Thermodynamically stable form of SCO-101

Abstract

The present invention relates to an improved crystalline form of SCO-101, its preparation and use.Furthermore, the present invention relates to an intermediate crystalline form of SCO-101 which can be converted into the improved crystalline form of SCO-101.

Description

[Technical field]

[0001] The present invention relates to an improved crystalline form of SCO-101, its preparation and use.Furthermore, the present invention relates to an intermediate crystalline form of SCO-101 which can be converted into the improved crystalline form of SCO-101. [Background technology]

[0002] Cancer represents an overwhelming burden to society, with approximately 18 million new cases diagnosed in 2019. Despite the introduction of many novel treatment options, de novo or acquired resistance to the applied treatments remains the leading cause of cancer deaths.

[0003] The compound SCO-101, also known as NS3728, was first described in WO2000 / 24707. SCO-101 was later shown to be an effective enhancer of various anticancer drugs and is currently being developed as a combination cancer therapy, particularly for the treatment of resistant cancers. WO2017 / 198700 describes SCO-101 and its use in combination cancer treatment.

[0004] Various substituted diphenylureas, including SCO-101, can be prepared as described in WO2000 / 24707 by mixing suitable starting materials that are soluble in toluene, whereupon SCO-101 precipitates upon formation. SCO-101 prepared in toluene using the conditions of WO2000 / 24707 is crystalline. Summary of the Invention

[0005] The inventors have discovered that the polymorphic form SCO-101 prepared by the method of WO2000 / 24707 is not a thermodynamically stable form, but rather a hygroscopic metastable polymorphic form. The polymorphic form SCO-101 prepared as in WO2000 / 24707 is referred to herein as crystal form II. Furthermore, SCO-101 has been shown to readily form solvates, and multiple polymorphs exist. Therefore, from the perspective of pharmaceutical development and patient safety, it is desirable to obtain a more stable crystalline form that is not solvated (anhydrous). Furthermore, it is desirable to provide a metastable form that can be converted to the desired thermodynamically stable form, referred to herein as crystal form I. The inventors have further demonstrated that the thermodynamically stable form, crystal form I, is unexpectedly non-hygroscopic, making SCO-101 crystal form I a more attractive crystalline form for clinical development.

[0006] In the first phase, SCO-101: [ka] and exhibiting at least peak maxima at 2-theta angles of 19.0±0.2, 21.2±0.2, and 23.4±0.2 in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation.

[0007] In the second phase, SCO-101: [ka] and exhibiting at least peak maxima at 2-theta angles of 11.1±0.2, 21.7±0.2, and 23.3±0.2 in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation.

[0008] In the third phase, SCO-101: [ka] The present invention provides crystalline Form IV of the compound of formula (I), which exhibits at least peak maxima at 2-theta angles of 22.6±0.2, 23.4±0.2, and 23.7±0.2 in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation.

[0009] In the fourth phase, SCO-101: [ka] which does not exhibit a peak maximum at 2-theta angles between 0 and 40 in an X-ray powder diffraction (XRPD) diffractogram when measured using CuKα radiation.

[0010] In a fifth aspect, there is provided an isopropanol solvate of SCO-101: [ka] The present invention provides a crystal form V of the formula (I) which exhibits at least peak maxima at 2 theta angles of 9.4±0.2, 21.1±0.2, and 22.2±0.2 in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation.

[0011] In a sixth aspect, there is provided a process for preparing Form I crystals of SCO-101 as defined herein, the process comprising: (a) dissolving SCO-101 in one or more polar aprotic solvents at a first predetermined temperature; (b) adding one or more polar protic solvents to one or more polar aprotic solvents over the course of a first predetermined period of time to obtain crystalline Form I of SCO-101; and (c) isolating type I crystals of SCO-101 The method includes the following continuous steps.

[0012] In a seventh aspect, there is provided a process for preparing crystalline Form III of SCO-101 as defined herein, the process comprising: (a) mixing SCO-101 with one or more polar protic solvents, such as methanol, to provide a mixture; (b) performing one or more temperature cycles, wherein the temperature is cycled between a fourth predetermined temperature and a fifth predetermined temperature, the fourth predetermined temperature being greater than the fifth predetermined temperature; (c) isolating crystalline Form III of SCO-101, as defined herein, from the mixture. The method includes the following continuous steps.

[0013] In an eighth aspect, there is provided a process for preparing crystalline Form IV of SCO-101 as defined herein, the process comprising: (a) providing a crystalline form III of SCO-101 as defined herein; (b) storing type III crystals of SCO-101 at 30° C. to 60° C. for at least 24 hours, thereby preparing type IV crystals of SCO-101. The method includes the following continuous steps.

[0014] In a ninth aspect, there is provided a process for preparing Form I crystals as defined herein from a metastable form of SCO-101, the process comprising: (a) providing a metastable form of SCO-101 that is a crystalline or amorphous form; (b) mixing the metastable form with crystalline Form I of SCO-101 as defined herein in a solvent mixture of: (i) one or more polar aprotic solvents and (ii) one or more polar protic solvents or one or more non-polar solvents; (c) stirring the solvent mixture at a sixth predetermined temperature for at least 1 hour, thereby obtaining Form I crystals of SCO-101. Includes.

[0015] In a tenth aspect, there is provided a method for preparing SCO-101 crystals of Form I, obtainable by a process as defined herein for preparing SCO-101 crystals: [ka] The present invention provides type I crystals of the compound.

[0016] In an eleventh aspect, there is provided a pharmaceutical composition comprising crystalline Form I of SCO-101 as defined herein and one or more pharma- ceutically acceptable adjuvants, excipients, carriers, buffers and / or diluents.

[0017] In a twelfth aspect, there is provided a method of treating a patient having cancer, the method comprising administering to the patient a crystalline form I of SCO-101 as defined herein, or a pharmaceutical composition as defined herein, and an anti-cancer agent. [Brief description of the drawings]

[0018] [Figure 1A] FIG. 1 shows an XRPD diffractogram of polymorph Form I of the compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N′-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101). [Figure 1B] FIG. 1 shows an XRPD diffractogram of polymorph Form II of the compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N′-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101). [Figure 1C] FIG. 1 shows an XRPD diffractogram of polymorph Form III of the compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N′-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101). [Figure 1D] FIG. 1 shows an XRPD diffractogram of polymorph Form IV of the compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N′-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101). [Figure 1E]1 shows an XRPD diffractogram of the amorphous form of the compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N′-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101). No 2-theta angle peaks are observed for the amorphous compound. [Figure 1F] FIG. 1 shows an XRPD diffractogram of the 2-propanol solvate of the compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N′-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101), designated as Form V or Pattern 5 (used interchangeably). [Figure 2A] Figure 2 shows the TG / DSC thermogram of polymorphic Form I of the compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101). Two stages of mass loss were observed in the TG trace: 48 wt% mass loss (C9H7F6N) between 211°C and 250°C, and 16 wt% (CH2N4) mass loss between 250°C and 300°C. Since no further mass loss was observed, it is concluded that Form I is a non-solvated anhydrous polymorph. In the DSC trace, an endothermic event with an onset at 221°C (melting point) was observed with a concomitant 48 wt% mass loss, followed by an exothermic decomposition event with an onset at 270°C with a concomitant 16 wt% mass loss. (a) Enthalpy (normalized): 121.68 J / g; Peak temperature: 228.92 °C; Onset temperature: 221.30 °C. (b) Enthalpy (normalized): 238.68 J / g; Peak temperature: 278.42 °C; Onset temperature: 269.84 °C. [Figure 2B]Figure 2 shows the TG / DSC thermogram of polymorph Form II of the compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101). Two stages of mass loss were observed in the TG trace: a 54 wt% mass loss between 189°C and 248°C, and a 20 wt% mass loss between 248°C and 300°C. Since no further mass loss was observed, it is concluded that Form II is a non-solvated anhydrous polymorph. In the DSC trace, an endothermic event with an onset at 214°C (melting point) was observed accompanied by a 54 wt% mass loss; this was followed by an exothermic decomposition event with an onset at 273°C accompanied by a 20 wt% mass loss. (a) Enthalpy (normalized): 67.701 J / g; Peak temperature: 222.81 °C; Onset temperature: 213.99 °C. (b) Enthalpy (normalized): 333.24 J / g; Peak temperature: 283.20 °C; Onset temperature: 272.94 °C. [Figure 2C]Figure 1 shows the TG / DSC thermogram of polymorphic Form III of the compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101). In the TG trace, two stages of mass loss due to decomposition of the API were observed: 52.0 wt% between 185°C and 250°C, and 17.4 wt% between 250°C and 300°C. No further mass loss was observed. In the DSC trace, another exothermic event was observed that was not present in Form I, starting at 162°C. Further analysis by VT-XRPD (variable temperature XRPD) revealed that this exothermic event was due to the conversion of Form III to Form IV, showing a mixture of Forms III and IV at 150°C, and complete conversion to Form IV at 155°C. This was followed by an endothermic event with an onset at 223°C (melting point) followed by an exothermic event with an onset at 272°C due to decomposition of the API. (a) Enthalpy (normalized): 15.517 J / g; Peak temperature: 171.12°C; Onset temperature: 161.86°C. (b) Enthalpy (normalized): 71.642 J / g; Peak temperature: 229.90°C; Onset temperature: 223.10°C. (c) Enthalpy (normalized): 162.97 J / g; Peak temperature: 280.15°C; Onset temperature: 271.68°C. [Figure 2D]Figure 1 shows the TG / DSC thermogram of polymorph Form IV of the compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101). In the TG trace, no mass loss was observed until two stages of mass loss were observed, which were attributed to the decomposition of the API. These were 54.3 wt% between 190°C and 255°C, and 16.7 wt% between 255°C and 300°C. Since no further mass loss was observed, it is concluded that Form IV is a non-solvated anhydrous polymorph. An endothermic event with an onset at 225°C was observed, followed by an exothermic event with an onset at 271°C, which was attributed to the decomposition of the API. (a) Enthalpy (normalized): 68.722 J / g; peak temperature: 231.40°C; onset temperature: 225.20°C. (b) Enthalpy (normalized): 116.26 J / g; Peak temperature: 278.52 °C; Onset temperature: 270.65 °C. [Figure 2E] 1 shows the TG / DSC thermogram of the amorphous form of the compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N′-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101). In the TG trace, a mass loss of 3.4 wt % (0.3 equivalents of acetone or 0.97 equivalents of water) was observed between 90° C. and 155° C. This was followed by a two-stage mass loss due to decomposition of the API of 49 wt % between 180° C. and 247° C. and 18 wt % between 247° C. and 305° C. In the DSC trace, a small exothermic event was observed starting at 141° C., concurrent with the acetone mass loss. Additionally, an endothermic event starting at 215° C. and a subsequent exothermic event starting at 273° C. were observed concurrent with the mass loss due to decomposition. (a) Enthalpy (normalized): 16.389 J / g; Peak temperature: 147.62 °C; Onset temperature: 141.31 °C. (b) Enthalpy (normalized): 46.123 J / g; Peak temperature: 223.34 °C; Onset temperature: 215.33 °C. (c) Enthalpy (normalized): 192.48 J / g; Peak temperature: 280.08 °C; Onset temperature: 273.03 °C. [Figure 2F]Figure 1 shows the TG / DSC thermogram of the 2-propanol (isopropanol) solvate form of compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101), Form V. In the TG trace, a single mass loss step was observed that was not present in the as-received raw material. A mass loss of 11.2 wt% (1.0 equivalent of 2-propanol or 3.5 equivalents of water) between 100°C and 150°C. This was followed by a two-step mass loss due to API decomposition of 46.6 wt% between 180°C and 250°C and 15.6 wt% between 250°C and 305°C. In the DSC trace, another endothermic event was observed that was not observed in Form I, which occurred at 124°C simultaneously with the 2-propanol mass loss. This was followed by an endothermic event with an onset at 220° C., followed by an exothermic event with an onset at 271° C., due to decomposition of the API. These data support that Form V is an isopropanol solvate. (a) Enthalpy (normalized): 81.609 J / g; Peak temperature: 132.09° C.; Onset temperature: 123.79° C. (b) Enthalpy (normalized): 67.328 J / g; Peak temperature: 228.55° C.; Onset temperature: 220.37° C. (c) Enthalpy (normalized): 175.03 J / g; Peak temperature: 278.52° C.; Onset temperature: 270.72° C. [Figure 3A] Figure 1 shows the DVS (Dynamic Vapor Sorption) diagram of the polymorphic form I of the compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101). The diagram shows that form I is non-hygroscopic as no increase in mass is observed for a sample of form I upon increasing the relative humidity to 90%. [Figure 3B]Figure 1 shows the DVS diagram of polymorph Form II of the compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101). Approximately 6% mass increase is observed at 90% relative humidity. The 3% weight increase upon increasing RH from 70% to 80% corresponds to the formation of the monohydrate, and a total of 6% weight increase corresponds to the dihydrate. The diagram shows that Form II is hygroscopic. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] definition The term "polymorph" or "polymorphic form" as used herein refers to a polymorphic form of SCO-101. A solid that exists in either amorphous or crystalline form is also referred to herein as a crystalline form. In a crystalline form, the molecules of the crystal are arranged in three-dimensional lattice sites. When a compound recrystallizes from a solution or slurry, it may crystallize in different spatial lattice arrangements; this property is called "polymorphism" and includes different crystalline forms, individually called "polymorphs". Different polymorphic forms of a given substance may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, crystal type, compaction behavior, flow properties, and / or solid state stability. In the case of a chemical substance that exists in two (or more) polymorphic forms, the less stable form generally converts to a more thermodynamically stable form after a sufficient period of time at a given temperature. If this conversion is not rapid, the thermodynamically unstable form is called a "metastable" form.

[0020] Unless otherwise specified, the units of 2 theta angle are degrees (°). When 2 theta angles are used to characterize different XRPD maximum peak values ​​of a polymorph, each 2 theta angle includes ±0.2° as an error margin. Thus, an XRPD peak maximum defined by a 2 theta angle of 10.0 includes 9.8 and 10.2, and any value therebetween, represented as 10.0±0.2.

[0021] The term "onset temperature" as used herein refers to the designed intersection of the extrapolated baseline and the inflected tangent at the beginning of melting in a DSC / TG experiment.

[0022] The term "peak temperature" as used herein refers to a maximum or minimum temperature measurable by differential scanning calorimetry (DSC), known to those skilled in the art.

[0023] As used herein, the term "seeding" refers to the technique of adding one or more "seed" crystals to a crystallization solution to promote the formation of crystals.

[0024] The term "amorphous form" as used herein refers to a non-crystalline form of a substance as determined by X-ray powder diffraction (XRPD). The term "amorphous" form includes solids with a disordered arrangement of molecules and without a distinct crystal lattice.

[0025] The term "polymorphic form" refers to the property of SCO-101 existing as different crystalline forms having different crystal lattices that provide crystalline material differences, for example, in crystal hardness, morphology and size. Different crystalline forms or forms can be identified and examined by crystallographic techniques (such as XRPD and DSC / TG) or indirectly by evaluation of differences in physical and / or chemical properties associated with each particular polymorph. Different polymorphs differ in physical properties (solubility, dissolution, solid state stability, etc.) and processing behavior with respect to powder flow and compression during tableting.

[0026] As used herein, the term "anti-cancer agent" includes, but is not limited to, chemotherapeutic agents that have activity against susceptible tumors.

[0027] The term "polar protic solvent" refers to a polar solvent that can exchange protons with a reagent and that contains a polarizable proton.

[0028] The term "polar aprotic solvent" refers to a polar solvent that does not contain an acidic hydrogen and does not act as a hydrogen bond donor.

[0029] The term "non-polar solvent" refers to a solvent that has a low dielectric constant (ε), preferably less than 9.5, and is immiscible with water.

[0030] The term "relative humidity" or "RH" refers to the ratio, in percent, of the partial pressure of water vapor to the equilibrium vapor pressure of water at a given temperature.

[0031] The term "hygroscopic" is used herein to describe a compound or polymorphic form that takes up water by either absorption, adsorption, or a combination of these two processes.

[0032] The terms "Form I" and "Form I crystals" are used interchangeably herein, as are Form I, Form II, Form III, Form IV, and Form V.

[0033] SCO-101 crystal form Type I crystal Form I SCO-101 has been shown to be non-hygroscopic and the thermodynamically most stable SCO-101 polymorph. Moreover, Form I shows superior properties compared to other non-solvated and solvated forms of SCO-101 (such as Form II). Form I has a higher melting point than Form II (Figures 2A and 2B); and together with the results of the competitive slurry experiment (Example 7), it can be concluded that Form I is the more thermodynamically stable polymorph of SCO-101 compared to the other forms identified. Furthermore, DVS analysis of Form I (Figure 3A) and Form II (Figure 3B) showed that Form I is essentially non-hygroscopic, while Form II absorbs approximately 6% (w / w) water at 90% RH. These experimental observations support that Form I crystals of SCO-101 are the most attractive crystalline form for clinical development in terms of stability and non-hygroscopicity.

[0034] Thus, in one embodiment, SCO-101: [ka] and exhibiting at least peak maxima at 2-theta angles of 19.0±0.2, 21.2±0.2, and 23.4±0.2 in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation.

[0035] In one embodiment, the Form I crystal further exhibits one or more peak maxima in an X-ray powder diffraction (XRPD) diffractogram at 2 theta angles selected from the group consisting of 13.9±0.2, 19.9±0.2, and 26.9±0.2 when measured using CuKα radiation.

[0036] In one embodiment, crystal Form I exhibits at least peak maxima at the following 2-theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 13.9±0.2, 19.0±0.2, 19.9±0.2, and 21.2±0.2.

[0037] In one embodiment, the Form I crystals are measured using CuKα radiation. The X-ray powder diffraction (XRPD) diffractogram shows at least peak maxima at 2 theta angles: 13.9±0.2, 19.0±0.2, 19.9±0.2, 21.2±0.2, and 23.4±0.2.

[0038] In one embodiment, the Form I crystal exhibits at least peak maxima at the following 2 theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 13.9±0.2, 19.0±0.2, 19.9±0.2, 21.2±0.2, 23.4±0.2, and 26.9±0.2.

[0039] In one embodiment, the Form I crystal exhibits at least peak maxima at the following 2-theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 12.0±0.2, 13.9±0.2, 19.0±0.2, 19.9±0.2, 21.2±0.2, 23.4±0.2, and 26.9±0.2.

[0040] In one embodiment, the Form I crystals exhibit at least peak maxima at the following 2-theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 12.0±0.2, 13.9±0.2, 19.0±0.2, 19.9±0.2, 21.2±0.2, 23.4±0.2, 26.9±0.2, and 27.4±0.2.

[0041] In one embodiment, the Form I crystals exhibit at least peak maxima at the following 2-theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 12.0±0.2, 13.9±0.2, 19.0±0.2, 19.9±0.2, 20.4±0.2, 21.2±0.2, 23.4±0.2, 26.9±0.2, and 27.4±0.2.

[0042] In one embodiment, the Form I crystals exhibit at least peak maxima at the following 2 theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 12.0±0.2, 13.9±0.2, 19.0±0.2, 19.9±0.2, 20.4±0.2, 21.2±0.2, 23.2±0.2, 23.4±0.2, 26.9±0.2, and 27.4±0.2.

[0043] In one embodiment, crystalline Form I exhibits at least a peak maximum at 2 theta angles according to Table 1 in an X-ray powder diffraction (XRPD) diffractogram when measured using CuKα radiation.

[0044] [Table 1]

[0045] In one embodiment, crystalline Form I exhibits an XRPD diffractogram according to FIG. 1A when measured using CuKα radiation.

[0046] Form I crystals: Melting point (endothermic event) In addition to the XRPD diffractogram, polymorphs are also defined by their melting points. Melting points can be measured as endothermic events observed by differential scanning calorimetry (DSC) that are not associated with mass loss. Melting points are defined by either the onset or peak temperature of the endothermic event, or both.

[0047] In one embodiment, the Form I crystals exhibit an onset temperature in differential scanning calorimetry (DSC) of 218°C to 226°C (such as 219°C to 224°C, such as 220°C to 222°C, for example 221°C) using a heating rate of 10°C / min.

[0048] In one embodiment, the I-type crystal exhibits a peak temperature of 224°C to 234°C (e.g., 225°C to 233°C, e.g., 226°C to 232°C, e.g., 227°C to 231°C, e.g., 228°C to 230°C, e.g., 229°C) in differential scanning calorimetry (DSC) using a heating rate of 10°C / min. In one embodiment, the I-type crystal exhibits a peak temperature of 229°C in differential scanning calorimetry (DSC) using a heating rate of 10°C / min.

[0049] Type II crystal The polymorphic form of SCO-101 prepared as in WO2000 / 24707 is Form II. SCO-101: [ka] Crystalline Form II of is characterized by exhibiting at least peak maxima at 2-theta angles of 18.8±0.2, 23.2±0.2, and 20.5±0.2 in an X-ray powder diffraction (XRPD) diffractogram measured using CuKα radiation.

[0050] Crystalline Form II of SCO-101 can be identified using the 2-theta values ​​shown in Table II.

[0051] [Table 2]

[0052] Type III crystal The nonsolvated crystalline form of SCO-101 (Form III) can be obtained by temperature cycling a slurry of amorphous SCO-101 in methanol as shown by Example 5. The nonsolvated crystalline form of SCO-101 (Form III) can then be converted to crystalline Form I as shown by Example 7.

[0053] Thus, in one embodiment, SCO-101: [ka] The present invention provides Form III crystals of the compound of formula (I), wherein the crystals exhibit at least peak maxima at 2 theta angles of 11.1±0.2, 21.7±0.2, and 23.3±0.2 in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation.

[0054] In one embodiment, the Form III crystal further exhibits one or more peak maxima in an X-ray powder diffraction (XRPD) diffractogram at 2 theta angles selected from the group consisting of 19.9±0.2, 22.2±0.2, and 26.2±0.2 when measured using CuKα radiation.

[0055] In one embodiment, crystalline Form III exhibits at least peak maxima at the following 2-theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 11.1±0.2, 21.7±0.2, 23.3±0.2, and 26.2±0.2.

[0056] In one embodiment, crystalline Form III exhibits at least peak maxima at the following 2-theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 11.1±0.2, 19.9±0.2, 21.7±0.2, 23.3±0.2, and 26.2±0.2.

[0057] In one embodiment, the Form III crystal exhibits at least peak maxima at the following 2-theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 11.1±0.2, 19.9±0.2, 21.7±0.2, 22.2±0.2, 23.3±0.2, and 26.2±0.2.

[0058] In one embodiment, the Form III crystal exhibits at least peak maxima at the following 2-theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 11.1±0.2, 16.6±0.2, 19.9±0.2, 21.7±0.2, 22.2±0.2, 23.3±0.2, and 26.2±0.2.

[0059] In one embodiment, the Form III crystal exhibits at least peak maxima at the following 2-theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 11.1±0.2, 16.6±0.2, 19.9±0.2, 21.7±0.2, 22.2±0.2, 22.5±0.2, 23.3±0.2, and 26.2±0.2.

[0060] In one embodiment, the Form III crystal exhibits at least peak maxima at the following 2 theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 11.1±0.2, 16.6±0.2, 19.2±0.2, 19.9±0.2, 21.7±0.2, 22.2±0.2, 22.5±0.2, 23.3±0.2, and 26.2±0.2.

[0061] In one embodiment, the Form III crystals exhibit at least peak maxima at the following 2 theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 11.1±0.2, 16.6±0.2, 18.0±0.2, 19.2±0.2, 19.9±0.2, 21.7±0.2, 22.2±0.2, 22.5±0.2, 23.3±0.2, and 26.2±0.2.

[0062] In one embodiment, crystalline Form III exhibits at least a peak maximum value at 2 theta angles according to Table III in an X-ray powder diffraction (XRPD) diffractogram when measured using CuKα radiation.

[0063] [Table 3]

[0064] In one embodiment, crystalline Form III exhibits an XRPD diffractogram according to FIG. 1C when measured using CuKα radiation.

[0065] Form III crystals: Melting point (endothermic event) In addition to the XRPD diffractogram, polymorphs are also defined by their melting points. Melting points can be measured as endothermic events observed by differential scanning calorimetry (DSC) that are not associated with mass loss. Melting points are defined by either the onset or peak temperature of the endothermic event, or both.

[0066] In one embodiment, the III crystal exhibits an onset temperature of 220°C to 228°C (such as 221°C to 226°C, such as 222°C to 224°C, for example 223°C) in differential scanning calorimetry (DSC) using a heating rate of 10°C / min. In one embodiment, the III crystal exhibits an onset temperature of 223°C in differential scanning calorimetry (DSC) using a heating rate of 10°C / min.

[0067] In one embodiment, the Type III crystals exhibit a peak temperature of 225°C to 235°C (such as 226°C to 234°C, such as 226°C to 234°C, such as 227°C to 233°C, such as 228°C to 232°C, such as 229°C to 231°C, for example 230°C) in differential scanning calorimetry (DSC) using a heating rate of 10°C / min.

[0068] In one embodiment, crystalline Form III exhibits a peak temperature in differential scanning calorimetry (DSC) of 230° C. using a heating rate of 10° C. / min.

[0069] Type IV crystal The unsolvated crystalline form of SCO-101 (Form IV) can be obtained by storing Form III crystals in an open vial at 40° C. / 75% relative humidity (RH) for 3 days as shown by Example 5. The unsolvated crystalline form of SCO-101 (Form IV) can then be converted to Form I crystals as shown by Example 7.

[0070] Thus, in one embodiment, SCO-101: [ka] The present invention provides Form IV crystals of the compound of formula (I), wherein the crystals exhibit at least peak maxima at 2 theta angles of 22.6±0.2, 23.4±0.2, and 23.7±0.2 in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation.

[0071] In one embodiment, crystalline Form IV exhibits at least peak maxima at the following 2-theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 21.6±0.2, 22.6±0.2, 23.4±0.2, 23.7±0.2, and 24.1±0.2.

[0072] In one embodiment, the Form IV crystal further exhibits one or more peak maxima in an X-ray powder diffraction (XRPD) diffractogram at 2 theta angles selected from the group consisting of 21.6±0.2, 24.1±0.2, and 27.2±0.2 when measured using CuKα radiation.

[0073] In one embodiment, crystalline Form IV exhibits at least peak maxima at the following 2 theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 21.6±0.2, 22.6±0.2, 23.4±0.2, 23.7±0.2, 24.1±0.2, and 27.2±0.2.

[0074] In one embodiment, crystalline Form IV exhibits at least peak maxima at the following 2 theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 21.6±0.2, 20.1±0.2, 22.6±0.2, 23.4±0.2, 23.7±0.2, 24.1±0.2, and 27.2±0.2.

[0075] In one embodiment, crystalline Form IV exhibits at least peak maxima at the following 2 theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 21.6±0.2, 20.1±0.2, 22.6±0.2, 23.4±0.2, 23.7±0.2, 24.1±0.2, 25.6±0.2, and 27.2±0.2.

[0076] In one embodiment, the Form IV crystals exhibit at least peak maxima at the following 2 theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 13.5±0.2, 21.6±0.2, 20.1±0.2, 22.6±0.2, 23.4±0.2, 23.7±0.2, 24.1±0.2, 25.6±0.2, and 27.2±0.2.

[0077] In one embodiment, crystalline Form IV exhibits at least peak maxima at the following 2-theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 21.6±0.2, 22.6±0.2, 23.4±0.2, 23.7±0.2, and 24.1±0.2.

[0078] In one embodiment, the Form IV crystals exhibit at least peak maxima at the following 2 theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 13.5±0.2, 20.1±0.2, 21.6±0.2, 22.6±0.2, 23.4±0.2, 23.7±0.2, 24.1±0.2, 25.6±0.2, 27.4±0.2, and 30.2±0.2.

[0079] In one embodiment, crystalline Form IV exhibits at least a peak maximum at 2 theta angles according to Table IV in an X-ray powder diffraction (XRPD) diffractogram when measured using CuKα radiation.

[0080] [Table 4]

[0081] In one embodiment, crystalline Form IV exhibits an XRPD diffractogram according to FIG. 1D when measured using CuKα radiation.

[0082] Form IV crystal: Melting point (endothermic event) In addition to the XRPD diffractogram, polymorphs are also defined by their melting points. Melting points can be measured as endothermic events observed by differential scanning calorimetry (DSC) that are not associated with mass loss. Melting points are defined by either the onset or peak temperature of the endothermic event, or both.

[0083] In one embodiment, the IV crystals exhibit an onset temperature of 222°C to 230°C (such as 223°C to 228°C, such as 224°C to 226°C, for example 225°C) in differential scanning calorimetry (DSC) using a heating rate of 10°C / min. In one embodiment, the IV crystals exhibit an onset temperature of 225°C in differential scanning calorimetry (DSC) using a heating rate of 10°C / min.

[0084] In one embodiment, the IV crystal exhibits a peak temperature of 226°C to 236°C (e.g., 227°C to 235°C, 228°C to 234°C, 229°C to 233°C, 230°C to 232°C, e.g., 231°C) in differential scanning calorimetry (DSC) using a heating rate of 10°C / min. In one embodiment, the IV crystal exhibits a peak temperature of 231°C in differential scanning calorimetry (DSC) using a heating rate of 10°C / min.

[0085] V type crystal The crystalline isopropanol solvate of SCO-101 was identified as crystal Form V. Crystal Form V can be converted to crystal Form I as shown in Example 7.

[0086] In one embodiment, the isopropanol solvate of SCO-101: [ka] The present invention provides Form V crystals of the compound of formula (I), wherein the crystals exhibit at least peak maxima at 2 theta angles of 9.4±0.2, 21.1±0.2, and 22.2±0.2 in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation.

[0087] In one embodiment, the Form V crystals further exhibit one or more peak maxima in an X-ray powder diffraction (XRPD) diffractogram at 2 theta angles selected from the group consisting of 8.2±0.2, 10.5±0.2, and 24.2±0.2 when measured using CuKα radiation.

[0088] In one embodiment, crystal Form V exhibits at least peak maxima at the following 2-theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 8.2±0.2, 9.4±0.2, 21.1±0.2, and 22.2±0.2.

[0089] In one embodiment, crystals of Form V exhibit at least peak maxima at the following 2-theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 8.2±0.2, 9.4±0.2, 10.5±0.2, 21.1±0.2, and 22.2±0.2.

[0090] In one embodiment, crystals of Form V exhibit at least peak maxima at the following 2-theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 8.2±0.2, 9.4±0.2, 10.5±0.2, 21.1±0.2, 22.2±0.2, and 24.2±0.2.

[0091] In one embodiment, crystals of Form V exhibit at least peak maxima at the following 2-theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 8.2±0.2, 9.4±0.2, 10.5±0.2, 21.1±0.2, 22.2±0.2, 24.2±0.2, and 28.5±0.2.

[0092] In one embodiment, the Form V crystals exhibit at least peak maxima at the following 2-theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 8.2±0.2, 9.4±0.2, 10.5±0.2, 21.1±0.2, 22.2±0.2, 24.2±0.2, 25.5±0.2, and 28.5±0.2.

[0093] In one embodiment, the Form V crystals exhibit at least peak maxima at the following 2 theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 8.2±0.2, 9.4±0.2, 10.5±0.2, 21.1±0.2, 22.2±0.2, 24.2±0.2, 24.6±0.2, 25.5±0.2, and 28.5±0.2.

[0094] In one embodiment, the Form V crystals exhibit at least peak maxima at the following 2-theta angles in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: 8.2±0.2, 9.4±0.2, 10.5±0.2, 21.1±0.2, 22.2±0.2, 23.7±0.2, 24.2±0.2, 24.6±0.2, 25.5±0.2, and 28.5±0.2.

[0095] In one embodiment, crystal Form V exhibits at least a peak maximum at 2 theta angles according to Table V in an X-ray powder diffraction (XRPD) diffractogram when measured using CuKα radiation.

[0096] [Table 5]

[0097] In one embodiment, crystalline Form V exhibits an XRPD diffractogram according to FIG. 1F when measured using CuKα radiation.

[0098] V-type crystal: Melting point (endothermic event) In addition to the XRPD diffractogram, polymorphs are also defined by their melting points. Melting points can be measured as endothermic events observed by differential scanning calorimetry (DSC) that are not associated with mass loss. Melting points are defined by either the onset or peak temperature of the endothermic event, or both.

[0099] In one embodiment, the V-type crystals exhibit an onset temperature of 216°C to 224°C (such as 217°C to 223°C, such as 218°C to 222°C, such as 219°C to 221°C, for example 220°C) in differential scanning calorimetry (DSC) using a heating rate of 10°C / min. In one embodiment, the V-type crystals exhibit an onset temperature of 220°C in differential scanning calorimetry (DSC) using a heating rate of 10°C / min.

[0100] In one embodiment, the V-type crystals exhibit a peak temperature of 224°C to 234°C (e.g., 225°C to 233°C, e.g., 226°C to 232°C, e.g., 227°C to 231°C, e.g., 228°C to 230°C, e.g., 229°C) in differential scanning calorimetry (DSC) using a heating rate of 10°C / min. In one embodiment, the V-type crystals exhibit a peak temperature of 229°C in differential scanning calorimetry (DSC) using a heating rate of 10°C / min.

[0101] Amorphous SCO-101 Amorphous SCO-101 can be prepared by the method shown in Example 2.

[0102] In one embodiment, SCO-101: [ka] wherein the amorphous form does not exhibit a peak maximum at 2-theta angles between 0 and 40 in an X-ray powder diffraction (XRPD) diffractogram when measured using CuKα radiation.

[0103] The XRPD diffractogram of an amorphous material, such as the amorphous form of SCO-101, is not exactly horizontal, but one of skill in the art will understand that a convex baseline such as that in FIG. 1E does not represent a peak maximum.

[0104] In one embodiment, the amorphous form exhibits an XRPD diffractogram according to FIG. 1E when measured using CuKα radiation.

[0105] In one embodiment, the amorphous form exhibits an onset temperature in differential scanning calorimetry (DSC) of 211° C. to 219° C. (such as 212° C. to 218° C., such as 213° C. to 217° C., such as 214° C. to 216° C., for example 215° C.) using a heating rate of 10° C. / min. In one embodiment, the amorphous form exhibits an onset temperature in differential scanning calorimetry (DSC) of 215° C. using a heating rate of 10° C. / min.

[0106] In one embodiment, the amorphous form exhibits a peak temperature in differential scanning calorimetry (DSC) of 218°C to 228°C (such as 219°C to 227°C, such as 220°C to 226°C, such as 221°C to 225°C, such as 222°C to 224°C, for example 223°C) using a heating rate of 10°C / min.

[0107] In one embodiment, the amorphous form exhibits a peak temperature in Differential Scanning Calorimetry (DSC) of 223° C. using a heating rate of 10° C. / min.

[0108] Metastable form of SCO-101 In one embodiment, SCO-101: [ka] and which converts to Form I crystals under storage or by a process as defined herein for the preparation of Form I crystals; the metastable form is not a Form II crystal of SCO-101 that exhibits at least peak maxima at 2-theta angles of 18.8±0.2, 23.2±0.2, and 20.5±0.2 in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation.

[0109] In one embodiment, under storage refers to storage at room temperature (e.g., 20°C to 25°C). In one embodiment, under storage refers to storage at 35°C to 50°C. In one embodiment, under storage refers to storage at 2°C to 8°C.

[0110] In one embodiment, under storage refers to storage of the metastable form for one month after preparation. In one embodiment, under storage refers to storage of the metastable form for one month or more after preparation (such as two months or more, such as three months or more, such as four months or more, such as five months or more, such as six months or more).

[0111] Preparation of type I crystals Type I crystal: Preparation SCO-101 can be prepared using the method described in Example 1. The SCO-101 product obtained using the method of Example 1 is Form II crystals, which can be converted to Form I crystals, for example, using the method described in Example 4 or the method described in Example 7. In one embodiment, the SCO-101 used to prepare Form I crystals is dried, optionally in vacuum, prior to step (a).

[0112] In one embodiment, there is provided a process for preparing Form I crystals of SCO-101 as defined herein, the process comprising: (a) dissolving SCO-101 in one or more polar aprotic solvents at a first predetermined temperature; (b) adding one or more polar protic solvents to one or more polar aprotic solvents for a first predetermined period of time to provide Form I crystals of SCO-101; and (c) isolating type I crystals of SCO-101 The method includes the following continuous steps.

[0113] In one embodiment, there is provided a process for preparing Form I crystals of SCO-101 as defined herein, the process comprising: (a) dissolving SCO-101 in one or more polar protic solvents at a first predetermined temperature; (b) adding one or more polar aprotic solvents to the one or more polar protic solvents for a first predetermined period of time to provide Form I crystals of SCO-101; and (c) isolating type I crystals of SCO-101 The method includes the following continuous steps.

[0114] In one embodiment, there is provided a process for preparing Form I crystals of SCO-101 as defined herein, the process comprising: (a) dissolving SCO-101 in one or more polar aprotic solvents at a first predetermined temperature; (b) adding one or more non-polar solvents to the one or more polar aprotic solvents for a first predetermined period of time to provide Form I crystals of SCO-101; and (c) isolating type I crystals of SCO-101 The method includes the following continuous steps.

[0115] In one embodiment, the process further comprises a pre-crystallization step prior to step (a), the pre-crystallization step comprising: (i) mixing a composition comprising SCO-101 and one or more impurities with 2-propanol to provide a mixture; (ii) heating the mixture at or to a second predetermined temperature that is higher than the first predetermined temperature; (iii) adding water to the mixture for a second predetermined period of time; (iv) cooling the mixture to a third predetermined temperature lower than the second predetermined temperature to provide SCO-101 as a solid, and optionally further isolating the solid by filtration. Includes.

[0116] solvent In one embodiment, the one or more polar aprotic solvents are selected from the group consisting of acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropyleneurea, dimethylsulfoxide, ethyl acetate, 2-MeTHF, and tetrahydrofuran, hi one embodiment, the polar aprotic solvent is acetone.

[0117] In one embodiment, the one or more polar protic solvents are selected from the group consisting of water, methanol, ethanol, isopropanol, and acetic acid, hi one embodiment, the polar protic solvent is water.

[0118] In one embodiment, the one or more non-polar solvents are selected from the group consisting of pentane, heptane, cyclohexane, and methylcyclohexane.

[0119] temperature In one embodiment, the first predetermined temperature is between 0°C and 20°C (such as 10°C ±5°C).

[0120] In one embodiment, the second predetermined temperature is 31°C to 80°C (such as 31°C to 35°C, such as 35°C to 40°C, such as 40°C to 45°C, such as 45°C to 50°C, such as 50°C to 55°C, such as 55°C to 60°C, such as 60°C to 65°C, such as 65°C to 70°C, such as 70°C to 75°C, such as 75°C to 80°C, for example, 50°C).

[0121] In one embodiment, the third predetermined temperature is 10°C to 30°C (such as 10°C to 12°C, such as 12°C to 14°C, such as 14°C to 16°C, such as 16°C to 18°C, such as 18°C ​​to 20°C, such as 20°C to 22°C, such as 22°C to 24°C, such as 24°C to 26°C, such as 26°C to 28°C, such as 28°C to 30°C, for example, 20°C).

[0122] time In one embodiment, the first predefined period of time is between 10 minutes and 360 minutes (such as between 70 minutes and 90 minutes).

[0123] In one embodiment, the second predetermined period of time is 1 minute to 120 minutes (such as 1 minute to 10 minutes, such as 10 minutes to 20 minutes, such as 20 minutes to 30 minutes, such as 30 minutes to 40 minutes, such as 40 minutes to 50 minutes, such as 50 minutes to 60 minutes, such as 60 minutes to 70 minutes, such as 70 minutes to 80 minutes, such as 80 minutes to 90 minutes, such as 90 minutes to 100 minutes, such as 100 minutes to 110 minutes, such as 110 minutes to 120 minutes, etc.). In one embodiment, the second predetermined period of time is 30 minutes.

[0124] impurities In one embodiment, the one or more impurities are selected from the group consisting of 4-bromo-2-(1H-1,2,3,4-tetraazol-5-yl)aniline, 3,5-bis(trifluoromethyl)-phenyl isocyanate, and toluene. One or more or all of these impurities can be effectively removed by the processes disclosed herein, for example, as shown by Example 4.

[0125] Seeding In one embodiment, the process disclosed herein includes adding one or more seed crystals of SCO-101 Form I crystals. The one or more seed crystals can be added before, during, or after any of the steps disclosed herein in the preparation of SCO-101 Form I crystals. In one embodiment, the one or more seed crystals are added before step (a) of the process disclosed herein.

[0126] In one embodiment, a non-seeded process is provided.

[0127] Preparation of Form I crystals from the metastable form The slurry experiments in Example 7 demonstrated that the crystalline nonsolvated Form I of SCO-101 is a thermodynamically stable polymorph. Furthermore, these methods / processes can also be used to convert metastable forms to Form I crystals.

[0128] In one embodiment, there is provided a process for preparing crystalline Form I of SCO-101 as defined herein from a metastable form, the process comprising: (a) providing a metastable form of SCO-101 that is a crystalline or amorphous form; (b) mixing the metastable form with crystalline Form I of SCO-101 as defined herein in a solvent mixture of: (i) one or more polar aprotic solvents and (ii) one or more polar protic solvents or one or more non-polar solvents; (c) stirring the solvent mixture at a sixth predetermined temperature for at least one hour, thereby providing Form I crystals of SCO-101. Includes.

[0129] In one embodiment, the solvent mixture in step (c) is stirred for 6 hours or more, such as 12 hours or more, such as 1 day or more, such as 2 days or more, such as 3 days or more, such as 4 days or more, such as 5 days or more, such as 6 days or more, such as 7 days or more.

[0130] In one embodiment, the Form I crystals of SCO-101 obtained in step (c) are separated from the solvent mixture, optionally by filtration.

[0131] metastable type In one embodiment, the metastable form of SCO-101 is (i) SCO-101, which exhibits at least peak maxima at 2-theta angles of 18.8±0.2, 23.2±0.2, and 20.5±0.2 in an X-ray powder diffraction (XRPD) diffractogram as measured using CuKα radiation: [ka] Form II crystals of; (ii) SCO-101 crystalline Form III, as defined herein; (iii) SCO-101 crystalline Form IV as defined herein; and (iv) SCO-101 Type V crystals as defined herein is selected from the group consisting of:

[0132] temperature In one embodiment, the sixth predetermined temperature is 30°C to 60°C (e.g., 30°C to 32°C, such as 32°C to 34°C, such as 34°C to 36°C, such as 36°C to 38°C, such as 38°C to 40°C, such as 40°C to 42°C, such as 42°C to 44°C, such as 44°C to 46°C, such as 46°C to 48°C, such as 48°C to 50°C, such as 50°C to 52°C, such as 52°C to 54°C, such as 54°C to 56°C, such as 56°C to 58°C, such as 58°C to 60°C, for example, 40°C).

[0133] In one embodiment, the sixth predetermined temperature is 30°C to 60°C (such as 31°C to 58°C, such as 32°C to 56°C, such as 33°C to 54°C, such as 34°C to 52°C, such as 35°C to 50°C, such as 36°C to 48°C, such as 37°C to 46°C, such as 38°C to 44°C, such as 39°C to 42°C, for example 40°C).

[0134] In one embodiment, the solvent mixture in step (c) is stirred for 6 hours or more, such as 12 hours or more, such as 1 day or more, such as 2 days or more, such as 3 days or more, such as 4 days or more, such as 5 days or more, such as 6 days or more, such as 7 days or more.

[0135] solvent In one embodiment, the one or more polar aprotic solvents are selected from the group consisting of acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropyleneurea, dimethylsulfoxide, ethyl acetate, 2-MeTHF, and tetrahydrofuran.

[0136] In one embodiment, the one or more polar protic solvents are selected from the group consisting of water, methanol, ethanol, isopropanol, and acetic acid.

[0137] In one embodiment, the one or more non-polar solvents are selected from the group consisting of heptane, hexane, pentane, cyclohexane, toluene, and diethyl ether.

[0138] In one embodiment, the polar aprotic solvent is acetone and the polar protic solvent is water, hi one embodiment, the polar aprotic solvent is acetone and the non-polar solvent is heptane.

[0139] In one embodiment, SCO-101: [ka] The present invention provides type I crystals of the compound.

[0140] Type III crystal: Preparation In one embodiment, there is provided a process for preparing crystalline Form III of SCO-101 as defined herein, the process comprising: (a) mixing SCO-101 with one or more polar protic solvents, such as methanol, to provide a mixture; (b) performing one or more temperature cycles, wherein the temperature is cycled between a fourth predetermined temperature and a fifth predetermined temperature, the fourth predetermined temperature being greater than the fifth predetermined temperature; (c) isolating crystalline Form III of SCO-101, as defined herein, from the mixture. The method includes the following continuous steps.

[0141] In one embodiment, the SCO-101 in step (a) is an amorphous form of SCO-101 as defined herein.

[0142] Temperature Cycling In one embodiment, the one or more temperature cycles are 2 to 6 cycles (such as 2 to 3 cycles, such as 3 to 4 cycles, such as 4 to 5 cycles, such as 5 to 6 cycles).

[0143] temperature In one embodiment, the fourth predetermined temperature is 31°C to 60°C (such as 31°C to 35°C, such as 35°C to 40°C, such as 40°C to 45°C, such as 45°C to 50°C, such as 50°C to 55°C, such as 55°C to 60°C).

[0144] In one embodiment, the fifth predetermined temperature is between 15°C and 30°C (such as between 15°C and 20°C, such as between 20°C and 25°C, such as between 25°C and 30°C).

[0145] Drying In one embodiment, the SCO-101 is dried, optionally in a vacuum, before step (c).In one embodiment, the SCO-101 is dried, optionally in a vacuum, after step (c).

[0146] In one embodiment, the SCO-101 is dried, optionally in vacuum, for at least 6 hours at 30° C. to 60° C. prior to step (c). In one embodiment, the SCO-101 is dried, optionally in vacuum, for at least 6 hours at 30° C. to 60° C. after step (c).

[0147] In one embodiment, the SCO-101 is dried at 30° C. to 60° C., optionally in vacuum, for 6 to 72 hours prior to step (c). In one embodiment, the SCO-101 is dried at 30° C. to 60° C., optionally in vacuum, for 6 to 72 hours after step (c).

[0148] Type IV crystal: Preparation In one embodiment, there is provided a process for preparing crystalline Form IV of SCO-101 as defined herein, the process comprising: (a) providing a crystalline form III of SCO-101 as defined herein; and (b) storing the SCO-101 type III crystals at 30°C to 60°C for at least 24 hours, thereby preparing the SCO-101 type IV crystals. The method includes the following continuous steps.

[0149] In one embodiment, SCO-101 Form III crystals are stored for 1 day or more (such as 2 days or more, such as 3 days or more, such as 4 days or more, such as 5 days or more, such as 6 days or more, such as 7 days or more).

[0150] V type crystal: Preparation Form V crystals can be provided as an intermediate crystal form to Form I crystals. In particular, the first part of the method as described in Example 4 before solvation of SCO-101 in acetone can be used to provide Form V crystals. Form V crystals can be further converted to improved Form I crystals using the methods described herein and as illustrated in particular in Example 4. Form V crystals can also be converted to Form I crystals as illustrated by Example 7.

[0151] In one embodiment, there is provided a process for preparing Form V crystals of SCO-101 as defined herein, the process comprising: (a) mixing a composition comprising SCO-101 with isopropanol to provide a mixture; (b) heating the mixture to or at a seventh predetermined temperature; (c) adding water to the mixture over a third predetermined period of time; (d) adjusting the temperature of the mixture to an eighth predetermined temperature over a fourth predetermined period of time to provide a solid composition; (e) isolating the solid composition, and optionally drying the solid composition to provide SCO-101 Form V crystals. The method includes the following continuous steps.

[0152] temperature In one embodiment, the seventh predetermined temperature is 30°C to 82°C (e.g., 31°C to 80°C, 32°C to 78°C, 33°C to 76°C, 34°C to 74°C, 35°C to 72°C, 36°C to 70°C, 38°C to 68°C, 39°C to 66°C, 40°C to 64°C, 41°C to 62°C, 42°C to 60°C, 43°C to 58°C, 44°C to 56°C, 45°C to 55°C, 46°C to 54°C, 47°C to 52°C, 48°C to 52°C, 49°C to 51°C, for example, 50°C).

[0153] In one embodiment, the eighth predetermined temperature is 2°C to 29°C (such as 4°C to 28°C, such as 6°C to 27°C, such as 8°C to 26°C, such as 10°C to 25°C, such as 12°C to 24°C, such as 14°C to 24°C, such as 16°C to 24°C, such as 17°C to 23°C, such as 18°C ​​to 22°C, such as 19°C to 21°C, for example 20°C).

[0154] time In one embodiment, the third predetermined period of time is within 1 hour (such as within 50 minutes, such as within 40 minutes, such as within 30 minutes).

[0155] In one embodiment, the third predetermined period is from 1 minute to 60 minutes (such as from 5 minutes to 55 minutes, such as from 10 minutes to 50 minutes, such as from 15 minutes to 45 minutes, such as from 20 minutes to 40 minutes, such as from 25 minutes to 35 minutes, for example, 30 minutes).

[0156] In one embodiment, the fourth predetermined period of time is 1 minute or more (such as 10 minutes or more, such as 20 minutes or more, such as 30 minutes or more, such as 40 minutes or more, such as 50 minutes or more, such as 60 minutes or more).

[0157] In one embodiment, the fourth predetermined period of time is from 1 minute to 12 hours (such as from 5 minutes to 10 hours, such as from 10 minutes to 8 hours, such as from 20 minutes to 6 hours, such as from 20 minutes to 4 hours, such as from 30 minutes to 2 hours, for example, 1 hour).

[0158] Amorphous SCO-101: Preparation In one embodiment, there is provided a process for preparing an amorphous form of SCO-101 as defined herein, the process comprising: (a) mixing a composition comprising SCO-101 with one or more polar aprotic solvents to obtain a clear solution with no visible solids, indicating complete dissolution of the composition; (b) evaporating the one or more polar aprotic solvents, optionally under vacuum, at a ninth predetermined temperature to provide a solid composition; (c) optionally further drying the solid composition to provide an amorphous form of SCO-101. The method includes the following continuous steps.

[0159] solvent In one embodiment, the one or more polar aprotic solvents are selected from the group consisting of acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropyleneurea, dimethylsulfoxide, ethyl acetate, 2-MeTHF, and tetrahydrofuran, hi one embodiment, the polar aprotic solvent is acetone.

[0160] temperature In one embodiment, the ninth predetermined temperature is the boiling point of the one or more polar aprotic solvents.

[0161] In one embodiment, the ninth predetermined temperature is 30°C to 60°C (such as 31°C to 58°C, such as 32°C to 56°C, such as 33°C to 54°C, such as 34°C to 52°C, such as 35°C to 50°C, such as 36°C to 48°C, such as 37°C to 46°C, such as 38°C to 44°C, such as 39°C to 42°C, for example 40°C).

[0162] Pharmaceutical Compositions In one embodiment, there is provided a pharmaceutical composition as disclosed herein, wherein the pharmaceutical composition is formulated for oral administration. Such a composition may be in the form of a tablet or capsule.

[0163] In one embodiment, a pharmaceutical composition is provided, comprising any one of the crystalline or amorphous forms of SCO-101 as defined herein and one or more pharma- ceutically acceptable adjuvants, excipients, carriers, buffers and / or diluents.

[0164] In one embodiment, a pharmaceutical composition is provided, comprising any one of the crystalline or amorphous forms of SCO-101 as defined herein (provided that the crystalline form is not crystalline Form II of SCO-101), and one or more pharma- ceutically acceptable adjuvants, excipients, carriers, buffers and / or diluents.

[0165] In one embodiment, a pharmaceutical composition is provided, comprising any one of SCO-101 crystalline Form I, crystalline Form III, crystalline Form IV, crystalline Form V or amorphous forms as defined herein, and one or more pharma- ceutically acceptable adjuvants, excipients, carriers, buffers and / or diluents.

[0166] In one embodiment, a pharmaceutical composition is provided, comprising crystalline Form I of SCO-101 as defined herein and one or more pharma- ceutically acceptable adjuvants, excipients, carriers, buffers and / or diluents.

[0167] Form I crystals in cancer treatment In one embodiment, there is provided a method of treating a patient having cancer comprising administering to the patient a pharmaceutical composition as defined herein and one or more anti-cancer agents. A therapeutic effect can be obtained by administering a pharmaceutical composition comprising any crystalline or amorphous form of SCO-101 in combination with one or more of the anti-cancer agents disclosed herein.

[0168] In one embodiment, there is provided a method of treating a patient having cancer comprising administering to the patient crystalline Form I of SCO-101 as defined herein or a pharmaceutical composition as defined herein and one or more anti-cancer agents.

[0169] In one embodiment, crystalline Form I of SCO-101 as defined herein or a pharmaceutical composition as defined herein is administered to a patient daily.

[0170] In one embodiment, the present disclosure provides Form I crystals of SCO-101 as defined herein for use in the treatment of cancer, wherein the Form I crystals of SCO-101 are administered in combination with one or more anti-cancer agents.

[0171] In one embodiment, the present disclosure provides the use of Form I crystals of SCO-101 as defined herein for the preparation of a therapeutic medicament for the treatment of cancer, wherein the Form I crystals of SCO-101 are administered in combination with one or more anti-cancer agents.

[0172] The one or more anti-cancer agents may be administered simultaneously, sequentially, or separately with SCO-101.

[0173] In one embodiment, the one or more anti-cancer agents are selected from the group consisting of topoisomerase inhibitors, anti-hormones, alkylating agents, mitotic inhibitors, antimetabolites, antitumor antibiotics, corticosteroids, targeted anti-cancer therapies, differentiation inducers, and immunotherapy.

[0174] Topoisomerase inhibitors In one embodiment, the anti-cancer agent is a topoisomerase I inhibitor or a topoisomerase II inhibitor.

[0175] In one embodiment, the anticancer agent is a topoisomerase I inhibitor selected from the group consisting of irinotecan, its active metabolite SN-38, and topotecan.

[0176] Antihormonal drugs In one embodiment, the anticancer agent is (a) an antiestrogen selected from the group consisting of fulvestrant, tamoxifen, toremifene, and clomiphene; or (b) an antiprogestogen selected from the group consisting of mifepristone, ulipristal acetate, aglepristone, lilopristone and onapristone; It is an anti-hormonal agent.

[0177] In one embodiment, the anti-estrogen is fulvestrant or tamoxifen.

[0178] In one embodiment, the antiprogestogen is onapristone.

[0179] Alkylating drugs

[0180] In one embodiment, the anticancer agent is (a) a nitrogen mustard selected from the group consisting of mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, and melphalan; (b) a nitrosourea selected from the group consisting of streptozocin, carmustine, and lomustine; (c) an alkyl sulfonate selected from the group consisting of busulfan; (d) a triazine selected from the group consisting of dacarbazine (DTIC) and temozolomide; or (e) an ethylenimine selected from the group consisting of thiotepa and altretamine (hexamethylmelamine); It is an alkylating agent.

[0181] In one embodiment, the alkylating agent is temozolomide.

[0182] Antimetabolites In one embodiment, the anticancer agent is an antimetabolite selected from the group consisting of 5-fluorouracil, 6-mercaptopurine, capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, and pemetrexed.

[0183] In one embodiment, the antimetabolite is 5-fluorouracil or gemcitabine.

[0184] Mitotic inhibitors In one embodiment, the anticancer agent is (a) a taxane selected from the group consisting of paclitaxel and docetaxel; (b) ixabepilone; (c) a vinca alkaloid selected from the group consisting of vinblastine, vincristine, and vinorelbine; or (d) Estramustine It is a mitotic inhibitor.

[0185] In one embodiment, the mitotic inhibitor is paclitaxel or docetaxel.

[0186] Further anti-cancer drugs In one embodiment, the anti-cancer agent is administered in combination with one or more additional anti-cancer agents.

[0187] In one embodiment, the anticancer agent is administered in combination with an additional anticancer agent (5-fluorouracil). In one embodiment, the anticancer agent is administered in combination with 5-fluorouracil and folinic acid. In one embodiment, the anticancer agent is irinotecan and is administered in combination with 5-fluorouracil and folinic acid.

[0188] immunotherapy In one embodiment, the anti-cancer agent is an immunotherapeutic agent that is given to an individual with cancer to help the immune system recognize the cancer and attack the cancer cells.

[0189] There are different types of immunotherapies. Active immunotherapies stimulate the body's own immune system to fight disease. Passive immunotherapies do not rely on the body to fight disease; they are immune system components (such as antibodies) created outside the body and administered to the body to fight cancer.

[0190] Examples of effective immunotherapeutic agents include: Monoclonal antibody therapies, such as rituximab (Rituxan®) and alemtuzumab (Campath®) Non-specific immunotherapy and adjuvants (other substances or cells that enhance the immune response), such as BCG, interleukin-2 (IL-2), and interferon alpha Immunomodulators (such as thalidomide and lenalidomide (Revlimid®)) Includes.

[0191] In one embodiment, the anti-cancer agent is a PD-1 inhibitor (or a PD-L1 inhibitor (such as an antibody capable of inhibiting PD-1 or PD-L1).

[0192] Cancer vaccines are a type of specific active immunotherapy.

[0193] cancer In one embodiment, the cancer is a solid tumor or leukemia.

[0194] In one embodiment, the cancer is a solid tumor (such as a solid tumor selected from a sarcoma, carcinoma, and lymphoma).

[0195] In one embodiment, the cancer is selected from the group consisting of colorectal cancer, breast cancer, lung cancer (non-small cell lung cancer and small cell lung cancer), glioblastoma, head and neck cancer, malignant melanoma, basal cell skin cancer, squamous cell skin cancer, liver cancer, pancreatic cancer, prostate cancer, anal cancer, cervical cancer, bladder cancer, uterine cancer, ovarian cancer, gallbladder cancer, sarcoma, leukemia (bone marrow and lymphoid), lymphoma, myelomatosis, and cholangiocarcinoma.

[0196] In one embodiment, the cancer is metastatic cancer. In one embodiment, the cancer is colorectal cancer (such as metastatic colorectal cancer). In one embodiment, the cancer is pancreatic cancer (such as metastatic pancreatic cancer). In one embodiment, the cancer is breast cancer (such as metastatic breast cancer).

[0197] In one embodiment, the leukemia is acute myeloid leukemia (AML).

[0198] In one embodiment, the cancer is a resistant cancer that is resistant to the anti-cancer agent when administered alone, hi one embodiment, the resistance is de novo resistance or acquired resistance.

[0199] Working Example Example 1: Preparation of crude SCO-101 (form II) material The following materials were used: 4-bromo-2-(1H-1,2,3,4-tetraazol-5-yl)aniline was produced in-house; 3,5-bis(trifluoromethyl)-phenyl isocyanate was purchased from DONA FINE CHEMICALS SJ.

[0200] method To a stirred solution of 4-bromo-2-(1H-1,2,3,4-tetraazol-5-yl)aniline (3.2 kg) in toluene (62 L) was added 3,5-bis(trifluoromethyl)-phenylisocyanate (3.5 kg). The tubing used for the addition of 3,5-bis(trifluoromethyl)-phenylisocyanate was washed with toluene (3.8 L) which was added to the reactor. The reaction mixture was heated to 55° C. and stirred for 11 hours. In-process control (IPC) confirmed the conversion of starting material and the reaction mixture was cooled to 23° C. over 2 hours and 30 minutes. The resulting suspension was filtered and the filter cake was washed with toluene (17 L) and dried at 45° C. for 16 hours to give a solid composition.

[0201] result 6.5 kg of SCO-101 was obtained as a crystalline material, which was analyzed by XRPD (FIG. 1B), DVS (FIG. 3B), and DSC-TGA (FIG. 2B). The obtained crystalline form is the metastable, Form II.

[0202] conclusion SCO-101 can be prepared in a metastable form II using the methods described in this example. Form II is not the most stable crystalline form of SCO-101 and will absorb water to form hydrates at increased relative humidity (RH), such as 70% RH or higher. This makes Form II of SCO-101 an inferior form in terms of clinical development, compared to Form I, which is a heat-stable form.

[0203] Example 2: Preparation of amorphous SCO-101 material The following materials were used: SCO-101 Form I was produced at 3 L scale using the process described in Example 4. A 268 g batch was obtained.

[0204] method 3 g of Form I SCO-101 was dissolved in 30 mL of acetone using sonication to aid in dissolution. The clear solution was syringe filtered into a 50 mL round bottom flask and the solvent was removed by rotary evaporation over a 40° C. water bath and left on the rotary evaporator for an additional hour to ensure the material was completely dried. A solid was obtained. The solid was carefully transferred to a crystallization dish, covered with tissue paper, and dried in a vacuum oven at 40° C. under vacuum overnight (approximately 17 hours). The dried solid was analyzed by XRPD, which confirmed good amorphization (see FIG. 1E).

[0205] result Amorphous SCO-101 can be prepared using the method of this example.

[0206] Example 3: Polymorphism screening of SCO-101 Method A: Solubility test and evaporation treatment To approximately 10 mg of amorphous SCO-101, aliquots of the listed solvent were added until dissolution was observed, resulting in a clear solution (following Method A2), or 1 mL was added to form a slurry (following Method A1). Samples were manually stirred and heated to approximately 40° C. in a block connected to a water bath between each dissolution run.

[0207] Method A1: The slurry was stored at room temperature overnight and then filtered by centrifugation.

[0208] Method A2: The clear solution was opened and allowed to evaporate at room temperature.

[0209] The solids obtained from the slurry (Method A1) or from the evaporation process (Method A2) were analyzed by XRPD.

[0210] Method B: Solvent Drop Grinding 10 μl of the appropriate saturated solution (if available) or solvent was added to 20 mg of amorphous SCO-101 in a 2 mL bead mill vial with two steel piece balls.

[0211] The vials were bead milled using the following program: · Speed: 6000rpm Cycle: 40 x 90 seconds · Pause: 10 seconds

[0212] Method C: Temperature Cycling A slurry of amorphous SCO-101 was prepared in vials. All vials were capped and sealed with parafilm and temperature cycled between room temperature and 40° C. on a thermostatic shaker with shaking for 4 hour cycles. After 3 days, all slurries and wet solids were filtered by centrifugation and analyzed by XRPD.

[0213] result Starting from amorphous SCO-101, the following crystalline forms were obtained depending on the solvent and crystallization technique used (see Table 1).

[0214] [Table 6]

[0215] conclusion Anhydrous, nonsolvated crystalline forms of SCO-101 can be prepared using the conditions of entries 1, 13, and 14 of Table 1, which give Forms I, III, and IV, respectively.

[0216] Furthermore, this example shows that various solvates can be formed resulting in different crystal forms (patterns) of SCO-101. By selecting the conditions listed in Table 1, the desired crystal form can be provided.

[0217] Example 4: Preparation of Form I Crystals material Crude SCO-101 was prepared using the method described in Example 1.

[0218] method Crude SCO-101 (50 g, 1.0 equiv., 101 mmol) was dissolved in 2-propanol (257 g) in a 1 L reaction vessel. The reaction mixture was heated at 50° C. until a clear solution was obtained. To this solution, water (326 g) was added in small portions over 30 min. After the resulting slurry was cooled to 20° C. over 1 h, the crude SCO-101 was isolated by filtration. The filter cake was washed with a mixture of 2-propanol / water (50 / 50% w / w, 39 g) and then the crude SCO-101 was redissolved in acetone (154 g) at 10±5° C. To this solution, water (195 g) was then added over 70-90 min. The crystallized SCO-101 was isolated and washed with a mixture of acetone / water (45:55% w / w, 180 g). The product was dried in an oven at 45° C. under low pressure.

[0219] result SCO-101 Form I, prepared by the above method, was analyzed by XRPD (FIG. 1A), TG / DSC (FIG. 2A) and DVS (FIG. 3A); and was further subjected to competitive slurry experiments as described in Example 7.

[0220] conclusion Form I SCO-101 was shown to be the non-hygroscopic and thermodynamically most stable polymorph of SCO-101. Moreover, Form I showed superior properties compared to other non-solvated and solvated forms of SCO-101. Form I has the highest melting point, and together with the results of competitive slurry experiments, it can be concluded that Form I is the thermodynamically most stable polymorph of SCO-101. Furthermore, DVS analysis of Forms I and II showed that Form I is essentially non-hygroscopic, while Form II absorbs approximately 6% (w / w) water at 90% RH.

[0221] Example 5: Preparation of III-type crystals (Pattern 24) material Amorphous SCO-101 was prepared as described in Example 2.

[0222] method A slurry of amorphous SCO-101 in methanol was prepared in a scintillation vial, which was capped, sealed with parafilm, and temperature cycled between room temperature and 40° C. in a thermostatic shaker over a 4 hour cycle.

[0223] After 24 hours, the wet sample showed the formation of pattern 38. The solid was collected by centrifugation and dried at 40° C. for 24 hours.

[0224] result The solid was analyzed by XRPD, which confirmed the formation of pattern 24 (FIG. 1C). TG / DSC analysis (FIG. 2C) confirms the formation of the nonsolvated crystalline form of SCO-101. DSC analysis shows an exothermic event with an onset at 162° C. VT-XRPD confirmed that this exothermic event was due to conversion to pattern 29 (Form IV).

[0225] conclusion The nonsolvated crystalline form of SCO-101 (Form III, Pattern 24) is obtained by temperature cycling of a slurry of amorphous SCO-101 in methanol.

[0226] Example 6: Preparation of Type IV Crystal (Pattern 29) material Form III SCO-101 was prepared as described in Example 5.

[0227] method 200 mg of SCO-101, Form III (Pattern 24) was placed at 40° C. / 75% RH in an open vial covered with tissue for 3 days.

[0228] result After 3 days, the solid was analyzed by XRPD, which confirmed the formation of Pattern 29 (Form IV) (Figure ID). TG / DSC analysis (Figure 2D) confirmed the formation of a nonsolvated crystalline form of SCO-101.

[0229] conclusion The nonsolvated crystalline form of SCO-101 (Form IV, Pattern 29) was obtained by storage of Form III at 40° C. / 75% relative humidity (RH) in an open vial for 3 days.

[0230] Example 7: Conversion of the metastable crystalline form to the thermodynamically stable form I material The following materials were used for the competitive slurry experiments aimed at providing thermodynamically stable polymorphs of SCO-101: Non-solvated: Form I, (Example 1), Form II (Example 1), Form III (Example 5), and Form IV (Example 6). Solvates: Pattern 5, Pattern 22, and Pattern 23 (Example 3)

[0231] method Saturated solutions of SCO-101 in acetone:water (50:50% v / v) and acetone:heptane (50:50% v / v) were prepared by stirring a slurry of SCO-101 in these solvent systems for 15 minutes at 40° C. and then filtering the slurry into a pre-warmed vial using a pre-warmed syringe. For each experiment, the amount of the relevant type / pattern of SCO-101 listed in Table 2 was added to the indicated volume of saturated solution to form a slurry. The slurry was stirred at 40° C. for 3 days. After 3 days, the solids were filtered by centrifugation and analyzed by XRPD.

[0232] result The results of the competitive slurry experiments are listed in Table 2.

[0233] [Table 7] All forms / patterns described in Table 2 could be successfully converted to Form I. Pattern 5 is also referred to herein as Form V.

[0234] conclusion Slurry experiments indicate that the crystalline nonsolvated Form I of SCO-101 is a thermodynamically stable polymorph. All experiments in the solvent systems tested resulted in the formation of Form I.

[0235] Example 8: Methods of Analysis X-ray Powder Diffraction (XRPD) XRPD analysis was performed on a PANalytical X'pert pro equipped with a PIXcel detector (128 channels) scanning the sample from 3° to 50° 2θ. The material was gently ground to release any aggregates and mounted on a multi-well plate with a Mylar polymer film to support the sample. The multi-well plate was then placed in the diffractometer and analyzed using CuK radiation (α1λ=1.54060 Å; α2=1.54443 Å; β=1.39225 Å; α1:α2 ratio=0.5) performed in transfer mode (step size=0.0130° 2θ, step time=18.87 s) with a generator setting of 40 kV / 40 mA. Data were visualized and images were generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017).

[0236] Polarized Light Microscopy (PLM) The presence of crystallinity (birefringence) was determined using a BX53 microscope equipped with an Olympus cross-polarized lens and a Motic camera. Images were captured using Motic Images Plus 3.0. All images were recorded using a 20x objective magnification unless otherwise specified.

[0237] Thermogravimetry / Differential Scanning Calorimetry (TGA / DSC) Approximately 5-10 mg of material was added into a pre-tared open aluminum pan and loaded into a TA Instruments Discovery SDT 650 Auto-Simultaneous DSC and held at room temperature. The sample was then heated from 30°C to 400°C at a rate of 10°C / min, during which time the change in sample weight was recorded along with the heat flow response (DSC). Nitrogen was introduced at 200 cm 3 1000 s was used as the sample purge gas at a flow rate of 100 / min.

[0238] Differential Scanning Calorimetry (DSC) Approximately 1-5 mg of material was weighed into a DSC aluminum pan and non-hermetically covered with an aluminum lid. The sample pan was then loaded into a differential scanning calorimeter, TA Instruments Discovery DSC 2500, equipped with a RC90 cooler. The sample and reference were heated to 200°C at a scan rate of 10°C / min and the resulting heat flow response was monitored. The sample was re-cooled to -80°C and then heated again to 200°C at 10°C / min. Nitrogen was introduced at 50 cm 3 1000 s was used as the sample purge gas at a flow rate of 100 / min.

[0239] Infrared Spectroscopy (IR) Infrared spectroscopy was performed on a Bruker ALPHA P spectrometer. Sufficient material was placed in the center of the spectrometer plate and spectra were acquired using the following parameters: Resolution: 4cm -1 Number of background scans: 16 scans Number of sample scans: 16 scans Data collection: 4000~400cm -1 Obtained spectrum: Transmission method Software: OPUS version 6

[0240] nuclear magnetic resonance (NMR) NMR experiments were performed on a Bruker AVIIIHD spectrometer equipped with a PRODIGY cryoprobe operating at 500.23 MHz for protons or a Bruker AVIIIHD spectrometer equipped with a DCH cryoprobe operating at 500.12 MHz for protons. Experiments were performed in deuterated dimethylsulfoxide and each sample was prepared to a concentration of approximately 10 mM.

[0241] Dynamic Vapor Sorption (DVS) Approximately 10-20 mg of sample was placed in a vapor sorption mesh balance pan and loaded into a DVS Intrinsic or Advantage Dynamic Vapor Sorption Balance by Surface Measurement Systems. The sample was subjected to a ramping profile of 40% to 90% relative humidity (RH) in 10% increments, with the sample held at 25° C. until a stable weight was achieved (dm / dt=0.004%, minimum step length=30 min, maximum step length=120 min). After completion of the sorption cycle, the sample was dried to 0% RH using the same procedure and then returned to 40% RH for a second sorption cycle. Two cycles were performed. The weight change over the course of the sorption / desorption cycle was plotted, allowing the hygroscopic nature of the sample to be determined. XRPD analysis was then performed on any solids that were retained.

Claims

1. It is a type I crystal of SCO-101 represented by the following formula, 【Chemical 1】 When measured by CuKα irradiation, in the X-ray powder diffraction (XRPD) diffractogram, at least the maximum value of the peak is at 2θ angles: 19.0 ± 0.2, 21.2 ± 0.2, and 23.4 ± 0.2, Optionally, when the type I crystal is measured by CuKα irradiation, in the X-ray powder diffraction (XRPD) diffractogram, at least the maximum value of the peak is shown at 2θ angles: 13.9 ± 0.2, 19.0 ± 0.2, 19.9 ± 0.2, and 21.2 ± 0.2, For example, when the type I crystal is measured by CuKα irradiation, in the X-ray powder diffraction (XRPD) diffractogram, at least the maximum value of the peak is shown at 2θ angles: 12.0 ± 0.2, 13.9 ± 0.2, 19.0 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 21.2 ± 0.2, 23.2 ± 0.2, 23.4 ± 0.2, 26.9 ± 0.2, and 27.4 ± 0.2 Type I crystal.

2. It is the type I crystal of the above SCO-101, (a)When measured by CuKα irradiation, it shows the X-ray powder diffraction (XRPD) diffractogram described in Figure 1A, (b)In differential scanning calorimetry (DSC), it shows a starting temperature from 218 °C to 226 °C, for example from 219 °C to 224 °C, for example 221 °C, at a heating rate of 10 °C / min, and / or (c)In differential scanning calorimetry (DSC), it shows a peak temperature from 224 °C to 234 °C, for example from 225 °C to 233 °C, for example from 226 °C to 232 °C, for example from 227 °C to 231 °C, for example from 228 °C to 230 °C, for example 229 °C, at a heating rate of 10 °C / min The type I crystal according to Claim 1.

3. It is a type III crystal of SCO-101 represented by the following formula, [[Chemical 2]] When measured by CuKα irradiation, in the X-ray powder diffraction (XRPD) diffractogram, at least the maximum value of the peak is at 2θ angles: 11.1 ± 0.2, 21.7 ± 0.2, and 23.3 ± 0.2, Optionally, when the type III crystal is measured by CuKα irradiation, in the X-ray powder diffraction (XRPD) diffractogram, at least the maximum value of the peak is shown at 2θ angles: 11.1 ± 0.2, 21.7 ± 0.2, 23.3 ± 0.2, and 26.2 ± 0.2, For example, when measured by CuKα irradiation, in the X-ray powder diffraction (XRPD) diffractogram, the type III crystal shows at least the maximum value of the peak at 2θ angles: 11.1 ± 0.2, 16.6 ± 0.2, 18.0 ± 0.2, 19.2 ± 0.2, 19.9 ± 0.2, 21.7 ± 0.2, 22.2 ± 0.2, 22.5 ± 0.2, 23.3 ± 0.2, and 26.2 ± 0.2 Type III crystal

4. The type III crystal of SCO-101, (a) When measured by CuKα irradiation, shows the X-ray powder diffraction (XRPD) diffractogram described in FIG. 1C, (b) In differential scanning calorimetry (DSC), shows a starting temperature from 220 °C to 228 °C, for example from 221 °C to 226 °C, for example from 222 °C to 224 °C, for example 223 °C, at a heating rate of 10 °C / min, and / or (c) In differential scanning calorimetry (DSC), shows a peak temperature from 225 °C to 235 °C, for example from 226 °C to 234 °C, for example from 226 °C to 234 °C, for example from 227 °C to 233 °C, for example from 228 °C to 232 °C, for example from 229 °C to 231 °C, for example 230 °C, at a heating rate of 10 °C / min The type III crystal according to claim 3

5. The type IV crystal of SCO-101 represented by the following formula, 【Chemical Formula 3】 When measured by CuKα irradiation, in the X-ray powder diffraction (XRPD) diffractogram, shows at least the maximum value of the peak at 2θ angles: 22.6 ± 0.2, 23.4 ± 0.2, and 23.7 ± 0.2, Optionally, when measured by CuKα irradiation, the type IV crystal shows at least the maximum value of the peak at 2θ angles: 21.6 ± 0.2, 22.6 ± 0.2, 23.4 ± 0.2, 23.7 ± 0.2, and 24.1 ± 0.2 in the X-ray powder diffraction (XRPD) diffractogram, For example, when measured by CuKα irradiation, the type IV crystal shows at least the maximum value of the peak at 2θ angles: 13.5 ± 0.2, 20.1 ± 0.2, 21.6 ± 0.2, 22.6 ± 0.2, 23.4 ± 0.2, 23.7 ± 0.2, 24.1 ± 0.2, 25.6 ± 0.2, 27.4 ± 0.2, and 30.2 ± 0.2 in the X-ray powder diffraction (XRPD) diffractogram Type IV crystal

6. The type IV crystal of SCO-101, (a) When measured by CuKα irradiation, shows the X-ray powder diffraction (XRPD) diffractogram described in FIG. 1D, (b) In differential scanning calorimetry (DSC), it shows a starting temperature from 222 °C to 230 °C, for example from 223 °C to 228 °C, for example from 224 °C to 226 °C, for example 225 °C, at a heating rate of 10 °C / min, and / or (c) In differential scanning calorimetry (DSC), it shows a peak temperature from 225 °C to 235 °C, for example from 226 °C to 236 °C, for example from 227 °C to 235 °C, for example from 228 °C to 234 °C, for example from 229 °C to 233 °C, for example from 230 °C to 232 °C, for example 231 °C, at a heating rate of 10 °C / min The type-IV crystal according to claim 5.

7. An amorphous form of SCO-101 represented by the following formula, [Chemical Formula 4] When measured by CuKα irradiation, it does not show a maximum peak value at a 2θ angle of 0 to 40 in the X-ray powder diffraction (XRPD) diffractogram, Amorphous form.

8. The amorphous form of the above SCO-101, (a) When measured by CuKα irradiation, it shows the X-ray powder diffraction (XRPD) diffractogram described in FIG. 1E, (b) In differential scanning calorimetry (DSC), it shows a starting temperature from 211 °C to 219 °C, for example from 212 °C to 218 °C, for example from 213 °C to 217 °C, for example from 214 °C to 216 °C, for example 215 °C, at a heating rate of 10 °C / min, and / or (c) In differential scanning calorimetry (DSC), it shows a peak temperature from 218 °C to 228 °C, for example from 219 °C to 227 °C, for example from 220 °C to 226 °C, for example from 221 °C to 225 °C, for example from 222 °C to 224 °C, for example 223 °C, at a heating rate of 10 °C / min The amorphous form according to claim 7.

9. A type-V crystal of an isopropanol solvate of SCO-101 represented by the following formula, 【Chemical Formula 5】 When measured by CuKα irradiation, it shows at least a maximum peak value at 2θ angles of 9.4 ± 0.2, 21.1 ± 0.2, and 22.2 ± 0.2 in the X-ray powder diffraction (XRPD) diffractogram, Optionally, when the type-V crystal is measured by CuKα irradiation, it shows at least a maximum peak value at 2θ angles of 8.2 ± 0.2, 9.4 ± 0.2, 21.1 ± 0.2, and 22.2 ± 0.2 in the X-ray powder diffraction (XRPD) diffractogram, For example, when measured by CuKα irradiation, the V-type crystal shows at least the maximum value of the peak at 2θ angles: 8.2 ± 0.2, 9.4 ± 0.2, 10.5 ± 0.2, 21.1 ± 0.2, 22.2 ± 0.2, 23.7 ± 0.2, 24.2 ± 0.2, 24.6 ± 0.2, 25.5 ± 0.2, and 28.5 ± 0.2 in the X-ray powder diffraction (XRPD) diffractogram. V-type crystal.

10. The V-type crystal of the isopropanol solvate of SCO-101, (a) When measured by CuKα irradiation, it shows the X-ray powder diffraction (XRPD) diffractogram described in FIG. 1F, (b) In differential scanning calorimetry (DSC), it shows a starting temperature from 216 °C to 224 °C, for example from 217 °C to 223 °C, for example from 218 °C to 222 °C, for example from 219 °C to 221 °C, for example 220 °C, at a heating rate of 10 °C / min, and / or (c) In differential scanning calorimetry (DSC), it shows a peak temperature from 225 °C to 233 °C, for example from 226 °C to 232 °C, for example from 227 °C to 231 °C, for example from 228 °C to 230 °C, for example 229 °C, at a heating rate of 10 °C / min. The V-type crystal according to claim 9.

11. The preparation process of the type I crystal of SCO-101 according to claim 1 or 2, (a) A step of dissolving the SCO-101 in one or more polar aprotic solvents, The polar aprotic solvent is selected from the group consisting of acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropyleneurea, dimethyl sulfoxide, ethyl acetate, 2-MeTHF, and tetrahydrofuran. For example, when the polar aprotic solvent is acetone, a step of dissolving at a first predetermined temperature of 0 °C to 20 °C, for example 10 ± 5 °C. (b) A step of adding one or more polar protic solvents to the one or more polar aprotic solvents to provide the type I crystal of the SCO-101, The one or more polar protic solvents are selected from the group consisting of water, methanol, ethanol, isopropanol, and acetic acid. For example, when the polar protic solvent is water, a step of adding it to the one or more polar aprotic solvents at the first predetermined temperature over 10 minutes to 360 minutes, for example 70 minutes to 90 minutes. (c) A step of isolating the type I crystal of the SCO-101 The preparation process includes.

12. The preparation process further includes a crystallization step preceding the step (a), and the crystallization step includes: (i) mixing a composition containing the SCO-101 and one or more impurities with 2-propanol to provide a mixture; (ii) heating the mixture to a temperature higher than the first predetermined temperature, or to a second predetermined temperature of 31°C to 80°C, such as 50°C; (iii) adding the mixture over a second predetermined time of 1 minute to 120 minutes, such as 30 minutes; (iv) optionally, cooling the mixture at a temperature lower than the second predetermined temperature, or at a third predetermined temperature of 10°C to 30°C, such as 20°C, thereby providing the SCO-101 in a solid state, and optionally isolating the solid by filtration; wherein the one or more impurities are selected from the group consisting of 4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)aniline, 3,5-bis(trifluoromethyl)phenyl isocyanate, and toluene; step The preparation process according to claim 11, further comprising:

13. A preparation process for preparing the type I crystal of the SCO-101 according to claim 1 or 2 from a metastable form, comprising: (a) providing the metastable form from a crystalline or amorphous form of the SCO-101; (b) mixing the type I crystal of the SCO-101 and the metastable form according to claim 1 or 2 in a mixture of (i) one or more polar aprotic solvents and (ii) one or more polar protic solvents, (i) the polar aprotic solvent is selected from the group consisting of acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropyleneurea, dimethylsulfoxide, ethyl acetate, 2-MeTHF, and tetrahydrofuran; (ii) the polar protic solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, and acetic acid, or the polar protic solvent may be one or more nonpolar solvents selected from the group consisting of heptane, hexane, pentane, cyclohexane, toluene, and diethyl ether; for example, the polar aprotic solvent is acetone and the protic solvent is water step (c) a step of stirring the solvent mixture at a temperature of 30 °C to 60 °C for at least 1 hour to provide the crystalline form of the SCO-101 represented by the following formula, wherein [Chemical Formula 6] (i) the crystalline form of the SCO-101 is when measured by CuKα irradiation, a type I crystal or a type II crystal showing at least a maximum peak value at 2θ angles: 18.8 ± 0.2, 23.2 ± 0.2, 20.5 ± 0.2 in an X-ray powder diffraction (XRPD) diffractogram, (ii) the type III crystal according to claim 3 or 4, (iii) the type IV crystal according to claim 5 or 6, (iv) the type V crystal according to claim 9 or 10, or the amorphous form according to claim 7 or 8 the step and a preparation process comprising.

14. A pharmaceutical composition comprising the type I crystal according to claim 1 or 2 and one or more pharmaceutically acceptable adjuvants, additives, carriers, buffers and / or diluents.

15. the type I crystal according to claim 1 or 2, or the pharmaceutical composition according to claim 14, which is used in combination with one or more anti-cancer agents, wherein optionally, the anti-cancer agent is selected from the group consisting of topoisomerase inhibitors, anti-hormone agents, alkylating agents, mitosis inhibitors, antimetabolites, antitumor antibiotics, corticosteroids, targeted anti-cancer agent therapies, differentiation inducers and immunotherapies.

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