Crystalline forms of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one and its salts

Abstract

The present disclosure relates to crystalline forms of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one free base and its HCl salt.

Description

[Technical field]

[0001] (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one free base (also referred to herein as compound (1)) having the following structure: [ka] Disclosed herein are crystalline forms of compound (1), as well as its salts and solid forms, which are potent inhibitors of Bruton's tyrosine kinase ("BTK") and may therefore be useful in the treatment of diseases or disorders resulting from excessive BTK signaling. [Background technology]

[0002] One factor in assessing the suitability of a compound as a therapeutic agent is whether the compound can be synthesized in a manner suitable for large-scale production and isolation with minimal waste and impurities. This factor is often taken into consideration when considering the suitability of a bench-scale process to make the larger quantities required for commercial production. For example, compound (1) and a method for preparing it are disclosed in Example 3 of U.S. Pat. No. 9,688,676, as follows:

[0003] In a 100 mL round bottom flask was placed (R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (150 mg, 0.37 mmol, 1.00 equiv), DCM-CH3OH (6 mL), TEA (113 mg, 1.12 mmol, 3.00 equiv). This was followed by the dropwise addition of prop-2-enoyl chloride (40.1 mg, 0.44 mmol, 1.20 equiv) over a period of 5 min with stirring at 0° C. The resulting solution was stirred at 0° C. for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was applied onto a silica gel column with dichloromethane / methanol (30:1). The crude product (100 mg) was purified using the following conditions (column, XBridge Prep C18 OBD Column, 5 μm, 19 * Purification was performed by preparative HPLC using 150 mm; mobile phase, water containing 0.05% TFA and ACN (25.0% ACN to 45.0% in 8 min). As described above, this synthesis yielded 100 mg of crude compound (1), which had to be purified by column chromatography to produce 54.5 mg of purified compound (1).

[0004] Another desirable aspect to be realized is that the compound as a therapeutic agent can be administered in a form that is easily absorbed by the body and is also storage stable. The pharmacologically active substances used to prepare the therapeutic agent should be as pure as possible, and their stability in long-term storage should be guaranteed under various environmental conditions. These characteristics are useful to prevent the appearance of unintended decomposition products in the pharmaceutical composition, which may be potentially toxic and simply reduce the efficacy of the composition.

[0005] The primary concern for large-scale manufacturing of pharmaceutical compounds is that the active substance should have a stable crystal morphology to ensure consistent processing parameters and pharmaceutical quality. If an unstable crystal form is used, the crystal morphology may change during manufacturing and / or storage, resulting in quality control issues and formulation variability. Such changes may affect the reproducibility of the manufacturing process, thereby resulting in a final formulation that does not meet the high quality and stringent requirements imposed on the formulation of pharmaceutical compositions. In this regard, it should generally be noted that the transformation of a pharmaceutical composition into a solid state, which may improve its physical and chemical stability, offers a significant advantage over a more unstable form of the same drug.

[0006] When a compound crystallizes from a solution or slurry, it may crystallize in a variety of spatial lattice arrangements, a property called "polymorphism." Each crystalline form is a "polymorph." Polymorphs of a given substance have the same chemical composition, but they may differ from each other with respect to one or more physical properties, such as solubility, dissociation, true density, dissolution, melting point, crystal shape, compaction behavior, flowability, and / or solid state stability. Summary of the Invention [Means for solving the problem]

[0007] According to the present specification, the present disclosure relates to a substantially crystalline compound of formula (1).

[0008] In one embodiment, the substantially crystalline compound of formula (1) is a free base.

[0009] In another embodiment, the substantially crystalline compound of formula (1) is a compound of formula (1)·HCl.

[0010] Additional objects and advantages will be set forth in part in the description which follows and in part will be understood from the description or may be learned by practice. The objects and advantages will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0011] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the scope of the claims.

[0012] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate one or more embodiments and, together with the description, serve to explain the principles described herein. [Brief description of the drawings]

[0013] [Figure 1] 1 shows the XRPD pattern of Compound (1) crystalline free base form 1 obtained using CuKα radiation. [Diagram 2] 1 shows the XRPD pattern of Compound (1) crystalline free base form 2 obtained using CuKα radiation. [Figure 3A] 1 shows an ORTEP diagram of the molecular structure of Compound (1) crystalline free base Form 1. [Figure 3B] ORTEP diagram of the molecular structure of Compound (1) crystalline free base form 1 down the short axis: showing an illustration of molecular packing with a focus on the hydrogen bond network (dotted lines). [Figure 4] 1 shows a simulated powder diffraction pattern from the single crystal structure of Compound (1) crystalline free base Form 1. [Diagram 5] The XRPD pattern of compound (1)·HCl crystalline form 1 obtained using CuKα radiation is shown. [Figure 6A] The ORTEP diagram of the molecular structure of compound (1)·HCl crystalline form 1 is shown. [Figure 6B] ORTEP diagram of the molecular structure of compound (1)·HCl crystalline form 1 below the b axis: Diagram of molecular packing is shown. [Figure 7]A simulated powder diffraction pattern from the single crystal structure of Compound (1)·HCl crystalline Form 1 is shown. [Figure 8] The XRPD pattern of compound (1)·HCl crystalline form 2 obtained using CuKα radiation is shown. [Figure 9A] The ORTEP diagram of the molecular structure of compound (1)·HCl crystalline form 2 is shown. [Figure 9B] ORTEP diagram of the molecular structure of compound (1)·HCl crystalline form 2: Diagram of molecular packing. [Figure 10] A simulated powder diffraction pattern from the single crystal structure of Compound (1)·HCl crystalline form 2 is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Reference will now be made in detail to certain embodiments, examples of which are illustrated in the accompanying drawings. While the present disclosure provides illustrated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the present invention is intended to encompass all alternatives, modifications, and equivalents that may be included within the scope of the present disclosure, as defined by the appended claims.

[0015] Any section headings used herein are merely for organizational purposes and should not be construed as limiting the desired subject matter in any way. In the event that any document incorporated by reference conflicts with any term defined herein, the present specification shall control. Although the teachings of the present invention are described in connection with various embodiments, it is not intended that the teachings of the present invention be limited to such embodiments. On the contrary, the teachings of the present invention encompass various alternatives, modifications, and equivalents, as will be appreciated by those skilled in the art.

[0016] I. Definition Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meanings.

[0017] As used herein, a “BTK inhibitor”, “BTK inhibitor compound”, “compound of formula (1)”, “compound (1)”, and “the compound” refer to (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one having the following structure: [ka] (also known as "trebrutinib"), and 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-(prop-2-enoyl)piperidin-3-yl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one, having the following structure: [ka] and / or a pharma- ceutically acceptable salt thereof.

[0018] The present disclosure relates to a substantially crystalline compound of formula (1).

[0019] In some embodiments, the substantially crystalline compound of Formula (1) is at least 50% crystalline, e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% crystalline.

[0020] As used herein, the term "crystalline" or "crystalline solid form" refers to a solid form that is substantially free of any amorphous solid form.

[0021] In some embodiments, "substantially free" refers to less than about 10% w / w, less than about 9% w / w, less than about 8% w / w, less than about 7% w / w, less than about 6% w / w, less than about 5% w / w, less than about 4% w / w, less than about 3% w / w, less than about 2.5% w / w, less than about 2% w / w, less than about 1.5% w / w, less than about 1% w / w, less than about 0.75% w / w, less than about 0.50% w / w, less than about 0.25% w / w, less than about 0.10% w / w, or less than about 0.05% w / w of other crystalline forms and amorphous compounds of the compound. In some embodiments, "substantially free" refers to undetectable amounts of other crystalline forms and amorphous compounds of the compound.

[0022] As used herein, the terms "substantially pure" or "substantially crystalline" mean that the crystalline form contains at least 90 percent, such as at least 95 percent, such as at least 97 percent, or even at least 99 percent, by weight of the indicated crystalline form, relative to the total weight of all forms of the compound.

[0023] Alternatively, "substantially pure" or "substantially crystalline" will be understood to mean that the crystalline form contains less than 10 percent by weight, such as less than 5 percent, such as less than 3 percent, or even less than 1 percent, of impurities, including other polymorphs, solvates, or amorphous forms, relative to the total weight of the compound in all forms.

[0024] In some embodiments, the substantially crystalline compound of Formula (1) is Form 1. In at least one embodiment, the substantially crystalline compound of Formula (1) Form 1 is characterized by an XRPD pattern substantially similar to Figure 1. In at least one embodiment, the substantially crystalline compound of Formula (1) Form 1 is characterized by an XRPD pattern including one or more peaks selected from peaks at about 7.66 °2θ, 7.86 °2θ, 10.03 °2θ, 10.51 °2θ, 10.97 °2θ, 11.99 °2θ, 13.19 °2θ, 13.59 °2θ, and 13.96 °2θ.

[0025] In some embodiments, a crystalline solid form characterized as crystalline Form 1 is at least 50% crystalline, e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% crystalline.

[0026] In some embodiments, the substantially crystalline compound of Formula (1) is Form 2. In at least one embodiment, the substantially crystalline compound of Formula (1) Form 2 is characterized by an XRPD pattern substantially similar to Figure 2. In at least one embodiment, the substantially crystalline compound of Formula (1) Form 2 is characterized by an XRPD pattern including one or more peaks selected from peaks at about 4.15 °2θ, 10.22 °2θ, 10.41 °2θ, 11.03 °2θ, 14.41 °2θ, 14.85 °2θ, 15.63 °2θ, 16.55 °2θ, and 17.73 °2θ.

[0027] In some embodiments, a crystalline solid form characterized as crystalline Form 2 is at least 50% crystalline, e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% crystalline.

[0028] The present disclosure also relates to substantially crystalline forms of the compound of formula (1).HCl.

[0029] In some embodiments, the substantially crystalline compound of Formula (1)·HCl is Form 1. In at least one embodiment, the substantially crystalline compound of Formula (1)·HCl Form 1 is characterized by an XRPD pattern substantially similar to Figure 5. In at least one embodiment, the substantially crystalline compound of Formula (1)·HCl Form 1 is characterized by an XRPD pattern including one or more peaks selected from peaks at about 6.309 °2θ, 9.480 °2θ, 10.933 °2θ, 12.261 °2θ, 12.647 °2θ, 14.482 °2θ, 14.918 °2θ, 16.253 °2θ, and 16.425 °2θ.

[0030] In some embodiments, the crystalline solid form characterized as crystalline Formula (1)·HCl Form 1 is at least 50% crystalline, e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% crystalline.

[0031] In some embodiments, the substantially crystalline compound of Formula (1)·HCl is Form 2. In at least one embodiment, the substantially crystalline compound of Formula (1)·HCl Form 2 is characterized by an XRPD pattern substantially similar to Figure 8. In at least one embodiment, the substantially crystalline compound of Formula (1)·HCl Form 2 is characterized by an XRPD pattern including one or more peaks selected from peaks at about 8.00 °2θ, 10.11 °2θ, 11.98 °2θ, 13.33 °2θ, 14.40 °2θ, 14.92 °2θ, 15.66 °2θ, 16.05 °2θ, 16.72 °2θ, and 17.28 °2θ.

[0032] In some embodiments, the crystalline solid form characterized as crystalline Formula (1)·HCl Form 2 is at least 50% crystalline, e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% crystalline.

[0033] In some embodiments, the substantially crystalline compound of formula (1) is at least 85% crystalline. In some embodiments, the substantially crystalline compound of formula (1) is at least 90% crystalline. In some embodiments, the substantially crystalline compound of formula (1) is at least 95% crystalline. In some embodiments, the substantially crystalline compound of formula (1) is at least 97% crystalline. In some embodiments, the substantially crystalline compound of formula (1) is at least 99% crystalline.

[0034] The following abbreviations may be relevant to this application:

[0035] [Table 1] EXAMPLES

[0036] II. Examples Example 1. Characterization of Compound (1) Compound (1), made according to the method disclosed in the above-mentioned U.S. Pat. No. 9,688,676, was subjected to crystallization attempts and gave two forms as determined by XRPD analysis.

[0037] 1.1 Compound (1) Crystal form 1 Ethyl acetate (AcOEt) was added to compound (1) and heated to 50°C. The heating device was turned off and the sample was allowed to cool to ambient temperature. The solids at the bottom of the vial were scraped off and slurried with AcOEt at room temperature for 2 days. More AcOEt was added and the slurry was allowed to stand at room temperature for 3 days. More AcOEt was added and the solution was then vacuum filtered.

[0038] Compound 1, Form 1 was subjected to XRPD analysis performed on a Bruker D2-Phaser diffractometer according to these parameters: ·Source CuKa1, l=1.5406Å. Generator: 30kV~10mA. Detector: Lynxeye SSD160 (1D mode) Powder sample holder Rotating sample holder: 30 rpm Angle range: 2° to 40° in 2θ Bragg. Step size: 0.03° Step Time: 0.5 seconds per step ·PSD aperture: 4.8° Detector slit: 8mm X-ray generator slit: 0.6mm Sample preparation: Gentle grinding ·Space group: P21 The unit cell parameters are shown below: a(Å)=8.9182b(Å)=11.7707c(Å)=11.9324α(°)=97.197β(°)=107.211γ(°)=96.440

[0039] FIG. 1 shows the XRPD pattern of compound (1) Form 1 obtained using CuKα radiation (wavelength: λ(Cu)=1.54178 Å).

[0040] The peaks identified in FIG.

[0041] [Table 2]

[0042] Example 1.2 Compound (1) Crystal Form 2 Isopropyl acetate (iPrOAc) was added to Compound 1 to form a slurry, which was allowed to stand at room temperature for 3 days, then allowed to stand as a cold slurry for 4 days. Additional iPrOAc was added, followed by a room temperature slurry for 1 day. Additional iPrOAc was added, and then the solution was vacuum filtered.

[0043] Compound 1 Form 2 was subjected to XRPD analysis performed on a Bruker D2-Phaser diffractometer according to these parameters: ·Source CuKa1, l=1.5406Å. Generator: 30kV~10mA. Detector: Lynxeye SSD160 (1D mode) Powder sample holder Rotating sample holder: 30 rpm Angle range: 2° to 40° in 2θ Bragg. Step size: 0.03° Step Time: 0.5 seconds per step ·PSD aperture: 4.8° Detector slit: 8mm X-ray generator slit: 0.6mm Sample preparation: Gentle grinding ·Space group: P21 The unit cell parameters are shown below: a(Å)=8.6381b(Å)=42.2015c(Å)=6.1873α(°)=90.000β(°)=90.433γ(°)=90.000

[0044] Figure 2 shows the XRPD pattern of Compound (1) Form 2 obtained using CuKα radiation (wavelength: 1(Cu)=1.54178 Å). Peaks identified in Figure 2 include those listed in Table 2.

[0045] [Table 3]

[0046] Example 2. Single crystal data for Compound (1) Form 1 A single crystal from a batch made as described in Example 1.1 was selected by observation under a binocular microscope and mounted on the goniometer head of a Bruker APEX2 Instrument diffractometer (Bruker AXS (2011).APEX2 suite V2011.2-0 Madison, Wisconsin, USA). Intensities were collected at low temperature (T=112 K) using a microfocus ImuS CuKα line wavelength (λ=1.54178 Å). A systematic examination of the diffraction nodes indicates that the crystal belongs to the triclinic system according to the fundamental Bravais lattice. The unit cell parameters are given below: a(Å)=8.81b(Å)=11.58c(Å)=11.77α(°)=97.75β(°)=107.23γ(°)=94.97

[0047] Considering the number of atoms in a molecule of compound (1) and the unit cell volume, this unit cell corresponds to a calculated density of 1.342, as shown in formula C 26 H 25 It was concluded that the ion beam must contain two molecules with N5O3. The number of reflections collected was 27,267, of which 7,140 were distinct.

[0048] Based on the statistical distribution of the intensities, non-centrosymmetric structures are inferred.

[0049] The structure was solved by direct methods using the XT dual space module of SHELX; F was solved by exact least squares using SHELXTL, as described in Sheldrick, GM “A short history of SHELX”, Acta Crystallogr. Sect. A (2008) A64, 112-122. 2All non-hydrogen atoms were refined with anisotropic displacement parameters; a riding model was used for hydrogen atoms. The final match values ​​are R1 = 0.0267 (observed reflections) and wR2 = 0.0722 (all data) for 7140 reflections and 625 parameters with a goodness of fit of 1.242.

[0050] Compound (1) crystallizes in space group P1, and the asymmetric unit of the crystal is made up of two molecules of Compound (1) Form 1, therefore two formulas are present in the unit cell. See Figures 3A and 3B. No additional molecules such as organic solvents or water were observed. Examination of the molecular structure confirmed that all bond angles and lengths were within the standard range values. There appeared to be no disorder in the crystal.

[0051] The crystallographic data, X-ray experimental parameters and structure refinement are shown in Table 3.

[0052] [Table 4]

[0053] A simulated diffraction pattern (Figure 4) was generated from the experimentally determined crystal structure. The experimental powder diffraction pattern can be compared to this theoretical pattern to demonstrate the nature of the crystal structure. Minor differences (if any) can be explained by asymmetric crystal morphology, grain size, or preferred orientation in the powder.

[0054] Example 3. Synthesis and characterization of compound (1)·HCl Overview. Compound (1).HCl was prepared as shown in the following scheme. Batch sizes for these reactions are typically 14-60 kg and can be run on a scale up to about 100 kg. [ka]

[0055] Detailed synthesis 2.1 Preparation of compound (1)·HCl. Purified water (7.5 vol) and K2CO3 (at least 3.0 equiv.) were added to compound (3) oxalate (hydrate; corresponding to 1 equiv. of compound (3)) in DCM (12 vol.) at 20° C., and the reaction mixture was stirred for at least 2 h. The reaction mixture was then allowed to settle and separate. The organic layer was collected and washed 1-2 times with water (7.5 vol.) to give compound (3) in a DCM solution. The solution was concentrated to 12 vol. and mixed with DIPEA (4 equiv.) at 20° C. Then, a solution of 3-chloropropanoic acid (1.05 equiv.) in DCM (2.3 vol.) and T3P (50% DCM solution, 1 equiv.) were added at 20° C. Compound 2 was formed in situ. DBU (4 equiv.) was then added to the reaction mixture at 30° C. over at least 30 min, and the resulting mixture was kept at 30° C. for at least 2 h. The organic layer was washed 3-5 times with HCl (1N, 10 vol) at 20 °C. The organic layer was then concentrated to 2.73 vol and the temperature was adjusted to 35 °C. Compound 1·HCl seeds (0.1 kg / kg) were added to the organic layer at 35 °C and the temperature was maintained for at least 1 h. Ethyl acetate (2 vol) was then added and the temperature of 35 °C was maintained for at least 1 h. The reaction mixture was then cooled to 10 °C and ACN (1.07 vol) was added. The mixture was cooled to 0 °C. The resulting suspension was charged to a filter drier and reslurried with DCM (0.72 vol) / AcOEt (0.63 vol) / ACN (0.45 vol) at 0 °C. The solid was filtered and washed twice with AcOEt (1.8 vol) and twice with ACN (1.8 vol). The resulting compound 1·HCl was dried at a maximum temperature of 50 °C. The following elemental analyses were performed by Galbraith Laboratories: carbon, hydrogen, and nitrogen determination using a PerkinElmer 2400 Series II CHNS / O Analyzer and total halogen or total halide determination by potentiometric titration.

[0056] [Table 5]

[0057] 3.2 Crystal data for compound (1)·HCl form 1 Ethyl acetate (AcOEt) was added to compound (1).HCl and heated to 50° C. The heating device was turned off and the sample was allowed to cool to ambient temperature. The solids at the bottom of the vial were scraped off and slurried in AcOEt at room temperature for 2 days. More AcOEt was added and the slurry was allowed to stand at room temperature for 3 days. More AcOEt was added and the solution was then vacuum filtered.

[0058] Compound 1·HCl was subjected to XRPD analysis performed on a Bruker D2-Phaser diffractometer according to these parameters: ·Source CuKa1, l=1.5406Å. Generator: 30kV~10mA. Detector: Lynxeye SSD160 (1D mode) Powder sample holder Rotating sample holder: 30 rpm Angle range: 2° to 40° in 2θ Bragg. Step size: 0.03° Step Time: 0.5 seconds per step ·PSD aperture: 4.8° Detector slit: 8mm X-ray generator slit: 0.6mm Sample preparation: Gentle grinding ·Space group: P21 The unit cell parameters are shown below: a(Å)=14.1097b(Å)=12.2212c(Å)=14.5523α(°)=90.00β(°)=97.653γ(°)=90.00

[0059] FIG. 5 shows the XRPD pattern of compound (1)·HCl form 1 obtained using CuKα radiation (wavelength: λ(Cu)=1.54178 Å).

[0060] The peaks identified in FIG.

[0061] [Table 6]

[0062] 3.3 Single crystal data and structure refinement of compound (1)·HCl form 1 Single crystals of compound 1·HCl form 1 (grown in a mixture of ACN and DCM) were selected by observation under a binocular microscope and attached to the goniometer head of a Bruker APEX DUO Instrument (Bruker AXS(2015).APEX3 suite V2014.2-0 Madison, Wisconsin, USA) equipped with a microfocus X-ray source. Intensities were collected with the diffractometer at low temperature (T=100 K) using graphite monochromatized CuKα radiation wavelength (λ=1.54178 Å). A systematic examination of the diffraction nodes indicates that the crystal belongs to the monoclinic system according to the fundamental Bravais lattice. The unit cell parameters are given below: a(Å)=13.62b(Å)=12.06c(Å)=14.74α(°)=90.00β(°)=97.06γ(°)=90.00

[0063] Considering the number of atoms in one molecule of compound (1)·HCl and the unit cell volume, this unit cell corresponds to a calculated density of 1.359, as shown in formula C 26 H 26 It was concluded that the ion beam must contain four molecules with ClN5O3. The number of reflections collected was 35,059, of which 8,540 were distinct.

[0064] Space group determination was unambiguously achieved due to the presence of unique systematic annihilation along the monoclinic axes.

[0065] The structure was solved by direct methods using the XT dual space module of SHELX; F was solved by exact least squares using SHELXTL, as described in Sheldrick, GM “A short history of SHELX”, Acta Crystallogr. Sect. A (2008) A64, 112-122.2 All non-hydrogen atoms were refined with anisotropic displacement parameters; a riding model was used for hydrogen atoms. The final match values ​​are R1 = 0.0352 (observed reflections) and wR2 = 0.1131 (all data) for 8540 reflections and 631 parameters with a goodness of fit of 0.917.

[0066] The compound crystallizes in space group P21, and the asymmetric unit of the crystal is made up of two molecules of compound 1 associated with their respective counterions, and therefore four formulae are present in the unit cell. See Figures 6A and 6B. The asymmetric cell therefore contains 2[C 26 H 26 N5O3, Cl]. No additional molecules such as organic solvents or water are seen. Examination of the molecular structure confirms that all bond angles and lengths are within standard range values. There is no atomic disorder in the crystal. A salt bridge is established by the chlorine atom with the amino-imidazopyridine nitrogen atom. Other non-covalent interactions are also present in the structure.

[0067] The crystallographic data, X-ray experimental parameters and structure refinement are shown in Table 5.

[0068] [Table 7]

[0069] A simulated diffraction pattern (Figure 7) was generated from the experimentally determined crystal structure. The experimental powder diffraction pattern can be compared to this theoretical pattern to demonstrate the nature of the crystal structure. Minor differences (if any) can be explained by asymmetric crystal morphology, grain size, or preferred orientation in the powder.

[0070] 3.4 Crystal data for compound (1)·HCl form 2 Ethyl acetate (AcOEt) and acetonitrile (ACN) in a ratio of 5 / 0.1 vol / vol were added to compound 1·HCl Form 2 to form a slurry that was allowed to stand at room temperature for 3 days, then allowed to stand as a cold slurry for 4 days. More AcOEt / ACN mixture was added, followed by a room temperature slurry for 1 day. More AcOEt / ACN mixture was added, then the solution was vacuum filtered.

[0071] Compound (1)·HCl Form 2 was subjected to XRPD analysis performed on a Bruker D2-Phaser diffractometer according to these parameters: ·Source CuKa1, l=1.5406Å. Generator: 30kV~10mA. Detector: Lynxeye SSD160 (1D mode) Powder sample holder Rotating sample holder: 30 rpm Angle range: 2° to 40° in 2θ Bragg. Step size: 0.03° Step Time: 0.5 seconds per step ·PSD aperture: 4.8° Detector slit: 8mm X-ray generator slit: 0.6mm Sample preparation: Gentle grinding ·Space group: P1 The unit cell parameters are shown below: a(Å)=9.3589b(Å)=12.3992c(Å)=12.6660α(°)=64.095β(°)=70.641γ(°)=74.644;

[0072] FIG. 8 shows the XRPD pattern of compound (1)·HCl form 2 obtained using CuKα radiation (wavelength: λ(Cu)=1.54178 Å).

[0073] The peaks identified in FIG. 8 include those listed in Table 6.

[0074] [Table 8]

[0075] 3.5 Single crystal data and structure refinement for compound (1)·HCl form 2 Single crystals of compound (1)·HCl form 2 (from crystals grown in a mixture of ethyl acetate (AcOEt) / acetonitrile (ACN)) were selected by observation under a binocular microscope and attached to the goniometer head of a Bruker APEX DUO Instrument (Bruker AXS(2015).APEX3 suite V2014.2-0 Madison, Wisconsin, USA) equipped with a microfocus X-ray source. Intensities were collected with the diffractometer at low temperature (T=112 K) using graphite monochromated CuKα radiation wavelength (λ=1.54178 Å). A systematic investigation of the diffraction nodes indicates that the crystal belongs to the triclinic system according to the fundamental Bravais lattice. The unit cell parameters are shown below: a(Å)=9.39b(Å)=12.31c(Å)=12.40α(°)=63.98β(°)=73.90γ(°)=69.66

[0076] Considering the number of atoms in the compound 1·HCl form 2 molecule and the unit cell volume, this unit cell corresponds to a calculated density of 1.368, formula C 26 H 26 It was concluded that the ion beam must contain two molecules with ClN5O3. The number of reflections collected was 16793, of which 6829 were distinct.

[0077] Based on the statistical distribution of intensities, a non-centrosymmetric structure was inferred.

[0078] The structure was solved by direct methods using the XT dual space module of SHELX; F was solved by exact least squares using SHELXTL, as described in Sheldrick, GM “A short history of SHELX”, Acta Crystallogr. Sect. A (2008) A64, 112-122.2 The molecular structure was fully determined and all non-hydrogen atoms were refined with anisotropic displacement parameters; a riding model was used for the hydrogen atoms. The final match values ​​are R1 = 0.0273 (observed reflections) and wR2 = 0.0776 (all data) for 6829 reflections and 631 parameters with a goodness of fit of 1.013.

[0079] The compound crystallizes in space group P1 (N°1), and the asymmetric unit of the crystal is made up of two molecules of compound (1) associated with their respective chloride counterions, and therefore two formulas are present in the unit cell (see Figures 9A and 9B). The asymmetric cell is therefore represented by [C 26 H 26 N5O3, Cl]. No additional molecules such as organic solvents or water are seen. Examination of the molecular structure confirms that all bond angles and lengths are within standard range values. There is no atomic disorder in the crystal. A salt bridge is established by the chlorine atom with the amino-imidazopyridine nitrogen atom. Other non-covalent interactions are also present in the structure.

[0080] The crystallographic data, X-ray experimental parameters and structure refinement are shown in Table 7.

[0081] [Table 9]

[0082] [Table 10]

[0083] A simulated diffraction pattern (FIG. 10) was generated from the experimentally determined crystal structure of Compound 1·HCl Form 2. The experimental powder diffraction pattern can be compared to this theoretical pattern to demonstrate the nature of the crystal structure. Minor differences (if any) can be explained by asymmetric crystal morphology, particle size, or preferred orientation in the powder.

[0084] Equivalent The above specification is believed to be sufficient to enable one skilled in the art to practice the embodiments. The above description and examples detail certain embodiments and explain the best mode contemplated by the inventors. However, no matter how detailed the above specification appears in text, it will be understood that the embodiments may be practiced in many ways and should be construed in accordance with the appended claims and any equivalents thereof.

[0085] As used herein, the term about refers to numerical values, including, for example, integers, ratios, and percentages, whether or not expressly stated. The term about generally refers to a range of numerical values ​​(e.g., + / - 5 to 10% of the stated range) that one of ordinary skill in the art would consider equivalent to the stated value (e.g., having the same function or result). When a term such as at least and about precedes a list of numerical values ​​or ranges, the term modifies all of the values ​​or ranges set forth in the list. In some cases, the term about may include numerical values ​​that are rounded to the nearest significant figure.

Claims

1. A substantially crystalline form of the compound of formula (1).HCl.

2. 2. The substantially crystalline compound of claim 1 , wherein the compound of Formula (1)·HCl is Form 1.

3. 3. The substantially crystalline compound of claim 2, wherein said compound of Formula (1).HCl Form 1 is characterized by an XRPD pattern substantially similar to FIG.

4. 3. The substantially crystalline compound of claim 2, wherein the compound of Formula (1).HCl Form 1 is characterized by an XRPD pattern including one or more peaks selected from peaks at about 6.309°2θ, 9.480°2θ, 10.933°2θ, 12.261°2θ, 12.647°2θ, 14.482°2θ, 14.918°2θ, 16.253°2θ, and 16.425°2θ.

5. 2. The substantially crystalline compound of claim 1 , wherein the compound of Formula (1)·HCl is Form 2.

6. 6. The substantially crystalline compound of claim 5, wherein said compound of Formula (1).HCl Form 2 is characterized by an XRPD pattern substantially similar to FIG.

7. 6. The substantially crystalline compound of claim 5, wherein the compound of Formula (1).HCl Form 2 is characterized by an XRPD pattern including one or more peaks selected from peaks at about 8.00 °2θ, 10.11 °2θ, 11.98 °2θ, 13.33 °2θ, 14.40 °2θ, 14.92 °2θ, 15.66 °2θ, 16.05 °2θ, 16.72 °2θ, and 17.28 °2θ.

8. 8. The substantially crystalline compound of any one of claims 1 to 7, wherein the substantially crystalline compound is at least 85% crystalline.

9. 9. The substantially crystalline compound of any one of claims 1 to 8, wherein the substantially crystalline compound is at least 90% crystalline.

10. 10. The substantially crystalline compound of any one of claims 1 to 9, wherein the substantially crystalline compound is at least 95% crystalline.

11. 11. The substantially crystalline compound of any one of claims 1 to 10, wherein the substantially crystalline compound is at least 97% crystalline.

12. 12. The substantially crystalline compound of any one of claims 1 to 11, wherein the substantially crystalline compound is at least 99% crystalline.

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