Macrocyclopyridine

Abstract

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

Description

[0001] Cross-reference

[0002] This application claims priority to U.S. Provisional Application No. 63 / 170,212, filed April 2, 2021, which is incorporated herein by reference in its entirety. Background Technology

[0003] Polycomb Repressive Complex 2 (PRC2) is a multi-subunit chromatin regulatory complex that plays a role in the repression of gene expression and is dysregulated in many human diseases. PRC2 comprises SUZ12 (a repressor of zeste 12), EED (embryonic ectoderm development), and the catalytic subunit EZH2 (an enhancer of zeste homolog 2), and represses genes by methylating histone H3 (H3K27me3) at and around the promoter region of the gene. EED mediates the repression of gene activity by binding to the H3K27me3 marker, where it allosterically activates the methyltransferase activity of PRC2 (e.g., trimethylation of lysine 27 on histone H3 (H3K27me3)). This key component of chromatin regulation is involved in the regulation of gene transcription and plays a crucial role in development, differentiation, and regeneration.

[0004] EED regulates PRC2 in the silencing of expression of genes and gene clusters involved in development (such as fetal orthologs (e.g., γ-globin), Hox genes) and in X chromosome inactivation. Aberrant expression of PRC2 has also been observed in various human cancers, such as hepatocellular carcinoma, breast cancer, and prostate cancer. Therefore, EED and / or PRC2 provide pharmacological targets for treating diseases or conditions (e.g., cancer and hematologic disorders) by influencing the transcription of specific target genes in, for example, blood and other tissues.

[0005] Polymorphism is the ability of a substance to crystallize in more than one lattice arrangement. Crystallization or polymorphism can affect many aspects of the solid-state properties of a drug substance. Crystalline substances can differ significantly from their amorphous forms, and different crystalline variants of a substance can differ significantly from each other in many ways, including solubility, dissolution rate, and / or bioavailability. Generally, it is difficult to predict whether a given compound will form any crystalline solid form. Even more difficult is predicting the physical properties of these crystalline solid forms. Furthermore, for certain formulations and / or methods of preparation, therapeutic agents in crystalline form may be advantageous. Summary of the Invention

[0006] This disclosure relates at least in part to the crystalline form of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene.

[0007] For example, this document discloses the 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]benzofurano[4,3-fg][1,4]oxazacyclononazone anhydrous free base, characterized by a powder X-ray diffraction pattern having characteristic peaks at approximately 7.6 degrees 2θ, for example characterized by peaks at approximately 7.6, 11.9, and 15 degrees 2θ. A powder X-ray diffraction pattern having a characteristic peak at approximately 7.6, 11.9, 14.5, 15.3, 20.7, and 22.6 degrees, specifically a powder X-ray diffraction pattern having a characteristic peak at approximately 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 ...20.7, and 22.6 degrees, specifically a powder X-ray diffraction pattern having a characteristic peak at approximately 7.6, 11.9, 14.5, 15.3, 16.

[0008] This document also discloses pharmaceutically acceptable 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene. For example, the disclosed crystalline salt forms may be selected from benzenesulfonate, citrate, fumarate, hydrochloride, maleate, L-malate, methanesulfonate, phosphate, pyruvate, sulfate, L-tartrate, and toluenesulfonate, as well as their crystalline hydrates and solvates.

[0009] (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene is, for example, a regulator of EED and / or a regulator of PRC2, and is represented by the following formula:

[0010]

[0011] This article further anticipates pharmaceutical compositions comprising, in the disclosed crystalline free base form or 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene, and pharmaceutically acceptable excipients, for example, for formulation of compositions for oral, subcutaneous, or intravenous administration. This document further anticipates the inclusion of a drug substance comprising at least a detectable amount of a disclosed crystalline free base or a disclosed crystalline 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]benzofurano[4,3-fg][1,4]oxazacyclononatrane. For example, this document discloses a drug substance comprising a substantially pure crystalline free base or a crystalline 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]benzofurano[4,3-fg][1,4]oxazacyclononatrane.

[0012] This article also provides methods for treating blood disorders (such as sickle cell disease or β-thalassemia) in patients with this need, including administering an effective dose ( S )-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7 H -[1,2,4]triazolo[4',3':1,6]pyrido[3,2- b ]Benzofurano[4,3- fg [1,4]Ozazacyclononatetraene is disclosed in its crystalline free base form or crystalline salt form. For example, methods for treating hematologic disorders (e.g., sickle cell disease or β-thalassemia) in patients with this need are provided herein, comprising administering to the patient an effective amount containing ( S )-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7 H -[1,2,4]triazolo[4',3':1,6]pyrido[3,2- b ]Benzofurano[4,3- fg [1,4] Disclosed crystalline free base forms of oxazacyclononatetraene or pharmaceutical compositions comprising ( S )-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7 H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2- b ]Benzofurano[4,3- fg Pharmaceutical compositions in the form of the disclosed crystalline salt of [1,4]oxazonite nonazone.

[0013] This article also provides methods for treating cancer in patients with this need, including 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene. For example, this article provides a method of treating cancer in a patient with this need, comprising administering to the patient an effective amount of a pharmaceutical composition in the form of a publicly disclosed crystalline free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene or in the form of a publicly disclosed crystalline 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene. Attached Figure Description

[0014] Figure 1 X-ray powder diffraction (XRPD) patterns of the crystal 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene anhydrous free base are depicted.

[0015] Figure 2 The characterization of crystal form P by differential scanning calorimetry (DSC) is described.

[0016] Figure 3 X-ray powder diffraction (XRPD) pattern of crystal 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base is depicted.

[0017] Figure 4The 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base form B is depicted.

[0018] Figure 5 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base form C are depicted.

[0019] Figure 6 The X-ray powder diffraction (XRPD) pattern of the free base 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene is depicted.

[0020] Figure 7 X-ray powder diffraction (XRPD) patterns were depicted for the 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base hydrate.

[0021] Figure 8 The form E was characterized by differential scanning calorimetry (DSC).

[0022] Figure 9 X-ray powder diffraction (XRPD) patterns were depicted for the free base 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene.

[0023] Figure 10X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base hydrate form H are depicted.

[0024] Figure 11 The form H was characterized by differential scanning calorimetry (DSC).

[0025] Figure 12 X-ray powder diffraction (XRPD) patterns were depicted for 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base.

[0026] Figure 13 X-ray powder diffraction (XRPD) patterns were depicted for the free base 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene.

[0027] Figure 14 X-ray powder diffraction (XRPD) patterns of the free base 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene are depicted.

[0028] Figure 15 The form K was characterized by differential scanning calorimetry (DSC).

[0029] Figure 16 X-ray powder diffraction (XRPD) patterns were depicted for the free base 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene.

[0030] Figure 17The 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base M is depicted.

[0031] Figure 18 X-ray powder diffraction (XRPD) patterns of N in the form of a free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene were depicted.

[0032] Figure 19 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base O were depicted.

[0033] Figure 20 The form O was characterized by differential scanning calorimetry (DSC).

[0034] Figure 21 X-ray powder diffraction (XRPD) patterns were depicted for the free base 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene.

[0035] Figure 22 X-ray powder diffraction (XRPD) patterns 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene in the form of R.

[0036] Figure 23 The form R was characterized by differential scanning calorimetry (DSC).

[0037] Figure 24X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base form of S are depicted.

[0038] Figure 25 X-ray powder diffraction (XRPD) patterns were depicted for the free base 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene.

[0039] Figure 26 The form T was characterized by differential scanning calorimetry (DSC).

[0040] Figure 27 The X-ray powder diffraction (XRPD) pattern of the free base 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene is depicted.

[0041] Figure 28 X-ray powder diffraction (XRPD) patterns were depicted for the free base 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene.

[0042] Figure 29 X-ray powder diffraction (XRPD) patterns were depicted for the free base 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene.

[0043] Figure 30X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaterenebenzenesulfonate form 1-A are depicted.

[0044] Figure 31 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaterenebenzenesulfonate form 1-B were depicted.

[0045] Figure 32 Form 1-B was characterized by differential scanning calorimetry (DSC).

[0046] Figure 33 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene citrate form 2-A were depicted.

[0047] Figure 34 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene citrate form 2-B were depicted.

[0048] Figure 35 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene citrate in 2-C form were depicted.

[0049] Figure 36 The form 2-C was characterized by differential scanning calorimetry (DSC).

[0050] Figure 37X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene fumarate form 3-A were depicted.

[0051] Figure 38 Form 3-A was characterized by differential scanning calorimetry (DSC).

[0052] Figure 39 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaquaternene hydrochloride in form 5-A is depicted.

[0053] Figure 40 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene hydrochloride in the form of 5-B were depicted.

[0054] Figure 41 Form 5-B was characterized by differential scanning calorimetry (DSC).

[0055] Figure 42 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene hydrochloride in 5-C form were depicted.

[0056] Figure 43 The form 5-C was characterized by differential scanning calorimetry (DSC).

[0057] Figure 44 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene hydrochloride in 5-D form were depicted.

[0058] Figure 45 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene maleate form 7-A were depicted.

[0059] Figure 46 Form 7-A was characterized by differential scanning calorimetry (DSC).

[0060] Figure 47 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene L-malate is depicted.

[0061] Figure 48 Form 8-A was characterized by differential scanning calorimetry (DSC).

[0062] Figure 49 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene L-malate form 8-B were depicted.

[0063] Figure 50 Form 8-B was characterized by differential scanning calorimetry (DSC).

[0064] Figure 51 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratemethanesulfonate form 9-A is depicted.

[0065] Figure 52X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratemethanesulfonate form 9-B were depicted.

[0066] Figure 53 Form 9-B was characterized by differential scanning calorimetry (DSC).

[0067] Figure 54 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratemethanesulfonate in 9-C form were depicted.

[0068] Figure 55 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine phosphate in 10-A form are depicted.

[0069] Figure 56 Form 10-A was characterized by differential scanning calorimetry (DSC).

[0070] Figure 57 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazahexacyclic nonaterenepyruvate form 11-A are depicted.

[0071] Figure 58 Form 11-A was characterized by differential scanning calorimetry (DSC).

[0072] Figure 59 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratete sulfate in the form of 12-A were depicted.

[0073] Figure 60 Form 12-A was characterized by differential scanning calorimetry (DSC).

[0074] Figure 61 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene L-tartrate were depicted.

[0075] Figure 62 Form 13-A was characterized by differential scanning calorimetry (DSC).

[0076] Figure 63 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene L-tartrate form 13-B were depicted.

[0077] Figure 64 Form 13-B was characterized by differential scanning calorimetry (DSC).

[0078] Figure 65 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene toluenesulfonate form 14-A is depicted.

[0079] Figure 66 X-ray powder diffraction (XRPD) patterns of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene toluenesulfonate form 14-B were depicted.

[0080] Figure 67X-ray powder diffraction (XRPD) patterns of the 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base were depicted. Line (1) depicts the material in form E, and line (2) depicts the amorphous material after evaporation of THF from form E at 50 °C under atmosphere and further drying of the residue at 50 °C under vacuum.

[0081] Figure 68 X-ray powder diffraction (XRPD) patterns were depicted for 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene obtained from crystallization in various solvents. Detailed Implementation

[0082] The features and other details of this disclosure will now be described in more specific terms. Before further describing this disclosure, certain terms used in the specification, embodiments, and appended claims are collected herein. These definitions should be read in light of the remainder of this 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 one of ordinary skill in the art.

[0083] definition

[0084] The term "crystalline form" refers to a crystal form or polymorph that can be characterized by analytical methods such as X-ray powder diffraction (XRPD) and / or differential scanning calorimetry (DSC). The crystalline compounds disclosed herein can exist in both solvated and non-solvated forms with solvents such as water and ethanol. Unless otherwise stated or inferred, the disclosed crystalline compounds are intended to include both solvated and non-solvated forms.

[0085] "Treatment" includes any effect that leads to improvement of a condition, disease, symptom, etc., such as relief, reduction, regulation, or elimination.

[0086] The term “symptom” means the term “disease,” “condition,” or “illness” and may be used interchangeably with it unless otherwise stated.

[0087] "Pharmaceutical or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other adverse reactions when properly administered to animals or humans. For human use, formulations should meet the sterility, pyrogenicity, and general safety and purity standards required by the FDA Office of Biologics Standards.

[0088] As used herein, the terms "pharmaceuticalally acceptable excipient" or "pharmaceuticalally acceptable carrier" refer to any and all solvents, dispersion media, coatings, isotonic agents, and absorption delay agents compatible with drug 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 complementary, additional, or enhanced therapeutic functions.

[0089] As used herein, the term "pharmaceutical composition" means a composition comprising at least one of the compounds disclosed herein formulated together with one or more pharmaceutically acceptable excipients.

[0090] The terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans. The compounds disclosed herein can be applied to mammals, such as humans, but can also be applied to other mammals, such as animals requiring veterinary treatment, such as domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammals treated in the methods of this disclosure are desirable mammals that require treatment for, for example, cancer or blood disorders. “Regulation” includes antagonistic effects (e.g., inhibition), agonistic effects, partially antagonistic effects, and / or partially agonistic effects.

[0091] In this specification, the terms "effective amount" or "therapeutic effective amount" refer to the amount of the subject compound that will elicit a biological or medical response in a tissue, system, or animal (e.g., a mammal or a human) sought by a researcher, veterinarian, physician, or other clinician. The compounds of this disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and / or preventative effect.

[0092] As used herein, the term "pharmaceutically acceptable salt" refers to a salt containing a basic group that can be present in the compound used in the composition. The basic compounds contained in the compositions of this invention are capable of forming a wide variety of salts with various inorganic and organic acids.

[0093] The term “and / or” is used in this disclosure to mean “and” or “or”, unless otherwise stated.

[0094] As used herein, the terms “a” and “an” are intended to include one or more / a combination of reagents, unless otherwise stated. For example, the term “a reagent” covers a single reagent and a combination of two or more reagents.

[0095] When the term "about" is used before a quantitative value, this disclosure also includes the specific quantitative value itself, unless otherwise specified. As used herein, "about" means ±10% variation from the nominal value, unless otherwise stated or inferred. In the context of a peak at 2θ (degrees), the term "about" means an uncertainty of ±0.5 (expressed as 2θ) in the measurement of 2θ, or an uncertainty of ±0.2 (expressed as 2θ) in the measurement of 2θ.

[0096] Crystalline form

[0097] This disclosure relates at least in part to the crystalline form of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene.

[0098] For example, this paper discloses the 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene anhydrous free base, characterized by a powder X-ray diffraction pattern (referred to herein as “crystalline form P”) with a characteristic peak at approximately 7.6 degrees 2θ.

[0099] In one embodiment, the crystalline form P of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaquaternene anhydrous free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 11.9 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 14.5 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 15.3 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 16.1 degrees 2θ. The powder X-ray diffraction pattern is characterized by having a characteristic peak at approximately 17.2 degrees 2θ, a characteristic peak at approximately 17.3 degrees 2θ, a characteristic peak at approximately 20.7 degrees 2θ, a characteristic peak at approximately 22.6 degrees 2θ, a characteristic peak at approximately 23.3 degrees 2θ, a characteristic peak at approximately 26.2 degrees 2θ, and / or a characteristic peak at approximately 24.5 degrees 2θ. In another embodiment, the crystalline form P is characterized by having a powder X-ray diffraction pattern having at least one or more characteristic peaks at approximately 7.6, 11.9, and 15.3 degrees 2θ. In a further embodiment, the crystalline form P is characterized by having a powder X-ray diffraction pattern having at least one or more characteristic peaks represented by degrees 2θ at approximately 7.6, 11.9, 14.5, 15.3, 20.7, and 22.6. In yet another embodiment, the crystalline form P is characterized by having a powder X-ray diffraction pattern having at least one or more characteristic peaks represented by degrees 2θ at approximately 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. For example, the desired crystalline form has Figure 1 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0100] The expected crystalline form P of the anhydrous free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene can be characterized by differential scanning calorimetry (DSC) curves, showing a characteristic endotherm with an onset temperature of approximately 252 °C and a peak temperature of approximately 253 °C. Crystalline form P can be characterized, for example, by... Figure 2 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0101] The expected crystalline form P of the anhydrous free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene can be characterized by thermogravimetric analysis (TGA) curves, showing a mass loss of approximately 0.46 wt% up to approximately 260 °C. In some embodiments, crystalline form P can be characterized by dynamic vapor adsorption (DVS) curves, showing a reversible total mass change of approximately 0.53 wt% at 25 °C between approximately 2 and approximately 92% relative humidity (RH). In other embodiments, crystalline form P can be characterized by optical microscopy, showing a rod-like and / or plate-like morphology.

[0102] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form A”) with a characteristic peak at approximately 8.5 degrees 2θ.

[0103] In one embodiment, the crystalline form A of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 5.9 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 9.3 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 9.5 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 10.0 degrees 2θ. Powder X-ray diffraction patterns, characterized by having a characteristic peak at approximately 10.7 degrees 2θ, characterized by having a characteristic peak at approximately 11.7 degrees 2θ, characterized by having a characteristic peak at approximately 14.4 degrees 2θ, characterized by having a characteristic peak at approximately 18.7 degrees 2θ, characterized by having a characteristic peak at approximately 19.0 degrees 2θ, characterized by having a characteristic peak at approximately 25.8 degrees 2θ, and / or characterized by having a characteristic peak at approximately 28.4 degrees 2θ. In yet another embodiment, crystalline form A is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline form has... Figure 3 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0104] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form B”) with a characteristic peak at approximately 8.5 degrees 2θ.

[0105] In one embodiment, the crystalline form B of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 5.1 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 9.4 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 9.5 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 10.0 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 10.7 degrees 2θ. Powder X-ray diffraction patterns with characteristic peaks expressed in degrees 2θ, characterized in that a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 11.5, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 11.7, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 14.4, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 15.7, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 18.6, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 20.6, and / or a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 21.4. In yet another embodiment, crystalline form B is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline form has... Figure 4 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation. In other embodiments, crystalline form B can be characterized by optical microscopy, which reveals a hair-like morphology.

[0106] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form C”) having a characteristic peak at approximately 9.0 degrees 2θ.

[0107] In one embodiment, the crystalline form C of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 4.0 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 5.3 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 7.6 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 9.7 degrees 2θ. Figure 1, characterized in that it has a powder X-ray diffraction pattern with a characteristic peak at approximately 11.2 degrees 2θ, characterized in that it has a powder X-ray diffraction pattern with a characteristic peak at approximately 12.3 degrees 2θ, characterized in that it has a powder X-ray diffraction pattern with a characteristic peak at approximately 12.9 degrees 2θ, characterized in that it has a powder X-ray diffraction pattern with a characteristic peak at approximately 13.7 degrees 2θ, characterized in that it has a powder X-ray diffraction pattern with a characteristic peak at approximately 14.5 degrees 2θ, characterized in that it has a powder X-ray diffraction pattern with a characteristic peak at approximately 15.9 degrees 2θ, and / or characterized in that it has a powder X-ray diffraction pattern with a characteristic peak at approximately 19.0 degrees 2θ. In yet another embodiment, crystalline form C is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline form has... Figure 5 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0108] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form D”) having a characteristic peak at approximately 8.6 degrees 2θ.

[0109] In one embodiment, the crystalline form D of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 7.3 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 10.6 degrees 2θ, and / or characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 12.9 degrees 2θ. In yet another embodiment, the crystalline form D is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at approximately 7.3, 8.6, 10.6, and 12.9 degrees 2θ. For example, the desired crystalline form has Figure 6 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0110] In another embodiment, different crystalline 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free alkali hydrate are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form E”) with a characteristic peak at approximately 4.6 degrees 2θ.

[0111] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene free base hydrate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 9.3 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 11.6 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 13.2 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 13.5 degrees 2θ. Powder X-ray diffraction patterns, characterized by having a characteristic peak at approximately 13.7 degrees 2θ, characterized by having a characteristic peak at approximately 15.1 degrees 2θ, characterized by having a characteristic peak at approximately 18.1 degrees 2θ, characterized by having a characteristic peak at approximately 18.5 degrees 2θ, characterized by having a characteristic peak at approximately 19.3 degrees 2θ, characterized by having a characteristic peak at approximately 25.7 degrees 2θ, and / or characterized by having a characteristic peak at approximately 27.0 degrees 2θ. In yet another embodiment, the crystalline form E is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline form has… Figure 7 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0112] The expected 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratete free alkaline hydrate can be characterized by differential scanning calorimetry (DSC) curves, showing characteristic endothermic peaks at an onset temperature of approximately 44 °C and a peak temperature of approximately 58 °C, characteristic endothermic peaks at an onset temperature of approximately 110 °C and a peak temperature of approximately 114 °C, and characteristic endothermic peaks at an onset temperature of approximately 166 °C and a peak temperature of approximately 177 °C. Crystal form E can be characterized, for example, by... Figure 8 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0113] The expected 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base hydrate can be characterized by thermogravimetric analysis (TGA) curves, showing a mass loss of approximately 5.1 wt% up to approximately 170 °C. In some embodiments, crystalline form E can be characterized by dynamic vapor adsorption (DVS) curves, showing a reversible total mass change of approximately 10.3 wt% at 25 °C between approximately 2 and approximately 92% relative humidity (RH). In other embodiments, crystalline form E can be characterized by optical microscopy, showing a hair-like morphology.

[0114] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form F”) with a characteristic peak at approximately 4.5 degrees 2θ.

[0115] In one embodiment, the crystalline form F of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 7.0 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 8.2 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 9.0 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 9.3 degrees 2θ. Figure 1, characterized in that it has a powder X-ray diffraction pattern with a characteristic peak at approximately 12.5 degrees 2θ, characterized in that it has a powder X-ray diffraction pattern with a characteristic peak at approximately 13.5 degrees 2θ, characterized in that it has a powder X-ray diffraction pattern with a characteristic peak at approximately 15.3 degrees 2θ, characterized in that it has a powder X-ray diffraction pattern with a characteristic peak at approximately 17.8 degrees 2θ, characterized in that it has a powder X-ray diffraction pattern with a characteristic peak at approximately 18.7 degrees 2θ, characterized in that it has a powder X-ray diffraction pattern with a characteristic peak at approximately 22.6 degrees 2θ, and / or characterized in that it has a powder X-ray diffraction pattern with a characteristic peak at approximately 26.8 degrees 2θ. In yet another embodiment, the crystalline form F is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline form has… Figure 9 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0116] In another embodiment, different crystalline 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free alkali hydrate are disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 8.5 degrees 2θ (referred to herein as "crystal form H").

[0117] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene free base hydrate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 5.3 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 7.2 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 10.4 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 12.4 degrees 2θ. Powder X-ray diffraction patterns, characterized by having a characteristic peak at approximately 13.3 degrees 2θ, characterized by having a characteristic peak at approximately 17.0 degrees 2θ, characterized by having a characteristic peak at approximately 19.5 degrees 2θ, characterized by having a characteristic peak at approximately 22.6 degrees 2θ, characterized by having a characteristic peak at approximately 24.5 degrees 2θ, characterized by having a characteristic peak at approximately 26.2 degrees 2θ, and / or characterized by having a characteristic peak at approximately 26.7 degrees 2θ. In yet another embodiment, the crystalline form H is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline form has... Figure 10 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0118] The expected 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratete free alkaline hydrate can be characterized by differential scanning calorimetry (DSC) curves, showing characteristic endothermic peaks at an onset temperature of approximately 58 °C and a peak temperature of approximately 84 °C, characteristic endothermic peaks at an onset temperature of approximately 63 °C and a peak temperature of approximately 89 °C, and characteristic endothermic peaks at an onset temperature of approximately 169 °C and a peak temperature of approximately 176 °C. Crystalline form H can be characterized, for example, by... Figure 11 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0119] The expected 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base hydrate can be characterized by thermogravimetric analysis (TGA) curves, showing a mass loss of approximately 6.3 wt% up to approximately 130 °C. In some embodiments, crystalline form H can be characterized by dynamic vapor adsorption (DVS) curves, showing a reversible total mass change of approximately 7.6 wt% at 25 °C between approximately 2 and approximately 92% relative humidity (RH). In other embodiments, crystalline form H can be characterized by optical microscopy, showing a hair-like morphology.

[0120] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form I”) with a characteristic peak at approximately 8.4 degrees 2θ.

[0121] In one embodiment, the crystalline form I of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 5.2 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 7.0 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 10.4 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 12.2 degrees 2θ. Powder X-ray diffraction patterns with characteristic peaks expressed in degrees 2θ, characterized in that a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 13.1, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 16.8, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 19.2, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 20.7, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 22.3, and / or a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 25.9. In yet another embodiment, crystalline form I is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 5.2, 7.0, 8.4, 10.4, 12.2, 13.1, 16.8, 19.2, 20.7, 22.3, and 25.9. For example, the desired crystalline form has… Figure 12 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation. In other embodiments, crystalline form I can be characterized by optical microscopy, which reveals a hair-like morphology.

[0122] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form J”) with a characteristic peak at approximately 4.1 degrees 2θ.

[0123] In one embodiment, the crystalline form J of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 6.2 degrees 2θ, and further characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 8.0 degrees 2θ, and further characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 9.3 degrees 2θ. The powder X-ray diffraction pattern is characterized by having a characteristic peak at approximately 12.8 degrees 2θ, a characteristic peak at approximately 16.6 degrees 2θ, a characteristic peak at approximately 18.4 degrees 2θ, a characteristic peak at approximately 23.8 degrees 2θ, a characteristic peak at approximately 24.4 degrees 2θ, and / or a characteristic peak at approximately 28.3 degrees 2θ. In another embodiment, the crystalline form J is characterized by having a powder X-ray diffraction pattern having at least one or more characteristic peaks at approximately 4.1, 6.2, 8.0, 9.3, 12.8, 16.6, 18.4, 23.8, 24.4, and 28.3 degrees 2θ. For example, the desired crystalline form has Figure 13 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation. In other embodiments, the crystalline form J can be characterized by optical microscopy, which reveals a hair-like morphology.

[0124] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form K”) with a characteristic peak at approximately 9.6 degrees 2θ.

[0125] In one embodiment, the crystalline form K of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 6.4 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 10.5 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 13.6 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 19.4 degrees 2θ. Powder X-ray diffraction patterns with characteristic peaks expressed in degrees 2θ, characterized in that a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 21.0, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 22.4, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 23.4, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 23.7, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 25.2, and / or a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 26.9. In yet another embodiment, the crystalline form K is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 6.4, 9.6, 10.5, 13.6, 19.4, 21.0, 22.4, 23.4, 23.7, 25.2, and 26.9. For example, the desired crystalline form has... Figure 14 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0126] The expected crystalline form K of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratete free base can be characterized by differential scanning calorimetry (DSC) plotting, showing characteristic endothermic peaks with an onset temperature of approximately 226 °C and a peak temperature of approximately 230 °C. Crystal form K can be characterized, for example, by... Figure 15 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0127] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form L”) with a characteristic peak at approximately 8.3 degrees 2θ.

[0128] In one embodiment, the crystalline form L of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 9.1 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 9.5 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 11.9 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 12.2 degrees 2θ. Powder X-ray diffraction patterns with characteristic peaks expressed in degrees 2θ, characterized in that a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 14.3, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 16.2, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 20.5, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 21.9, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 23.1, and / or a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 25.5. In yet another embodiment, the crystalline form L is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline form has... Figure 16 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0129] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 9.6 degrees 2θ (referred to herein as “form M”).

[0130] In one embodiment, the crystalline form M of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaterene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 6.8 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 8.3 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 12.7 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 13.4 degrees 2θ. Powder X-ray diffraction patterns with characteristic peaks expressed in degrees 2θ, characterized in that a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 14.3, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 17.3, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 19.6, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 21.0, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 23.9, and / or a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 26.5. In yet another embodiment, the crystalline form M is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline form has... Figure 17 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0131] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 8.4 degrees 2θ (referred to herein as “crystal form N”).

[0132] In one embodiment, the crystalline form N of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 5.6 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 6.1 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 6.9 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 7.2 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 11.8 degrees 2θ. Powder X-ray diffraction patterns with characteristic peaks expressed in degrees 2θ, characterized in that a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 13.7, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 14.5, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 17.3, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 19.8, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 21.9, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 24.9, and / or a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 25.7. In yet another embodiment, the crystalline form N is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline form has... Figure 18 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0133] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “form O”) with a characteristic peak at approximately 14.1 degrees 2θ.

[0134] In one embodiment, the crystalline form O of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 9.0 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 10.6 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 11.3 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 15.8 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 16.3 degrees 2θ. Powder X-ray diffraction patterns with characteristic peaks expressed in degrees 2θ, characterized in that a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 17.6, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 19.5, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 21.3, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 22.7, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 22.9, a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 25.1, and / or a powder X-ray diffraction pattern having a characteristic peak expressed in degrees 2θ at approximately 28.7. In yet another embodiment, crystalline form O is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline form has... Figure 19 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0135] The expected crystalline form O of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene free base can be characterized by differential scanning calorimetry (DSC) curves, showing characteristic endothermic peaks with an onset temperature of approximately 166 °C and a peak temperature of approximately 172 °C, and characteristic endothermic peaks with an onset temperature of approximately 196 °C and a peak temperature of approximately 204 °C. Crystalline form O can be characterized, for example, by... Figure 20 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0136] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form Q”) with a characteristic peak at approximately 7.7 degrees 2θ.

[0137] In one embodiment, the crystalline form Q of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 4.8 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 5.8 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 9.6 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 11.6 degrees 2θ. Powder X-ray diffraction patterns, characterized by having a characteristic peak at approximately 13.8 degrees 2θ, characterized by having a characteristic peak at approximately 14.7 degrees 2θ, characterized by having a characteristic peak at approximately 19.9 degrees 2θ, characterized by having a characteristic peak at approximately 21.5 degrees 2θ, characterized by having a characteristic peak at approximately 24.1 degrees 2θ, characterized by having a characteristic peak at approximately 24.7 degrees 2θ, and / or characterized by having a characteristic peak at approximately 27.4 degrees 2θ. In yet another embodiment, the crystalline form Q is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline form has... Figure 21 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0138] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form R”) with a characteristic peak at approximately 8.5 degrees 2θ.

[0139] In one embodiment, the crystalline form R of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 7.5 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 10.1 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 12.8 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 14.8 degrees 2θ. The diffraction pattern is characterized by having a characteristic peak at approximately 15.6 degrees 2θ, a characteristic peak at approximately 16.9 degrees 2θ, a characteristic peak at approximately 17.4 degrees 2θ, a characteristic peak at approximately 18.3 degrees 2θ, a characteristic peak at approximately 19.5 degrees 2θ, a characteristic peak at approximately 20.0 degrees 2θ, and / or a characteristic peak at approximately 21.8 degrees 2θ. In yet another embodiment, the crystalline form R is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline form has... Figure 22 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0140] The expected crystalline form R of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratete free base can be characterized by differential scanning calorimetry (DSC) curves, showing characteristic endothermic peaks at an onset temperature of approximately 148 °C and a peak temperature of approximately 152 °C, and characteristic endothermic peaks at an onset temperature of approximately 241 °C and a peak temperature of approximately 251 °C. Crystal form R can be characterized, for example, by... Figure 23 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0141] The expected crystalline form R of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base can be characterized by thermogravimetric analysis (TGA) curves, which show a first-step mass loss of about 0.87 wt% up to about 150 °C, a second-step mass loss of about 3.1 wt% between about 150 °C and about 200 °C, and a third-step mass loss of about 11.7 wt% between about 200 °C and about 240 °C.

[0142] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 5.0 degrees 2θ (referred to herein as “crystalline form S”).

[0143] In one embodiment, the crystalline form S of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 5.9 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 8.0 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 9.7 degrees 2θ, and / or a powder X-ray diffraction pattern having a characteristic peak at approximately 11.8 degrees 2θ. In yet another embodiment, the crystalline form S is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks expressed in degrees 2θ at approximately 5.0, 5.9, 8.0, 9.7, and 11.8. For example, the desired crystalline form has... Figure 24 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0144] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form T”) with a characteristic peak at approximately 8.7 degrees 2θ.

[0145] In one embodiment, the crystalline form T of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 7.0 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 10.3 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 11.8 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 14.1 degrees 2θ. Powder X-ray diffraction patterns with characteristic peaks represented by degrees 2θ, characterized in that a powder X-ray diffraction pattern has a characteristic peak represented by degrees 2θ at approximately 17.0, a powder X-ray diffraction pattern has a characteristic peak represented by degrees 2θ at approximately 20.9, a powder X-ray diffraction pattern has a characteristic peak represented by degrees 2θ at approximately 22.4, a powder X-ray diffraction pattern has a characteristic peak represented by degrees 2θ at approximately 24.5, a powder X-ray diffraction pattern has a characteristic peak represented by degrees 2θ at approximately 25.5, and / or a powder X-ray diffraction pattern has a characteristic peak represented by degrees 2θ at approximately 27.9. In yet another embodiment, the crystalline form T is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 7.0, 8.7, 10.3, 11.8, 14.1, 17.0, 20.9, 22.4, 24.5, 25.5, and 27.9. For example, the desired crystalline form has... Figure 25 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0146] The expected crystalline form T of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratete free base can be characterized by differential scanning calorimetry (DSC) curves, showing characteristic endothermic peaks at an onset temperature of approximately 83 °C and a peak temperature of approximately 84 °C, and characteristic endothermic peaks at an onset temperature of approximately 249 °C and a peak temperature of approximately 251 °C. Crystal form T can be characterized, for example, by... Figure 26 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0147] The expected crystalline form T of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base can be characterized by thermogravimetric analysis (TGA) curves, showing a first-step mass loss of approximately 13.8 wt% up to approximately 85 °C. In other embodiments, crystalline form T can be characterized by optical microscopy, showing needle-like and / or rod-like morphologies.

[0148] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form U”) with a characteristic peak at approximately 6.2 degrees 2θ.

[0149] In one embodiment, the crystalline form U of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 6.9 degrees 2θ, and is characterized by having a peak at approximately 7.6 degrees 2θ. A powder X-ray diffraction pattern having a characteristic peak at approximately 9.0 degrees 2θ, a characteristic peak at approximately 10.5 degrees 2θ, a characteristic peak at approximately 12.3 degrees 2θ, and / or a characteristic peak at approximately 14.5 degrees 2θ. In another embodiment, the crystalline form U is characterized by having a powder X-ray diffraction pattern having at least one or more characteristic peaks at approximately 6.2, 6.9, 7.6, 9.0, 10.5, 12.3, and 14.5 degrees 2θ. For example, the desired crystalline form has Figure 27 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0150] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form V”) with a characteristic peak at approximately 18.3 degrees 2θ.

[0151] In one embodiment, the crystalline form V of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 6.0 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 8.0 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 10.8 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 12.0 degrees 2θ. The powder X-ray diffraction pattern is characterized by having a characteristic peak at approximately 15.6 degrees 2θ, a powder X-ray diffraction pattern with a characteristic peak at approximately 15.9 degrees 2θ, a powder X-ray diffraction pattern with a characteristic peak at approximately 16.8 degrees 2θ, a powder X-ray diffraction pattern with a characteristic peak at approximately 19.7 degrees 2θ, a powder X-ray diffraction pattern with a characteristic peak at approximately 20.9 degrees 2θ, a powder X-ray diffraction pattern with a characteristic peak at approximately 21.0 degrees 2θ, and / or a powder X-ray diffraction pattern with a characteristic peak at approximately 26.3 degrees 2θ. In yet another embodiment, crystalline form V is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline form has... Figure 28 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0152] In another embodiment, different crystalline forms of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form W”) with a characteristic peak at approximately 8.6 degrees 2θ.

[0153] In one embodiment, the crystalline form W of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 4.3 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 12.9 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 15.2 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 23.3 degrees 2θ, and / or a powder X-ray diffraction pattern having a characteristic peak at approximately 26.0 degrees 2θ. In yet another embodiment, the crystalline form W is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks expressed in degrees 2θ at approximately 4.3, 8.6, 12.9, 15.2, 23.3, and 26.0. For example, the desired crystalline form has Figure 29 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0154] In another embodiment, the fundamental amorphous form of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base is disclosed herein.

[0155] In a further embodiment, pharmaceutical compositions 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base and pharmaceutically acceptable excipients are disclosed herein. For example, this document discloses pharmaceutical compositions comprising 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base and pharmaceutically acceptable excipients. For example, this document discloses pharmaceutical compositions formed from 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base. In some embodiments, the disclosed pharmaceutical composition may be a formulation for oral administration.

[0156] In yet another embodiment, 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base and a pharmaceutically acceptable excipient is disclosed herein.

[0157] In one embodiment, a pharmaceutical ingredient in a disclosed crystalline form comprising at least a detectable amount of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base is disclosed herein. In another embodiment, a pharmaceutical ingredient in a substantially pure crystalline form comprising (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base is disclosed herein. For example, this article discloses a drug substance comprising a substantially pure 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base.

[0158] This document also discloses a pharmaceutically 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene. In some embodiments, the salt may be selected from, for example, benzenesulfonates, citrates, fumarates, maleates, L-malates, methanesulfonates, phosphates, pyruvates, sulfates, L-tartrates, toluenesulfonates, and their hydrates and solvates. In some embodiments, the salt may be, for example, a benzenesulfonate. In some embodiments, the salt may be, for example, a citrate. In some embodiments, the salt may be, for example, a fumarate. In some embodiments, the salt may be, for example, a hydrochloride. In some embodiments, the salt may be, for example, an L-malate. In some embodiments, the salt may be, for example, a methanesulfonate. In some embodiments, the salt may be, for example, a phosphate. In some embodiments, the salt may be, for example, a pyruvate. In some embodiments, the salt may be, for example, a sulfate. In some embodiments, the salt may be, for example, an L-tartrate. In some embodiments, the salt may be, for example, a toluenesulfonate.

[0159] In further embodiments, pharmaceutical compositions comprising a 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene and a pharmaceutically acceptable excipient are disclosed herein. For example, pharmaceutical compositions formed from a 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene are disclosed herein. In some embodiments, the disclosed pharmaceutical composition is a formulation for oral administration.

[0160] In one embodiment, a pharmaceutical ingredient comprising at least a detectable amount of a 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]benzofurano[4,3-fg][1,4]oxazacyclononatrane is disclosed herein. In another embodiment, a pharmaceutical ingredient 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]benzofurano[4,3-fg][1,4]oxazacyclononatrane is disclosed herein.

[0161] This document also discloses 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene. In some embodiments, the crystalline salt form may be selected from, for example, benzenesulfonate, citrate, fumarate, hydrochloride, maleate, L-malate, methanesulfonate, phosphate, pyruvate, sulfate, L-tartrate, and toluenesulfonate, as well as their crystalline hydrates and solvates. 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, L-malate. In some embodiments, the crystalline salt form may be, for example, a methanesulfonate. In some embodiments, the crystalline salt form may be, for example, a phosphate. In some embodiments, the crystalline salt form may be, for example, a pyruvate. In some embodiments, the crystalline salt form may be, for example, a sulfate. In some embodiments, the crystalline salt form may be, for example, an L-tartrate. In some embodiments, the crystalline salt form may be, for example, a toluenesulfonate.

[0162] For example, this document discloses 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraenebenzenesulfonate, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form 1-A”) with a characteristic peak at approximately 6.5 degrees 2θ.

[0163] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaterenebenzenesulfonate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 5.1 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 6.8 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 7.0 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 9.6 degrees 2θ. The diffraction pattern is characterized by having a characteristic peak at approximately 12.1 degrees 2θ, a characteristic peak at approximately 14.8 degrees 2θ, a characteristic peak at approximately 15.1 degrees 2θ, a characteristic peak at approximately 15.5 degrees 2θ, a characteristic peak at approximately 16.4 degrees 2θ, a characteristic peak at approximately 18.6 degrees 2θ, and / or a characteristic peak at approximately 21.3 degrees 2θ. In yet another embodiment, the crystalline salt form 1-A is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 30 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of the crystalline salt form was obtained using Cu Kα radiation.

[0164] In another embodiment, different 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]benzofurano[4,3-fg][1,4]oxazacyclononatenenebenzenesulfonate are disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 6.7 degrees 2θ (referred to herein as "form 1-B").

[0165] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaterenebenzenesulfonate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 5.3 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 6.2 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 8.2 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 10.0 degrees 2θ. Powder X-ray diffraction patterns, characterized by having a characteristic peak at approximately 10.6 degrees 2θ, characterized by having a characteristic peak at approximately 12.3 degrees 2θ, characterized by having a characteristic peak at approximately 14.0 degrees 2θ, characterized by having a characteristic peak at approximately 15.6 degrees 2θ, characterized by having a characteristic peak at approximately 16.0 degrees 2θ, characterized by having a characteristic peak at approximately 16.2 degrees 2θ, and / or characterized by having a characteristic peak at approximately 22.1 degrees 2θ. In yet another embodiment, the crystalline salt form 1-B is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has Figure 31 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0166] The expected 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaterenebenzenesulfonate can be characterized by differential scanning calorimetry (DSC) curves, showing characteristic endothermic peaks at an onset temperature of approximately 33 °C and a peak temperature of approximately 71 °C, characteristic endothermic peaks at an onset temperature of approximately 120 °C and a peak temperature of approximately 133 °C, and characteristic endothermic peaks at an onset temperature of approximately 154 °C and a peak temperature of approximately 159 °C. Crystalline form 1-B can be characterized, for example, by... Figure 32 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0167] In another embodiment, 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene citrate is disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 7.0 degrees 2θ (referred to herein as "crystal form 2-A").

[0168] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaquaternene citrate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 4.7 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 7.9 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 9.1 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 10.2 degrees 2θ. Powder X-ray diffraction patterns, characterized by having a characteristic peak at approximately 11.4 degrees 2θ, characterized by having a characteristic peak at approximately 12.5 degrees 2θ, characterized by having a characteristic peak at approximately 13.7 degrees 2θ, characterized by having a characteristic peak at approximately 14.1 degrees 2θ, characterized by having a characteristic peak at approximately 15.1 degrees 2θ, characterized by having a characteristic peak at approximately 18.3 degrees 2θ, and / or characterized by having a characteristic peak at approximately 19.0 degrees 2θ. In yet another embodiment, the crystalline salt form 2-A is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 33 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0169] In another embodiment, different 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene citrate are disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 15.2 degrees 2θ (referred to herein as "crystal form 2-B").

[0170] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaquaternene citrate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 6.7 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 7.9 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 9.3 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 11.2 degrees 2θ. Powder X-ray diffraction patterns, characterized by having a characteristic peak at approximately 12.5 degrees 2θ, characterized by having a characteristic peak at approximately 13.8 degrees 2θ, characterized by having a characteristic peak at approximately 17.0 degrees 2θ, characterized by having a characteristic peak at approximately 18.4 degrees 2θ, characterized by having a characteristic peak at approximately 19.5 degrees 2θ, characterized by having a characteristic peak at approximately 22.3 degrees 2θ, and / or characterized by having a characteristic peak at approximately 28.5 degrees 2θ. In yet another embodiment, the crystalline salt form 2-B is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 34 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0171] In another embodiment, different 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene citrate are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form 2-C”) with a characteristic peak at approximately 15.0 degrees 2θ.

[0172] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaquaternene citrate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 6.7 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 7.9 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 9.1 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 12.5 degrees 2θ. Powder X-ray diffraction patterns, characterized by having a characteristic peak at approximately 13.6 degrees 2θ, characterized by having a characteristic peak at approximately 14.3 degrees 2θ, characterized by having a characteristic peak at approximately 16.9 degrees 2θ, characterized by having a characteristic peak at approximately 18.2 degrees 2θ, characterized by having a characteristic peak at approximately 19.2 degrees 2θ, characterized by having a characteristic peak at approximately 22.1 degrees 2θ, and / or characterized by having a characteristic peak at approximately 29.0 degrees 2θ. In yet another embodiment, the crystalline salt form 2-B is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 35 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0173] The expected 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaquaternene citrate can be characterized by differential scanning calorimetry (DSC), showing characteristic endothermic peaks at an onset temperature of approximately 33 °C and a peak temperature of approximately 60 °C, at an onset temperature of approximately 96 °C and a peak temperature of approximately 116 °C, at an onset temperature of approximately 160 °C and a peak temperature of approximately 169 °C, and at an onset temperature of approximately 141 °C and a peak temperature of approximately 177 °C. Crystalline form 2-C can be characterized, for example, by... Figure 36 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0174] In another embodiment, 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene fumarate is disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 7.1 degrees 2θ (referred to herein as "crystalline form 3-A").

[0175] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonarate fumarate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 8.2 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 14.3 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 16.5 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 18.0 degrees 2θ. The powder X-ray diffraction pattern is characterized by having a characteristic peak at approximately 18.9 degrees 2θ, a characteristic peak at approximately 21.9 degrees 2θ, a characteristic peak at approximately 22.1 degrees 2θ, a characteristic peak at approximately 22.4 degrees 2θ, a characteristic peak at approximately 24.5 degrees 2θ, a characteristic peak at approximately 24.8 degrees 2θ, and / or a characteristic peak at approximately 25.4 degrees 2θ. In yet another embodiment, the crystalline salt form 3-A is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 37 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0176] The expected 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaterene fumarate can be characterized by differential scanning calorimetry (DSC), showing a characteristic endothermic peak with an onset temperature of approximately 237 °C and a peak temperature of approximately 241 °C. Crystalline form 3-A can be characterized, for example, by... Figure 38 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0177] In another embodiment, 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene hydrochloride is disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 7.8 degrees 2θ (referred to herein as “crystal form 5-A”).

[0178] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene hydrochloride is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 5.0 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 8.1 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 9.3 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 12.2 degrees 2θ. The diffraction pattern is characterized by having a characteristic peak at approximately 13.5 degrees 2θ, a characteristic peak at approximately 13.9 degrees 2θ, a characteristic peak at approximately 14.1 degrees 2θ, a characteristic peak at approximately 19.3 degrees 2θ, a characteristic peak at approximately 20.3 degrees 2θ, a characteristic peak at approximately 21.3 degrees 2θ, and / or a characteristic peak at approximately 25.2 degrees 2θ. In yet another embodiment, the crystalline salt form 5-A is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 39 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0179] The expected 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene hydrochloride can be characterized by thermogravimetric analysis (TGA) curves, showing a mass loss of approximately 3.1 wt% up to approximately 110 °C and a further mass loss of approximately 7.6 wt% between approximately 110 °C and approximately 195 °C. In some embodiments, crystalline form 5-A can be characterized by dynamic vapor adsorption (DVS) curves, showing a reversible total mass change of approximately 3.1 wt% between approximately 2 and approximately 92% relative humidity (RH) at 25 °C. In a further embodiment, crystalline form 5-A can be characterized by a Karl-Fischer titration curve, showing a water content of approximately 10.7%. In other embodiments, crystalline form 5-A can be characterized by optical microscopy, showing a rod-like or plate-like morphology.

[0180] In another embodiment, different 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene hydrochloride are disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 9.1 degrees 2θ (referred to herein as "form 5-B").

[0181] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaquaternene hydrochloride is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 7.4 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 9.9 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 11.7 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 14.2 degrees 2θ. Powder X-ray diffraction patterns, characterized by having a characteristic peak at approximately 17.5 degrees 2θ, characterized by having a characteristic peak at approximately 20.0 degrees 2θ, characterized by having a characteristic peak at approximately 21.2 degrees 2θ, characterized by having a characteristic peak at approximately 21.8 degrees 2θ, characterized by having a characteristic peak at approximately 23.9 degrees 2θ, characterized by having a characteristic peak at approximately 25.7 degrees 2θ, and / or characterized by having a characteristic peak at approximately 27.6 degrees 2θ. In yet another embodiment, the crystalline salt form 5-B is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 40 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0182] The expected 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaquaternene hydrochloride can be characterized by differential scanning calorimetry (DSC), showing characteristic endothermic peaks at an onset temperature of approximately 68 °C and a peak temperature of approximately 82 °C, characteristic endothermic peaks at an onset temperature of approximately 111 °C and a peak temperature of approximately 130 °C, and characteristic endothermic peaks at an onset temperature of approximately 193 °C and a peak temperature of approximately 211 °C. Crystalline form 5-B can be characterized, for example, by... Figure 41 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0183] In another embodiment, different 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene hydrochloride are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form 5-C”) with a characteristic peak at approximately 21.5 degrees 2θ.

[0184] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaquaternene hydrochloride is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 10.7 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 11.8 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 12.9 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 16.2 degrees 2θ. The powder X-ray diffraction pattern is characterized by having a characteristic peak at approximately 18.1 degrees 2θ, a characteristic peak at approximately 20.5 degrees 2θ, a characteristic peak at approximately 22.4 degrees 2θ, a characteristic peak at approximately 23.9 degrees 2θ, a characteristic peak at approximately 26.4 degrees 2θ, a characteristic peak at approximately 27.0 degrees 2θ, and / or a characteristic peak at approximately 28.9 degrees 2θ. In yet another embodiment, the crystalline salt form 5-C is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 42 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0185] The expected 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaquaternene hydrochloride can be characterized by differential scanning calorimetry (DSC), showing characteristic endothermic peaks at an onset temperature of approximately 140 °C and a peak temperature of approximately 145 °C, and characteristic endothermic peaks at an onset temperature of approximately 213 °C and a peak temperature of approximately 230 °C. Crystalline form 5-C can be characterized, for example, by... Figure 43 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0186] In another embodiment, different 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene hydrochloride are disclosed herein, characterized by a powder X-ray diffraction pattern (referred to herein as “crystal form 5-D”) with a characteristic peak at approximately 8.4 degrees 2θ.

[0187] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene hydrochloride is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 7.8 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 12.7 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 14 degrees 2θ. A powder X-ray diffraction pattern having a characteristic peak at approximately 15.0 degrees (2θ), a powder X-ray diffraction pattern having a characteristic peak at approximately 17.0 degrees (2θ), a powder X-ray diffraction pattern having a characteristic peak at approximately 22.9 degrees (2θ), a powder X-ray diffraction pattern having a characteristic peak at approximately 25.6 degrees (2θ), and / or a powder X-ray diffraction pattern having a characteristic peak at approximately 26.0 degrees (2θ). In another embodiment, the crystalline salt form 5-D is characterized by having a powder X-ray diffraction pattern having at least one or more characteristic peaks at approximately 7.8, 8.4, 12.7, 14.0, 15.0, 17.0, 22.9, 25.6, and 26.0 degrees (2θ). For example, the intended crystalline salt form has... Figure 44The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0188] In another embodiment, 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaquaternium maleate is disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 21.5 degrees 2θ (referred to herein as "crystal form 7-A").

[0189] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaterene maleate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 7.2 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 8.3 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 14.3 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 14.9 degrees 2θ. Powder X-ray diffraction patterns, characterized by having a characteristic peak at approximately 16.5 degrees 2θ, characterized by having a characteristic peak at approximately 18.9 degrees 2θ, characterized by having a characteristic peak at approximately 22.7 degrees 2θ, characterized by having a characteristic peak at approximately 25.3 degrees 2θ, characterized by having a characteristic peak at approximately 25.9 degrees 2θ, characterized by having a characteristic peak at approximately 27.2 degrees 2θ, and / or characterized by having a characteristic peak at approximately 27.5 degrees 2θ. In yet another embodiment, the crystalline salt form 7-A is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 45 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0190] The expected 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaquaternene maleate can be characterized by differential scanning calorimetry (DSC), showing characteristic endothermic peaks at an onset temperature of approximately 215 °C and a peak temperature of approximately 221 °C, and characteristic endothermic peaks at an onset temperature of approximately 216 °C and a peak temperature of approximately 225 °C. Crystalline form 7-A can be characterized, for example, by... Figure 46 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0191] In another embodiment, 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene L-malate is disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 15.0 degrees 2θ (referred to herein as "crystal form 8-A").

[0192] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratel L-malate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 7.3 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 8.3 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 11.0 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 14.3 degrees 2θ. The powder X-ray diffraction pattern is characterized by having a characteristic peak at approximately 16.6 degrees 2θ, a characteristic peak at approximately 19.0 degrees 2θ, a characteristic peak at approximately 21.6 degrees 2θ, a characteristic peak at approximately 22.0 degrees 2θ, a characteristic peak at approximately 24.7 degrees 2θ, a characteristic peak at approximately 25.5 degrees 2θ, and / or a characteristic peak at approximately 27.3 degrees 2θ. In yet another embodiment, the crystalline salt form 8-A is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 47 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0193] The expected 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratel-M-malate can be characterized by differential scanning calorimetry (DSC), showing characteristic endothermic peaks at an onset temperature of approximately 177 °C and a peak temperature of approximately 201 °C, at an onset temperature of approximately 186 °C and a peak temperature of approximately 207 °C, at an onset temperature of approximately 205 °C and a peak temperature of approximately 211 °C, and at an onset temperature of approximately 208 °C and a peak temperature of approximately 216 °C. Crystalline form 8-A can be characterized, for example, by... Figure 48The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0194] In another embodiment, different 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]benzofurano[4,3-fg][1,4]oxazacyclononazone L-malate are disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 5.9 degrees 2θ (referred to herein as "form 8-B").

[0195] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratel L-malate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 9.1 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 11.6 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 16.3 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 17.6 degrees 2θ. X-ray diffraction patterns, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 18.2 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 19.1 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 21.2 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 22.9 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 23.8 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 27.1 degrees 2θ, and / or characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 28.4 degrees 2θ. In yet another embodiment, the crystalline salt form 8-B is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 49 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0196] The expected 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaquaternene L-malate can be characterized by differential scanning calorimetry (DSC), showing characteristic endothermic peaks at an onset temperature of approximately 189 °C and a peak temperature of approximately 192 °C, and characteristic endothermic peaks at an onset temperature of approximately 186 °C and a peak temperature of approximately 202 °C. Crystalline form 8-B can be characterized, for example, by... Figure 50 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0197] The expected 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene L-malate can be characterized by thermogravimetric analysis (TGA) curves, showing a mass loss of approximately 0.46 wt% up to approximately 175 °C. In some embodiments, crystalline form 8-B can be characterized by dynamic vapor adsorption (DVS) curves, showing a reversible total mass change of approximately 0.82 wt% at 25 °C between approximately 2 and approximately 92% relative humidity (RH).

[0198] In another embodiment, 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene methanesulfonate is disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 9.5 degrees 2θ (referred to herein as “crystal form 9-A”).

[0199] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratemethanesulfonate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 4.5 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 5.4 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 7.5 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 9.1 degrees 2θ. The diffraction pattern is characterized by having a characteristic peak at approximately 10.1 degrees 2θ, a characteristic peak at approximately 14.7 degrees 2θ, a characteristic peak at approximately 15.0 degrees 2θ, a characteristic peak at approximately 15.7 degrees 2θ, a characteristic peak at approximately 18.0 degrees 2θ, a characteristic peak at approximately 20.1 degrees 2θ, and / or a characteristic peak at approximately 21.5 degrees 2θ. In yet another embodiment, the crystalline salt form 9-A is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has Figure 51 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0200] In another embodiment, different 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene methanesulfonate are disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 8.2 degrees 2θ (referred to herein as "form 9-B").

[0201] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonatrane methanesulfonate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 8.7 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 13.7 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 14.7 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 16.2 degrees 2θ. The powder X-ray diffraction pattern is characterized by having a characteristic peak at approximately 18.9 degrees 2θ, a characteristic peak at approximately 22.3 degrees 2θ, a characteristic peak at approximately 22.8 degrees 2θ, a characteristic peak at approximately 24.4 degrees 2θ, a characteristic peak at approximately 27.0 degrees 2θ, a characteristic peak at approximately 27.5 degrees 2θ, and / or a characteristic peak at approximately 28.9 degrees 2θ. In yet another embodiment, the crystalline salt form 9-B is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 52 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0202] The expected 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaterene methanesulfonate can be characterized by differential scanning calorimetry (DSC) curves, showing characteristic endothermic peaks at an onset temperature of approximately 51 °C and a peak temperature of approximately 74 °C, and characteristic endothermic peaks at an onset temperature of approximately 177 °C and a peak temperature of approximately 187 °C. Crystalline form 9-B can be characterized, for example, by... Figure 53 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0203] In another embodiment, different 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene methanesulfonate are disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 9.5 degrees 2θ (referred to herein as "crystal form 9-C").

[0204] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaterene methanesulfonate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 4.5 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 7.6 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 9.2 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 10.2 degrees 2θ. Powder X-ray diffraction patterns, characterized by having a characteristic peak at approximately 10.9 degrees 2θ, characterized by having a characteristic peak at approximately 14.8 degrees 2θ, characterized by having a characteristic peak at approximately 15.0 degrees 2θ, characterized by having a characteristic peak at approximately 15.9 degrees 2θ, characterized by having a characteristic peak at approximately 18.2 degrees 2θ, characterized by having a characteristic peak at approximately 20.4 degrees 2θ, and / or characterized by having a characteristic peak at approximately 21.8 degrees 2θ. In yet another embodiment, the crystalline salt form 9-C is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 54 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0205] In another embodiment, 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene phosphate is disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 12.3 degrees 2θ (referred to herein as "crystal form 10-A").

[0206] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonarate phosphate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 6.2 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 8.5 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 10.2 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 10.8 degrees 2θ. Powder X-ray diffraction patterns, characterized by having a characteristic peak at approximately 11.5 degrees 2θ, characterized by having a characteristic peak at approximately 15.7 degrees 2θ, characterized by having a characteristic peak at approximately 18.4 degrees 2θ, characterized by having a characteristic peak at approximately 20.5 degrees 2θ, characterized by having a characteristic peak at approximately 21.2 degrees 2θ, characterized by having a characteristic peak at approximately 22.9 degrees 2θ, and / or characterized by having a characteristic peak at approximately 25.8 degrees 2θ. In yet another embodiment, the crystalline salt form 10-A is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 55 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0207] The expected 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene phosphate can be characterized by differential scanning calorimetry (DSC) curves, showing characteristic endothermic peaks with an onset temperature of approximately 282 °C and a peak temperature of approximately 290 °C, and characteristic endothermic peaks with an onset temperature of approximately 283 °C and a peak temperature of approximately 294 °C. Crystalline form 10-A can be characterized, for example, by... Figure 56 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0208] The expected 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene phosphate can be characterized by thermogravimetric analysis (TGA) curves, which show a mass loss of approximately 0.22 wt%. In some embodiments, crystalline form 10-A can be characterized by dynamic vapor adsorption (DVS) curves, which show a reversible total mass change of approximately 1.4 wt% at 25 °C between approximately 2 and approximately 92% relative humidity (RH).

[0209] In another embodiment, 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]benzofurano[4,3-fg][1,4]oxazahexacyclic nonaterenepyruvate is disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 7.5 degrees 2θ (referred to herein as “crystal form 11-A”).

[0210] 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]benzofurano[4,3-fg][1,4]oxazahexacyclic nonaterenepyruvate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 4.4 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 4.9 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 7.2 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 8.6 degrees 2θ. The powder X-ray diffraction pattern is characterized by having a characteristic peak at approximately 9.1 degrees 2θ, a characteristic peak at approximately 9.9 degrees 2θ, a characteristic peak at approximately 11.4 degrees 2θ, a characteristic peak at approximately 13.1 degrees 2θ, a characteristic peak at approximately 14.5 degrees 2θ, a characteristic peak at approximately 14.7 degrees 2θ, and / or a characteristic peak at approximately 17.2 degrees 2θ. In yet another embodiment, the crystalline salt form 11-A is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 57 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0211] The expected 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaterenepyruvate can be characterized by differential scanning calorimetry (DSC), showing characteristic endothermic peaks at an onset temperature of approximately 76 °C and a peak temperature of approximately 88 °C, at an onset temperature of approximately 134 °C and a peak temperature of approximately 142 °C, and at an onset temperature of approximately 149 °C and a peak temperature of approximately 157 °C. Crystalline form 11-A can be characterized, for example, by... Figure 58 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0212] In another embodiment, 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene sulfate is disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 5.9 degrees 2θ (referred to herein as "crystalline form 12-A").

[0213] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene sulfate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 6.6 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 7.9 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 8.2 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 9.6 degrees 2θ. The diffraction pattern is characterized by having a characteristic peak at approximately 11.8 degrees 2θ, a characteristic peak at approximately 14.7 degrees 2θ, a characteristic peak at approximately 15.3 degrees 2θ, a characteristic peak at approximately 17.1 degrees 2θ, a characteristic peak at approximately 17.7 degrees 2θ, a characteristic peak at approximately 18.9 degrees 2θ, and / or a characteristic peak at approximately 22.6 degrees 2θ. In yet another embodiment, the crystalline salt form 12-A is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 59 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0214] The expected 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]benzofurano[4,3-fg][1,4]oxazapyridine nonazone sulfate can be characterized by differential scanning calorimetry (DSC), showing characteristic endothermic peaks at an onset temperature of approximately 48 °C and a peak temperature of approximately 81 °C, characteristic endothermic peaks at an onset temperature of approximately 169 °C and a peak temperature of approximately 185 °C, and characteristic endothermic peaks at an onset temperature of approximately 229 °C and a peak temperature of approximately 241 °C. Crystalline form 12-A can be characterized, for example, by... Figure 60 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0215] In another embodiment, 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene L-tartrate is disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 15.9 degrees 2θ (referred to herein as "crystalline form 13-A").

[0216] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratel L-tartrate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 8.0 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 8.7 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 11.1 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 14.2 degrees 2θ. X-ray diffraction patterns, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 17.3 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 19.5 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 21.6 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 23.1 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 23.6 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 26.9 degrees 2θ, and / or characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 28.2 degrees 2θ. In yet another embodiment, the crystalline salt form 13-A is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 61 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0217] The expected 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratel L-tartrate can be characterized by differential scanning calorimetry (DSC), showing a characteristic endothermic peak with an onset temperature of approximately 213 °C and a peak temperature of approximately 222 °C. Crystalline form 13-A can be characterized, for example, by... Figure 62 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0218] The expected 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene L-tartrate can be characterized by thermogravimetric analysis (TGA) curves, showing a mass loss of approximately 0.63 wt% up to approximately 185 °C. In some embodiments, crystalline form 13-A can be characterized by dynamic vapor adsorption (DVS) curves, showing a reversible total mass change of approximately 0.97 wt% at 25 °C between approximately 2 and approximately 92% relative humidity (RH).

[0219] In another embodiment, different 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene L-tartrate are disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 16.9 degrees 2θ (referred to herein as "crystal form 13-B").

[0220] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratel L-tartrate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 7.1 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 8.7 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at approximately 11.8 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at approximately 20.8 degrees 2θ. X-ray diffraction patterns, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 21.8 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 22.2 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 24.1 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 25.1 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 25.3 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 27.0 degrees 2θ, and / or characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 27.7 degrees 2θ. In yet another embodiment, the crystalline salt form 13-B is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 63 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0221] The expected 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratel L-tartrate can be characterized by differential scanning calorimetry (DSC), showing characteristic endothermic peaks at an onset temperature of approximately 89 °C and a peak temperature of approximately 115 °C, at an onset temperature of approximately 157 °C and a peak temperature of approximately 167 °C, and at an onset temperature of approximately 181 °C and a peak temperature of approximately 195 °C. Crystalline form 13-B can be characterized, for example, by... Figure 64 The differential scanning calorimetry curves shown in the figure are used to characterize it.

[0222] In another embodiment, 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene toluenesulfonate is disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 17.5 degrees 2θ (referred to herein as "crystalline form 14-A").

[0223] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonachloride toluene sulfonate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 4.4 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 6.1 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 6.4 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 6.7 degrees 2θ. The powder X-ray diffraction pattern is characterized by having a characteristic peak at approximately 8.8 degrees 2θ, a characteristic peak at approximately 9.5 degrees 2θ, a characteristic peak at approximately 10.3 degrees 2θ, a characteristic peak at approximately 15.3 degrees 2θ, a characteristic peak at approximately 21.3 degrees 2θ, a characteristic peak at approximately 21.9 degrees 2θ, and / or a characteristic peak at approximately 27.2 degrees 2θ. In yet another embodiment, the crystalline salt form 14-A is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks, expressed in degrees 2θ, at approximately 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. For example, the desired crystalline salt form has... Figure 65 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0224] In another embodiment, different 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene toluenesulfonate are disclosed herein, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 7.7 degrees 2θ (referred to herein as "crystal form 14-B").

[0225] 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]benzofurano[4,3-fg][1,4]oxazapyridine nonachloride toluene sulfonate is characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 6.8 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 12.9 ... 5.3 Powder X-ray diffraction pattern of a characteristic peak represented in degrees 2θ, characterized in that it has a powder X-ray diffraction pattern of a characteristic peak represented in degrees 2θ at approximately 17.2, a powder X-ray diffraction pattern of a characteristic peak represented in degrees 2θ at approximately 21.4, a powder X-ray diffraction pattern of a characteristic peak represented in degrees 2θ at approximately 22.4, a powder X-ray diffraction pattern of a characteristic peak represented in degrees 2θ at approximately 24.7, and / or a powder X-ray diffraction pattern of a characteristic peak represented in degrees 2θ at approximately 25.9. In another embodiment, the crystalline salt form 13-B is characterized by having a powder X-ray diffraction pattern of at least one or more characteristic peaks represented in degrees 2θ at approximately 6.8, 7.7, 12.9, 15.3, 17.2, 21.4, 22.4, 24.7, and 25.9. For example, the intended crystalline salt form has Figure 66 The powder X-ray diffraction pattern shown is illustrated. In one embodiment, the powder X-ray diffraction pattern of this crystalline form was obtained using Cu Kα radiation.

[0226] In further embodiments, pharmaceutical compositions 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene and pharmaceutically acceptable excipients are disclosed herein. For example, pharmaceutical compositions 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene are disclosed herein. In some embodiments, the disclosed pharmaceutical composition is a formulation for oral administration.

[0227] In one embodiment, a disclosed pharmaceutical ingredient in the form of a crystalline salt comprising at least a detectable amount of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene is disclosed herein. In another embodiment, a substantially pure pharmaceutical ingredient in the form of a crystalline salt comprising (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene is disclosed herein.

[0228] Composition

[0229] Another aspect of this disclosure provides pharmaceutical compositions comprising the crystalline compounds disclosed herein formulated with pharmaceutically acceptable excipients. In particular, this disclosure provides pharmaceutical compositions comprising the crystalline compounds disclosed herein formulated with one or more pharmaceutically acceptable excipients. These formulations include those suitable for oral, topical (e.g., transdermal), buccal, ocular, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the extent and severity of the condition being treated and the nature of the particular compound used. For example, the disclosed compositions may be formulated into unit doses and / or may be formulated for oral, subcutaneous, or intravenous administration.

[0230] The exemplary pharmaceutical compositions of this disclosure can be used in the form of pharmaceutical formulations, such as solid, semi-solid, or liquid forms, containing one or more compounds of this disclosure as active ingredients, which are mixed with organic or inorganic excipients or excipients suitable for external, enteral, or parenteral administration. The active ingredient can be formulated, for example, with common, non-toxic, pharmaceutically acceptable excipients used in tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable forms. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the course or condition of the disease.

[0231] To prepare solid compositions such as tablets, the main active ingredient can be mixed with pharmaceutical excipients, such as conventional tableting ingredients like corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium hydrogen phosphate, or gum, and other pharmaceutical diluents (e.g., water) to form a homogeneous solid preform composition containing the compound of this disclosure or a non-toxic, pharmaceutically acceptable salt thereof. When these preform compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, such that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0232] In solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) for oral administration, the subject composition is mixed with one or more pharmaceutically acceptable excipients (e.g., sodium citrate or dicalcium hydrogen phosphate) and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicate; (2) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents, such as acetyl alcohol. (7) alcohol and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) colorants. In the case of capsules, tablets, and pills, the composition may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules that use excipients such as lactose or milk sugars and high molecular weight polyethylene glycol.

[0233] Tablets can be prepared by compression or molding, optionally together with one or more excipients. Compression tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch-hydroxyacetate or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of the subject composition wetted with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as sugar-coated pills, capsules, pellets, and granules, can optionally be scored or prepared with coatings and shells (e.g., enteric coatings and other coatings known in the field of pharmaceutical formulation).

[0234] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, nanosuspensions, syrups, and elixirs. In addition to the subject composition, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuranol, fatty acid esters of polyethylene glycol and sorbitol, cyclodextrins, and mixtures thereof.

[0235] In addition to the main composition, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum and mixtures thereof.

[0236] Formulations for rectal or vaginal application may be given in suppository form, which can be prepared by mixing the subject composition with one or more suitable non-irritating excipients or excipients containing, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate, and are solid at room temperature but liquid at body temperature, and thus will melt in the body cavity and release the active agent.

[0237] Dosage forms for transdermal application of the subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active ingredient can be mixed under aseptic conditions with pharmaceutically acceptable excipients and with any preservatives, buffers, or propellants that may be required.

[0238] In addition to the main composition, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, tragacanth gums, cellulose derivatives, polyethylene glycols, organosilicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0239] In addition to the main composition, powders and aerosols may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Aerosols may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0240] The compositions and compounds disclosed herein can alternatively be administered via aerosols. This is achieved by preparing aqueous aerosols, liposome formulations, or solid particles containing the compound. Non-aqueous suspensions (e.g., fluorocarbon propellants) can be used. Sonic aerosols can be used because they minimize reagent exposure to shear, which could lead to degradation of the compounds contained in the subject composition. Aqueous aerosols are typically prepared by formulating an aqueous solution or suspension of the subject composition with conventional pharmaceutically acceptable excipients and stabilizers. Excipients and stabilizers vary depending on the requirements of the specific subject composition but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), harmless proteins such as serum albumin, sorbitol esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are typically prepared from isotonic solutions.

[0241] The pharmaceutical compositions disclosed herein suitable for parenteral administration comprise a combination of the subject composition with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions just before use, and may contain antioxidants, buffers, antibacterial agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0242] Examples of suitable aqueous and non-aqueous excipients that can be used in the pharmaceutical compositions of this 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. For example, by using a coating material such as lecithin, the desired particle size can be maintained in the case of a dispersion, and by using a surfactant, appropriate flowability can be maintained. For example, the crystalline forms provided herein can be milled to obtain specific particle sizes, and in at least some embodiments, such crystalline forms can remain substantially stable under milling.

[0243] The amount of the crystalline compound described herein in the formulation can vary depending on a variety of factors, such as an individual's disease state, age, sex, and weight. Dosing regimens can be adjusted to provide the best therapeutic response. For example, a single bolus injection can be administered, several separate doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by an emergency in the treatment situation. For ease of administration and uniform dosage, it is particularly advantageous to formulate the parenteral composition in unit dosage form. As used herein, unit dosage form refers to a physically discrete unit suitable as a unit dose for use in a mammalian subject to be treated; each unit contains a predetermined amount of the active crystalline compound calculated to produce the desired therapeutic effect, along with the required drug carrier.

[0244] The specifications of the dosage unit form of this disclosure are determined by and directly depend on the following factors: (a) the unique characteristics of the selected crystalline compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations in the field of compounding such active crystalline compounds for the treatment of individual sensitivities.

[0245] The disclosed compositions can be formulated into solutions, microemulsions, liposomes, or other ordered structures suitable for high drug concentrations. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. For example, by using a coating such as lecithin, the desired particle size can be maintained in the case of a dispersion, and by using a surfactant, appropriate flowability can be maintained. In many cases, the composition is suitable to contain isotonic agents, such as sugars, polyols (e.g., mannitol, sorbitol), or sodium chloride. Prolonged absorption of injectable compositions can be achieved by including agents that delay absorption, such as monostearate and gelatin.

[0246] The disclosed crystalline compounds can be administered as timed-release formulations, such as compositions comprising sustained-release polymers. The crystalline compounds can be prepared using carriers that protect the compound from rapid release, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and polylactic acid-polyglycolic acid copolymers (PLG). Many methods for preparing such formulations are generally known to those skilled in the art.

[0247] According to an alternative aspect of this disclosure, the disclosed crystalline compound may be formulated together with one or more additional compounds that enhance the solubility of the compound.

[0248] method

[0249] In some embodiments, this disclosure provides a method for treating a disease or condition related to the regulation of embryonic ectodermal development (EED) in a patient with this need, 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 The publicly disclosed crystalline forms of the free base of benzofuran[4,3-fg][1,4]oxazacyclononatrane, such as the publicly 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]benzofuran[4,3-fg][1,4]oxazacyclononatrane. In other embodiments, this disclosure provides a method of treating a disease or condition related to the regulation of embryonic ectodermal development (EED) in a patient with this need, comprising administering to the patient an effective amount of a pharmaceutical composition comprising 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] The disclosed crystalline forms of the free base of pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatraene, for example, 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene.

[0250] In some embodiments, this disclosure provides a method of treating a disease or condition associated with the regulation of polycomb protein inhibitory complex 2 (PRC2) in a patient in need, 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] The publicly known crystalline forms of the free base of [-b]benzofurano[4,3-fg][1,4]oxazacyclononatrane, such as the publicly known 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]benzofurano[4,3-fg][1,4]oxazacyclononatrane. In other embodiments, this disclosure provides a method of treating a disease or condition associated with the regulation of polycomb protein inhibitory complex 2 (PRC2) in a patient with this need, comprising administering to the patient an effective amount of a pharmaceutical composition comprising 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 The publicly disclosed crystalline forms of the free base of [,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatrane, such as the publicly 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]benzofurano[4,3-fg][1,4]oxazacyclononatrane.

[0251] In some implementations, the disease or condition may be a blood disorder. In some embodiments, this disclosure provides a method of treating a blood disorder in a patient in need, comprising administering to the patient an effective amount of a disclosed crystalline compound, such as 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene. In other embodiments, this disclosure provides a method of treating a blood disorder in a patient with this need, comprising administering to the patient an effective amount of a pharmaceutical composition comprising 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] The publicly disclosed crystalline forms of the free base of benzofuran[4,3-fg][1,4]oxazacyclononatrane, such as the publicly 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]benzofuran[4,3-fg][1,4]oxazacyclononatrane.

[0252] In some implementations, the blood disorders may be selected from, for example, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (ANIL), amyloidosis, anemia, aplastic anemia, bone marrow failure syndrome, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), deep vein thrombosis (DVT), Diamond-Blackfananemia, diffuse large B-cell lymphoma, congenital keratosis (DKC), eosinophilic disorder, essential thrombocytosis, Fanconi anemia, follicular lymphoma, Gaucher disease, hemochromatosis, hemolytic anemia, hemophilia, hereditary spherocytosis, and Hodgkin's lymphoma. Lymphoma, idiopathic thrombocytopenic purpura (ITP), hereditary bone marrow failure syndrome, iron deficiency anemia, Langerhans ceilhistiocytosis, large granular lymphocytic (LGL) leukemia, leukemia, leukopenia, mast cell polycythemia, monoclonal gammopathy, multiple myeloma, myelodysplastic syndrome (MDS), myelofibrosis, myeloproliferative neoplasm (MPN), non-Hodgkin's lymphoma, paroxysmal nocturnal hemoglobinuria (PNH), pernicious anemia (B12 deficiency), polycythemia vera, porphyria, post-transplant lymphoproliferative disorder (PTLD), pulmonary embolism (PE), Shwachman-Diamond syndrome. The blood disorders include sickle cell disease (SCD), β-thalassemia, thrombocytopenia, thrombotic thrombocytopenic purpura (TTP), venous thromboembolism, von Willebrand disease, and Valdenstrom's macroglobulinemia (lymphoplasmacytic lymphoma). In some embodiments, the blood disorder is sickle cell disease (SCD). In other embodiments, the blood disorder is β-thalassemia.

[0253] In some implementations, the disease or condition can be cancer. In some embodiments, this disclosure provides a method of treating cancer in a patient with this need, comprising administering to the patient an effective amount of a disclosed crystalline compound, such as 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene. In other embodiments, this disclosure provides a method of treating cancer in a patient with this need, comprising administering to the patient an effective amount of a pharmaceutical composition comprising 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] Disclosed crystalline forms of the free base of benzofurano[4,3-fg][1,4]oxazacyclononatrane, 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]benzofurano[4,3-fg][1,4]oxazacyclononatrane.

[0254] In some implementations, the cancer may be selected from, for example, mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct cancer 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 carcinoma, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumors, uterine tumors and soft tissue sarcoma.

[0255] In other embodiments, this disclosure provides methods for treating thoracic aortic aneurysms, coronary artery disease, stenotic disease, pulmonary hypertension (PAR), liver fibrosis, allergic inflammation, retinitis pigmentosa, septic shock, herpes simplex virus, human cytomegalovirus, alpha-thalassemia, familial atrial fibrillation, common variant immunodeficiency, aneurysm-osteoarthritis syndrome, and acquired immunodeficiency syndrome in patients with such need, comprising administering to the patient an effective amount of the disclosed crystalline compound, such as (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7 The disclosed crystalline forms of the free base of a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene, 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene.

[0256] In other embodiments, this disclosure provides methods for treating thoracic aortic aneurysms, coronary artery disease, stenotic disease, pulmonary hypertension (PAR), liver fibrosis, allergic inflammation, retinitis pigmentosa, septic shock, herpes simplex virus, human cytomegalovirus, alpha-thalassemia, familial atrial fibrillation, common variant immunodeficiency, aneurysm-osteoarthritis syndrome, and acquired immunodeficiency syndrome in patients with such need, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a disclosed crystalline compound, such as (S)-12-fluoro-4-(2-methyl) Disclosed crystalline forms of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatraene, 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene.

[0257] In particular, in some embodiments, this disclosure provides a method of treating the aforementioned medical indications, comprising administering an effective amount of the crystalline compound disclosed herein to a patient in need. In some other embodiments, this disclosure provides a method of treating the aforementioned medical condition in a patient in need, comprising administering, orally, subcutaneously, or intravenously, to the patient a composition comprising the disclosed crystalline form.

[0258] The crystalline compounds disclosed herein can be used as pharmaceutical or pharmaceutically acceptable compositions, for example, in the form of pharmaceutical formulations for oral, enteral, parenteral, or topical administration, and the contemplated methods disclosed herein may include oral, enteral, parenteral, or topical administration of the disclosed crystalline compounds, or compositions comprising or formed from such disclosed crystalline compounds. For example, when administered via a specific route (e.g., oral) or in a specific formulation, the disclosed crystalline form may be able to control one or more pharmacokinetic properties (e.g., longer or shorter release profiles) compared to different routes (e.g., subcutaneous) or other formulations (e.g., formulations having an amorphous form). In one embodiment, the disclosed crystalline form can provide substantial reproducibility from one formulation to another.

[0259] This document also discloses pharmaceutical compositions comprising the disclosed crystalline compound and at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent may be selected from, for example, anticancer agents, immunomodulators, anti-allergic agents, antiemetics, analgesics, cytoprotective agents, anti-sickling agents, and combinations thereof. In other embodiments, the additional therapeutic agent may be, for example, an EZH2 inhibitor. For example, in some embodiments, the additional therapeutic agent may be selected from 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-benzodioxane-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) l6126), (R)-5,8-dichloro-7-(methoxy(oxetane-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinoline-1(2H)-one (PF-06821497), SHR2554 and combinations thereof.

[0260] In a further embodiment, the adjunctive therapeutic agent may be, for example, hydroxyurea. In some embodiments, the adjunctive therapeutic agent may be selected from, for example, 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (voxelotor, GBT-440), P-selectin antibody, L-glutamine, and combinations thereof.

[0261] In some embodiments, the adjunctive therapeutic agent may be, for example, an anti-adhesion agent. For instance, in some embodiments, the adjunctive therapeutic agent may be selected from crizanlizumab (SEG101), (2S)-2-[(2R,3R,4S,5S,6R)-3-benzoyloxy-2-[(1R,2R,3S,5R)-3-[(2,4-dioxo-1H-pyrimidin-6-carbonyl)amino]-5-[2-[[2-[2-[2-[2-oxo-2-[(3,6,8-trisulfonylnaphthyl-1-yl)amino]ethoxy]ethoxy]acetyl]amino]ethylcarbamoyl]-2-[(2S,3S,4R,5S,6S)-3,4,5-trihydroxy-6-methyloxacyclohexane-2-yl]oxycyclohexyl]oxy- 5-Hydroxy-6-(hydroxymethyl)oxacyclohexane-4-yl]oxy-3-cyclohexylpropionic acid (rivipansel, GMI-1070), sevuparin, 6-[(3I,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidine-3-yl]-1-(oxacyclohexane-4-yl)-5H-pyrazolo[3,4-d]pyrimidin-4-one (PF-04447943), inclacumab (LC1004-002), 3-[3-[4-(l-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine (miransertib, ARQ092) and combinations thereof.

[0262] In other embodiments, the adjunctive therapeutic agent may be, for example, an anti-sickle agent. For example, in some embodiments, the adjunctive therapeutic agent may be selected from 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (Voselotor, 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.

[0263] In further embodiments, the adjunctive therapeutic agent may be, for example, an antidote. For instance, in some embodiments, the adjunctive therapeutic agent may be LJPC-401. In some embodiments, the adjunctive therapeutic agent may be selected from, for example, anti-inflammatory agents, antithrombotic agents, and combinations thereof. For example, in some embodiments, the additional therapeutic agent may be selected from (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, tricagrelor), (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-hydroxypropionamide (olinciguat), NKTT120, and combinations thereof.

[0264] In some embodiments, the adjunctive therapeutic agent may be, for example, sanguinate. In other embodiments, the adjunctive therapeutic agent may be, for example, an agent that causes destruction of PRC2. In a further embodiment, the adjunctive therapeutic agent is, for example, AZD9291.

[0265] Example

[0266] The compounds described herein can be prepared in a variety of ways based on the teachings contained herein and synthetic procedures known in the art. The following non-limiting examples illustrate this disclosure.

[0267] X-ray powder diffraction was performed using a Bruker D8 Advance equipped with a Lynxeye detector in reflection mode (Bragg-Brentano geometry). Samples were prepared on Si zero-return wafers. The parameters of the XRPD method used are listed in Table 1 below.

[0268] Table 1

[0269]

[0270] X-ray powder diffraction was also performed using a Rigaku MiniFlex 600 in reflection mode (Bragg-Brentano geometry). Samples were prepared on silicon zero-gravity wafers. The parameters of the XRPD method used are listed in Table 2 below.

[0271] Table 2

[0272]

[0273] Using Mettler Toledo DSC 3+ Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were performed. The sample (3-5 mg) was weighed directly in an airtight aluminum pan with pinholes and analyzed according to the parameters in Table 3A below.

[0274] Table 3A

[0275]

[0276] Dynamic vapor adsorption (DVS) analysis was performed using the DVS Intrinsic 1. The sample (25 mg) was loaded into a sample tray, suspended over a microbalance, and exposed to a humidified nitrogen flow. The sample was held at each level for at least 5 minutes, and the next humidity level was only advanced if the weight change between measurements (interval: 60 seconds) was <0.002% or if 240 minutes had elapsed. The following procedure was used as shown in Table 3B:

[0277] Table 3B

[0278] 1) Equilibrate at 50% RH

[0279] 2) 50% to 2% (50%, 40%, 30%, 20%, 10% and 2%)

[0280] 3) 2% to 95% (2%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%)

[0281] 4) 95% to 2% (95%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 2%)

[0282] 5) 2% to 50% (2%, 10%, 20%, 30%, 40%, 50%)

[0283] Optical microscopy was performed using the Zeiss AxioScope A1, equipped with 2.5×, 10×, 20×, and 40× objectives and polarizers. Images were captured using the built-in Axiocam 105 digital camera and processed using Zeiss's ZEN 2 (blue edition) software.

[0284] Example 1

[0285] The following preparation was made of crystal 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene free base. Approximately 25 mg of crystal 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene free base was dissolved in acetone (50 v / v) at 50 °C. The solution was immediately transferred to a heptane solution (400 volumes) at 50°C while rapidly stirring until a white slurry formed. The solid was collected at 50°C and dried overnight. XRPD analysis showed that the material was crystalline, and its spectrum was consistent with that of crystal form P.

[0286] The following method was also used to prepare crystal 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base: Approximately 25 mg of crystal 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base was dissolved in isopropanol (25 volumes) at 50 °C. The solution was immediately transferred to an aqueous solution (100 volumes) at 50°C while rapidly stirring until a white slurry formed. The solid was collected at 50°C and dried overnight. XRPD analysis showed that the material was crystalline, and its spectrum was consistent with that of crystal form P.

[0287] The XRPD spectrum of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene in crystal form P is shown. Figure 1 The characteristic peaks include one or more peaks shown in Table 4.

[0288] Table 4

[0289]

[0290]

[0291] Figure 2 Differential scanning calorimetry (DSC) curves for crystalline form P were plotted. For example... Figure 2 As shown, crystal form P exhibits a characteristic endothermic peak with an onset temperature of approximately 252°C and a peak temperature of approximately 253°C.

[0292] The crystalline form P of the anhydrous free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene exhibits thermogravimetric analysis (TGA) curves showing a mass loss of approximately 0.46 wt% up to approximately 260 °C. Crystalline form P also exhibits dynamic vapor adsorption (DVS) curves showing a reversible total mass change of approximately 0.53 wt% at 25 °C between approximately 2 and approximately 92% relative humidity (RH). By optical microscopy, crystalline form P displays a rod-like and / or plate-like morphology. Crystalline form P shows stability for at least one week under dry and high humidity conditions (40 °C and 75% RH). Through wet milling studies (ball mill, 30 seconds, milling with 1 volume of water), crystal form P maintained crystallinity and purity in solid form.

[0293] Example 2

[0294] The following preparation was made of crystal 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene free base. NH4OH (14.5 M) was added dropwise to a methanol 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene hydrochloride. Upon further addition of 1 mL NH4OH, the solution became a non-flowing gel. An additional 2 volumes of MeOH were added to the gel, mixed manually, 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 flowable, off-white slurry. XRPD analysis of the extracted sample showed that the material was crystalline, with a spectrum consistent with crystal form A.

[0295] The XRPD spectrum of crystal form A of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene is shown in... Figure 3 The characteristic peaks include one or more peaks shown in Table 5.

[0296] Table 5

[0297]

[0298] Example 3

[0299] The following method was used to prepare crystal 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene free base. NH4OH (14.5 M) was added dropwise to a methanol 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene hydrochloride. After adding another 1 mL of NH4OH, the solution became a non-flowing gel. Another 6 volumes of MeOH were added to the gel, mixed manually, and stirred overnight. The next morning, opaque white fibrous particles were observed in the gel. The mixture was sonicated, producing a very fluid, off-white slurry. A sample was extracted for XRPD analysis, revealing the crystalline form – crystal form B. The slurry was stirred for another 5 hours at room temperature. The solid was collected by filtration and washed with 4 volumes of MeOH:water (1:3 volume). The wet filter cake was pressed onto an XRPD plate and analyzed. XRPD analysis of the extracted sample showed that the material was crystalline, with a spectrum consistent with crystal form B. Optical microscopy revealed that crystal form P exhibited a hair-like morphology.

[0300] The XRPD spectrum 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene in crystal form B is shown. Figure 4 The characteristic peaks include one or more peaks shown in Table 6.

[0301] Table 6

[0302]

[0303]

[0304] Example 4

[0305] Crystal 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base was prepared as follows. The wet filter cake crystal form B obtained in Example 3 above was dried overnight at 50°C in a vacuum oven equipped with a rotary oil vacuum pump. XRPD analysis of the dried sample showed that the material was crystalline, and its spectrum was consistent with that of crystal form C.

[0306] The XRPD spectrum of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene in crystal form C is shown. Figure 5 The characteristic peaks include one or more peaks shown in Table 7.

[0307] Table 7

[0308]

[0309]

[0310] Example 5

[0311] The following preparation was performed to obtain crystal form D of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene. 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene hydrochloride was dissolved in 18 volumes of MeOH at 50 °C. Half of the required amount of NH4OH for precipitation was added, followed by seeding with crystal form B, resulting in the immediate precipitation of a loose solid. The remaining half of the NH4OH was added, and the slurry was stirred at 50°C for 2 hours. The slurry was then cooled to room temperature and stirred for 1.25 hours. The solid was collected by filtration, washed three times with 1 mL of water, and dried at 50°C for 3 days in a vacuum oven equipped with an oil rotary vacuum pump. XRPD analysis of the dried solid showed that the material was crystalline, and its spectrum was consistent with crystal form D.

[0312] The XRPD spectrum of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene in crystal form D is shown. Figure 6 The characteristic peaks include one or more peaks shown in Table 8.

[0313] Table 8

[0314]

[0315] Example 6

[0316] The following preparation was performed to obtain crystal 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene free alkali hydrate. 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene hydrochloride was added to a vial, followed by 2 mL (~60 volumes) of saturated NaHCO3 (water) solution. The slurry was stirred at 50°C for 1 hour. The slurry solids were collected by filtration, and the wet filter cake was analyzed by XRPD. XRPD analysis showed that the wet filter cake material was crystalline, and its spectrum was consistent with crystal form E.

[0317] The XRPD spectrum of crystal 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base hydrate is shown in Figure 7 The characteristic peaks include one or more peaks shown in Table 9.

[0318] Table 9

[0319]

[0320]

[0321] Figure 8 Differential scanning calorimetry (DSC) curves for crystal form E were plotted. For example... Figure 8 As shown, crystal form E exhibits a characteristic endothermic peak with an onset temperature of approximately 44°C and a peak temperature of approximately 58°C, a characteristic endothermic peak with an onset temperature of approximately 110°C and a peak temperature of approximately 114°C, and a characteristic endothermic peak with an onset temperature of approximately 166°C and a peak temperature of approximately 177°C.

[0322] 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base hydrate exhibits thermogravimetric analysis (TGA) curves showing a mass loss of approximately 5.1 wt% up to approximately 170 °C. Crystalline form E also exhibits dynamic vapor adsorption (DVS) curves showing a reversible total mass change of approximately 10.3 wt% between approximately 2 and approximately 92% relative humidity (RH) at 25 °C. Crystalline form E displays a hair-like morphology under optical microscopy. Crystalline form E shows stability for at least one week at 40 °C and 75% relative humidity (RH).

[0323] Example 7

[0324] The following preparations were made of crystal 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene free base. A sample of crystal 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene free base hydrate was further dried overnight at 50°C in a vacuum oven equipped with an oil rotary vacuum pump. XRPD analysis showed that the material is crystalline, and its spectrum is consistent with crystal form F.

[0325] The XRPD spectrum of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene in crystal form F is shown. Figure 9 The characteristic peaks include one or more peaks shown in Table 10.

[0326] Table 10

[0327]

[0328] Example 8

[0329] Crystalline material 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free alkali hydrate was prepared as follows. A slurry of crystalline material E 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, and its spectrum was consistent with that of crystalline material H.

[0330] 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base hydrate was also prepared as follows: 10 volumes of MeOH were added to 0.21 g of crystalline form P material, which had been dried in a 20 mL vial. The resulting slurry was crystallized using crystalline form H material. After 2 hours, the slurry was sampled and an XRPD spectrum consistent with crystalline form H was displayed. After stirring the slurry overnight, another 10 volumes of MeOH were added, and the slurry was transferred to a 4 mL vial and stirred further. 15 μL of water was added. The slurry was heated to 50 °C, crystallized again using crystalline form H material, and stirred at 50 °C for 40 min. The slurry was cooled to room temperature, the solid was collected by filtration, washed once with 2 volumes of MeOH, and then dried in a vacuum oven at 50°C. XRPD analysis showed that the dried material was crystalline, and its spectrum was consistent with crystal form H.

[0331] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base hydrate crystal form H is shown in Figure 10 The characteristic peaks include one or more peaks shown in Table 11.

[0332] Table 11

[0333]

[0334] Figure 11 Differential scanning calorimetry (DSC) curves for crystalline form H were plotted. For example... Figure 11As shown, crystal form H exhibits a characteristic endothermic peak with an initial temperature of approximately 58°C and a peak temperature of approximately 84°C, a characteristic endothermic peak with an initial temperature of approximately 63°C and a peak temperature of approximately 89°C, and a characteristic endothermic peak with an initial temperature of approximately 169°C and a peak temperature of approximately 176°C.

[0335] 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base hydrate exhibits thermogravimetric analysis (TGA) curves showing a mass loss of approximately 6.3 wt% up to approximately 130 °C. Crystalline form H also exhibits dynamic vapor adsorption (DVS) curves showing a reversible total mass change of approximately 7.6 wt% between approximately 2 and approximately 92% relative humidity (RH) at 25 °C. By optical microscopy, crystalline form H displays a hair-like morphology. Crystalline form H shows stability for at least one week at 40 °C and 75% relative humidity (RH).

[0336] Example 9

[0337] 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base was prepared as follows. A slurry of crystalline form E was stirred in EtOH at room temperature for 3 days. The slurry solid was filtered, and the wet filter cake was analyzed by XRPD. XRPD analysis showed that the wet filter cake material was crystalline, and its spectrum was consistent with crystalline form I.

[0338] 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base was also prepared as follows: Crystalline form E was dissolved in EtOH (30 volumes) at 50 °C. The stirred solution was cooled from 50 °C to room temperature at a rate of 5 °C / hour by decreasing the hot plate 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, and its spectrum was consistent with that of crystalline form I. By optical microscopy, crystalline form I showed a hair-like morphology.

[0339] The XRPD spectrum of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene in crystal form I is shown. Figure 12 The characteristic peaks include one or more peaks shown in Table 12.

[0340] Table 12

[0341]

[0342]

[0343] Example 10

[0344] Crystalline material 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base was prepared as follows. A slurry of crystalline material E was stirred in acetone at room temperature for 3 days. The slurry solid was filtered, and the wet filter cake was analyzed by XRPD. XRPD analysis showed that the wet filter cake material was crystalline, and its spectrum was consistent with that of crystalline material J.

[0345] Crystalline material 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base was also prepared as follows: Crystalline material E was dissolved in acetone (34 volumes) at 50 °C. The stirred solution was cooled from 50 °C to room temperature at a rate of 5 °C / hour by decreasing the temperature of the hot plate 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, and its spectrum was consistent with that of crystalline J. By optical microscopy, crystalline material J showed a hair-like morphology.

[0346] The XRPD spectrum of the free base 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene is shown in Figure 13 The characteristic peaks include one or more peaks shown in Table 13.

[0347] Table 13

[0348]

[0349]

[0350] Example 11

[0351] Crystalline material 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base was prepared as follows. A slurry of crystalline material E was stirred in MeCN at room temperature for 3 days. The slurry solids were filtered, and the wet filter cake was analyzed by XRPD. XRPD analysis showed that the wet filter cake material was crystalline, and its spectrum was consistent with that of crystalline material K.

[0352] Crystalline material 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base was also prepared as follows: Crystalline material E was dissolved in MeCN (60 volumes) at 50 °C. The stirred solution was cooled from 50 °C to room temperature at a rate of 5 °C / hour by decreasing the hot plate 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, and its spectrum was consistent with that of crystalline material K.

[0353] The XRPD spectrum of the free base 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene is shown in Figure 14 The characteristic peaks include one or more peaks shown in Table 14.

[0354] Table 14

[0355]

[0356]

[0357] Figure 15 Differential scanning calorimetry (DSC) curves for crystal form K were plotted. For example... Figure 15 As shown, crystal form K exhibits a characteristic endothermic peak with an onset temperature of approximately 226°C and a peak temperature of approximately 230°C.

[0358] Example 12

[0359] 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base was prepared as follows. A slurry of crystalline form E was stirred in MeCN at 50°C for 3 days. The slurry solids were filtered, and the wet filter cake was analyzed by XRPD. XRPD analysis showed that the wet filter cake material was crystalline, and its spectrum was consistent with crystalline form L.

[0360] The XRPD spectrum of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene in crystal form L is shown. Figure 16 The characteristic peaks include one or more peaks shown in Table 15.

[0361] Table 15

[0362]

[0363]

[0364] Example 13

[0365] Crystalline material 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base was prepared as follows. The wet filter cake material of crystallization L obtained in Example 12 was further dried in a vacuum oven at 50°C for 16 hours. XRPD analysis showed that the dried material was crystalline, and its spectrum was consistent with that of crystallization M.

[0366] The XRPD spectrum 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene in crystal form M is shown. Figure 17 The characteristic peaks include one or more peaks shown in Table 16.

[0367] Table 16

[0368]

[0369]

[0370] Example 14

[0371] 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base was prepared as follows. Crystalline 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 a rate of 5 °C / hour by decreasing the hot plate 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 filter cake was analyzed by XRPD. XRPD analysis showed that the wet filter cake material was crystalline, and its spectrum was consistent with that of crystalline form N.

[0372] The XRPD spectrum of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene in crystal form N is shown. Figure 18 The characteristic peaks include one or more peaks shown in Table 17.

[0373] Table 17

[0374]

[0375] Example 15

[0376] Crystalline material 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base was prepared as follows: Approximately 25 mg of crystalline material E was dissolved in DMSO (5 volumes) at room temperature. Water (10 volumes) was added dropwise to the stirred DMSO solution in four portions over 60 minutes. The resulting slurry solid was collected by filtration and dried overnight. XRPD analysis showed that the material was crystalline, and its spectrum was consistent with that of crystalline material O.

[0377] The XRPD spectrum of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene in crystal form O is shown. Figure 19 The characteristic peaks include one or more peaks shown in Table 18.

[0378] Table 18

[0379]

[0380] Figure 20 Differential scanning calorimetry (DSC) curves for crystalline form O were plotted. For example... Figure 20 As shown, crystal form O exhibits a characteristic endothermic peak with an onset temperature of approximately 166°C and a peak temperature of approximately 172°C, as well as a characteristic endothermic peak with an onset temperature of approximately 196°C and a peak temperature of approximately 204°C.

[0381] The crystalline form O of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene shows a thermogravimetric analysis (TGA) curve, which shows a first-step mass loss of about 0.23 wt% up to about 150 °C, a second-step mass loss of about 1.7 wt% between about 150 °C and about 200 °C, a third-step mass loss of about 1.3 wt% between about 200 °C and about 250 °C, and a fourth-step mass loss of about 4.7 wt% between about 250 °C and about 280 °C.

[0382] Example 16

[0383] Crystalline material 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base was prepared as follows. Approximately 28 mg of crystal form E was loaded into a grinding capsule and 1 volume of MeCN was added, along with 1 / 4” steel balls as the grinding medium. The solid was ground with a Wig-L-bug at 3500 rpm for 30 seconds, then collected and analyzed by XRPD. XRPD analysis of the wet filter cake material showed that the material was crystalline, and its spectrum was consistent with that of crystal form Q.

[0384] The XRPD spectrum 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene in crystal form Q is shown. Figure 21 The characteristic peaks include one or more peaks shown in Table 19.

[0385] Table 19

[0386]

[0387]

[0388] Example 17

[0389] Crystalline material 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base was prepared as follows. Crystalline material E was dissolved in N,N-dimethylacetamide (9 volumes) at 50 °C. The stirred solution was cooled from 50 °C to room temperature at a rate of 5 °C / hour by decreasing the hot plate 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 overnight under vacuum at 50 °C. XRPD analysis showed that the material was crystalline, and its spectrum was consistent with that of crystalline material R.

[0390] The XRPD spectrum 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene crystal form R is shown in Figure 22 The characteristic peaks include one or more peaks shown in Table 20.

[0391] Table 20

[0392]

[0393]

[0394] Figure 23 Differential scanning calorimetry (DSC) curves for crystal form R were plotted. For example... Figure 23As shown, crystal form R exhibits a characteristic endothermic peak with an onset temperature of approximately 148°C and a peak temperature of approximately 152°C, as well as a characteristic endothermic peak with an onset temperature of approximately 241°C and a peak temperature of approximately 251°C.

[0395] The expected crystalline form R of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonanotecrene shows a thermogravimetric analysis (TGA) curve, which shows a first-step mass loss of about 0.87 wt% up to about 150 °C, a second-step mass loss of about 3.1 wt% between about 150 °C and about 200 °C, and a third-step mass loss of about 11.7 wt% between about 200 °C and about 240 °C.

[0396] Example 18

[0397] Crystalline material S, consisting of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base, was prepared as follows. The wet filter cake material of crystallization Q obtained in Example 16 was further dried under vacuum. XRPD analysis showed that the dried material was crystalline, and its spectrum was consistent with that of crystallization S.

[0398] The XRPD spectrum of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene in crystal form S is shown. Figure 24 The characteristic peaks include one or more peaks shown in Table 21.

[0399] Table 21

[0400]

[0401] Example 19

[0402] Crystalline material 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base was prepared as follows. A saturated solution of crystal form P was produced by preparing a slurry of crystal form P in isopropanol:water (1:4 volume) and stirring overnight. The solid was allowed to settle, and the supernatant was transferred to a vial containing approximately 5 mg of each of crystal form E, crystal form H, and crystal form P. The competing slurries were stirred at room temperature for 24 hours. XRPD analysis of the collected solids showed that the material was crystalline, and its spectrum was consistent with that of crystal form T.

[0403] The XRPD spectrum of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene in crystal form T is shown. Figure 25 The characteristic peaks include one or more peaks shown in Table 22.

[0404] Table 22

[0405]

[0406]

[0407] Figure 26 Differential scanning calorimetry (DSC) curves for crystal form T were plotted. For example... Figure 26 As shown, crystal form T exhibits a characteristic endothermic peak with an onset temperature of approximately 83°C and a peak temperature of approximately 84°C, as well as a characteristic endothermic peak with an onset temperature of approximately 249°C and a peak temperature of approximately 251°C.

[0408] The expected crystalline form T of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene is shown in thermogravimetric analysis (TGA) curves, revealing a first-step mass loss of approximately 13.8 wt% up to approximately 85 °C. Microscopic imaging reveals crystalline form T to exhibit needle-like and / or rod-like morphologies.

[0409] Example 20

[0410] Crystalline material 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base was prepared as follows. The wet filter cake material of crystallization N obtained in Example 14 was further dried overnight under vacuum at 50°C. XRPD analysis showed that the dried material was crystalline, and its spectrum was consistent with that of crystallization U.

[0411] The XRPD spectrum of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene in crystal form U is shown. Figure 27 The characteristic peaks include one or more peaks shown in Table 23.

[0412] Table 23

[0413]

[0414] Example 21

[0415] Crystalline material 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene free base was prepared as follows. Approximately 12 mg of crystalline material P was loaded 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 the slurry was observed the next day. The slurry solid was collected and analyzed by XRPD. XRPD analysis showed that the material was crystalline, and its spectrum was consistent with that of crystalline material V.

[0416] The XRPD spectrum of the free base of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene in crystal form V is shown. Figure 28 The characteristic peaks include one or more peaks shown in Table 24.

[0417] Table 24

[0418]

[0419]

[0420] Example 22

[0421] The following preparation was performed to obtain crystal 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene free base. 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene maleate (crystal form 7-A) was loaded into a vial. 1 mL of water was added, and the mixture was heated to 37°C. Adding additional water to the slurry significantly thinned it, and then fine white solids began to precipitate. This was considered a possible disproportionation, and no additional water was added. The mixture was stirred overnight, and the fine solids suspended in the solution were collected the next day and analyzed by XRPD. Disproportionation of maleate was observed during the slurry time. XRPD analysis revealed the formation of a new crystalline form 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene, termed crystal form W.

[0422] The XRPD spectrum 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene in crystal form W is shown. Figure 29 The characteristic peaks include one or more peaks shown in Table 25.

[0423] Table 25

[0424]

[0425] Example 23

[0426] The 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]benzofurano[4,3-fg][1,4]oxazapyridine nonaratete free base was prepared as follows: Approximately 30 mg of crystalline E material was dissolved in 5 volumes of THF at 50 °C without capping or stirring, allowing the solvent to evaporate. A yellow gel remained at the bottom of the vial and was dried overnight in a vacuum oven at 50 °C. The brittle glass was broken with a spatula, and the solid was analyzed by XRPD, revealing an amorphous spectrum. Figure 67 ).

[0427] Example 24 - Salt Screening

[0428] A stock solution of the crystalline form of the (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazahexacyclic nonapatite free base was prepared in 2,2,2-trifluoroethanol (50.8 mg / mL). A stock solution of the counterion was prepared in EtOH.

[0429] Salt formation was carried out in 2 mL vials at room temperature. 25.4 mg of crystalline P free base material (500 μL stock solution) and 1.1 equivalents of counterions were added to each vial. The solvent was allowed to evaporate overnight at 40 °C with stirring. Almost half of the vials did not completely evaporate overnight. These vials were held on a hot plate to continue evaporation (temperature increased to 50 °C), while the drier samples were further dried under vacuum at 50 °C for 3 hours. Samples still containing solvent at the end of the day were stirred at 30 °C throughout the weekend to complete solvent evaporation. These samples were then further dried under vacuum at 50 °C for 3 hours.

[0430] Approximately 20 volumes (0.5 mL) of solvent were added to each vial containing the dried solids. The three solvents chosen were EtOH, EtOAc, and IPA:water (9:1 volume). Once the solvents were added, the mixture (or solution) was stirred at room temperature. When a slurry was formed, the solids were filtered for XRPD analysis.

[0431] XRPD analysis was performed in three stages. All collected samples underwent wet filter cake XRPD. The unique solid was then left on the XRPD plate and dried under vacuum at 50°C. XRPD of the dried unique solid was then performed. The solid was subsequently exposed to 95%+ relative humidity for one day, and XRPD was performed on the resulting solid. A humid environment was created by placing a beaker of saturated potassium sulfate in water in a sealed container. All XRPD spectra were compared with counterion XRPD spectra (if solid). A summary of the results is given in Table 26. The nomenclature scheme for crystalline salt forms is the counterion number followed by a letter corresponding to the unique spectrum observed for that counterion. For example, crystal form 8-B would specify the second unique spectrum observed with the L-malic acid counterion.

[0432] Table 26

[0433]

[0434]

[0435] Am = amorphous

[0436] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatenite benzenesulfonate in crystalline salt form 1-A is shown in Figure 30 The characteristic peaks include one or more peaks shown in Table 27.

[0437] Table 27

[0438]

[0439]

[0440] XRPD spectra of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatranbenzenesulfonate in crystalline salt form 1-B are shown in Figure 31 The characteristic peaks include one or more peaks shown in Table 28.

[0441] Table 28

[0442]

[0443]

[0444] Figure 32 Differential scanning calorimetry (DSC) curves for crystalline salt form 1-B were plotted. Figure 32 As shown, crystalline salt form 1-B exhibits a characteristic endothermic peak with an onset temperature of approximately 33°C and a peak temperature of approximately 71°C, a characteristic endothermic peak with an onset temperature of approximately 120°C and a peak temperature of approximately 133°C, and a characteristic endothermic peak with an onset temperature of approximately 154°C and a peak temperature of approximately 159°C.

[0445] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatraene citrate in crystalline form 2-A is shown in Figure 33 The characteristic peaks include one or more peaks shown in Table 29.

[0446] Table 29

[0447]

[0448]

[0449] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatraene citrate in crystalline salt form 2-B is shown in Figure 34 The characteristic peaks include one or more peaks shown in Table 30.

[0450] Table 30

[0451]

[0452]

[0453] The XRPD spectrum of the 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene citrate in 2-C form is shown in... Figure 35 The characteristic peaks include one or more peaks shown in Table 31.

[0454] Table 31

[0455]

[0456]

[0457] Figure 36 Differential scanning calorimetry (DSC) curves for the crystalline salt form 2-C were plotted. For example... Figure 36 As shown, the crystalline salt form 2-C exhibits characteristic endothermic peaks with an initial temperature of approximately 33°C and a peak temperature of approximately 60°C, characteristic endothermic peaks with an initial temperature of approximately 96°C and a peak temperature of approximately 116°C, characteristic endothermic peaks with an initial temperature of approximately 160°C and a peak temperature of approximately 169°C, and characteristic endothermic peaks with an initial temperature of approximately 141°C and a peak temperature of approximately 177°C.

[0458] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaratetraene fumarate in crystalline salt form 3-A is shown in... Figure 37 The characteristic peaks include one or more peaks shown in Table 32.

[0459] Table 32

[0460]

[0461]

[0462] Figure 38 Differential scanning calorimetry (DSC) curves for the crystalline salt form 3-A were plotted. For example... Figure 38 As shown, the crystalline salt form 3-A exhibits a characteristic endothermic peak with an onset temperature of approximately 237°C and a peak temperature of approximately 241°C.

[0463] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatraene hydrochloride in crystalline salt form 5-A is shown in Figure 39 The characteristic peaks include one or more peaks shown in Table 33.

[0464] Table 33

[0465]

[0466]

[0467] The expected 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene hydrochloride exhibits thermogravimetric analysis (TGA) curves showing a mass loss of approximately 3.1 wt% up to approximately 110 °C and a further mass loss of approximately 7.6 wt% between approximately 110 °C and approximately 195 °C. Crystalline form 5-A exhibits dynamic vapor adsorption (DVS) curves showing a reversible total mass change of approximately 3.1 wt% between approximately 2 and approximately 92% relative humidity (RH) at 25 °C. Crystalline form 5-A can be characterized by Karl Fischer titration, showing a water content of approximately 10.7%. Optical microscopy revealed that crystal form 5-A exhibits a rod-like or plate-like morphology.

[0468] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatraene hydrochloride in crystalline salt form 5-B is shown in Figure 40 The characteristic peaks include one or more peaks shown in Table 34.

[0469] Table 34

[0470]

[0471] Figure 41 Differential scanning calorimetry (DSC) curves for the crystalline salt form 5-B were plotted. Figure 41 As shown, the crystalline salt form 5-B exhibits a characteristic endothermic peak with an onset temperature of approximately 68°C and a peak temperature of approximately 82°C, a characteristic endothermic peak with an onset temperature of approximately 111°C and a peak temperature of approximately 130°C, and a characteristic endothermic peak with an onset temperature of approximately 193°C and a peak temperature of approximately 211°C.

[0472] The XRPD spectrum of the 5-C 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene hydrochloride is shown in… Figure 42 The characteristic peaks include one or more peaks shown in Table 35.

[0473] Table 35

[0474]

[0475] Figure 43 Differential scanning calorimetry (DSC) curves for the crystalline salt form 5-C were plotted. For example... Figure 43 As shown, the crystalline salt form 5-C exhibits a characteristic endothermic peak with an onset temperature of approximately 140°C and a peak temperature of approximately 145°C, as well as a characteristic endothermic peak with an onset temperature of approximately 213°C and a peak temperature of approximately 230°C.

[0476] Crystalline 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene hydrochloride was prepared as follows. Crystalline form 5-B was prepared by adding 50 volumes of IPA:water (9:1 volume). The slurry was sonicated in an ultrasonic bath for 5.5 hours, maintaining the bath temperature between 17°C and 31°C. The solid was collected by filtration and analyzed by XRPD. XRPD analysis showed that the material was crystalline, and its spectrum was consistent with that of crystalline form 5-D.

[0477] The XRPD spectrum of 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]benzofurano[4,3-fg][1,4]oxazacyclononatraene hydrochloride is shown in... Figure 44 The characteristic peaks include one or more peaks shown in Table 36.

[0478] Table 36

[0479]

[0480] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatrane maleate in crystalline form 7-A is shown in Figure 45 The characteristic peaks include one or more peaks shown in Table 37.

[0481] Table 37

[0482]

[0483]

[0484] Figure 46Differential scanning calorimetry (DSC) curves for the crystalline salt form 7-A were plotted. For example... Figure 46 As shown, the crystalline salt form 7-A exhibits a characteristic endothermic peak with an onset temperature of approximately 215°C and a peak temperature of approximately 221°C, as well as a characteristic endothermic peak with an onset temperature of approximately 216°C and a peak temperature of approximately 225°C.

[0485] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononacyclene L-malate in crystalline form 8-A is shown in Figure 47 The characteristic peaks include one or more peaks shown in Table 38.

[0486] Table 38

[0487]

[0488]

[0489] Figure 48 Differential scanning calorimetry (DSC) curves for the crystalline salt form 8-A were plotted. For example... Figure 48 As shown, the crystalline salt form 8-A exhibits a characteristic endothermic peak with an initial temperature of approximately 177°C and a peak temperature of approximately 201°C, a characteristic endothermic peak with an initial temperature of approximately 186°C and a peak temperature of approximately 207°C, a characteristic endothermic peak with an initial temperature of approximately 205°C and a peak temperature of approximately 211°C, and a characteristic endothermic peak with an initial temperature of approximately 208°C and a peak temperature of approximately 216°C.

[0490] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononacyclene L-malate in crystalline form 8-B is shown in Figure 49 The characteristic peaks include one or more peaks shown in Table 39.

[0491] Table 39

[0492]

[0493]

[0494] Figure 50 Differential scanning calorimetry (DSC) curves for the crystalline salt form 8-B were plotted. For example... Figure 50As shown, the crystalline salt form 8-B exhibits a characteristic endothermic peak with an onset temperature of approximately 189°C and a peak temperature of approximately 192°C, as well as a characteristic endothermic peak with an onset temperature of approximately 186°C and a peak temperature of approximately 202°C.

[0495] The 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene L-malate exhibits thermogravimetric analysis (TGA) curves showing a mass loss of approximately 0.46 wt% up to approximately 175 °C. Crystalline form 8-B can be characterized by dynamic vapor adsorption (DVS) curves, showing a reversible total mass change of approximately 0.82 wt% at 25 °C between approximately 2 and approximately 92% relative humidity (RH).

[0496] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatrane methanesulfonate in crystalline salt form 9-A is shown in Figure 51 The characteristic peaks include one or more peaks shown in Table 40.

[0497] Table 40

[0498]

[0499]

[0500] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene methanesulfonate in crystalline salt form 9-B is shown in Figure 52 The characteristic peaks include one or more peaks shown in Table 41.

[0501] Table 41

[0502]

[0503] Figure 53 Differential scanning calorimetry (DSC) curves for the crystalline salt form 9-B were plotted. Figure 53As shown, the crystalline salt form 9-B exhibits a characteristic endothermic peak with an onset temperature of approximately 189°C and a peak temperature of approximately 192°C, as well as a characteristic endothermic peak with an onset temperature of approximately 186°C and a peak temperature of approximately 202°C.

[0504] The XRPD spectrum of the 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene methanesulfonate in 9-C is shown in Figure 54 The characteristic peaks include one or more peaks shown in Table 42.

[0505] Table 42

[0506]

[0507]

[0508] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene phosphate in crystalline salt form 10-A is shown in Figure 55 The characteristic peaks include one or more peaks shown in Table 43.

[0509] Table 43

[0510]

[0511] Figure 56 Differential scanning calorimetry (DSC) curves for the crystalline salt form 10-A were plotted. Figure 56 As shown, the crystalline salt form 10-A exhibits a characteristic endothermic peak with an onset temperature of approximately 282°C and a peak temperature of approximately 290°C, as well as a characteristic endothermic peak with an onset temperature of approximately 283°C and a peak temperature of approximately 294°C.

[0512] 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene phosphate exhibits thermogravimetric analysis (TGA) curves showing a mass loss of approximately 0.22 wt%. Crystalline form 10-A also exhibits dynamic vapor adsorption (DVS) curves showing a reversible total mass change of approximately 1.4 wt% at 25 °C between approximately 2 and approximately 92% relative humidity (RH).

[0513] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazapyridine nonaterenepyruvate in crystalline salt form 11-A is shown in... Figure 57 The characteristic peaks include one or more peaks shown in Table 44.

[0514] Table 44

[0515]

[0516] Figure 58 Differential scanning calorimetry (DSC) curves for the crystalline salt form 11-A were plotted. Figure 58 As shown, crystalline salt form 11-A exhibits a characteristic endothermic peak with an onset temperature of approximately 76°C and a peak temperature of approximately 88°C, a characteristic endothermic peak with an onset temperature of approximately 134°C and a peak temperature of approximately 142°C, and a characteristic endothermic peak with an onset temperature of approximately 149°C and a peak temperature of approximately 157°C.

[0517] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene sulfate in crystalline form 12-A is shown in Figure 59 The characteristic peaks include one or more peaks shown in Table 45.

[0518] Table 45

[0519]

[0520]

[0521]

[0522] Figure 60 Differential scanning calorimetry (DSC) curves for the crystalline salt form 12-A were plotted. Figure 58 As shown, the crystalline salt form 12-A exhibits a characteristic endothermic peak with an onset temperature of approximately 48°C and a peak temperature of approximately 81°C, a characteristic endothermic peak with an onset temperature of approximately 169°C and a peak temperature of approximately 185°C, and a characteristic endothermic peak with an onset temperature of approximately 229°C and a peak temperature of approximately 241°C.

[0523] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatraene L-tartrate in crystalline salt form 13-A is shown in Figure 61 The characteristic peaks include one or more peaks shown in Table 46.

[0524] Table 46

[0525]

[0526]

[0527] Figure 62 Differential scanning calorimetry (DSC) curves for the crystalline salt form 13-A were plotted. Figure 62 As shown, the crystalline salt form 13-A exhibits a characteristic endothermic peak with an onset temperature of approximately 213°C and a peak temperature of approximately 222°C.

[0528] 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene L-tartrate exhibits thermogravimetric analysis (TGA) curves showing a mass loss of approximately 0.63 wt% up to approximately 185 °C. Crystalline form 13-A also exhibits dynamic vapor adsorption (DVS) curves showing a reversible total mass change of approximately 0.97 wt% between approximately 2 and approximately 92% relative humidity (RH) at 25 °C.

[0529] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatetraene L-tartrate in crystalline salt form 13-B is shown in Figure 63The characteristic peaks include one or more peaks shown in Table 47.

[0530] Table 47

[0531]

[0532] Figure 64 Differential scanning calorimetry (DSC) curves for the crystalline salt form 13-B were plotted. For example... Figure 64 As shown, crystalline salt form 13-B exhibits a characteristic endothermic peak with an onset temperature of approximately 89°C and a peak temperature of approximately 115°C, a characteristic endothermic peak with an onset temperature of approximately 157°C and a peak temperature of approximately 167°C, and a characteristic endothermic peak with an onset temperature of approximately 181°C and a peak temperature of approximately 195°C.

[0533] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononatranetotetraene toluenesulfonate in crystalline salt form 14-A is shown in Figure 65 The characteristic peaks include one or more peaks shown in Table 48.

[0534] Table 48

[0535]

[0536] The XRPD spectrum of (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofurano[4,3-fg][1,4]oxazacyclononazone toluene sulfonate in crystalline salt form 14-B is shown in Figure 66 The characteristic peaks include one or more peaks shown in Table 49.

[0537] Table 49

[0538]

[0539] Example 25. Crystallization Study

[0540] The aim of this study was to develop a reliable crystallization process with reproducible particle size distribution (PSD) control. The solubility of crystalline P was measured in a DMSO / EtOH / water system at the evaluated temperature. Crystalline P was slurried in the selected solvent system for 2–3 hours, and the mother liquor was then collected for solubility testing by high-performance liquid chromatography (HPLC). The results in Table 50 show that solubility decreases significantly with increasing water content.

[0541] Table 50

[0542]

[0543]

[0544] Based on the solubility data of crystalline form P in the DMSO / EtOH / water system in Example 25, experiments were conducted (Experiment 1 in Table 51 below). Coarse crystalline form P was dissolved in DMSO / EtOH 3V / 3V at 50°C, followed by the addition of 0.6V of water to create supersaturation for crystallization. Subsequently, 11.4V of water was metered into the seed crystal suspension in two steps (2.4V / 6h, 9V / 4h), and the suspension was further aged for approximately 12h. The solid was separated by filtration and vacuum dried at 50°C.

[0545] Several additional experiments (Experiments 2, 3, 4, 5, 7, and 8) were conducted to investigate the effects 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 smaller seed size resulted in smaller product particle size; however, scale had no significant effect on product particle size.

[0546] Furthermore, in Experiment 6, wet milling was used to obtain uniform and small product particles. Based on the factory's experimental conditions, the wet milling parameters in the laboratory were set as follows: rotor 6F, tip speed 19.5 m / s. Finally, a comparison of the product particle size before and after wet milling showed that wet milling with a 6F rotor is not the preferred method for reducing particle size.

[0547] Additional studies were conducted to evaluate the impurity removal capability of the crystallization system, and the experiment was monitored by HPLC at different time points. HPLC data showed that impurities at a relative retention time (RRT) of 1.08 could be reduced to <0.13% (specification standard), with the yield reduced from 95% to 70%.

[0548] The granularity data is summarized in Table 51.

[0549] Table 51

[0550]

[0551]

[0552] Example 26. Crystallization Study

[0553] The aim of this study is 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]benzofurano[4,3-fg][1,4]oxazacyclononatetraene that controls the solid form and chemical stability.

[0554] The material was characterized by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), particle size distribution analysis (PSD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). Characterization results showed that the starting material was crystalline and matched the reference spectrum of crystal form P. The starting material exhibited small birefringent particles with D90, D50, and D10 values ​​of 5.35, 3.33, and 1.99 μm, respectively. Thermal results indicated that the starting material was anhydrous and possessed a single endothermic melting peak at an onset temperature of 251.15 °C.

[0555] A comprehensive study was conducted to evaluate the optimal solvent system for crystallization. Simplified polymorph / solvate screening and approximate solubility determination were performed using each of the Class III solvents listed in ICH Guidelines Q3C and several Class II solvents. Approximate solubilities >10 mg / mL were observed in all tested solvents: acetone, dimethyl sulfoxide (DMSO), ethanol (EtOH), N-methylpyrrolidone (NMP), methyl ethyl ketone (MEK), 2-methyl-1-propanol, 2-propanol, methanol (MeOH), and tetrahydrofuran (THF). Crystal form changes were observed in EtOH (crystal form H), 1-propanol, and MeOH (crystal form H with an additional peak) in these solvents. See [link to relevant documentation] Figure 68TGA of samples from EtOH and MeOH did not show weight loss corresponding to stoichiometric solvates, while the 1-propanol sample showed a 9.31% weight loss. Competing slurries of crystalline forms P and H in two solvents other than EtOH from room temperature to 70°C resulted in conversion to crystalline form P, indicating that it was the most stable crystalline form under the tested conditions. Crystalline form P was found to be more stable than crystalline form H in EtOH at 70°C. Crystalline form P was selected as the target polymorph for crystallization. Throughout this study, dissolution of any crystalline form at 50°C was observed to produce crystalline form P in a non-solventizing solvent. At temperatures up to 70°C, the equilibrium solubility of several of these with lower boiling points did not reach the target solubility of 100 mg / mL. The highest observed solubility (without crystalline form change) was 56.68 mg / mL in EtOH at 70°C. To achieve 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). Furthermore, the potential degradation of this solvent system was examined at 80 °C, and a purity of 99.9% was determined after 24 hours of slurry preparation.

[0556] Small-scale (50-100 mg) crystallization experiments revealed that H2O was the most suitable antisolvent. However, adding H2O upon cooling resulted in amorphous powder. Crystallization at 60 °C by adding H2O without seed crystals yielded crystalline form P. At a 1 gram scale, parameters such as total antisolvent volume, antisolvent addition rate, crystallization point, and seed loading were individually optimized, and their effects on particle size, yield polymorph, filterability, residual solvent, purity, mother liquor concentration, and yield were closely monitored. Two additional 1-gram crystallizations were performed to attempt to reduce the total volume of solvent required, but poor filterability and DMSO content exceeding 5000 ppm were observed.

[0557] The optimized crystallization process was carried out on a 10-gram scale. Two 10-gram crystallizations were performed, with the first (crystal 1) used as seed crystals and the second (crystal 2) using the initial 10-gram batch product as seed crystals.

[0558] The difference between the two experiments lies in the seed crystals used. For the sample in crystallization 1, a ground crystal form P was used as the seed crystal. For the sample in crystallization 2, a crystal from crystallization 1 was used as the seed crystal to determine the expected grain size variation when using a larger crystal (from a previous batch) compared to using ground material for seed crystallization.

[0559] Both crystallizations were carried out in a 300 mL jacketed ChemGlass reactor. The solvent system used was EtOH / DMSO (80 / 20 v / v) with an initial concentration of ~100 mg / mL at 70 °C. An anchor stir bar was used at a stirring rate of 400 rpm. Once a clear solution was obtained at 70 °C, 1 part (or 10 volumes) of H2O was added. The solution was kept clear. 0.5% w / w seed crystals were added to the solution and aged for 30 min. 0.5 parts (or 5 volumes) of H2O were added to the suspension at a controlled rate of 1.2 mL / min. Subsequently, the suspension was cooled from 70 °C to 20 °C at a rate of 10 °C / h. Once the temperature reached 20 °C, the solids were separated by vacuum filtration using a 150 mL sintered filter with medium porosity. Washing with 2 parts (or 20 volumes) of H2O was used to remove any residual organic solvent. No cracking, washing away of fines, or puck formation was observed in either of the two 10-gram samples of dried filter cake. The solids were then transferred to a vacuum oven and dried overnight on a tray at room temperature.

[0560] In the second batch, crystals with rod-like morphology and lengths greater than 200 μm were observed. Two final scaled-up batches were performed. A 43 g batch was produced as a small seed crystal, and a 22 g batch was produced using the first 10 g batch (crystal 1) as a large seed crystal to assess the effect of different seed crystal sizes on the process. Scanning electron microscopy (SEM) was used to supplement polarized light microscopy (PLM) and particle size distribution (PSD) measurements. Observations showed that in the 22 g batch, initial growth on the seed crystal produced aggregates of rods larger than 200 μm, followed by primary nucleation, producing crystals smaller than 50 μm. This was not observed in the 43 g batch, possibly because the increased surface area provided by the milled seed crystal offered significantly more crystal growth sites, while the larger seed crystal used in the 22 g batch had a smaller overall surface area, resulting in slower desaturation and primary nucleation, leading to the growth of smaller particles on larger rods.

[0561] The conditions and results of crystallization are shown in Table 52.

[0562] Table 52

[0563]

[0564] Incorporated

[0565] All publications and patents mentioned herein, including those listed below, are incorporated herein by reference in their entirety for all purposes, as if each individual publication or patent were specifically and separately incorporated herein by reference. In case of conflict, this application (including any definitions herein) shall prevail.

[0566] Equivalent scheme

[0567] While specific embodiments of this disclosure have been discussed, the foregoing description is illustrative and not restrictive. Many variations of this disclosure will become apparent to those skilled in the art upon reading this specification. The full scope of this disclosure should be determined by reference to the claims (together with the full scope of their equivalents) and the description (together with such variations).

[0568] Unless otherwise stated, all figures representing amounts of ingredients, reaction conditions, etc., used in the specification and claims should be understood to be modified by the term "approximately" in all cases. Therefore, unless stated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximate values ​​that may vary depending on the desired properties sought to be obtained from this disclosure.

Claims

1. ( S )-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7 H -[1,2,4]triazolo[4',3':1,6]pyrido[3,2- b ]Benzofurano[4,3- fg The crystalline form (crystal form P) of the anhydrous free base of [1,4]oxazacyclononatetraene is characterized by... A powder X-ray diffraction pattern having characteristic peaks at 7.6±0.2, 11.9±0.2 and 15.3±0.2, expressed in degrees 2θ, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

2. The crystalline form according to claim 1, characterized in that... Powder X-ray diffraction patterns with characteristic peaks at 7.6±0.2, 11.9±0.2, 14.5±0.2, 15.3±0.2, 20.7±0.2 and 22.6±0.2, expressed in degrees 2θ.

3. The crystalline form according to claim 2, characterized in that... Powder X-ray diffraction patterns with characteristic peaks at 7.6±0.2, 11.9±0.2, 14.5±0.2, 15.3±0.2, 16.1±0.2, 17.2±0.2, 17.3±0.2, 20.7±0.2, 22.6±0.2, 23.3±0.2, 26.2±0.2 and 24.5±0.2, expressed in degrees 2θ.

4. The crystalline form according to any one of claims 1-3, characterized in that... Differential scanning calorimetry (DSC) curves with characteristic endothermic peaks at an initial temperature of 252℃ and a peak temperature of 253℃.

5. A pharmaceutical composition comprising the crystalline form according to any one of claims 1-4 and a pharmaceutically acceptable excipient.

6. The pharmaceutical composition according to claim 5, wherein the composition is a formulation for oral administration.

7. A pharmaceutical ingredient comprising at least a detectable amount of the crystalline form according to any one of claims 1-4.

8. A pharmaceutical ingredient comprising pure crystalline form according to any one of claims 1-4.

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