62]

[0073] 1 shows characterization of Form 13-A by Differential Scanning Calorimetry (DSC). [Figure 63]

[0074] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-tartrate salt form 13-B. [Figure 64]

[0075] 1 shows characterization of Form 13-B by Differential Scanning Calorimetry (DSC). [Figure 65]

[0076] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, toluenesulfonate salt form 14-A. [Figure 66]

[0077] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, toluenesulfonate salt form 14-B. [Figure 67]

[0078] 1 shows the X-ray powder diffraction (XRPD) pattern of amorphous (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base. After evaporation of THF from Form E at 50° C. under atmospheric pressure and further drying of the residue under reduced pressure at 50° C., line (1) represents Form E material and line (2) represents amorphous material. [Figure 68]

[0079] Figure 2 shows X-ray powder diffraction (XRPD) patterns of various solid forms of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine obtained by crystallization from various solvents. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Detailed Description

[0080] The features and other details of the present disclosure will be described more specifically hereinafter.Before further description of the present disclosure, certain terms used in the specification, examples and appended claims are collected here.These definitions should be read in light of the remainder of the disclosure and as understood by those skilled in the art.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0014] definition

[0081] The term "crystalline form" refers to a crystalline form or crystalline change that can be characterized by analytical methods such as, for example, X-ray powder diffraction (XRPD) and / or differential scanning calorimetry (DSC). The crystalline compounds disclosed herein can exist in solvated and unsolvated forms with solvents such as water, ethanol, etc. Unless otherwise indicated or implied, it is intended that the disclosed crystalline compounds include both solvated and unsolvated forms.

[0015]

[0082] "Treatment" includes any effect that results in the improvement of a condition, disease, disorder, etc., such as lowering, alleviating, modulating, or elimination.

[0016]

[0083] The term "disorder" refers to, and is used interchangeably with, the terms "disease," "condition," or "illness," unless otherwise indicated.

[0017]

[0084] "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

[0018]

[0085] The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used herein refers to any solvent, dispersion medium, coating, isotonicity agent, absorption delaying agent, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide supplementary, additional, or enhanced therapeutic functions.

[0019]

[0086] The term "pharmaceutical composition" as used herein refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharma- ceutically acceptable excipients.

[0020]

[0087] "Individual", "patient" or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, most preferably humans. The compounds of the present disclosure may be administered to mammals, such as humans, but also to other mammals, such as animals requiring veterinary treatment, for example, pets (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.) and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammal treated in the methods of the present disclosure is desirably a mammal in need of treatment, for example, for cancer or a blood disorder. "Modulation" includes antagonism (e.g., inhibition), agonism, partial antagonism and / or partial agonism.

[0021]

[0088] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of the present invention that elicits a biological or medical response in a tissue, system or animal, such as a mammal or human, as desired by a researcher, veterinarian, physician or other clinician. The compounds of the present disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount necessary to achieve the desired therapeutic and / or prophylactic effect.

[0022]

[0089] The term "pharmaceutically acceptable salt" as used herein refers to salts of basic groups that may be present in the compounds used in the compositions. Compounds included in the compositions of the present invention that are basic are capable of forming a wide variety of salts with various inorganic and organic acids.

[0023]

[0090] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated.

[0024]

[0091] As used herein, the words "a" and "an" mean one or more, unless otherwise specified. For example, the term "an agent" includes both a single agent and a combination of two or more agents.

[0025]

[0092] When the term "about" is used before a quantitative value, the disclosure also includes the specific quantitative value itself unless otherwise stated. As used herein, the term "about" refers to a ±10% variation from the nominal value unless otherwise indicated or implied. The term "about" means that with respect to the peak at 2θ°, there is an uncertainty in the measurement of 2θ of ±0.5 (expressed in 2θ) or there is an uncertainty in the measurement of 2θ of ±0.2 (expressed in 2θ).

[0026] Crystal morphology

[0093] The present disclosure relates, at least in part, to a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base.

[0027]

[0094] For example, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, anhydrous free base (herein referred to as "Form P"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.6 2θ degrees.

[0028]

[0095] In one embodiment, the crystalline form P of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, anhydrous free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.1 degrees 2θ; In another embodiment, crystalline form P is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks at about 17.2 degrees 2θ, about 17.3 degrees 2θ, about 20.7 degrees 2θ, about 22.6 degrees 2θ, about 23.3 degrees 2θ, about 26.2 degrees 2θ, and / or about 24.5 degrees 2θ. In another embodiment, crystalline form P is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks at about 7.6, 11.9, and 15.3 degrees 2θ. In a further embodiment, crystalline form P is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.6, 11.9, 14.5, 15.3, 20.7, and 22.6 degrees 2θ. In yet another embodiment, crystalline form P is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.6, 11.9, 14.5, 15.3, 16.1, 17.2, 17.3, 20.7, 22.6, 23.3, 26.2, and 24.5 degrees 2θ. For example, a possible crystalline form has the X-ray powder diffraction pattern shown in FIG. 1.In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0029]

[0096] Possible crystalline form P of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, anhydrous free base, can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 252° C. and a peak at about 253° C. Form P can be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0030]

[0097] Possible crystalline form P of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, anhydrous free base, may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.46% by weight up to about 260° C. In certain embodiments, crystalline form P may be characterized by a dynamic vapor sorption (DVS) profile exhibiting a reversible total mass change of about 0.53% by weight at about 2 to about 92% relative humidity (RH) at 25° C. In other embodiments, crystalline form P may be characterized by optical microscopy and exhibits rod and / or plate-like morphology.

[0031]

[0098] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.5 2θ degrees (herein referred to as "Form A").

[0032]

[0099] In one embodiment, the crystalline Form A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 5.9 2θ degrees; an X-ray powder diffraction pattern having a characteristic peak at about 9.3 2θ degrees; an X-ray powder diffraction pattern having a characteristic peak at about 9.5 2θ degrees; an X-ray powder diffraction pattern having a characteristic peak at about 10.0 2θ degrees; and an X-ray powder diffraction pattern having a characteristic peak at about 10.0 2θ degrees. In yet another embodiment, crystalline Form A is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks at about 5.9, 8.5, 9.3, 9.5, 10.0, 10.7, 11.7, 14.4, 18.7, 19.0, 25.8, and 28.4 degrees 2θ. For example, a possible crystalline form has the powder X-ray diffraction pattern shown in Figure 3. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0033]

[0100] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.5 2θ degrees (herein referred to as "Form B").

[0034]

[0101] In one embodiment, the crystalline form B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 5.1 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 9.4 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 9.5 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 10.0 degrees 2θ; and an X-ray powder diffraction pattern having a characteristic peak at about 10.7 degrees 2θ. characterized by an X-ray diffraction pattern, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.5 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.7 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.4 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.7 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.6 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.6 2θ degrees, and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.4 2θ degrees. In yet another embodiment, crystalline form B is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 5.1, 8.5, 9.4, 10.0, 10.7, 11.5, 11.7, 14.4, 15.7, 18.6, 19.8, 20.6, and 21.4 degrees 2θ. For example, a possible crystalline form has the X-ray powder diffraction pattern shown in FIG. 4. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation. In another embodiment, crystalline form B may be characterized by optical microscopy and exhibits a hairy morphology.

[0035]

[0102] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.0 degrees 2θ (herein referred to as "Form C").

[0036]

[0103] In one embodiment, the crystalline form C of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 4.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 5.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11. In yet another embodiment, crystalline Form C is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks at about 4.0, 5.3, 7.6, 9.0, 9.7, 11.2, 12.3, 12.9, 13.7, 14.5, 15.9, and / or 19.0 degrees 2θ. For example, a possible crystalline form has the powder X-ray diffraction pattern shown in Figure 5. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0037]

[0104] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.6 2θ degrees (herein referred to as "Form D").

[0038]

[0105] In one embodiment, crystalline form D of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.3 2θ°, an X-ray powder diffraction pattern having a characteristic peak at about 10.6 2θ°, and / or an X-ray powder diffraction pattern having a characteristic peak at about 12.9 2θ°. In yet another embodiment, crystalline form D is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.3, 8.6, 10.6, and 12.9 2θ°. For example, a possible crystalline form has the X-ray powder diffraction pattern shown in FIG. 6. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0039]

[0106] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate (herein referred to as "Form E"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 4.6 2θ degrees.

[0040]

[0107] In one embodiment, the crystalline form E of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.7 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.1 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.1 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.5 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.3 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.7 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.0 2θ degrees. In yet another embodiment, crystalline form E is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 4.6, 9.3, 11.6, 13.2, 13.5, 13.7, 15.1, 18.1, 18.5, 19.3, 25.7, and 27.0 degrees 2θ. For example, a possible crystalline form has the X-ray powder diffraction pattern shown in Figure 7. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0041]

[0108] Possible crystalline form E of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate, may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 44° C. and a peak at about 58° C., a characteristic endotherm with an onset of about 110° C. and a peak at about 114° C., and a characteristic endotherm with an onset of about 166° C. and a peak at about 177° C. Form E may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0042]

[0109] Possible crystalline form E of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 5.1% by weight up to about 170° C. In certain embodiments, crystalline form E may be characterized by a dynamic vapor sorption (DVS) profile exhibiting a reversible total mass change of about 10.3% by weight at about 2 to about 92% relative humidity (RH) at 25° C. In other embodiments, crystalline form E may be characterized by optical microscopy and exhibits a hairy morphology.

[0043]

[0110] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 4.5 2θ degrees (herein referred to as "Form F").

[0044]

[0111] In one embodiment, crystalline Form F of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern with a characteristic peak at about 7.0 degrees 2θ; an X-ray powder diffraction pattern with a characteristic peak at about 8.2 degrees 2θ; an X-ray powder diffraction pattern with a characteristic peak at about 9.0 degrees 2θ; an X-ray powder diffraction pattern with a characteristic peak at about 9.3 degrees 2θ; and an X-ray powder diffraction pattern with a characteristic peak at about 12. In yet another embodiment, crystalline form F is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks at about 4.5, 7.0, 8.2, 9.0, 9.3, 12.5, 13.5, 15.3, 17.8, 18.7, 22.6, and / or 26.8 degrees 2θ. For example, a possible crystalline form has the powder X-ray diffraction pattern shown in Figure 9. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0045]

[0112] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate (herein referred to as "Form H"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.5 2θ degrees.

[0046]

[0113] In one embodiment, the crystalline form H of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 5.3 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.2 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 10.4 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.4 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about In yet another embodiment, crystalline form H is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks at about 5.3, 7.2, 8.5, 10.4, 12.4, 13.3, 17.0, 19.5, 22.6, 24.5, 26.2, and / or 26.7 degrees 2θ. For example, a possible crystalline form has the powder X-ray diffraction pattern shown in Figure 10. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0047]

[0114] Possible crystalline form H of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate, may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 58° C. and a peak at about 84° C., a characteristic endotherm with an onset of about 63° C. and a peak at about 89° C., and a characteristic endotherm with an onset of about 169° C. and a peak at about 176° C. Form H may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0048]

[0115] Possible crystalline form H of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 6.3% by weight up to about 130° C. In certain embodiments, crystalline form H may be characterized by a dynamic vapor sorption (DVS) profile exhibiting a reversible total mass change of about 7.6% by weight at about 2 to about 92% relative humidity (RH) at 25° C. In other embodiments, crystalline form H may be characterized by optical microscopy and exhibits a hairy morphology.

[0049]

[0116] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.4 2θ degrees (herein referred to as "Form I").

[0050]

[0117] In one embodiment, the crystalline Form I of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 5.2 2θ degrees, an X-ray powder diffraction pattern having a characteristic peak at about 7.0 2θ degrees, an X-ray powder diffraction pattern having a characteristic peak at about 10.4 2θ degrees, and an X-ray powder diffraction pattern having a characteristic peak at about 12.2 2θ degrees. The crystalline form I is characterized by an X-ray diffraction pattern having a characteristic peak at about 13.1 2θ°, an X-ray powder diffraction pattern having a characteristic peak at about 16.8 2θ°, an X-ray powder diffraction pattern having a characteristic peak at about 19.2 2θ°, an X-ray powder diffraction pattern having a characteristic peak at about 20.7 2θ°, an X-ray powder diffraction pattern having a characteristic peak at about 22.3 2θ°, and / or an X-ray powder diffraction pattern having a characteristic peak at about 25.9 2θ°. In yet another embodiment, the crystalline form I is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 5.2, 7.0, 8.4, 10.4, 12.2, 13.1, 16.8, 19.2, 20.7, 22.3, and 25.9 2θ°. For example, a possible crystalline form has the X-ray powder diffraction pattern shown in FIG. 12. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation. In another embodiment, the crystalline form I may be characterized by optical microscopy and exhibits a hairy morphology.

[0051]

[0118] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 4.1 2θ degrees (herein referred to as "Form J").

[0052]

[0119] In one embodiment, the crystalline form J of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.2 2θ degrees, an X-ray powder diffraction pattern having a characteristic peak at about 8.0 2θ degrees, an X-ray powder diffraction pattern having a characteristic peak at about 9.3 2θ degrees, and an X-ray powder diffraction pattern having a characteristic peak at about 12. 13.8 2θ°, about 16.6 2θ°, about 18.4 2θ°, about 23.8 2θ°, about 24.4 2θ°, and / or about 28.3 2θ°. In yet another embodiment, crystalline form J is characterized by an X-ray powder diffraction pattern with at least one or more characteristic peaks at about 4.1, 6.2, 8.0, 9.3, 12.8, 16.6, 18.4, 23.8, 24.4, and 28.3 2θ°. For example, possible crystalline forms have the X-ray powder diffraction pattern shown in FIG. 13. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation. In another embodiment, the crystalline form J may be characterized by optical microscopy and exhibits a hairy morphology.

[0053]

[0120] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.6 2θ degrees (herein referred to as "Form K").

[0054]

[0121] In one embodiment, the crystalline form K of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.4 2θ degrees, an X-ray powder diffraction pattern having a characteristic peak at about 10.5 2θ degrees, an X-ray powder diffraction pattern having a characteristic peak at about 13.6 2θ degrees, and an X-ray powder diffraction pattern having a characteristic peak at about 19.4 2θ degrees. In yet another embodiment, crystalline form K is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks at about 6.4, 9.6, 10.5, 13.6, 19.4, 21.0, 22.4, 23.4, 23.7, 25.2, and / or 26.9 degrees 2θ. For example, a possible crystalline form has the powder X-ray diffraction pattern shown in Figure 14. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0055]

[0122] Possible crystalline form K of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 226° C. and a peak at about 230° C. Form K may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0056]

[0123] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.3 2θ degrees (herein referred to as "Form L").

[0057]

[0124] In one embodiment, the crystalline form L of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.1 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 9.5 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 11.9 degrees 2θ, and an X-ray powder diffraction pattern having a characteristic peak at about 12.2 degrees 2θ. In yet another embodiment, crystalline form L is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks at about 6.7, 8.3, 9.1, 9.5, 11.9, 12.2, 14.3, 16.2, 20.5, 21.9, 23.1, and 25.5 degrees 2θ. For example, a possible crystalline form has the powder X-ray diffraction pattern shown in Figure 16. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0058]

[0125] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.6 2θ degrees (herein referred to as "Form M").

[0059]

[0126] In one embodiment, the crystalline form M of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.8 2θ degrees, an X-ray powder diffraction pattern having a characteristic peak at about 8.3 2θ degrees, an X-ray powder diffraction pattern having a characteristic peak at about 12.7 2θ degrees, and an X-ray powder diffraction pattern having a characteristic peak at about 13.4 2θ degrees. In yet another embodiment, crystalline form M is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks at about 6.4, 6.8, 8.3, 9.6, 12.7, 13.4, 14.3, 17.3, 19.6, 20.0, 21.0, 23.9, and 26.5 degrees 20. For example, a possible crystalline form has the powder X-ray diffraction pattern shown in Figure 17. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0060]

[0127] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.4 2θ degrees (herein referred to as "Form N").

[0061]

[0128] In one embodiment, the crystalline form N of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 5.6 2θ degrees, an X-ray powder diffraction pattern having a characteristic peak at about 6.1 2θ degrees, an X-ray powder diffraction pattern having a characteristic peak at about 6.9 2θ degrees, an X-ray powder diffraction pattern having a characteristic peak at about 7.2 2θ degrees, and an X-ray powder diffraction pattern having a characteristic peak at about 11.8 2θ degrees. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.7 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.5 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.3 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.8 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.9 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.9 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.7 2θ degrees. In yet another embodiment, the crystalline form N is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 5.6, 6.1, 6.9, 7.2, 8.4, 11.8, 13.7, 14.5, 17.3, 19.8, 21.9, 24.9, and 25.7 degrees 2θ. For example, a possible crystalline form has the X-ray powder diffraction pattern shown in Figure 18. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0062]

[0129] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.1 degrees 2θ (herein referred to as "Form O").

[0063]

[0130] In one embodiment, crystalline form O of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.0 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 10.6 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 11.3 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 15.8 degrees 2θ; and an X-ray powder diffraction pattern having a characteristic peak at about 16.3 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.6 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.5 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.3 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.7 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.9 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.1 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.7 2θ degrees. In yet another embodiment, crystalline form O is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 9.0, 10.6, 11.3, 14.1, 15.8, 16.3, 17.6, 19.5, 21.3, 22.7, 22.9, 25.1, and 28.7 degrees 2θ. For example, a possible crystalline form has the X-ray powder diffraction pattern shown in Figure 19. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0064]

[0131] Possible crystalline form O of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 166° C. and a peak at about 172° C., and a characteristic endotherm with an onset of about 196° C. and a peak at about 204° C. Form O may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0065]

[0132] Crystallinity and solid form purity were maintained throughout preliminary wet milling testing (ball mill, milled with 1 volume of water for 30 seconds). In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by a powder X-ray diffraction pattern with a characteristic peak at about 7.7 2θ° (herein referred to as "Form Q").

[0066]

[0133] In one embodiment, the crystalline form Q of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 4.8 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 5.8 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.6 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.6 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13. In yet another embodiment, crystalline form Q is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 4.8, 5.8, 7.7, 9.6, 11.6, 13.8, 14.7, 19.9, 21.5, 21.5, 21.5° 2θ, 21.6, 21.7, 21.8, 21.9, 22.1, 22.2, and / or 22.4° 2θ. For example, a possible crystalline form has the powder X-ray diffraction pattern shown in Figure 21. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0067]

[0134] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.5 2θ degrees (herein referred to as "Form R").

[0068]

[0135] In one embodiment, the crystalline form R of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 10.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.8 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16. In yet another embodiment, crystalline form R is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks at about 7.5, 8.5, 10.1, 12.8, 14.8, 15.6, 16.9, 17.4, 18.3, 19.5, 20.0, and / or 21.8 degrees 2θ. For example, a possible crystalline form has the powder X-ray diffraction pattern shown in Figure 22. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0069]

[0136] Possible crystalline form R of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 148° C. and a peak at about 152° C., and a characteristic endotherm with an onset of about 241° C. and a peak at about 251° C. Form R may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0070]

[0137] Possible crystalline form R of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a first stage mass loss of about 0.87 wt % up to about 150° C., a second stage mass loss of about 3.1 wt % from about 150° C. to about 200° C., and a third stage mass loss of about 11.7 wt % from about 200° C. to about 240° C.

[0071]

[0138] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 5.0 degrees 2θ (herein referred to as "Form S").

[0072]

[0139] In one embodiment, crystalline form S of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern with a characteristic peak at about 5.9 2θ degrees, an X-ray powder diffraction pattern with a characteristic peak at about 8.0 2θ degrees, an X-ray powder diffraction pattern with a characteristic peak at about 9.7 2θ degrees, and / or an X-ray powder diffraction pattern with a characteristic peak at about 11.8 2θ degrees. In yet another embodiment, crystalline form S is characterized by an X-ray powder diffraction pattern with at least one or more characteristic peaks at about 5.0, 5.9, 8.0, 9.7, and 11.8 2θ degrees. For example, a possible crystalline form has the powder X-ray diffraction pattern shown in Figure 24. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0073]

[0140] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.7 2θ degrees (herein referred to as "Form T").

[0074]

[0141] In one embodiment, the crystalline form T of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.0 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 10.3 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 11.8 degrees 2θ, and an X-ray powder diffraction pattern having a characteristic peak at about 14.1 degrees 2θ. In yet another embodiment, crystalline form T is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.0, 8.7, 10.3, 11.8, 14.1, 17.0, 20.9, 22.4, 24.5, 25.5, and 27.9 degrees 2θ. For example, a possible crystalline form has the powder X-ray diffraction pattern shown in Figure 25. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0075]

[0142] Possible crystalline form T of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 83° C. and a peak at about 84° C., and a characteristic endotherm with an onset of about 249° C. and a peak at about 251° C. Form T may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0076]

[0143] Possible crystalline form T of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a first stage mass loss of about 13.8% by weight up to about 85° C. In other embodiments, crystalline form T may be characterized by optical microscopy and exhibits a needle and / or rod morphology.

[0077]

[0144] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.2 2θ degrees (herein referred to as "Form U").

[0078]

[0145] In an embodiment, the crystalline form U of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 10.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.3 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.5 degrees 2θ. In yet another embodiment, crystalline form U is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.2, 6.9, 7.6, 9.0, 10.5, 12.3, and 14.5 degrees 2θ. For example, a possible crystalline form has the X-ray powder diffraction pattern shown in Figure 27. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0079]

[0146] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.3 2θ degrees (herein referred to as "Form V").

[0080]

[0147] In one embodiment, crystalline Form V of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.0 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 8.0 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 10.8 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 12.0 degrees 2θ; and an X-ray powder diffraction pattern having a characteristic peak at about 14.0 degrees 2θ. In yet another embodiment, crystalline Form V is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks at about 6.0, 8.0, 10.8, 12.0, 15.6, 15.9, 16.8, 18.3, 19.7, 20.9, 21.0, and / or 26.3 2θ degrees. For example, a possible crystalline form has the powder X-ray diffraction pattern shown in Figure 28. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0081]

[0148] In another embodiment, disclosed herein is a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.6 2θ degrees (herein referred to as "Form W").

[0082]

[0149] In an embodiment, the crystalline form W of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 4.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.3 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.0 degrees 2θ. In yet another embodiment, crystalline form W is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 4.3, 8.6, 12.9, 15.2, 23.3, and 26.0 degrees 2θ. For example, a possible crystalline form has the X-ray powder diffraction pattern shown in Figure 29. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0083]

[0150] In another embodiment, disclosed herein is a substantially amorphous form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base.

[0084]

[0151] In further embodiments, disclosed herein is a pharmaceutical composition comprising the disclosed crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, and a pharmaceutically acceptable excipient. For example, disclosed herein is a pharmaceutical composition comprising the disclosed crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, and a pharmaceutically acceptable excipient. For example, disclosed herein is a pharmaceutical composition formed from (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, crystalline form P. In certain embodiments, the disclosed pharmaceutical compositions can be formulations for oral administration.

[0085]

[0152] In yet another embodiment, disclosed herein is a pharmaceutical composition comprising the disclosed amorphous form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, and a pharma- ceutically acceptable excipient.

[0086]

[0153] In one embodiment, disclosed herein is a drug substance comprising at least a detectable amount of the disclosed crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base. In another embodiment, disclosed herein is a drug substance comprising a substantially pure crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base. For example, disclosed herein is a drug substance comprising a substantially pure crystalline form P of the free base, (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine.

[0087]

[0154] Also disclosed herein are pharma- ceutically acceptable salts of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine. In some embodiments, the salt may be selected from the group consisting of, for example, benzenesulfonate, citrate, fumarate, maleate, L-malate, methanesulfonate, phosphate, pyruvate, sulfate, L-tartrate, toluenesulfonate, and hydrates and solvates thereof. In some embodiments, the salt may be, for example, benzenesulfonate. In some embodiments, the salt may be, for example, citrate. In some embodiments, the salt may be, for example, fumarate. In some embodiments, the salt may be, for example, hydrochloride. In some embodiments, the salt may be, for example, L-malate. In some embodiments, the salt may be, for example, a methanesulfonate salt. In some embodiments, the salt may be, for example, a phosphate salt. In some embodiments, the salt may be, for example, a pyruvate salt. In some embodiments, the salt may be, for example, a sulfate salt. In some embodiments, the salt may be, for example, an L-tartrate salt. In some embodiments, the salt may be, for example, a toluenesulfonate salt.

[0088]

[0155] In further embodiments, disclosed herein are pharmaceutical compositions comprising the disclosed salts of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine and pharma- ceutical acceptable excipients. For example, disclosed herein are pharmaceutical compositions formed from the disclosed salts of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine. In some embodiments, the disclosed pharmaceutical compositions are formulations for oral administration.

[0089]

[0156] In one embodiment, disclosed herein is a drug substance comprising at least a detectable amount of the disclosed salt of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine. In another embodiment, disclosed herein is a drug substance comprising a substantially pure salt of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine.

[0090]

[0157] Further disclosed herein is a crystalline pharma- ceutically acceptable salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine. In some embodiments, the crystalline salt form may be selected from the group consisting of, for example, benzenesulfonate, citrate, fumarate, hydrochloride, maleate, L-malate, methanesulfonate, phosphate, pyruvate, sulfate, L-tartrate, and toluenesulfonate, and crystalline hydrates and solvates thereof. In some embodiments, the crystalline salt form may be, for example, benzenesulfonate. In some embodiments, the crystalline salt form may be, for example, citrate. In some embodiments, the crystalline salt form may be, for example, fumarate. In some embodiments, the crystalline salt form may be, for example, hydrochloride. In some embodiments, the crystalline salt form may be, for example, an L-malate salt. In some embodiments, the crystalline salt form may be, for example, a methanesulfonate salt. In some embodiments, the crystalline salt form may be, for example, a phosphate salt. In some embodiments, the crystalline salt form may be, for example, a pyruvate salt. In some embodiments, the crystalline salt form may be, for example, a sulfate salt. In some embodiments, the crystalline salt form may be, for example, an L-tartrate salt. In some embodiments, the crystalline salt form may be, for example, a toluenesulfonate salt.

[0091]

[0158] For example, disclosed herein is a pharma- ceutically acceptable crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, benzenesulfonate (herein referred to as "Form 1-A"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.5 2θ degrees.

[0092]

[0159] In one embodiment, the crystalline salt Form 1-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, benzenesulfonate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 5.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.0 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.6 degrees 2θ. , characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.6 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.3 degrees 2θ. In yet another embodiment, the crystalline salt form 1-A is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 5.1, 6.5, 6.8, 7.0, 9.6, 12.1, 14.8, 15.1, 15.5, 16.4, 18.6, and 21.3 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 30. In one embodiment, the X-ray powder diffraction pattern of the crystalline salt form was obtained using Cu Kα radiation.

[0093]

[0160] In another embodiment, disclosed herein is a crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, benzenesulfonate (herein referred to as "Form 1-B"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.7 2θ degrees.

[0094]

[0161] In one embodiment, the crystalline salt Form 1-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, benzenesulfonate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 5.3 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.2 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.2 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 10.0 2θ degrees. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 10.6 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.3 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.0 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.6 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.0 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.2 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.1 2θ degrees. In yet another embodiment, the crystalline salt form 1-B is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 5.3, 6.2, 6.7, 8.2, 10.0, 10.6, 12.3, 14.0, 15.6, 16.0, 16.2, and 22.1 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 31. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0095]

[0162] Possible crystalline Form 1-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, benzenesulfonate, may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 33° C. and a peak at about 71° C., a characteristic endotherm with an onset of about 120° C. and a peak at about 133° C., and a characteristic endotherm with an onset of about 154° C. and a peak at about 159° C. Form 1-B may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0096]

[0163] In another embodiment, disclosed herein is a crystalline pharma- ceutically acceptable salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, citrate salt (herein referred to as "Form 2-A"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.0 degrees 2θ.

[0097]

[0164] In one embodiment, the crystalline salt Form 2-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, citrate, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 4.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 10.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.4 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.5 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.7 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.1 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.1 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.3 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.0 2θ degrees. In yet another embodiment, the crystalline salt form 2-A is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 4.7, 7.0, 7.9, 9.1, 10.2, 11.4, 12.5, 13.7, 14.1, 15.1, 18.3, and 19.0 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 33. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0098]

[0165] In another embodiment, disclosed herein is a crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, citrate salt (herein referred to as "Form 2-B"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.2 2θ degrees.

[0099]

[0166] In one embodiment, the crystalline salt form 2-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, citrate, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.7 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.9 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.3 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.2 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.5 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.8 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.0 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.4 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.5 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.3 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.5 2θ degrees. In yet another embodiment, the crystalline salt form 2-B is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.7, 7.9, 9.3, 11.2, 12.5, 13.8, 15.2, 17.0, 18.4, 19.5, 22.3, and 28.5 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 34. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0100]

[0167] In another embodiment, disclosed herein is a crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, citrate salt (herein referred to as "Form 2-C"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.0 degrees 2θ.

[0101]

[0168] In one embodiment, the crystalline salt form 2-C of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, citrate, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.6 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.3 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.9 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.2 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.2 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.1 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 29.0 2θ degrees. In yet another embodiment, the crystalline salt form 2-B is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.7, 7.9, 9.1, 12.5, 13.6, 14.3, 15.0, 16.9, 18.2, 19.2, 22.1, and 29.0 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 35. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0102]

[0169] Possible crystalline form 2-C of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, citrate salt may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 33° C. and a peak at about 60° C., a characteristic endotherm with an onset of about 96° C. and a peak at about 116° C., a characteristic endotherm with an onset of about 160° C. and a peak at about 169° C., and a characteristic endotherm with an onset of about 141° C. and a peak at about 177° C. Form 2-C may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0103]

[0170] In another embodiment, disclosed herein is a crystalline pharma- ceutically acceptable salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, fumarate (herein referred to as "Form 3-A"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.1 degrees 2θ.

[0104]

[0171] In one embodiment, the crystalline salt Form 3-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, fumarate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.9 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.9 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.1 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.4 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.5 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.8 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.4 2θ degrees. In yet another embodiment, the crystalline salt form 3-A is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.1, 8.2, 14.3, 16.5, 18.0, 18.9, 21.9, 22.1, 22.4, 24.5, 24.8, and 25.4 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 37. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0105]

[0172] Possible crystalline Form 3-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, fumarate salt may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 237° C. and a peak at about 241° C. Form 3-A may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0106]

[0173] In another embodiment, disclosed herein is a pharma- ceutically acceptable crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride (herein referred to as "Form 5-A"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.8 2θ degrees.

[0107]

[0174] In one embodiment, the crystalline salt form 5-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 5.0 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 8.1 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 9.3 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 12.2 degrees 2θ; and an X-ray powder diffraction pattern having a characteristic peak at about 14.2 degrees 2θ. In yet another embodiment, crystalline salt Form 5-A is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks at about 5.0, 7.8, 8.1, 9.3, 12.2, 13.5, 13.9, 14.1, 19.3, 20.3, 21.3, and / or 25.2 2θ degrees. For example, a contemplated crystalline salt form has the powder X-ray diffraction pattern shown in Figure 39. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0108]

[0175] Possible crystalline form 5-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride salt may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 3.1% by weight up to about 110° C. and an additional mass loss of about 7.6% by weight from about 110° C. to about 195° C. In certain embodiments, crystalline form 5-A may be characterized by a dynamic water vapor sorption (DVS) profile exhibiting a total reversible mass change of about 3.1% by weight at about 2 to about 92% relative humidity (RH) at 25° C. In further embodiments, crystalline form 5-A may be characterized by a Karl Fischer titration profile exhibiting a water content of about 10.7%. In other embodiments, crystalline form 5-A may be characterized by optical microscopy and exhibits rod-like or plate-like morphology.

[0109]

[0176] In another embodiment, disclosed herein is a crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride (herein referred to as "Form 5-B"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.1 2θ degrees.

[0110]

[0177] In one embodiment, the crystalline salt form 5-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.5 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.0 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.2 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.8 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.9 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.7 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.6 2θ degrees. In yet another embodiment, the crystalline salt form 5-B is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.4, 9.1, 9.9, 11.7, 14.2, 17.5, 20.0, 21.2, 21.8, 23.9, 25.7, and 27.6 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 40. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0111]

[0178] Possible crystalline form 5-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride salt, may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 68° C. and a peak at about 82° C., a characteristic endotherm with an onset of about 111° C. and a peak at about 130° C., and a characteristic endotherm with an onset of about 193° C. and a peak at about 211° C. Form 5-B may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0112]

[0179] In another embodiment, disclosed herein is a crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride (herein referred to as "Form 5-C"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.5 2θ degrees.

[0113]

[0180] In one embodiment, the crystalline salt form 5-C of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 10.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.1 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.5 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.4 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.9 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.4 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.0 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.9 2θ degrees. In yet another embodiment, the crystalline salt form 5-C is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 10.7, 11.8, 12.9, 16.2, 18.1, 20.5, 21.5, 22.4, 23.9, 26.4, 27.0, and 28.9 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 42. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0114]

[0181] Possible crystalline form 5-C of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride salt, may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 140° C. and a peak at about 145° C., and a characteristic endotherm with an onset of about 213° C. and a peak at about 230° C. Form 5-C may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0115]

[0182] In another embodiment, disclosed herein is a crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride (herein referred to as "Form 5-D"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.4 2θ degrees.

[0116]

[0183] In one embodiment, the crystalline salt form 5-D of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.8 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 12.7 degrees 2θ, and an X-ray powder diffraction pattern having a characteristic peak at about 14.0 degrees 2θ. The crystalline salt form 5-D is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.0 2θ degrees, an X-ray powder diffraction pattern having a characteristic peak at about 17.0 2θ degrees, an X-ray powder diffraction pattern having a characteristic peak at about 22.9 2θ degrees, an X-ray powder diffraction pattern having a characteristic peak at about 25.6 2θ degrees, and / or an X-ray powder diffraction pattern having a characteristic peak at about 26.0 2θ degrees. In yet another embodiment, the crystalline salt form 5-D is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.8, 8.4, 12.7, 14.0, 15.0, 17.0, 22.9, 25.6, and 26.0 2θ degrees. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 44. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0117]

[0184] In another embodiment, disclosed herein is a crystalline pharma- ceutically acceptable salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, maleate (herein referred to as "Form 7-A"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.5 2θ degrees.

[0118]

[0185] In one embodiment, the crystalline salt form 7-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, maleate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.5 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.9 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.7 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.3 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.9 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.2 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.5 2θ degrees. In yet another embodiment, the crystalline salt form 7-A is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.2, 8.3, 14.3, 14.9, 16.5, 18.9, 21.5, 22.7, 25.3, 25.9, 27.2, and 27.5 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 45. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0119]

[0186] Possible crystalline form 7-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, maleate salt may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 215° C. and a peak at about 221° C., and a characteristic endotherm with an onset of about 216° C. and a peak at about 225° C. Form 7-A may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0120]

[0187] In another embodiment, disclosed herein is a pharma- ceutically acceptable crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-malate (herein referred to as "Form 8-A"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.0 degrees 2θ.

[0121]

[0188] In one embodiment, the crystalline salt form 8-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-malate, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.3 degrees 2θ. , characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.6 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.0 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.6 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.0 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.7 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.5 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.3 2θ degrees. In yet another embodiment, the crystalline salt form 8-A is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.3, 8.3, 11.0, 14.3, 15.0, 16.6, 19.0, 21.6, 22.0, 24.7, 25.5, and 27.3 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 47. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0122]

[0189] Possible crystalline Form 8-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-malate salt may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 177° C. and a peak at about 201° C., a characteristic endotherm with an onset of about 186° C. and a peak at about 207° C., a characteristic endotherm with an onset of about 205° C. and a peak at about 211° C., and a characteristic endotherm with an onset of about 208° C. and a peak at about 216° C. Form 8-A may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0123]

[0190] In another embodiment, disclosed herein is a crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-malate (herein referred to as "Form 8-B"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 5.9 2θ degrees.

[0124]

[0191] In one embodiment, the crystalline salt form 8-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-malate, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.3 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.6 degrees 2θ. , characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.2 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.1 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.2 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.9 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.8 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.1 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.4 2θ degrees. In yet another embodiment, the crystalline salt form 8-B is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 5.9, 9.1, 11.6, 16.3, 17.6, 18.2, 19.1, 21.2, 22.9, 23.8, 27.1, and 28.4 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 49. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0125]

[0192] Possible crystalline form 8-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-malate salt may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 189° C. and a peak at about 192° C., and a characteristic endotherm with an onset of about 186° C. and a peak at about 202° C. Form 8-B may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0126]

[0193] Possible crystalline form 8-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-malate salt may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.46% by weight up to about 175° C. In certain embodiments, crystalline form 8-B may be characterized by a dynamic water vapor sorption (DVS) profile exhibiting a reversible total mass change of about 0.82% by weight at 25° C. and from about 2 to about 92% relative humidity (RH).

[0127]

[0194] In another embodiment, disclosed herein is a crystalline pharma- ceutically acceptable salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, methanesulfonate (herein referred to as "Form 9-A"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.5 2θ degrees.

[0128]

[0195] In one embodiment, the crystalline salt Form 9-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, methanesulfonate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 4.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 5.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.5 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.1 degrees 2θ. , characterized by an X-ray powder diffraction pattern having a characteristic peak at about 10.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.1 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.5 degrees 2θ. In yet another embodiment, the crystalline salt form 9-A is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 4.5, 5.4, 7.5, 9.1, 9.5, 10.1, 14.7, 15.0, 15.7, 18.0, 20.1, and 21.5 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 51. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0129]

[0196] In another embodiment, disclosed herein is a crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, methanesulfonate (herein referred to as "Form 9-B"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.2 2θ degrees.

[0130]

[0197] In one embodiment, the crystalline salt form 9-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, methanesulfonate, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.7 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.7 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.7 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.2 2θ degrees. and / or is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.9 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.3 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.8 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.4 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.0 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.5 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.9 2θ degrees. In yet another embodiment, the crystalline salt form 9-B is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 8.2, 8.7, 13.7, 14.7, 16.2, 18.9, 22.3, 22.8, 24.4, 27.0, 27.5, and 28.9 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 52. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0131]

[0198] Possible crystalline form 9-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, methanesulfonate salt may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 51° C. and a peak at about 74° C., and a characteristic endotherm with an onset of about 177° C. and a peak at about 187° C. Form 9-B may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0132]

[0199] In another embodiment, disclosed herein is a crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, methanesulfonate (herein referred to as "Form 9-C"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.5 2θ degrees.

[0133]

[0200] In one embodiment, the crystalline salt form 9-C of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, methanesulfonate, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 4.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.2 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 10.2 degrees 2θ. , characterized by an X-ray powder diffraction pattern having a characteristic peak at about 10.9 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.8 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.0 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.9 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.2 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.4 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.8 2θ degrees. In yet another embodiment, the crystalline salt form 9-C is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 4.5, 7.6, 9.2, 9.5, 10.2, 10.9, 14.8, 15.0, 15.9, 18.2, 20.4, and 21.8 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 54. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0134]

[0201] In another embodiment, disclosed herein is a crystalline pharma- ceutically acceptable salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, phosphate (herein referred to as "Form 10-A"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.3 degrees 2θ.

[0135]

[0202] In one embodiment, the crystalline salt form 10-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, phosphate, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 10.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 10.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.5 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.7 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.4 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.5 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.2 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.9 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.8 2θ degrees. In yet another embodiment, the crystalline salt form 10-A is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.2, 8.5, 10.2, 10.8, 11.5, 12.3, 15.7, 18.4, 20.5, 21.2, 22.9, and 25.8 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 55. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0136]

[0203] Possible crystalline form 10-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, phosphate salt may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 282° C. and a peak at about 290° C., and a characteristic endotherm with an onset of about 283° C. and a peak at about 294° C. Form 10-A may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0137]

[0204] Possible crystalline form 10-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, phosphate salt may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.22% by weight. In certain embodiments, crystalline form 10-A may be characterized by a dynamic vapor sorption (DVS) profile exhibiting a reversible total mass change of about 1.4% by weight at about 2 to about 92% relative humidity (RH) at 25°C.

[0138]

[0205] In another embodiment, disclosed herein is a crystalline pharma- ceutically acceptable salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, pyruvate (herein referred to as "Form 11-A"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.5 2θ degrees.

[0139]

[0206] In one embodiment, the crystalline salt Form 11-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, pyruvate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 4.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 4.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.2 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.6 degrees 2θ. , an X-ray powder diffraction pattern having a characteristic peak at about 9.1 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 9.9 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 11.4 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 13.1 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 14.5 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 14.7 degrees 2θ, and / or an X-ray powder diffraction pattern having a characteristic peak at about 17.2 degrees 2θ. In yet another embodiment, crystalline salt form 11-A is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 4.4, 4.9, 7.2, 7.5, 8.6, 9.1, 9.9, 11.4, 13.1, 14.5, 14.7, and 17.2 degrees 2θ. For example, a contemplated crystalline salt form has the powder X-ray diffraction pattern shown in Figure 57. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0140]

[0207] Possible crystalline form 11-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, pyruvate, may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 76° C. and a peak at about 88° C., a characteristic endotherm with an onset of about 134° C. and a peak at about 142° C., and a characteristic endotherm with an onset of about 149° C. and a peak at about 157° C. Form 11-A may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0141]

[0208] In another embodiment, disclosed herein is a pharma- ceutically acceptable crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, sulfate (herein referred to as "Form 12-A"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 5.9 2θ degrees.

[0142]

[0209] In one embodiment, the crystalline salt form 12-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, sulfate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.6 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.9 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.2 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.6 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 10.0 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.0 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.0 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.0 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.0 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.0 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.0 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.0 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.0 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.0 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.0 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.0 2θ degrees, characterized by an X-ray characterized by an X-ray powder diffraction pattern having a characteristic peak at about 1.8 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.7 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.3 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.1 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.7 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.9 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.6 2θ degrees. In yet another embodiment, the crystalline salt form 12-A is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 5.9, 6.6, 7.9, 8.2, 9.6, 11.8, 14.7, 15.3, 17.1, 17.7, 18.9, and 22.6 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 59. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0143]

[0210] Possible crystalline form 12-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, sulfate, may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 48° C. and a peak at about 81° C., a characteristic endotherm with an onset of about 169° C. and a peak at about 185° C., and a characteristic endotherm with an onset of about 229° C. and a peak at about 241° C. Form 12-A may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0144]

[0211] In another embodiment, disclosed herein is a crystalline pharma- ceutically acceptable salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-tartrate (herein referred to as "Form 13-A"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.9 2θ degrees.

[0145]

[0212] In one embodiment, the crystalline salt form 13-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-tartrate, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.1 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.2 degrees 2θ. , characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.3 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.5 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.6 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.1 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.6 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.9 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.2 2θ degrees. In yet another embodiment, the crystalline salt form 13-A is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 8.0, 8.7, 11.1, 14.2, 15.9, 17.3, 19.5, 21.6, 23.1, 23.6, 26.9, and 28.2 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 61. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0146]

[0213] Possible crystalline form 13-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-tartrate salt may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 213° C. and a peak at about 222° C. Form 13-A may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0147]

[0214] Possible crystalline form 13-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-tartrate salt may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.63% by weight up to about 185° C. In certain embodiments, crystalline form 13-A may be characterized by a dynamic vapor sorption (DVS) profile exhibiting a reversible total mass change of about 0.97% by weight at 25° C. and from about 2 to about 92% relative humidity (RH).

[0148]

[0215] In another embodiment, disclosed herein is a crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-tartrate (herein referred to as "Form 13-B"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.9 2θ degrees.

[0149]

[0216] In one embodiment, the crystalline salt form 13-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-tartrate, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.8 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.8 degrees 2θ. , characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.8 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.2 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.1 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.1 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.3 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.0 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.7 2θ degrees. In yet another embodiment, the crystalline salt form 13-B is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.1, 8.7, 11.8, 16.9, 20.8, 21.8, 22.2, 24.1, 25.1, 25.3, 27.0, and 27.7 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 63. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0150]

[0217] Possible crystalline form 13-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-tartrate salt, may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 89° C. and a peak at about 115° C., a characteristic endotherm with an onset of about 157° C. and a peak at about 167° C., and a characteristic endotherm with an onset of about 181° C. and a peak at about 195° C. Form 13-B may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0151]

[0218] In another embodiment, disclosed herein is a pharma- ceutically acceptable crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, toluenesulfonate (herein referred to as "Form 14-A"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.5 2θ degrees.

[0152]

[0219] In one embodiment, the crystalline salt form 14-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, toluenesulfonate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 4.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.7 degrees 2θ. and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.8 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.5 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 10.3 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.3 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.3 2θ degrees; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.9 2θ degrees; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.2 2θ degrees. In yet another embodiment, the crystalline salt form 14-A is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 4.4, 6.1, 6.4, 6.7, 8.8, 9.5, 10.3, 15.3, 17.5, 21.3, 21.9, and 27.2 degrees 2θ. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 65. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0153]

[0220] In another embodiment, disclosed herein is a crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, toluenesulfonate (herein referred to as "Form 14-B"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.7 degrees 2θ.

[0154]

[0221] In one embodiment, the crystalline salt form 14-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, toluenesulfonate, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.8 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 12.9 degrees 2θ, and an X-ray powder diffraction pattern having a characteristic peak at about 15.3 degrees 2θ. 66, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.2 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.4 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.4 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.7 2θ degrees, and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.9 2θ degrees. In yet another embodiment, the crystalline salt form 13-B is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.8, 7.7, 12.9, 15.3, 17.2, 21.4, 22.4, 24.7, and 25.9 2θ degrees. For example, a contemplated crystalline salt form has the X-ray powder diffraction pattern shown in Figure 66. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0155]

[0222] In further embodiments, disclosed herein is a pharmaceutical composition comprising the disclosed crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine and a pharmaceutically acceptable excipient. For example, disclosed herein is a pharmaceutical composition formed from the disclosed crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine. In some embodiments, the disclosed pharmaceutical composition is a formulation for oral administration.

[0156]

[0223] In one embodiment, disclosed herein is a drug substance comprising at least a detectable amount of the disclosed crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine. In another embodiment, disclosed herein is a drug substance comprising a substantially pure crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine.

[0157] composition

[0224] Another aspect of the present disclosure provides pharmaceutical compositions comprising the crystalline compounds disclosed herein formulated together with a pharma- ceutically acceptable excipient. In particular, the present disclosure provides pharmaceutical compositions comprising the crystalline compounds disclosed herein formulated together with one or more pharma- ceutically acceptable excipients. These formulations include those suitable for oral, topical (e.g., transdermal), buccal, intraocular, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable administration form in any given case will depend on the extent and severity of the condition being treated and the nature of the specific compound being used. For example, the disclosed compositions may be formulated as a unit dose and / or may be formulated for oral, subcutaneous, or intravenous administration.

[0158]

[0225] Exemplary pharmaceutical compositions of the present disclosure may be used in the form of pharmaceutical preparations, for example, in solid, semi-solid or liquid form, containing one or more of the compounds of the present disclosure as active ingredients in a mixture with organic or inorganic excipients or excipients suitable for external, enteral or parenteral application. The active ingredients may be formulated with conventional non-toxic pharmaceutically acceptable excipients for, for example, tablets, pellets, capsules, suppositories, liquids, emulsions, suspensions, and any other forms suitable for use. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0159]

[0226] To prepare solid compositions such as tablets, the main active ingredient can be mixed with pharmaceutical excipients, such as conventional tableting ingredients, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a homogenous mixture of the compound of the present disclosure, or a non-toxic pharma-ceutically acceptable salt thereof. When these preformulation compositions are referred to as homogenous, it is meant that the active ingredient is evenly dispersed throughout the composition, such that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0160]

[0227] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the compositions of the invention may be formulated with one or more pharma- ceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as agar-agar. , calcium carbonate, potato or tapioca starch, alginic acid, some silicates, and sodium carbonate; (5) solution retarders, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents, such as acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the composition may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

[0161]

[0228] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents or dispersants. Molded tablets can be made by molding a mixture of the composition of the present invention moistened with an inert liquid diluent in a suitable machine. Tablets, as well as other solid dosage forms such as dragees, capsules, pills and granules, can be optionally segmented or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art.

[0162]

[0229] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders.Liquid dosage forms for oral administration include pharma-ceutically acceptable emulsions, microemulsions, solutions, suspensions, nanosuspensions, syrups and elixirs.In addition to the compositions of the present invention, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0163]

[0230] Suspensions may contain, in addition to the compositions of this invention, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0164]

[0231] Formulations for rectal or vaginal administration may be presented as suppositories, which may be prepared by mixing the compositions of the present invention with one or more suitable non-irritating excipients or excipients including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which are solid at room temperature but liquid at body temperature and therefore will melt in the body cavity and release the active agent.

[0165]

[0232] Dosage forms for transdermal administration of the compositions of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredient may be mixed under sterile conditions with a pharma- ceutically acceptable excipient, and with any preservatives, buffers, or propellants which may be required.

[0166]

[0233] The ointments, pastes, creams and gels may contain, in addition to the compositions of the present invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0167]

[0234] Powders and sprays can contain, in addition to the compositions of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0168]

[0235] The compositions and compounds of the present disclosure may alternatively be administered by aerosol. This may be accomplished by preparing an aqueous aerosol, liposomal formulation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension may be used. An ultrasonic nebulizer may be used to minimize exposure of the agent to shear, which may cause degradation of the compounds contained in the compositions of the present invention. Typically, aqueous aerosols are made by formulating an aqueous solution or suspension of the compositions of the present invention together with conventional pharma- ceutically acceptable excipients and stabilizers. Excipients and stabilizers vary according to the requirements of the particular compositions of the present invention, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycols), innocuous proteins such as serum albumin, sorbitan esters, amino acids such as oleic acid, lecithin, glycine, buffers, salts, sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0169]

[0236] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include the compositions of the present invention in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately prior to use.

[0170]

[0237] Examples of suitable aqueous and non-aqueous excipients that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate, and cyclodextrin.Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersion, and by using surfactants.For example, the crystalline forms provided herein can be milled to obtain a specific particle size, and in at least some embodiments, such crystalline forms can remain substantially stable when milled.

[0171]

[0238] The amount of the crystalline compound described herein in the formulation may vary according to factors such as individual's condition, age, sex, and weight. The dosage regimen may be adjusted to provide optimal therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the requirements of the therapeutic situation. For ease of administration and uniformity of administration, it is particularly advantageous to formulate parenteral compositions in dosage unit form. As used herein, dosage unit form refers to a physically discrete unit suitable as a unitary administration for the mammalian subject to be treated; each unit contains a predetermined amount of the active crystalline compound calculated to produce the desired therapeutic effect together with the necessary pharmaceutical carrier.

[0172]

[0239] The specifications for the dosage unit forms of the present disclosure are influenced by and directly dependent on (a) the unique characteristics of the crystalline compound selected and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such active crystalline compounds for the treatment of hypersensitivity in an individual.

[0173]

[0240] The disclosed compositions can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable for high drug concentration. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. In many cases, it is suitable to include an isotonic agent in the composition, for example, sugar, polyalcohol, for example, mannitol, sorbitol, or sodium chloride. Prolonged absorption of an injectable composition can be brought about by including an agent that delays absorption, for example, monostearate salts and gelatin in the composition.

[0174]

[0241] The disclosed crystalline compounds can be administered in sustained release formulations, for example in compositions containing sustained release polymers. The crystalline compounds can be prepared with carriers that prevent rapid release of the compounds, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and polylactic-polyglycolic acid copolymers (PLG). Many methods for the preparation of such formulations are generally known to those skilled in the art.

[0175]

[0242] According to an alternative embodiment of the present disclosure, the disclosed crystalline compounds may be formulated with one or more additional compounds that enhance the solubility of the compound.

[0176] method

[0243] In certain embodiments, the disclosure provides a method of treating a disease or disorder associated with regulation of embryonic ectoderm development (EED) in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed crystalline compound, e.g., (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, a disclosed crystalline form of the free base, e.g., a disclosed crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine. In other embodiments, the disclosure provides a method of treating a disease or disorder associated with regulation of embryonic ectoderm development (EED) in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising an effective amount of a disclosed crystalline compound, e.g., (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, a disclosed crystalline form of the free base, e.g., a disclosed crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine.

[0177]

[0244] In certain embodiments, the disclosure provides a method of treating a disease or disorder associated with modulation of polycomb repressive complex 2 (PRC2) in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed crystalline compound, e.g., (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, a disclosed crystalline form of the free base, e.g., a disclosed crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine. In other embodiments, the disclosure provides a method of treating a disease or disorder associated with modulation of polycomb repressive complex 2 (PRC2) in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising an effective amount of a disclosed crystalline compound, e.g., (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, a disclosed crystalline form of the free base, e.g., a disclosed crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine.

[0178]

[0245] In some embodiments, the disease or disorder may be a blood disorder. In certain embodiments, the disclosure provides a method of treating a blood disorder in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed crystalline compound, such as (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, a disclosed crystalline form of the free base, such as a disclosed crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine. In other embodiments, the disclosure provides a method of treating a hematological disorder in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising an effective amount of a disclosed crystalline compound, e.g., (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, a disclosed crystalline form of the free base, e.g., a disclosed crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine.

[0179]

[0246] In certain embodiments, the hematological disease is, for example, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (ANIL), amyloidosis, anemia, aplastic anemia, bone marrow failure syndromes, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), deep vein thrombosis (DVT), Diamond-Blackfan anemia, diffuse large B-cell lymphoma, dyskeratosis congenita (DKC), eosinophilic disorders, essential thrombocythemia, Fanconi anemia, follicular lymphoma, Gaucher disease, hemochromatosis, hemolytic anemia, hemophilia, hereditary spherocytosis, Hodgkin's lymphoma, idiopathic thrombocytopenic purpura (ITP), hereditary bone marrow failure syndromes, iron deficiency anemia, Langerhans cell histiocytosis, large granular lymphocyte anemia, The hematological disorder may be selected from the group consisting of chronic myeloma (LGL), leukemia, leukopenia, mastocytosis, monoclonal gammopathy, multiple myeloma, myelodysplastic syndrome (MDS), myelofibrosis, myeloproliferative neoplasms (MPN), non-Hodgkin's lymphoma, paroxysmal nocturnal hemoglobinuria (PNH), pernicious anemia (B12 deficiency), polycythemia vera, porphyria, post-transplant lymphoproliferative disorder (PTLD), pulmonary embolism (PE), Schwachman-Diamond syndrome (SDS), sickle cell disease (SCD), β-thalassemia, thrombocytopenic thrombocytopenic purpura (TTP), venous thromboembolism, von Willebrand's disease, and Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma). In one embodiment, the hematological disorder is sickle cell disease (SCD). In another embodiment, the blood disorder is β-thalassemia.

[0180]

[0247] In some embodiments, the disease or disorder may be cancer. In certain embodiments, the present disclosure provides a method for treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of the disclosed crystalline compound, such as (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, the disclosed crystalline form of the free base, such as the disclosed crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine. In other embodiments, the disclosure provides a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising an effective amount of a disclosed crystalline compound, e.g., (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, a disclosed crystalline form of the free base, e.g., a disclosed crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine.

[0181]

[0248] In certain embodiments, the cancer may be selected from the group consisting of, for example, mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer, brain tumors including neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor, and soft tissue sarcoma.

[0182]

[0249] In other embodiments, the present disclosure provides a method of treating thoracic aortic aneurysm, coronary heart disease, stenosis disease, pulmonary arterial hypertension (PAR), liver fibrosis, allergic inflammation, retinitis pigmentosa, septic shock, herpes simplex virus, human cytomegalovirus, α-thalassemia, familial atrial fibrillation, common variable immunodeficiency, aneurysm-osteoarthritis syndrome, and acquired immune deficiency syndrome in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed crystalline compound, such as (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a, 7a-diamino-1,1-diphenylmethanesulfonyl ether ... and administering to a patient a disclosed crystalline form of the free base, such as a disclosed crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine.

[0183]

[0250] In other embodiments, the present disclosure provides a method of treating thoracic aortic aneurysm, coronary heart disease, stenosis disease, pulmonary arterial hypertension (PAR), liver fibrosis, allergic inflammation, retinitis pigmentosa, septic shock, herpes simplex virus, human cytomegalovirus, α-thalassemia, familial atrial fibrillation, common variable immunodeficiency, aneurysm-osteoarthritis syndrome, and acquired immune deficiency syndrome in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed crystalline compound, such as (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,1 The present invention provides a method for treating rheumatoid arthritis, comprising administering to a patient a pharmaceutical composition comprising the disclosed crystalline forms of 3,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, a free base, such as the disclosed crystalline salt forms of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine.

[0184]

[0251] In particular, in certain embodiments, the present disclosure provides a method of treating the above medical indications comprising administering to a patient in need thereof an effective amount of a crystalline compound disclosed herein. In certain other embodiments, the present disclosure provides a method of treating the above medical conditions in a patient in need thereof comprising administering to the patient orally, subcutaneously, or intravenously a composition comprising the disclosed crystalline form.

[0185]

[0252] The crystalline compounds disclosed herein can be used as drugs or pharma- ceutical acceptable compositions, for example, in the form of pharmaceuticals for oral, enteral, parenteral, or topical administration, and possible methods disclosed herein can include administering the disclosed crystalline compounds or compositions comprising or formed from such disclosed crystalline compounds orally, enterally, parenterally, or topically.For example, the disclosed crystalline forms can be capable of controlling one or more pharmacokinetic properties (e.g., longer or shorter release profiles) when administered by a particular route (e.g., oral) or in a particular formulation, compared to a different route (e.g., subcutaneous) or other formulation, for example, a formulation having an amorphous form.In one embodiment, the disclosed crystalline forms can allow for considerable reproducibility from one formulation to another.

[0186]

[0253] Also disclosed herein is a pharmaceutical composition comprising the disclosed crystalline compound and at least one additional therapeutic agent.In some embodiments, the additional therapeutic agent can be selected from the group consisting of, for example, anticancer agents, immunomodulatory agents, antiallergic agents, antiemetics, analgesics, cytoprotective agents, antisickling agents, and combinations thereof.In other embodiments, the additional therapeutic agent can be, for example, an EZH2 inhibitor. For example, in certain embodiments, the additional therapeutic agent is N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide (tazemetostat), (2R)-7-chloro-2-[4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide (valemetostat, DS-3201b), N-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-2-methyl-1[(1R)-1-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]ethyl]indole-3-carboxamide (CPI-1205), (S)-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indole-4-carboxamide (GSK28 1 6126), (R)-5,8-dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497), SHR2554, and combinations thereof.

[0187]

[0254] In further embodiments, the additional therapeutic agent may be, for example, hydroxyurea. In certain embodiments, the additional therapeutic agent may be, for example, selected from the group consisting of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (Voxerotol, GBT-440), P-selectin antibodies, L-glutamine, and combinations thereof.

[0188]

[0255] In certain embodiments, the additional therapeutic agent may be, for example, an anti-adhesion agent. For example, in certain embodiments, the additional therapeutic agent may be crizanlizumab (SEG101), (2S)-2-[(2R,3R,4S,5S,6R)-3-benzoyloxy-2-[(1R,2R,3S,5R)-3-[(2,4-dioxo-1H-pyrimidine-6-carbonyl)amino]-5-[2-[[2-[2-[2-oxo-2-[(3,6,8-trisulfonaphthalen-1-yl)amino]ethoxy]ethoxy]acetyl]amino]ethylcarbamoyl]-2-[(2S,3S,4R,5S,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxycyclohexyl] oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3-cyclohexylpropanoic acid (Rivipanser, GMI-1070), sevuparin, 6-[(3I,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(oxan-4-yl)-5H-pyrazolo[3,4-d]pyrimidin-4-one (PF-04447943), inlacumab (LC1004-002), 3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine (Milansertib, ARQ 092), and combinations thereof.

[0189]

[0256] In other embodiments, the additional therapeutic agent may be, for example, an anti-sickling agent. For example, in certain embodiments, the additional therapeutic agent may be selected from the group consisting of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (boxerotol, GBT-440), 6-[(3S,4S)-4-methyl-1-(2-pyrimidinylmethyl)-3-pyrrolidinyl]-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (IMR-687), and combinations thereof.

[0190]

[0257] In further embodiments, the additional therapeutic agent can be, for example, an antidote. For example, in certain embodiments, the additional therapeutic agent can be LJPC-401. In certain embodiments, the additional therapeutic agent can be selected from, for example, an anti-inflammatory agent, an anti-thrombotic agent, and combinations thereof. For example, in certain embodiments, the additional therapeutic agent may be selected from the group consisting of (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (Brilinta, Ticagrelor), (2R)-3,3,3-trifluoro-2-[[[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]amino]methyl]-2-hydroxypropanamide (Olinciguat), NKTT120, and combinations thereof.

[0191]

[0258] In some embodiments, the additional therapeutic agent can be, for example, a sanguinate. In other embodiments, the additional therapeutic agent can be, for example, an agent that causes disruption of PRC2. In further embodiments, the additional therapeutic agent is, for example, AZD9291. EXAMPLES

[0192] Working Example

[0259] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. The following non-limiting examples illustrate the present disclosure.

[0193]

[0260] X-ray powder diffraction was performed using a Bruker D8 Advance equipped with a Lynxeye detector in reflector mode (Bragg-Brentano configuration). Samples were prepared on Si zero-return wafers. Parameters for the XRPD method used are listed in Table 1 below.

[0194] [Table 1]

[0195]

[0261] X-ray powder diffraction was also performed using a Rigaku MiniFlex 600 in reflection mode (Bragg-Brentano configuration). Samples were prepared on Si zero-return wafers. Parameters for the XRPD method used are listed in Table 2 below.

[0196] [Table 2]

[0197]

[0262] Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were performed using a Mettler Toledo DSC 3+ Samples (3-5 mg) were weighed directly into sealed aluminum pans with a pinhole and analyzed according to the parameters in Table 3A below.

[0198] [Table 3]

[0199]

[0263] Dynamic Vapor Sorption (DVS) analysis was performed using a DVS Intrinsic 1. Samples (25 mg) were loaded into a sample container, suspended from a microbalance, and exposed to a humidified nitrogen gas stream. Samples were held at each level for a minimum of 5 minutes and advanced to the next humidity level only if there was a weight change of <0.002% between measurements (interval: 60 seconds) or 240 minutes had elapsed. The following program was used, as shown in Table 3B:

[0200] [Table 4]

[0201]

[0264] Optical microscopy was performed using a Zeiss AxioScope A1 equipped with 2.5x, 10x, 20x and 40x objectives and polarizers. Images are captured by a built-in Axiocam 105 digital camera and processed using Zeiss' ZEN 2 (blue version) software.

[0202] Example 1

[0265] Crystalline Form P material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: Approximately 25 mg of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, Form E material was dissolved in acetone (50 volumes) at 50°C. The solution was transferred in one portion to a solution of heptane (400 vol) at 50° C. with rapid stirring until a white slurry was formed. The solid was collected at 50° C. and dried overnight. XRPD analysis showed that the material was crystalline with a pattern consistent with Form P.

[0203]

[0266] Crystalline Form P material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was also prepared as follows: Approximately 25 mg of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, Form E material was dissolved in isopropyl alcohol (25 volumes) at 50°C. The solution was transferred in one portion to a solution of water (100 vol) at 50° C. with rapid stirring until a white slurry was formed. The solid was collected at 50° C. and dried overnight. XRPD analysis showed that the material was crystalline with a pattern consistent with Form P.

[0204]

[0267] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form P, is shown in Figure 1. Characteristic peaks include one or more of the peaks shown in Table 4.

[0205] [Table 5]

[0206]

[0268] Figure 2 shows the differential scanning calorimetry (DSC) profile of crystalline form P. As shown in Figure 2, crystalline form P exhibits a characteristic endotherm with an onset of about 252°C and a peak at about 253°C.

[0207]

[0269] Crystalline form P of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, anhydrous free base, exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.46 wt% up to about 260 °C. Crystalline form P exhibited a dynamic vapor sorption (DVS) profile showing a reversible total mass change of about 0.53 wt% at 25 °C and from about 2 to about 92% relative humidity (RH). Crystalline form P exhibited rod-like and / or plate-like morphology by optical microscopy. Crystalline form P was shown to be stable under dry and high humidity conditions (40 °C and 75% relative humidity) for at least one week. Form P maintained its crystallinity and solid form purity throughout the wet milling study (ball mill, 30 seconds, milled with 1 volume of water).

[0208] Example 2

[0270] Crystalline Form A material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: NH4OH (14.5 M) was added dropwise to a methanolic solution of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride salt at room temperature. After further addition of 1 mL of NH4OH, the solution became a fixed gel. An additional 2 volumes of MeOH was added to the gel, mixed by hand, heated to 50° C., and stirred overnight. The next morning, opaque white fibrous particles were observed in the gel. The mixture was sonicated to produce a free-flowing off-white slurry. XRPD analysis of a pulled sample showed the material to be crystalline with a pattern consistent with Form A.

[0209]

[0271] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form A, is shown in Figure 3. Characteristic peaks include one or more of the peaks shown in Table 5.

[0210] [Table 6]

[0211] Example 3

[0272] Crystalline Form B material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: NH4OH (14.5 M) was added dropwise to a methanolic solution of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride salt at 50° C. After further addition of 1 mL of NH4OH, the solution became a fixed gel. An additional 6 volumes of MeOH was added to the gel, mixed by hand, and stirred overnight. The next morning, opaque white fibrous particles were observed in the gel. The mixture was sonicated to produce an off-white slurry with good flowability. A sample was pulled for XRPD analysis, showing a crystalline form, Form B. The slurry was stirred for an additional 5 hours at room temperature. The solids were collected by filtration and rinsed with 4 volumes of MeOH:water (1:3 by volume). The wet cake was pressed onto an XRPD plate and a sample was analyzed. XRPD analysis of the pulled sample showed that the material was crystalline with a pattern consistent with Form B. Crystalline Form P showed a hairy morphology by optical microscopy.

[0212]

[0273] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form B, is shown in Figure 4. Characteristic peaks include one or more of the peaks shown in Table 6.

[0213] [Table 7]

[0214] Example 4

[0274] Crystalline Form C material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: The wet cake Form B material obtained in Example 3 above was dried in a vacuum oven equipped with a rotary oil vacuum pump at 50° C. overnight. XRPD analysis of the dried sample showed that the material had a pattern consistent with Form C and was crystalline.

[0215]

[0275] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form C, is shown in Figure 5. Characteristic peaks include one or more of the peaks shown in Table 7.

[0216] [Table 8]

[0217] Example 5

[0276] Crystalline Form D material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: 51.6 mg of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride was dissolved in 18 volumes of MeOH at 50° C. After addition of half the determined amount of NH4OH required for precipitation, seeding with Form B occurred, resulting in immediate precipitation of a fluffy solid. The other half of the NH4OH addition was completed and the slurry was stirred at 50° C. for 2 hours. The slurry was allowed to cool to room temperature and stirred for 1.25 hours. The solid was collected by filtration, rinsed three times with 1 mL of water, and dried in a vacuum oven equipped with a rotary oil vacuum pump at 50° C. for 3 days. XRPD analysis of the dried solid showed that the material was crystalline with a pattern consistent with Form D.

[0218]

[0277] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form D, is shown in Figure 6. Characteristic peaks include one or more of the peaks shown in Table 8.

[0219] [Table 9]

[0220] Example 6

[0278] Crystalline form E material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate was prepared as follows: 33 mg of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride was added to a vial followed by 2 mL (approximately 60 volumes) of saturated NaHCO3 (aqueous) solution. The slurry was stirred at 50° C. for 1 hour. The slurry solids were collected by filtration and the wet cake was analyzed by XRPD, which showed that the wet cake material was crystalline with a pattern consistent with Form E.

[0221]

[0279] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate form E is shown in Figure 7. Characteristic peaks include one or more of the peaks shown in Table 9.

[0222] [Table 10]

[0223]

[0280] Figure 8 shows the differential scanning calorimetry (DSC) profile of crystalline form E. As shown in Figure 8, crystalline form E exhibits a characteristic endotherm with an onset of about 44°C and a peak at about 58°C, a characteristic endotherm with an onset of about 110°C and a peak at about 114°C, and a characteristic endotherm with an onset of about 166°C and a peak at about 177°C.

[0224]

[0281] Crystalline form E of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 5.1% by weight up to about 170 °C. Crystalline form E exhibited a dynamic water vapor sorption (DVS) profile showing a reversible total mass change of about 10.3% by weight at 25 °C and from about 2 to about 92% relative humidity (RH). Crystalline form E exhibited a hairy morphology by optical microscopy. Crystalline form E was shown to be stable for at least one week at 40 °C and 75% relative humidity (RH).

[0225] Example 7

[0282] Crystalline form F material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: A sample of crystalline form E material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, hydrate was further dried overnight at 50° C. in a vacuum oven equipped with a rotary oil vacuum pump. XRPD analysis showed that the material was crystalline with a pattern consistent with form F.

[0226]

[0283] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form F, is shown in Figure 9. Characteristic peaks include one or more of the peaks shown in Table 10.

[0227] [Table 11]

[0228] Example 8

[0284] Crystalline Form H material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate, was prepared as follows: A slurry of Form E material in MeOH was stirred at 50° C. for 3 days. The slurry solids were collected by filtration and dried in a vacuum oven at 50° C. for 16 hours. XRPD analysis showed that the material was crystalline with a pattern consistent with Form H.

[0229]

[0285] Crystalline form H material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate was also prepared as follows: 10 volumes of MeOH were added to 0.21 g of dried form P material in a 20 mL vial. The resulting slurry was seeded with form H material. After 2 hours, the slurry was sampled and showed an XRPD pattern consistent with crystalline pattern H. After stirring the slurry overnight, an additional 10 volumes of MeOH were added and the slurry was transferred to a 4 mL vial and stirring was continued. 15 μL of water was added. The slurry was heated to 50° C., seeded again with form H material, and stirred at 50° C. for 40 minutes. The slurry was cooled to room temperature and the solids were collected by filtration, rinsed once with 2 volumes of MeOH, and then dried in a vacuum oven at 50° C. XRPD analysis showed that the dried material had a pattern consistent with Form H and was crystalline.

[0230]

[0286] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate form H is shown in Figure 10. Characteristic peaks include one or more of the peaks shown in Table 11.

[0231] [Table 12]

[0232]

[0287] Figure 11 shows the differential scanning calorimetry (DSC) profile of crystalline form H. As shown in Figure 11, crystalline form H exhibits a characteristic endotherm with an onset of about 58°C and a peak at about 84°C, a characteristic endotherm with an onset of about 63°C and a peak at about 89°C, and a characteristic endotherm with an onset of about 169°C and a peak at about 176°C.

[0233]

[0288] Crystalline form H of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate, exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 6.3% by weight up to about 130 °C. Crystalline form H exhibited a dynamic water vapor sorption (DVS) profile showing a reversible total mass change of about 7.6% by weight at 25 °C and from about 2 to about 92% relative humidity (RH). Crystalline form H exhibited a hairy morphology by optical microscopy. Crystalline form H was shown to be stable for at least one week at 40 °C and 75% relative humidity (RH).

[0234] Example 9

[0289] Crystalline Form I material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: A slurry of Form E material in EtOH was stirred at room temperature for 3 days. The slurry solids were filtered and the wet cake was analyzed by XRPD. XRPD analysis showed that the wet cake material had a pattern consistent with Form I and was crystalline.

[0235]

[0290] Crystalline Form I material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was also prepared as follows: Form E material was dissolved in EtOH (30 volumes) at 50° C. The stirred solution was cooled from 50° C. to room temperature at 5° C. per hour, which was accomplished by decreasing the hotplate temperature by 2.5° C. every 30 minutes. The resulting slurry was further stirred at room temperature for 3 days and the slurry solids were collected by filtration. XRPD analysis showed that the material was crystalline with a pattern consistent with Form I. Crystalline Form I exhibited a hairy morphology by optical microscopy.

[0236]

[0291] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, Form I, is shown in Figure 12. Characteristic peaks include one or more of the peaks shown in Table 12.

[0237] [Table 13]

[0238] Example 10

[0292] Crystalline Form J material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: A slurry of Form E material in acetone was stirred at room temperature for 3 days. The slurry solids were filtered and the wet cake was analyzed by XRPD. XRPD analysis showed that the wet cake material had a pattern consistent with Form J and was crystalline.

[0239]

[0293] Crystalline form J material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was also prepared as follows: Form E material was dissolved in acetone (34 volumes) at 50° C. The stirred solution was cooled from 50° C. to room temperature at 5° C. per hour, which was accomplished by decreasing the hotplate temperature by 2.5° C. every 30 minutes. The resulting slurry was further stirred at room temperature for 3 days and the slurry solids were collected by filtration. XRPD analysis showed that the material was crystalline with a pattern consistent with form J. Crystalline form J exhibited a hairy morphology by optical microscopy.

[0240]

[0294] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form J, is shown in Figure 13. Characteristic peaks include one or more of the peaks shown in Table 13.

[0241] [Table 14]

[0242] Example 11

[0295] Crystalline form K material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: A slurry of form E material in MeCN was stirred at room temperature for 3 days. The slurry solids were filtered and the wet cake was analyzed by XRPD. XRPD analysis showed that the wet cake material had a pattern consistent with form K and was crystalline.

[0243]

[0296] Crystalline form K material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was also prepared as follows: Form E material was dissolved in MeCN (60 volumes) at 50° C. The stirred solution was cooled from 50° C. to room temperature at 5° C. per hour, which was accomplished by decreasing the hotplate temperature by 2.5° C. every 30 minutes. The resulting slurry was further stirred at room temperature for 3 days and the slurry solids were collected by filtration. XRPD analysis showed that the material had a pattern consistent with form K and was crystalline.

[0244]

[0297] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form K, is shown in Figure 14. Characteristic peaks include one or more of the peaks shown in Table 14.

[0245] [Table 15]

[0246]

[0298] Figure 15 shows the differential scanning calorimetry (DSC) profile of crystalline form K. As shown in Figure 15, crystalline form K exhibits a characteristic endotherm with an onset of about 226°C and a peak at about 230°C.

[0247] Example 12

[0299] Crystalline Form L material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: A slurry of Form E material in MeCN was stirred at 50° C. for 3 days. The slurry solids were filtered and the wet cake was analyzed by XRPD. XRPD analysis showed that the wet cake material had a pattern consistent with Form L and was crystalline.

[0248]

[0300] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base form L, is shown in Figure 16. Characteristic peaks include one or more of the peaks shown in Table 15.

[0249] [Table 16]

[0250] Example 13

[0301] Crystalline form M material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: Form L wet cake material from Example 12 was further dried in a vacuum oven at 50° C. for 16 hours. XRPD analysis showed that the dried material had a pattern consistent with form M and was crystalline.

[0251]

[0302] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form M, is shown in Figure 17. Characteristic peaks include one or more of the peaks shown in Table 16.

[0252] [Table 17]

[0253] Example 14

[0303] Crystalline Form N material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: Form E material was dissolved in MeCN:water (85:15, 12 volumes) at 50°C. The stirred solution was cooled from 50°C to room temperature at 5°C per hour, which was achieved by decreasing the hotplate temperature by 2.5°C every 30 minutes. The resulting slurry was further stirred at room temperature for 3 days. The slurry solids were filtered and the wet cake was analyzed by XRPD. XRPD analysis showed that the wet cake material had a pattern consistent with Form N and was crystalline.

[0254]

[0304] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form N, is shown in Figure 18. Characteristic peaks include one or more of the peaks shown in Table 17.

[0255] [Table 18]

[0256] Example 15

[0305] Crystalline Form O material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: Approximately 25 mg of Form E material was dissolved in DMSO (5 volumes) at room temperature. Water (10 volumes) was added dropwise in four portions over a period of 60 minutes to the stirred DMSO solution. The resulting slurry solid was collected by filtration and dried overnight. XRPD analysis showed that the material had a pattern consistent with Form O and was crystalline.

[0257]

[0306] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form O, is shown in Figure 19. Characteristic peaks include one or more of the peaks shown in Table 18.

[0258] [Table 19]

[0259]

[0307] Figure 20 shows the differential scanning calorimetry (DSC) profile of crystalline form O. As shown in Figure 20, crystalline form O exhibits a characteristic endotherm with an onset of about 166°C and a peak at about 172°C, as well as a characteristic endotherm with an onset of about 196°C and a peak at about 204°C.

[0260]

[0308] Crystalline Form O of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, exhibited a thermogravimetric analysis (TGA) profile showing a first stage mass loss of about 0.23 wt % up to about 150° C., a second stage mass loss of about 1.7 wt % from about 150° C. to about 200° C., a third stage mass loss of about 1.3 wt % from about 200° C. to about 250° C., and a fourth stage mass loss of about 4.7 wt % from about 250° C. to about 280° C.

[0261] Example 16

[0309] Crystalline form Q material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: Approximately 28 mg of form E was loaded into a grinding capsule and 1 volume of MeCN was added along with ¼ inch steel balls as grinding media. The solid was ground using a Wig-L-bug at 3500 rpm for 30 seconds, then collected and analyzed by XRPD. XRPD analysis of the wet cake material indicated that the material was crystalline with a pattern consistent with form Q.

[0262]

[0310] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base form Q, is shown in Figure 21. Characteristic peaks include one or more of the peaks shown in Table 19.

[0263] [Table 20]

[0264] Example 17

[0311] Crystalline form R material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: Form E material was dissolved in N,N-dimethylacetamide (9 volumes) at 50° C. The stirred solution was cooled from 50° C. to room temperature at 5° C. per hour, which was achieved by decreasing the hotplate temperature by 2.5° C. every 30 minutes. The resulting slurry was further stirred at room temperature for 3 days. The slurry solids were filtered and dried under vacuum at 50° C. overnight. XRPD analysis showed that the material was crystalline with a pattern consistent with form R.

[0265]

[0312] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form R, is shown in Figure 22. Characteristic peaks include one or more of the peaks shown in Table 20.

[0266] [Table 21]

[0267]

[0313] Figure 23 shows the differential scanning calorimetry (DSC) profile of crystalline form R. As shown in Figure 23, crystalline form R exhibits a characteristic endotherm with an onset of about 148°C and a peak at about 152°C, as well as a characteristic endotherm with an onset of about 241°C and a peak at about 251°C.

[0268]

[0314] Possible crystalline form R of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, exhibited a thermogravimetric analysis (TGA) profile showing a first stage mass loss of about 0.87 wt % up to about 150° C., a second stage mass loss of about 3.1 wt % from about 150° C. to about 200° C., and a third stage mass loss of about 11.7 wt % from about 200° C. to about 240° C.

[0269] Example 18

[0315] Crystalline Form S material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: Form Q wet cake material from Example 16 was further dried under reduced pressure. XRPD analysis showed that the dried material had a pattern consistent with Form S and was crystalline.

[0270]

[0316] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form S, is shown in Figure 24. Characteristic peaks include one or more of the peaks shown in Table 21.

[0271] [Table 22]

[0272] Example 19

[0317] Crystalline form T material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: A saturated solution of form P was generated by making a slurry of form P in isopropyl alcohol:water (1:4 by volume) and stirring overnight. The solids were allowed to settle and the supernatant was transferred into vials containing approximately 5 mg each of form E, form H, and form P. The competing slurries were stirred at room temperature for 24 hours. XRPD analysis of the collected solids showed that the material had a pattern consistent with form T and was crystalline.

[0273]

[0318] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form T, is shown in Figure 25. Characteristic peaks include one or more of the peaks shown in Table 22.

[0274] [Table 23]

[0275]

[0319] Figure 26 shows the differential scanning calorimetry (DSC) profile of crystalline form T. As shown in Figure 26, crystalline form T exhibits a characteristic endotherm with an onset of about 83°C and a peak at about 84°C, as well as a characteristic endotherm with an onset of about 249°C and a peak at about 251°C.

[0276]

[0320] Possible crystalline form T of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, exhibited a thermogravimetric analysis (TGA) profile showing a first stage mass loss of about 13.8 wt % up to about 85° C. Crystalline form T exhibited needle and / or rod morphology by microscopy.

[0277] Example 20

[0321] Crystalline form U material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: Form N wet cake material from Example 14 was further dried under vacuum at 50° C. overnight. XRPD analysis showed that the dried material had a pattern consistent with Form U and was crystalline.

[0278]

[0322] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form U, is shown in Figure 27. Characteristic peaks include one or more of the peaks shown in Table 23.

[0279] [Table 24]

[0280] Example 21

[0323] Crystalline Form V material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: Approximately 12 mg of Form P material was charged into a 2 mL vial. 2,2,2-trifluoroethanol was added in aliquots at room temperature until dissolved (solubility 167-333 mg / mL). The solution was stirred overnight and a slurry was observed the next day. The slurry solids were collected and analyzed by XRPD. XRPD analysis indicated that the material had a pattern consistent with Form V and was crystalline.

[0281]

[0324] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, form V, is shown in Figure 28. Characteristic peaks include one or more of the peaks shown in Table 24.

[0282] [Table 25]

[0283] Example 22

[0325] Crystalline Form W material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: Approximately 2.5 mg of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, maleate salt (Form 7-A) was charged into a vial. 1 mL of water was added and the mixture was warmed to 37°C. More water was added to the slurry, which thinned considerably and then appeared to begin to precipitate a fine white solid. This was deemed a likely disproportionation and no more water was added. The mixture was stirred overnight and the next day the fine solid suspended in solution was collected and analyzed by XRPD. It was observed that the maleate salt disproportionated with slurry time. XRPD analysis indicated that a new crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, designated as Form W, had been produced.

[0284]

[0326] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base form W, is shown in Figure 29. Characteristic peaks include one or more of the peaks shown in Table 25.

[0285] [Table 26]

[0286] Example 23

[0327] Amorphous form material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, was prepared as follows: Approximately 30 mg of Form E material was dissolved in 5 volumes of THF at 50° C. and left uncapped without stirring to allow the solvent to evaporate. A yellow gel remained at the base of the vial, which was dried in a vacuum oven at 50° C. overnight. The brittle glass was broken with a spatula and the solid was analyzed by XRPD, which showed an amorphous pattern (FIG. 67).

[0287] Example 24 - Salt Screening

[0328] A stock solution of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base form P, was prepared in 2,2,2-trifluoroethanol (50.8 mg / mL). A stock solution of the counterion was prepared in EtOH.

[0288]

[0329] Salt formation was carried out in 2 mL vials at room temperature. 25.4 mg of Form P free base material (500 μL of stock solution) and 1.1 equivalents of counterion were added to each vial. The solvent was allowed to evaporate overnight at 40° C. with stirring. Nearly half of the solvent in the vials did not evaporate completely overnight. The vials were left on a hot plate to continue evaporating (temperature was increased to 50° C.), while the additional dried samples were further dried under vacuum at 50° C. for 3 hours. Finally, the samples still containing solvent were left stirring at 30° C. over the weekend to complete evaporation of the solvent. The samples were further dried under vacuum at 50° C. for 3 hours.

[0289]

[0330] Approximately 20 volumes of solvent (0.5 mL) were added to each vial containing the dried solids. The three solvents chosen were EtOH, EtOAc, and IPA:water (9:1 by volume). After the solvent was added, the mixture (or solution) was stirred at room temperature. When a slurry was formed, the solids were filtered for XRPD analysis.

[0290]

[0331] XRPD analysis was performed in three stages. Wet cake XRPD was performed for all collected samples. The unique solids were then left on the XRPD plate, which were dried under vacuum at 50° C. The unique dried solids were then XRPD performed. The solids were then exposed to 95%+ relative humidity for one day, and XRPD was performed on the resulting solids. The humid environment was generated by placing a beaker of saturated potassium sulfate in water in a sealed container. All XRPD patterns were compared to the counterion XRPD patterns (for the solids). A summary of the results is shown in Table 26. The nomenclature system for the crystalline salt forms is the counterion number followed by a letter corresponding to the unique pattern observed for that counterion. For example, Form 8-B would represent the second unique pattern observed with the L-malic acid counterion.

[0291] [Table 27]

[0292] [Table 28]

[0293]

[0332] The XRPD pattern of the crystalline salt form 1-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, benzenesulfonate is shown in Figure 30. Characteristic peaks include one or more of the peaks shown in Table 27.

[0294] [Table 29]

[0295]

[0333] The XRPD pattern of the crystalline salt form 1-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, benzenesulfonate is shown in Figure 31. Characteristic peaks include one or more of the peaks shown in Table 28.

[0296] [Table 30]

[0297]

[0334] Figure 32 shows the differential scanning calorimetry (DSC) profile of crystalline salt form 1-B. As shown in Figure 32, crystalline salt form 1-B exhibits a characteristic endotherm with an onset of about 33°C and a peak at about 71°C, a characteristic endotherm with an onset of about 120°C and a peak at about 133°C, and a characteristic endotherm with an onset of about 154°C and a peak at about 159°C.

[0298]

[0335] The XRPD pattern of the crystalline salt form 2-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, citrate salt is shown in Figure 33. Characteristic peaks include one or more of the peaks shown in Table 29.

[0299] [Table 31]

[0300]

[0336] The XRPD pattern of the crystalline salt form 2-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, citrate salt is shown in Figure 34. Characteristic peaks include one or more of the peaks shown in Table 30.

[0301] [Table 32]

[0302]

[0337] The XRPD pattern of the crystalline salt form 2-C of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, citrate salt is shown in Figure 35. Characteristic peaks include one or more of the peaks shown in Table 31.

[0303] [Table 33]

[0304]

[0338] Figure 36 shows the differential scanning calorimetry (DSC) profile of crystalline salt form 2-C. As shown in Figure 36, crystalline salt form 2-C shows a characteristic endotherm with an onset of about 33°C and a peak at about 60°C, a characteristic endotherm with an onset of about 96°C and a peak at about 116°C, a characteristic endotherm with an onset of about 160°C and a peak at about 169°C, and a characteristic endotherm with an onset of about 141°C and a peak at about 177°C.

[0305]

[0339] The XRPD pattern of the crystalline salt form 3-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, fumarate salt is shown in Figure 37. Characteristic peaks include one or more of the peaks shown in Table 32.

[0306] [Table 34]

[0307]

[0340] Figure 38 shows the differential scanning calorimetry (DSC) profile of crystalline salt form 3-A. As shown in Figure 38, crystalline salt form 3-A exhibits a characteristic endotherm with an onset of about 237°C and a peak at about 241°C.

[0308]

[0341] The XRPD pattern of the crystalline salt form 5-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride, is shown in Figure 39. Characteristic peaks include one or more of the peaks shown in Table 33.

[0309] [Table 35]

[0310]

[0342] Possible crystalline form 5-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride salt exhibited a thermogravimetric analysis (TGA) profile indicating a mass loss of about 3.1% by weight up to about 110°C and a further mass loss of about 7.6% by weight from about 110°C to about 195°C. Crystalline form 5-A exhibited a dynamic water vapor sorption (DVS) profile indicating a reversible total mass change of about 3.1% by weight at 25°C and from about 2 to about 92% relative humidity (RH). Crystalline form 5-A may be characterized by a Karl Fischer titration profile indicating a water content of about 10.7%. Crystalline form 5-A exhibited rod or plate-like morphology by optical microscopy.

[0311]

[0343] The XRPD pattern of the crystalline salt form 5-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride, is shown in Figure 40. Characteristic peaks include one or more of the peaks shown in Table 34.

[0312] [Table 36]

[0313]

[0344] Figure 41 shows the differential scanning calorimetry (DSC) profile of crystalline salt form 5-B. As shown in Figure 41, crystalline salt form 5-B exhibits a characteristic endotherm with an onset of about 68°C and a peak at about 82°C, a characteristic endotherm with an onset of about 111°C and a peak at about 130°C, and a characteristic endotherm with an onset of about 193°C and a peak at about 211°C.

[0314]

[0345] The XRPD pattern of the crystalline salt form 5-C of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride, is shown in Figure 42. Characteristic peaks include one or more of the peaks shown in Table 35.

[0315] [Table 37]

[0316]

[0346] Figure 43 shows the differential scanning calorimetry (DSC) profile of crystalline salt form 5-C. As shown in Figure 43, crystalline salt form 5-C shows a characteristic endotherm with an onset of about 140°C and a peak at about 145°C, as well as a characteristic endotherm with an onset of about 213°C and a peak at about 230°C.

[0317]

[0347] Crystalline Form 5-D material of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride salt was prepared as follows: Form 5-B material was slurried in IPA:water (9:1 by volume) by adding 50 volumes. The slurry was sonicated in an ultrasonic bath for 5.5 hours while maintaining the bath temperature between 17°C and 31°C. The solids were collected by filtration and analyzed by XRPD. XRPD analysis showed that the material was crystalline with a pattern consistent with Form 5-D.

[0318]

[0348] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, hydrochloride, crystalline salt form 5-D is shown in Figure 44. Characteristic peaks include one or more of the peaks shown in Table 36.

[0319] [Table 38]

[0320]

[0349] The XRPD pattern of the crystalline salt form 7-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, maleate is shown in Figure 45. Characteristic peaks include one or more of the peaks shown in Table 37.

[0321] [Table 39]

[0322]

[0350] Figure 46 shows the differential scanning calorimetry (DSC) profile of crystalline salt form 7-A. As shown in Figure 46, crystalline salt form 7-A shows a characteristic endotherm with an onset of about 215°C and a peak at about 221°C, as well as a characteristic endotherm with an onset of about 216°C and a peak at about 225°C.

[0323]

[0351] The XRPD pattern of the crystalline salt form 8-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-malate is shown in Figure 47. Characteristic peaks include one or more of the peaks shown in Table 38.

[0324] [Table 40]

[0325]

[0352] Figure 48 shows the differential scanning calorimetry (DSC) profile of crystalline salt form 8-A. As shown in Figure 48, crystalline salt form 8-A exhibits a characteristic endotherm with an onset of about 177°C and a peak at about 201°C, a characteristic endotherm with an onset of about 186°C and a peak at about 207°C, a characteristic endotherm with an onset of about 205°C and a peak at about 211°C, and a characteristic endotherm with an onset of about 208°C and a peak at about 216°C.

[0326]

[0353] The XRPD pattern of the crystalline salt form 8-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-malate, is shown in Figure 49. Characteristic peaks include one or more of the peaks shown in Table 39.

[0327] [Table 41]

[0328]

[0354] Figure 50 shows the differential scanning calorimetry (DSC) profile of crystalline salt form 8-B. As shown in Figure 50, crystalline salt form 8-B shows a characteristic endotherm with an onset of about 189°C and a peak at about 192°C, as well as a characteristic endotherm with an onset of about 186°C and a peak at about 202°C.

[0329]

[0355] Crystalline form 8-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-malate salt exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.46 wt% up to about 175 °C. Crystalline form 8-B may be characterized by a dynamic water vapor sorption (DVS) profile showing a reversible total mass change of about 0.82 wt% at 25 °C and from about 2 to about 92% relative humidity (RH).

[0330]

[0356] The XRPD pattern of the crystalline salt form 9-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, methanesulfonate is shown in Figure 51. Characteristic peaks include one or more of the peaks shown in Table 40.

[0331] [Table 42]

[0332]

[0357] The XRPD pattern of the crystalline salt form 9-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, methanesulfonate, is shown in Figure 52. Characteristic peaks include one or more of the peaks shown in Table 41.

[0333] [Table 43]

[0334]

[0358] Figure 53 shows the differential scanning calorimetry (DSC) profile of crystalline salt form 9-B. As shown in Figure 53, crystalline salt form 9-B shows a characteristic endotherm with an onset of about 189°C and a peak at about 192°C, as well as a characteristic endotherm with an onset of about 186°C and a peak at about 202°C.

[0335]

[0359] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, methanesulfonate, crystalline salt form 9-C is shown in Figure 54. Characteristic peaks include one or more of the peaks shown in Table 42.

[0336] [Table 44]

[0337] [Table 45]

[0338]

[0360] The XRPD pattern of the crystalline salt form 10-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, phosphate salt is shown in Figure 55. Characteristic peaks include one or more of the peaks shown in Table 43.

[0339] [Table 46]

[0340]

[0361] Figure 56 shows the differential scanning calorimetry (DSC) profile of crystalline salt form 10-A. As shown in Figure 56, crystalline salt form 10-A shows a characteristic endotherm with an onset of about 282°C and a peak at about 290°C, as well as a characteristic endotherm with an onset of about 283°C and a peak at about 294°C.

[0341]

[0362] Crystalline form 10-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, phosphate salt exhibited a thermogravimetric analysis (TGA) profile indicating a mass loss of approximately 0.22 wt%. Crystalline form 10-A exhibited a dynamic water vapor sorption (DVS) profile indicating a reversible total mass change of approximately 1.4 wt% at 25 °C and from approximately 2 to approximately 92% relative humidity (RH).

[0342]

[0363] The XRPD pattern of the crystalline salt form 11-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, pyruvate is shown in Figure 57. Characteristic peaks include one or more of the peaks shown in Table 44.

[0343] [Table 47]

[0344]

[0364] Figure 58 shows the differential scanning calorimetry (DSC) profile of crystalline salt form 11-A. As shown in Figure 58, crystalline salt form 11-A shows a characteristic endotherm with an onset of about 76°C and a peak at about 88°C, a characteristic endotherm with an onset of about 134°C and a peak at about 142°C, and a characteristic endotherm with an onset of about 149°C and a peak at about 157°C.

[0345]

[0365] The XRPD pattern of the crystalline salt form 12-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, sulfate salt is shown in Figure 59. Characteristic peaks include one or more of the peaks shown in Table 45.

[0346] [Table 48]

[0347] [Table 49]

[0348]

[0366] Figure 60 shows the differential scanning calorimetry (DSC) profile of crystalline salt form 12-A. As shown in Figure 58, crystalline salt form 12-A exhibits a characteristic endotherm with an onset of about 48°C and a peak at about 81°C, a characteristic endotherm with an onset of about 169°C and a peak at about 185°C, and a characteristic endotherm with an onset of about 229°C and a peak at about 241°C.

[0349]

[0367] The XRPD pattern of the crystalline salt form 13-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-tartrate salt is shown in Figure 61. Characteristic peaks include one or more of the peaks shown in Table 46.

[0350] [Table 50]

[0351]

[0368] Figure 62 shows the differential scanning calorimetry (DSC) profile of crystalline salt form 13-A. As shown in Figure 62, crystalline salt form 13-A exhibits a characteristic endotherm with an onset of about 213°C and a peak at about 222°C.

[0352]

[0369] Crystalline form 13-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-tartrate salt exhibited a thermogravimetric analysis (TGA) profile indicating a mass loss of about 0.63 wt% up to about 185 °C. Crystalline form 13-A exhibited a dynamic water vapor sorption (DVS) profile indicating a reversible total mass change of about 0.97 wt% at 25 °C and from about 2 to about 92% relative humidity (RH).

[0353]

[0370] The XRPD pattern of the crystalline salt form 13-B of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, L-tartrate salt is shown in Figure 63. Characteristic peaks include one or more of the peaks shown in Table 47.

[0354] [Table 51]

[0355]

[0371] Figure 64 shows the differential scanning calorimetry (DSC) profile of crystalline salt form 13-B. As shown in Figure 64, crystalline salt form 13-B exhibits a characteristic endotherm with an onset of about 89°C and a peak at about 115°C, a characteristic endotherm with an onset of about 157°C and a peak at about 167°C, and a characteristic endotherm with an onset of about 181°C and a peak at about 195°C.

[0356]

[0372] The XRPD pattern of the crystalline salt form 14-A of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, toluenesulfonate is shown in Figure 65. Characteristic peaks include one or more of the peaks shown in Table 48.

[0357] [Table 52]

[0358]

[0373] The XRPD pattern of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, toluenesulfonate, crystalline salt form 14-B is shown in Figure 66. Characteristic peaks include one or more of the peaks shown in Table 49.

[0359] [Table 53]

[0360] Example 25. Crystallization test

[0374] The objective of this study was to develop a reliable crystallization process with reproducible particle size distribution (PSD) control. Solubility measurements of Form P were performed in DMSO / EtOH / water system at the evaluated temperatures. Form P was slurried in the selected solvent system for 2-3 hours and then the mother liquor was collected for solubility testing by high performance liquid chromatography (HPLC) assay. The results in Table 50 show that the solubility decreased significantly with increasing water content.

[0361] [Table 54]

[0362]

[0375] According to the solubility data of Form P in DMSO / EtOH / water system in Example 25, an experiment (Experiment 1 in Table 51 below) was performed. Crude Form P was dissolved in DMSO / EtOH 3V / 3V at 50° C., then 0.6V of water was charged to create supersaturation for seeding. Then, 11.4V of water was added to the seed suspension in two steps (2.4V / 6h, 9V / 4h) and the suspension was further aged for about 12 hours. The solid was isolated by filtration and dried under reduced pressure at 50° C.

[0363]

[0376] Several other experiments (Experiment 2, Experiment 3, Experiment 4, Experiment 5, Experiment 7, and Experiment 8) were conducted to investigate the effect of seed loading, seed size, and scale on the final product particle size. PSD data and polarized light microscopy (PLM) images showed that higher seed loading and lower seed size resulted in smaller product particle size, but the effect of scale on product particle size was not significant.

[0364]

[0377] Furthermore, in experiment 6, wet grinding was applied to obtain uniform and small particles of the product. According to the experimental conditions in the factory, the wet grinding parameters in the laboratory were set as follows: rotor 6F, tip speed 19.5 m / s. Finally, the comparison of the particle size of the product before and after wet grinding showed that wet grinding with one 6F rotor was not favorable for reducing the particle size.

[0365]

[0378] Further testing was performed to evaluate the impurity cleanup capability in the crystallization system, and the experiment was monitored by HPLC at various time points. HPLC data showed that the impurity at relative retention time (RRT) 1.08 could be reduced to <0.13% (specification criteria) at the expense of yield from 95% to 70%.

[0366]

[0379] Particle size data is summarized in Table 51.

[0367] [Table 55]

[0368] Example 26. Crystallization test

[0380] The objective of this study was to develop a crystallization process for (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine with control over solid form and chemical stability.

[0369]

[0381] The as-received material was characterized by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), particle size distribution (PSD), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Characterization results showed that the starting material was crystalline and matched the Form P reference pattern. The starting material exhibited small birefringent particles with D90, D50, and D10 of 5.35, 3.33, and 1.99 μm, respectively. Thermal results showed that the starting material had a single melting endotherm with an onset of 251.15° C. and was anhydrous.

[0370]

[0382] A thorough investigation was conducted to evaluate the optimal solvent system for crystallization. An abbreviated polymorph / solvate screen and approximate solubility determination was performed with each Class III solvent listed under ICH Guidelines Q3C and several Class II solvents. In all solvents tested, approximate solubilities of >10 mg / mL were observed in acetone, dimethyl sulfoxide (DMSO), ethanol (EtOH), N-methylpyrrolidone (NMP), methyl ethyl ketone (MEK), 2-methyl-1-propanol, 2-propanol, methanol (MeOH), and tetrahydrofuran (THF). Among these solvents, form changes were observed in EtOH (form H), 1-propanol, and MeOH (form H with additional peaks). See Figure 68. TGA of samples obtained from EtOH and MeOH showed no weight loss corresponding to the stoichiometric amount of solvate, while the 1-propanol sample showed a weight loss of 9.31%. Competitive slurries of forms P and H in two solvents other than EtOH at room temperature to 70° C. resulted in conversion to form P, indicating that it is the most stable form at the conditions tested. Form P was found to be more stable than form H at 70° C. in EtOH. Form P was selected as the polymorph of interest for crystallization. Throughout this study, it was observed that dissolution of any form at 50° C. in a non-solvating solvent would produce form P. The equilibrium solubility in some of these with low boiling points did not reach the target 100 mg / mL solubility at temperatures up to 70° C. The highest solubility observed without form change was in EtOH at 56.68 mg / mL at 70° C. In order to reach a solubility of 100 mg / mL, a mixture of EtOH / DMSO was prepared and the final solvent system selected was EtOH / DMSO (80 / 20 v / v). Additionally, this solvent system was examined at 80° C. for possible decomposition and a purity of 99.9% was measured after 24 hours of slurry.

[0371]

[0383] Small scale (50-100 mg) crystallization experiments showed that HO was the most suitable antisolvent. However, crystallization by cooling followed by addition of HO was found to produce an amorphous powder. Crystallization by addition of HO at 60° C. produced form P without the use of seeds. At the 1 gram scale, parameters such as total antisolvent volume, rate of antisolvent addition, seed point, and seed loading were individually optimized and their effects on particle size, resulting polymorph, filterability, residual solvent, purity, mother liquor concentration, and yield were carefully monitored. Two additional 1 gram crystallizations were performed to reduce the total volume of solvent required, but poor filterability and DMSO content above 5000 ppm were observed.

[0372]

[0384] The optimized crystallization process was carried out on a 10 gram scale. Two 10 gram crystallizations were performed, the first (crystallization 1) and the second (crystallization 2) using the original 10 gram batch product as seeds.

[0373]

[0385] The difference between these two experiments was the seeds used. For samples in crystallization 1, milled form P was used as the seed. For samples in crystallization 2, crystals from crystallization 1 were used as the seed to determine the particle size variation that could be expected when seeding with larger crystals (seeding from a previous batch) compared to seeding with milled material.

[0374]

[0386] Both crystallizations were carried out in a 300 mL jacketed ChemGlass reactor. The solvent system used was EtOH / DMSO (80 / 20 v / v) at 70° C. with a starting concentration of about 100 mg / mL. A stationary stir bar was used with a stirring speed of 400 rpm. After a clear solution was obtained at 70° C., 1 part (or 10 volumes) of H2O was added. The clear solution remained. 0.5% w / w seeds were added to the solution and aged for 30 minutes. 0.5 parts (or 5 volumes) of H2O were added to the suspension at a controlled rate of 1.2 mL / min. The suspension was then cooled from 70° C. to 20° C. at a rate of 10° C. / h. After the temperature reached 20° C., the solid was isolated using a 150 mL fritted filter with medium porosity using vacuum filtration. A wash of 2 parts (or 20 volumes) of H2O was used to remove residual organic solvent. No cracking, washing off of fines, or puck formation was observed in the dried cakes of both 10 gram samples. The solids were then transferred to a vacuum oven and tray dried at room temperature overnight.

[0375]

[0387] In the second batch, crystals with rod morphology and lengths greater than 200 μm were observed. Two final scale-up batches were performed. A 43 gram batch was produced as the small seed and a 22 gram batch was produced using the first 10 gram batch as the larger seed (Crystallization 1) to evaluate the effect of different sized seeds on the process. Scanning Electron Microscopy (SEM) was used to complement Polarized Light Microscopy (PLM) and Particle Size Distribution (PSD) measurements. Observations suggested the production of agglomerates of rods greater than 200 μm in size in the 22 gram batch that were first grown on the seeds, followed by primary nucleation resulting in crystals less than 50 μm in size. This was not observed in the 43 gram batch, probably because the increased surface area provided by the milled seeds provided much more sites for crystal growth, whereas the larger seeds used in the 22 gram batch have a smaller total surface area, resulting in slower desupersaturation and primary nucleation, resulting in smaller particles growing on the larger rods.

[0376]

[0388] The crystallization conditions and results are shown in Table 52.

[0377] [Table 56]

[0378] Incorporation by Reference

[0389] All publications and patents mentioned in this specification, including the items listed below, are incorporated herein by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0379] Equivalent

[0390] While specific embodiments of the present disclosure have been described, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art after reviewing this specification. The full scope of the present disclosure should be determined by reference to the claims, together with such variations, their full scope of equivalents, and the specification, together with the claims.

[0380]

[0391] Unless otherwise indicated, all numerical values ​​expressing quantities of ingredients, reaction conditions, and so forth in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless otherwise indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

1. A crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, anhydrous free base (Form P), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.6 2θ degrees.

2. 2. The crystalline form of claim 1, characterized by an X-ray powder diffraction pattern having characteristic peaks at about 7.6, 11.9, and 15.3 degrees 2θ, an X-ray powder diffraction pattern having characteristic peaks at about 7.6, 11.9, 14.5, 15.3, 20.7, and 22.6 degrees 2θ, or an X-ray powder diffraction pattern having characteristic peaks at about 7.6, 11.9, 14.5, 15.3, 16.1, 17.2, 17.3, 20.7, 22.6, 23.3, 26.2, and 24.5 degrees 2θ.

3. 2. The crystalline form of claim 1, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

4. 2. The crystalline form of claim 1, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 252° C. and a peak at about 253° C.

5. A crystalline form comprising: (a) a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base (Form A), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 5.9, 8.5, 9.3, 9.5, 10.0, 10.7, 11.7, 14.4, 18.7, 19.0, 25.8, and 28.4 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (b) a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having characteristic peaks at about 5.1, 8.5, 9.4, 10.0, 10.7, 11.5, 11.7, 14.4, 15.7, 18.6, 19.8, 20.6, and 21.4 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation (Form B); (c) a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.0, 5.3, 7.6, 9.0, 9.7, 11.2, 12.3, 12.9, 13.7, 14.5, 15.9, and 19.0 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (d) a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base, characterized by an X-ray powder diffraction pattern having characteristic peaks at about 7.3, 8.6, 10.6, and 12.9 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation (Form D); (e) A crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate (Form E), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.6, 9.3, 11.6, 13.2, 13.5, 13.7, 15.1, 18.1, 18.5, 19.3, 25.7, and 27.0 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; and optionally A crystalline form characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 44° C. and a peak at about 58° C., a characteristic endotherm with an onset of about 110° C. and a peak at about 114° C., and a characteristic endotherm with an onset of about 166° C. and a peak at about 177° C. (Form E); (f) a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base (Form F), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.5, 7.0, 8.2, 9.0, 9.3, 12.5, 13.5, 15.3, 17.8, 18.7, 22.6, and 26.8 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (g) A crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base hydrate (Form H), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 5.3, 7.2, 8.5, 10.4, 12.4, 13.3, 17.0, 19.5, 22.6, 24.5, 26.2, and 26.7 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; and optionally A crystalline form characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 58° C. and a peak at about 84° C., a characteristic endotherm with an onset of about 63° C. and a peak at about 89° C., and a characteristic endotherm with an onset of about 169° C. and a peak at about 176° C. (Form H); (h) a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base (Form I), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 5.2, 7.0, 8.4, 10.4, 12.2, 13.1, 16.8, 19.2, 20.7, 22.3, and 25.9 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (i) a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base (Form J), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.1, 6.2, 8.0, 9.3, 12.8, 16.6, 18.4, 23.8, 24.4, and 28.3 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (j) A crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base (Form K), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.4, 9.6, 10.5, 13.6, 19.4, 21.0, 22.4, 23.4, 23.7, 25.2, and 26.9 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; and optionally A crystalline form characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 226° C. and a peak at about 230° C. (Form K); (k) a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base (Form L), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.7, 8.3, 9.1, 9.5, 11.9, 12.2, 14.3, 16.2, 20.5, 21.9, 23.1, and 25.5 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (l) a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base (Form M), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.4, 6.8, 8.3, 9.6, 12.7, 13.4, 14.3, 17.3, 19.6, 21.0, 23.9, and 26.5 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (m) a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base (Form N), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 5.6, 6.1, 6.9, 7.2, 8.4, 11.8, 13.7, 14.5, 17.3, 19.8, 21.9, 24.9, and 25.7 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (n) A crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base (Form O), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 9.0, 10.6, 11.3, 14.1, 15.8, 16.3, 17.6, 19.5, 21.3, 22.7, 22.9, 25.1, and 28.7 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; and optionally A crystalline form characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 166° C. and a peak at about 172° C., and a characteristic endotherm with an onset of about 196° C. and a peak at about 204° C. (Form O); (o) a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base (Form Q), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.8, 5.8, 7.7, 9.6, 11.6, 13.8, 14.7, 19.9, 21.5, 24.1, 24.7, and 27.4 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (p) A crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base (Form R), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 7.5, 8.5, 10.1, 12.8, 14.8, 15.6, 16.9, 17.4, 18.3, 19.5, 20.0, and 21.8 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; and optionally A crystalline form characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 148° C. and a peak at about 152° C., and a characteristic endotherm with an onset of about 241° C. and a peak at about 251° C. (Form R); (q) a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base (Form S), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 5.0, 5.9, 8.0, 9.7, and 11.8 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (r) a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base (Form T), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 7.0, 8.7, 10.3, 11.8, 14.1, 17.0, 20.9, 22.4, 24.5, 25.5, and 27.9 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; and optionally A crystalline form characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 83° C. and a peak at about 84° C., and a characteristic endotherm with an onset of about 249° C. and a peak at about 251° C. (Form T); (s) a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base (Form U), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.2, 6.9, 7.6, 9.0, 10.5, 12.3, and 14.5 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (t) a crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base (Form V), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.0, 8.0, 10.8, 12.0, 15.6, 15.9, 16.8, 18.3, 19.7, 20.9, 21.0, and 26.3 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (u) A crystalline form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, free base (Form W), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.3, 8.6, 12.9, 15.2, 23.3, and 26.0 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation.

6. 13. A pharmaceutical composition comprising the crystalline form of claim 1 and a pharma- ceutically acceptable excipient.

7. 6. A pharmaceutical composition comprising the crystalline form of claim 5 and a pharma- ceutically acceptable excipient.

8. 2. A pharmaceutical composition formed from the crystalline form of claim 1.

9. The pharmaceutical composition of claim 6 , wherein the composition is a formulation for oral administration.

10. 13. A drug substance comprising at least a detectable amount of the crystalline form of claim 1.

11. 2. A drug substance comprising the substantially pure crystalline form of claim 1.

12. A pharma- ceutically acceptable salt of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, said salt being selected from the group consisting of benzenesulfonate, citrate, fumarate, maleate, L-malate, methanesulfonate, phosphate, pyruvate, sulfate, L-tartrate, toluenesulfonate, and hydrates and solvates thereof.

13. A pharmaceutically acceptable crystalline salt form of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine, said crystalline salt being selected from the group consisting of benzenesulfonate, citrate, fumarate, hydrochloride, maleate, L-malate, methanesulfonate, phosphate, pyruvate, sulfate, L-tartrate, and toluenesulfonate salts, and crystalline hydrates and solvates thereof.

14. The crystalline salt form is (a) a crystalline form (Form 1-A) of the Benzenesulfonate Salt, characterized by an X-ray powder diffraction pattern having characteristic peaks at about 5.1, 6.5, 6.8, 7.0, 9.6, 12.1, 14.8, 15.1, 15.5, 16.4, 18.6, and 21.3 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (b) a crystalline form (Form 1-B) of the Benzenesulfonate Salt, characterized by an X-ray powder diffraction pattern having characteristic peaks at about 5.3, 6.2, 6.7, 8.2, 10.0, 10.6, 12.3, 14.0, 15.6, 16.0, 16.2, and 22.1 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; and optionally a benzenesulfonate salt characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 33° C. and a peak at about 71° C., a characteristic endotherm with an onset of about 120° C. and a peak at about 133° C., and a characteristic endotherm with an onset of about 154° C. and a peak at about 159° C.; (c) a crystalline form of the Citrate Salt (Form 2-A), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.7, 7.0, 7.9, 9.1, 10.2, 11.4, 12.5, 13.7, 14.1, 15.1, 18.3, and 19.0 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (d) a crystalline form of the Citrate Salt (Form 2-B), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.7, 7.9, 9.3, 11.2, 12.5, 13.8, 15.2, 17.0, 18.4, 19.5, 22.3, and 28.5 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (e) a crystalline form of the Citrate Salt (Form 2-C), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.7, 7.9, 9.1, 12.5, 13.6, 14.3, 15.0, 16.9, 18.2, 19.2, 22.1, and 29.0 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; and optionally Citric acid characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 33° C. and a peak at about 60° C., a characteristic endotherm with an onset of about 96° C. and a peak at about 116° C., a characteristic endotherm with an onset of about 160° C. and a peak at about 169° C., and a characteristic endotherm with an onset of about 141° C. and a peak at about 177° C.; (f) a crystalline form (Form 3-A) of Fumarate Salt characterized by an X-ray powder diffraction pattern having characteristic peaks at about 7.1, 8.2, 14.3, 16.5, 18.0, 18.9, 21.9, 22.1, 22.4, 24.5, 24.8, and 25.4 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation, and optionally comprising: Fumaric acid, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 237° C. and a peak at about 241° C.; (g) the hydrochloride salt in a crystalline form (Form 5-A) characterized by an X-ray powder diffraction pattern having characteristic peaks at about 5.0, 7.8, 8.1, 9.3, 12.2, 13.5, 13.9, 14.1, 19.3, 20.3, 21.3, and 25.2 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (h) a crystalline form (Form 5-B) of the hydrochloride salt characterized by an X-ray powder diffraction pattern having characteristic peaks at about 7.4, 9.1, 9.9, 11.7, 14.2, 17.5, 20.0, 21.2, 21.8, 23.9, 25.7, and 27.6 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation, and optionally a hydrochloride salt characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 68° C. and a peak at about 82° C., a characteristic endotherm with an onset of about 111° C. and a peak at about 130° C., and a characteristic endotherm with an onset of about 193° C. and a peak at about 211° C.; (i) a crystalline form (Form 5-C) of the hydrochloride salt characterized by an X-ray powder diffraction pattern having characteristic peaks at about 10.7, 11.8, 12.9, 16.2, 18.1, 20.5, 21.5, 22.4, 23.9, 26.4, 27.0, and 28.9 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; and optionally a hydrochloride salt characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 140° C. and a peak at about 145° C., and a characteristic endotherm with an onset of about 213° C. and a peak at about 230° C.; (j) a crystalline form (Form 5-D) of the hydrochloride salt characterized by an X-ray powder diffraction pattern having characteristic peaks at about 7.8, 8.4, 12.7, 14.0, 15.0, 17.0, 22.9, 25.6, and 26.0 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (k) a crystalline form of the maleate Salt (Form 7-A), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 7.2, 8.3, 14.3, 14.9, 16.5, 18.9, 21.5, 22.7, 25.3, 25.9, 27.2, and 27.5 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation, and optionally a hydrochloride salt characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 215° C. and a peak at about 221° C., and a characteristic endotherm with an onset of about 216° C. and a peak at about 225° C.; (l) a crystalline form (Form 8-A) of L-Malate Salt characterized by an X-ray powder diffraction pattern having characteristic peaks at about 7.3, 8.3, 11.0, 14.3, 15.0, 16.6, 19.0, 21.6, 22.0, 24.7, 25.5, and 27.3 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation, and optionally L-Malic acid characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 177° C. and a peak at about 201° C., a characteristic endotherm with an onset of about 186° C. and a peak at about 207° C., a characteristic endotherm with an onset of about 205° C. and a peak at about 211° C., and a characteristic endotherm with an onset of about 208° C. and a peak at about 216° C.; (m) a crystalline form (Form 8-B) of L-Malate Salt characterized by an X-ray powder diffraction pattern having characteristic peaks at about 5.9, 9.1, 11.6, 16.3, 17.6, 18.2, 19.1, 21.2, 22.9, 23.8, 27.1, and 28.4 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation, and optionally L-Malic acid, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 189° C. and a peak at about 192° C., and a characteristic endotherm with an onset of about 186° C. and a peak at about 202° C.; (n) a crystalline form (Form 9-A) of the methanesulfonate salt characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.5, 5.4, 7.5, 9.1, 9.5, 10.1, 14.7, 15.0, 15.7, 18.0, 20.1, and 21.5 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (o) a crystalline form (Form 9-B) of Methanesulfonate, characterized by an X-ray powder diffraction pattern having characteristic peaks at about 8.2, 8.7, 13.7, 14.7, 16.2, 18.9, 22.3, 22.8, 24.4, 27.0, 27.5, and 28.9 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation, and optionally comprising: a methanesulfonate salt characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 51° C. and a peak at about 74° C., and a characteristic endotherm with an onset of about 177° C. and a peak at about 187° C.; (p) a crystalline form (Form 9-C) of the Methanesulfonate Salt, characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.5, 7.6, 9.2, 9.5, 10.2, 10.9, 14.8, 15.0, 15.9, 18.2, 20.4, and 21.8 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; (q) a crystalline form (Form 10-A) of Phosphate Salt characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.2, 8.5, 10.2, 10.8, 11.5, 12.3, 15.7, 18.4, 20.5, 21.2, 22.9, and 25.8 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation, and optionally a phosphate salt characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 282° C. and a peak at about 290° C., and a characteristic endotherm with an onset of about 283° C. and a peak at about 294° C.; (r) a crystalline form of Pyruvate (Form 11-A), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.4, 4.9, 7.2, 7.5, 8.6, 9.1, 9.9, 11.4, 13.1, 14.5, 14.7, and 17.2 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; and optionally a pyruvate salt characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 76° C. and a peak at about 88° C., a characteristic endotherm with an onset of about 134° C. and a peak at about 142° C., and a characteristic endotherm with an onset of about 149° C. and a peak at about 157° C.; (s) a crystalline form (Form 12-A) of Sulfate Salt characterized by an X-ray powder diffraction pattern having characteristic peaks at about 5.9, 6.6, 7.9, 8.2, 9.6, 11.8, 14.7, 15.3, 17.1, 17.7, 18.9, and 22.6 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; and optionally Sulfate Salt, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 48° C. and a peak at about 81° C., a characteristic endotherm with an onset of about 169° C. and a peak at about 185° C., and a characteristic endotherm with an onset of about 229° C. and a peak at about 241° C.; (t) a crystalline form (Form 13-A) of the L-Tartrate Salt characterized by an X-ray powder diffraction pattern having characteristic peaks at about 8.0, 8.7, 11.1, 14.2, 15.9, 17.3, 19.5, 21.6, 23.1, 23.6, 26.9, and 28.2 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; and optionally L-Tartrate salt characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 213° C. and a peak at about 222° C.; (u) a crystalline form (Form 13-B) of the L-Tartrate Salt, characterized by an X-ray powder diffraction pattern having characteristic peaks at about 7.1, 8.7, 11.8, 16.9, 20.8, 21.8, 22.2, 24.1, 25.1, 25.3, 27.0, and 27.7 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; and optionally the L-tartrate salt, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 89° C. and a peak at about 115° C., a characteristic endotherm with an onset of about 157° C. and a peak at about 167° C., and a characteristic endotherm with an onset of about 181° C. and a peak at about 195° C.; (v) a crystalline form (Form 14-A) of the Toluenesulfonate Salt, characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.4, 6.1, 6.4, 6.7, 8.8, 9.5, 10.3, 15.3, 17.5, 21.3, 21.9, and 27.2 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation; or 14. The crystalline salt form of claim 13, wherein (w) is a crystalline form (Form 14-B) of the toluenesulfonate salt characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.8, 7.7, 12.9, 15.3, 17.2, 21.4, 22.4, 24.7, and 25.9 degrees 2θ, wherein said X-ray powder diffraction pattern was obtained using Cu Kα radiation.

15. 15. A pharmaceutical composition comprising the crystalline salt form of claim 14 and a pharma- ceutically acceptable excipient.

16. 15. A pharmaceutical composition formed from the crystalline salt form of claim 14.

17. 15. A drug substance comprising at least a detectable amount of the crystalline salt form of claim 14.

18. 15. A drug substance comprising the substantially pure crystalline salt form of claim 14.

19. The pharmaceutical composition of claim 7, which is a formulation for oral administration.

20. A drug substance comprising at least a detectable amount of the crystalline form described in claim 5.

21. A drug substance comprising the substantially pure crystalline form of claim 5.

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