Thermodynamically stable form of sco-101, composition comprising the same and preparation process and use of the same

Abstract

This invention relates to an improved crystal form of SCO-101, its preparation, and its uses. Furthermore, this invention relates to an intermediate crystal form of SCO-101 that can be converted into an improved crystal form of SCO-101.

Description

[Technical Field]

[0001] This invention relates to an improved crystal form of SCO-101, its preparation, and its uses. Furthermore, this invention relates to an intermediate crystal form of SCO-101 that can be converted into an improved crystal form of SCO-101. [Previous Technology]

[0002] Cancer is a heavy burden on our society, with approximately 18 million new cancer cases diagnosed in 2019. Despite the introduction of many new treatment modalities / options, primary or acquired resistance to the applied treatment still represents the leading cause of cancer death.

[0003] Compound SCO-101, also known as NS3728, was first described in WO 2000 / 24707. SCO-101 has since been shown to be a potent enhancer of a series of anticancer agents and is currently being developed for use in combination therapies for cancer, particularly for the treatment of resistant cancers. WO 2017 / 198700 describes SCO-101 and its use in combination therapies for the treatment of cancer.

[0004] A series of substituted diphenylureas, including SCO-101, can be prepared as described in WO 2000 / 24707 by mixing suitable starting materials soluble in toluene, thereby causing SCO-101 to precipitate upon formation. SCO-101 prepared in toluene using the conditions of WO 2000 / 24707 is crystalline. [Summary of the Invention]

[0005] The inventors have discovered that the polymorphic form of SCO-101 prepared as described in WO 2000 / 24707 is not a thermally stable form, but rather a hygroscopic metastable polymorphic form. This polymorphic form of SCO-101 prepared as described in WO 2000 / 24707 is referred to herein as crystal form II. Furthermore, SCO-101 has shown a tendency to form solvates and exhibits several polymorphs. Therefore, from a pharmaceutical development and patient safety perspective, there is a need for a more stable crystal form that is free of solvates (anhydrous). In addition, there is a need to provide a metastable form that can be converted into the desired thermally stable form (referred to herein as crystal form I). The inventors have further demonstrated that the thermally stable crystal form I is unexpectedly non-hygroscopic, making crystal form I of SCO-101 a more attractive crystal form for clinical development.

[0006] In the first state sample, crystal form I of SCO-101 is provided: (SCO-101), which, when measured using Cu Kα radiation, exhibits peak maximum values ​​at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diffraction pattern: 19.0±0.2, 21.2±0.2 and 23.4±0.2.

[0007] In the second state sample, crystal form III of SCO-101 is provided: (SCO-101), which, when measured using Cu Kα radiation, exhibits peak maximum values ​​at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diffraction pattern: 11.1±0.2, 21.7±0.2 and 23.3±0.2.

[0008] In the third state sample, crystal form IV of SCO-101 is provided: (SCO-101), which, when measured using Cu Kα radiation, exhibits peak maximum values ​​at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diffraction pattern: 22.6±0.2, 23.4±0.2 and 23.7±0.2.

[0009] In the fourth state sample, the amorphous form of SCO-101 is provided: (SCO-101), which does not show a peak maximum value at the 2θ angle between 0 and 40 when measured using Cu K α radiation.

[0010] In the fifth state sample, crystal form V of SCO-101 isopropanol solvate is provided: isopropanol (SCO-101 isopropanol solvate), which, when measured using Cu Kα radiation, exhibits peak maximum values ​​at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diffraction pattern: 9.4±0.2, 21.1±0.2 and 22.2±0.2.

[0011] In the sixth state sample, a process for preparing crystalline form I of SCO-101 as defined herein is provided, the process comprising the following sequential steps: a) dissolving SCO-101 in one or more polar aprotic solvents at a first predefined temperature; b) adding one or more polar protic solvents to the one or more polar aprotic solvents over a first predefined time period to provide crystalline form I of SCO-101; and c) separating crystalline form I of SCO-101.

[0012] In the seventh state sample, a process for preparing crystalline form III of SCO-101 as defined herein is provided, the process comprising the following sequential steps: 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 cycles between a fourth predefined temperature and a fifth predefined temperature, wherein the fourth predefined temperature is higher than the fifth predefined temperature; c) separating crystalline form III of SCO-101 as defined herein from the mixture.

[0013] In the eighth state sample, a process for preparing crystalline form IV of SCO-101 as defined herein is provided, the process comprising the following sequential steps: a) providing crystalline form III of SCO-101 as defined herein; b) storing crystalline form III of SCO-101 at 30°C to 60°C for at least 24 hours, thereby preparing crystalline form IV of SCO-101.

[0014] In the ninth state, a process is provided for preparing crystalline form I of SCO-101 as defined herein from a metastable form, comprising: a) providing a metastable form, which is a crystalline or amorphous form of SCO-101; 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 nonpolar solvents; c) stirring the solvent mixture at a sixth predefined temperature for at least 1 hour, thereby providing crystalline form I of SCO-101.

[0015] In the tenth state sample, crystal form I of SCO-101 is provided: (SCO-101), which can be obtained by means of a process for preparing crystal form I of SCO-101 as defined herein.

[0016] In the eleventh state, a pharmaceutical composition is provided, comprising crystalline form I of SCO-101 as defined herein; and one or more pharmaceutically acceptable adjuvants, excipients, carriers, buffers and / or diluents.

[0017] In the twelfth embodiment, a method of treating a patient with cancer is provided, comprising administering to the patient crystalline form I of SCO-101 as defined herein or a pharmaceutical composition as defined herein; and an anticancer agent.

Implementation Method

[0032] Definition

[0033] The terms "polymorph" or "polymorphic form" as used herein refer to the polymorphic form of SCO-101. Solids exist in amorphous or crystalline forms; the crystalline form is also referred to herein as the crystal form. In the case of a crystalline form, the crystal molecules are located in three-dimensional lattice positions. When a compound recrystallizes from a solution or slurry, it may crystallize with different spatial lattice arrangements; this is a characteristic known as "polymorphism," in which different crystalline forms are referred to as "polymorphs." Different polymorphic forms of a given substance may differ from each other in one or more physical properties, such as solubility and dissociation, true density, crystal shape, compressive behavior, flow properties, and / or solid-state stability. In the case of a chemical substance existing in two (or more) polymorphic forms, the unstable form generally transforms into a more thermally stable form after a sufficient period of time at a given temperature. When this transition is not rapid, the thermally unstable form is called the "metastable" form.

[0034] Unless otherwise stated, the unit of 2θ angle is degrees (°). When 2θ angle is used to define the characteristic of the unique XRPD peak maximum of a homomorphic material, each 2θ angle includes ±0.2° to account for error margins. Therefore, the XRPD peak maximum defined by 2θ angle 10.0 will include 9.8 and 10.2, and any number in between, represented by 10.0 ± 0.2.

[0035] The term “onset temperature” as used herein refers to the designed intersection of the extrapolated baseline and the tangent line at the start of melting in the DSC / TG experiment.

[0036] As used herein, the term "peak temperature" refers to a local highest or lowest temperature that can be determined by means of differential scanning calorimetry (DSC), a method known to those skilled in the art.

[0037] The term “seeding” as used herein refers to the technique of adding one or more “seeds” to a crystallization solution to promote crystal formation.

[0038] As used herein, the term "amorphous form" refers to the non-crystalline form of a substance as determined by X-ray powder diffraction (XRPD). The term "amorphous" encompasses solids with disordered molecular arrangement and no distinguishable crystal lattice.

[0039] The term "isomorphic form" refers to the characteristic of SCO-101 existing in different crystal forms with different crystal lattices, which provides for differences in crystalline materials in aspects such as crystal hardness, shape, and size. Different crystal forms can be identified and examined by crystallographic techniques such as XRPD and DSC / TG, or indirectly by assessing differences in physical and / or chemical properties associated with each specific allomorph. Different allomorphs have different physical properties, such as solubility, dissolution, solid-state stability, and processing characteristics in terms of powder flow and compaction during tableting.

[0040] As used herein, the term "anti-cancer agent" includes, but is not limited to, chemotherapeutic agents that have activity against sensitive tumors.

[0041] The term "polar protic solvent" refers to a polar solvent that can exchange protons with a reagent and contains polarizable protons.

[0042] The term "polar aprotic solvent" refers to a polar solvent that does not contain acidic hydrogen and does not act as a hydrogen bond donor.

[0043] The term "apolar solvent" refers to a solvent having a low dielectric constant (ε) of less than 9.5 and being immiscible with water.

[0044] The term "relative humidity" or "RH" refers to the percentage ratio of the partial pressure of water vapor to the equilibrium vapor pressure of water at a given temperature.

[0045] The term "hygroscopic" is used herein to describe compounds or homocrystalline forms that adsorb water by means of absorption, adsorption, or a combination of both processes.

[0046] The terms "Form I" and "crystal form I" are used interchangeably herein. This also applies to Forms I, II, III, IV, and V. Crystal form I of SCO-101

[0047] Form I of SCO-101 has been shown to be nonhygroscopic and is the most thermally stable allomorph of SCO-101. Furthermore, Form I has demonstrated superior properties compared to other non-solvable and solvable forms of SCO-101 (such as Form II). Form I has a higher melting point than Form II (Figure 2A vs. Figure 2B), and together with results from competitive slurry experiments (Example 7), it can be inferred that Form I is a more thermally stable allomorph of SCO-101 compared to the other identified forms. In addition, DVS analysis of Form I (Figure 3A) and Form II (Figure 3B) has shown that Form I is substantially nonhygroscopic, while Form II absorbs approximately 6% water (w / w) at 90% RH. These experimental observations support the viewpoint that, from the perspective of stability and nonhygroscopicity, crystalline form I of SCO-101 is the most attractive crystalline form for clinical development.

[0048] Therefore, in a specific example, crystal form I of SCO-101 is provided: (SCO-101), which, when measured using Cu Kα radiation, exhibits peak maximum values ​​at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diffraction pattern: 19.0±0.2, 21.2±0.2 and 23.4±0.2.

[0049] In a specific example, when using Cu Kα radiation measurement, crystal form I further exhibits one or more peak maxima at the 2θ angle of a group selected from the following in the X-ray powder diffraction (XRPD) diagram: 13.9±0.2, 19.9±0.2 and 26.9±0.2.

[0050] In one specific example, when using Cu Kα radiation measurements, crystal form I exhibits peak maximum values ​​at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 13.9±0.2, 19.0±0.2, 19.9±0.2 and 21.2±0.2.

[0051] In one specific example, when using Cu Kα radiation measurement, crystal form I exhibits peak maximum values ​​at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 13.9±0.2, 19.0±0.2, 19.9±0.2, 21.2±0.2 and 23.4±0.2.

[0052] In one specific example, when using Cu Kα radiation measurements, crystal form I exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 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.

[0053] In one specific example, when using Cu Kα radiation measurements, crystal form I exhibits peak maximum values ​​at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 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.

[0054] In one specific example, when using Cu Kα radiation measurements, crystal form I exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 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.

[0055] In one specific example, when using Cu Kα radiation measurements, crystal form I exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) pattern: 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.

[0056] In one specific example, when using Cu Kα radiation measurements, crystal form I exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) pattern: 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.

[0057] In one specific instance, when using Cu Kα radiation measurements, crystal form I exhibits a peak maximum at least at the 2θ angle according to Table I in the X-ray powder diffraction (XRPD) diagram. serial number Position [°2θ] Relative strength [%) 1 11.9585 41.71 2 13.8972 43.84 3 16.2329 15.37 4 18.9886 61.48 5 19.9395 51.88 6 20.4410 37.94 7 21.1652 60.04 8 21.6459 17.95 9 23.2446 36.41 10 23.4382 100.00 11 24.7179 16.44 12 25.1360 17.98 13 25.8837 10.20 14 26.5267 23.46 15 26.8950 43.10 16 27.4212 40.74 17 28.2188 14.94 18 31.6990 9.67 19 31.8933 8.83 20 33.3755 8.92 Table I: 2θ values ​​and intensities of the 20 strongest peaks in crystal form I, see Figure 1A.

[0058] In a specific example, when using Cu Kα radiation measurements, crystal form I exhibits the XRPD diffraction pattern shown in Figure 1A. Crystal form I: Melting point (endothermic event)

[0059] In addition to the XRPD diffraction pattern, the homomorphic materials of the present invention are also defined by their melting point. The melting point can be determined as an endothermic event observed by differential scanning calorimetry (DSC), which is independent of mass loss. The melting point is defined by the onset temperature or peak temperature of the endothermic event, or both.

[0060] In one specific example, using a heating rate of 10°C / min, crystal form I exhibits an initial temperature of 218°C to 226°C, such as 219°C to 224°C, such as 220°C to 222°C, such as 221°C, in differential scanning calorimetry (DSC).

[0061] In one specific example, using a heating rate of 10°C / min, crystal form I exhibits a peak temperature of 224°C to 234°C, such as 225°C to 233°C, such as 226°C to 232°C, such as 227°C to 231°C, such as 228°C to 230°C, and for example, 229°C, in differential scanning calorimetry (DSC). In one specific example, using a heating rate of 10°C / min, crystal form I exhibits a peak temperature of 229°C in differential scanning calorimetry (DSC). Crystal form II

[0062] The isomorphic form of SCO-101 prepared as described in WO 2000 / 24707 is form II. Form II of SCO-101: (SCO-101), characterized by exhibiting peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) pattern when measured using Cu Kα radiation: 18.8±0.2, 23.2±0.2, and 20.5±0.2.

[0063] The crystal form II of SCO-101 can be identified using the 2θ values ​​presented in Table II. serial number Position [°2θ] Relative strength [%) 1 12.0071 56.83 2 12.7014 18.74 3 16.1955 11.95 4 18.8106 100.00 5 19.5973 18.63 6 19.9321 42.47 7 20.4635 65.95 8 21.3370 13.82 9 23.1813 95.04 10 23.6239 35.30 11 23.9071 40.55 12 25.0309 34.40 13 25.6762 18.46 14 26.3107 35.20 15 27.2015 29.22 16 28.5399 21.01 17 29.2316 5.78 18 31.6454 19.55 19 32.0931 12.33 20 43.1779 10.14 Table II: 2θ values ​​and intensities of the 20 strongest peaks in crystal form II (see Figure 1B). Crystal form III

[0064] As demonstrated in Example 5, the nonsolvent crystalline form (Form III) of SCO-101 can be obtained by temperature cycling of amorphous SCO-101 in a slurry of methanol. As demonstrated in Example 7, the nonsolvent crystalline form (Form III) of SCO-101 can then be transformed into crystalline form I.

[0065] Therefore, in a specific example, crystal form III of SCO-101 is provided: (SCO-101), which, when measured using Cu Kα radiation, exhibits peak maximum values ​​at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diffraction pattern: 11.1±0.2, 21.7±0.2 and 23.3±0.2.

[0066] In one specific instance, when using Cu Kα radiation measurements, crystal form III further exhibits one or more peak maxima at the 2θ angle in the X-ray powder diffraction (XRPD) pattern selected from the group consisting of: 19.9±0.2, 22.2±0.2 and 26.2±0.2.

[0067] In one specific example, when using Cu Kα radiation measurements, crystal form III exhibits peak maximum values ​​at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 11.1±0.2, 21.7±0.2, 23.3±0.2 and 26.2±0.2.

[0068] In one specific example, when using Cu Kα radiation measurements, crystal form III exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 11.1±0.2, 19.9±0.2, 21.7±0.2, 23.3±0.2 and 26.2±0.2.

[0069] In one specific example, when using Cu Kα radiation measurements, crystal form III exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 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.

[0070] In one specific example, when using Cu Kα radiation measurements, crystal form III exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 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.

[0071] In one specific example, when using Cu Kα radiation measurements, crystal form III exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 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.

[0072] In one specific example, when using Cu Kα radiation measurements, crystal form III exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 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.

[0073] In one specific example, when using Cu Kα radiation measurements, crystal form III exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 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.

[0074] In one specific instance, when using Cu Kα radiation measurements, crystal form III exhibits a peak maximum at least at the 2θ angle according to Table III in the X-ray powder diffraction (XRPD) diagram. serial number Position [°2θ] Relative strength [%) 1 11.1443 100.00 2 14.3752 10.77 3 15.3319 6.60 4 16.5742 29.71 5 17.9566 23.36 6 18.3639 20.78 7 19.1597 23.66 8 19.9219 31.97 9 20.7827 14.58 10 21.6544 37.34 11 22.1880 30.52 12 22.4986 25.21 13 23.2611 69.37 14 24.3506 20.96 15 25.4938 20.67 16 26.2430 36.19 17 28.0436 9.18 18 28.7361 21.80 19 30.1083 15.99 20 31.0739 7.82 Table III: 2θ values ​​and intensities of the 20 strongest peaks of crystal form III, see Figure 1C.

[0075] In a specific example, when using Cu Kα radiation measurements, crystal form III exhibits the XRPD diffraction pattern shown in Figure 1C. Crystal form III: Melting point (endothermic event)

[0076] In addition to the XRPD diffraction pattern, the homomorphic materials of the present invention are also defined by their melting point. The melting point can be determined by an endothermic event observed by differential scanning calorimetry (DSC), which is independent of mass loss. The melting point is defined by the onset temperature or peak temperature of the endothermic event, or both.

[0077] In one specific example, using a heating rate of 10°C / min, crystal form III exhibits an initial 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). In one specific example, using a heating rate of 10°C / min, crystal form III exhibits an initial temperature of 223°C in differential scanning calorimetry (DSC).

[0078] In one specific example, using a heating rate of 10°C / min, crystal form III exhibits 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, such as 230°C, in differential scanning calorimetry (DSC).

[0079] In one specific example, using a heating rate of 10°C / min, crystal form III exhibited a peak temperature of 230°C in differential scanning calorimetry (DSC). Crystal form IV

[0080] As demonstrated in Example 5, the nonsolvent form (form IV) of SCO-101 can be obtained, for example, by storing form III in an open vial at 40°C / 75% relative humidity (RH) for 3 days. As demonstrated in Example 7, the nonsolvent form (form IV) of SCO-101 can then be transformed into form I.

[0081] Therefore, in a specific example, crystal form IV of SCO-101 is provided: (SCO-101), which, when measured using Cu Kα radiation, exhibits peak maximum values ​​at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diffraction pattern: 22.6±0.2, 23.4±0.2 and 23.7±0.2.

[0082] In one specific example, when using Cu Kα radiation measurements, crystal form IV exhibits peak maximum values ​​at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 21.6±0.2, 22.6±0.2, 23.4±0.2, 23.7±0.2 and 24.1±0.2.

[0083] In one specific example, when using Cu Kα radiation measurements, crystal form IV further exhibits one or more peak maxima at the 2θ angle in the X-ray powder diffraction (XRPD) pattern selected from the group consisting of: 21.6±0.2, 24.1±0.2 and 27.2±0.2.

[0084] In one specific example, when using Cu Kα radiation measurements, crystal form IV exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 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.

[0085] In one specific example, when using Cu Kα radiation measurements, crystal form IV exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 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.

[0086] In one specific example, when using Cu Kα radiation measurements, crystal form IV exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 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.

[0087] In one specific example, when using Cu Kα radiation measurements, crystal form IV exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 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.

[0088] In one specific example, when using Cu Kα radiation measurements, crystal form IV exhibits peak maximum values ​​at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 21.6±0.2, 22.6±0.2, 23.4±0.2, 23.7±0.2 and 24.1±0.2.

[0089] In one specific example, when using Cu Kα radiation measurements, crystal form IV exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) pattern: 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.

[0090] In one specific instance, when using Cu Kα radiation measurements, crystal form IV exhibits a peak maximum at least at the 2θ angle according to Table IV in the X-ray powder diffraction (XRPD) diagram. serial number Position [°2θ] Relative strength [%) 1 11.3556 23.17 2 13.5131 29.44 3 13.8704 16.16 4 20.0964 31.38 5 20.3234 13.32 6 21.1111 16.87 7 21.5645 82.82 8 21.9786 18.10 9 22.5674 88.43 10 23.4016 93.09 11 23.7047 100.00 12 24.0659 43.32 13 24.6181 27.32 14 25.6391 30.09 15 25.9604 27.41 16 27.2077 33.26 17 27.5738 17.59 18 28.9019 20.22 19 30.2397 27.65 20 30.6414 24.05 Table IV: 2θ values ​​and intensities of the 20 strongest peaks in crystal form IV, see Figure 1D.

[0091] In a specific example, when using Cu Kα radiation measurements, crystal form IV exhibits the XRPD diffraction pattern according to Figure 1D. Crystal form IV: Melting point (endothermic event)

[0092] In addition to the XRPD diffraction pattern, the homomorphic materials of the present invention are also defined by their melting point. The melting point can be determined as an endothermic event observed by differential scanning calorimetry (DSC), which is independent of mass loss. The melting point is defined by the onset temperature or peak temperature of the endothermic event, or both.

[0093] In one specific example, using a heating rate of 10°C / min, crystal form IV exhibits an initial 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). In another specific example, using a heating rate of 10°C / min, crystal form IV exhibits an initial temperature of 225°C in differential scanning calorimetry (DSC).

[0094] In one specific example, using a heating rate of 10°C / min, crystal form IV exhibits a peak temperature of 226°C to 236°C, such as 227°C to 235°C, such as 228°C to 234°C, such as 229°C to 233°C, such as 230°C to 232°C, and for example, 231°C, in differential scanning calorimetry (DSC). In one specific example, using a heating rate of 10°C / min, crystal form IV exhibits a peak temperature of 231°C in differential scanning calorimetry (DSC). Crystal form V

[0095] The crystalline isopropanol solvate of SCO-101 was identified as crystal form V. As shown in Example 7, crystal form V can be converted into crystal form I.

[0096] In one specific example, a crystal form V of SCO-101 isopropanol solvate is provided: isopropanol (SCO-101 isopropanol solvate), which, when measured using Cu Kα radiation, exhibits peak maximum values ​​at at least the following 2θ angles in an X-ray powder diffraction (XRPD) pattern: 9.4±0.2, 21.1±0.2, and 22.2±0.2.

[0097] In a specific example, when using Cu Kα radiation measurement, crystal form V further exhibits one or more peak maxima at the 2θ angle in the X-ray powder diffraction (XRPD) pattern selected from the group consisting of: 8.2±0.2, 10.5±0.2 and 24.2±0.2.

[0098] In one specific instance, when using Cu Kα radiation measurements, crystal form V exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 8.2±0.2, 9.4±0.2, 21.1±0.2 and 22.2±0.2.

[0099] In one specific instance, when using Cu Kα radiation measurements, crystal form V exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 8.2±0.2, 9.4±0.2, 10.5±0.2, 21.1±0.2 and 22.2±0.2.

[0100] In one specific example, when using Cu Kα radiation measurements, crystal form V exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 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.

[0101] In one specific example, when using Cu Kα radiation measurements, crystal form V exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 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.

[0102] In one specific example, when using Cu Kα radiation measurements, crystal form V exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 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.

[0103] In one specific example, when using Cu Kα radiation measurements, crystal form V exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 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.

[0104] In one specific example, when using Cu Kα radiation measurements, crystal form V exhibits peak maxima at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 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.

[0105] In one specific instance, when using Cu Kα radiation measurements, crystal form V exhibits a peak maximum at least at the 2θ angle according to Table V in the X-ray powder diffraction (XRPD) diagram. serial number Position [°2θ] Relative strength [%) 1 8.2129 52.37 2 9.4091 79.34 3 10.5323 38.59 4 16.4408 18.93 5 17.8586 19.69 6 19.4907 11.32 7 20.0585 11.76 8 20.2728 12.23 9 20.7038 16.41 10 21.1492 100.00 11 22.1772 90.59 12 23.6773 20.13 13 24.1579 30.45 14 24.6082 20.73 15 24.8297 13.37 16 25.4742 18.83 17 25.5306 22.01 18 26.8722 13.93 19 28.5280 24.11 20 31.6350 14.51 Table V: 2θ values ​​and intensities of the 20 strongest peaks of crystal form V, see Figure 1F.

[0106] In a specific example, when using Cu Kα radiation measurements, crystal form V exhibits the XRPD diffraction pattern shown in Figure 1F. Crystal form V: melting point (endothermic event)

[0107] In addition to the XRPD diffraction pattern, the homomorphic materials of the present invention are also defined by their melting point. The melting point can be determined by the endothermic event observed by differential scanning calorimetry (DSC), which is independent of mass loss. The melting point is defined by the onset temperature or peak temperature of the endothermic event, or both.

[0108] In one specific example, using a heating rate of 10°C / min, crystalline V exhibits an initial 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). In one specific example, using a heating rate of 10°C / min, crystalline V exhibits an initial temperature of 220°C in differential scanning calorimetry (DSC).

[0109] In one specific example, using a heating rate of 10°C / min, crystalline V exhibits peak temperatures of 224°C to 234°C, such as 225°C to 233°C, such as 226°C to 232°C, such as 227°C to 231°C, such as 228°C to 230°C, and for example, 229°C, in differential scanning calorimetry (DSC). In one specific example, using a heating rate of 10°C / min, crystalline V exhibits a peak temperature of 229°C in differential scanning calorimetry (DSC). Amorphous SCO-101

[0110] Amorphous SCO-101 can be prepared as shown in Example 2.

[0111] In a specific example, an amorphous form of SCO-101 is provided: (SCO-101), which, when measured using Cu Kα radiation, does not exhibit a peak maximum at an angle of 2θ between 0 and 40 in the X-ray powder diffraction (XRPD) pattern.

[0112] Although the XRPD diffraction pattern of amorphous materials, such as SCO-101, is not strictly horizontal, those skilled in the art should know that the convex baseline in Figure 1E does not represent the peak maximum value.

[0113] In a specific instance, when using Cu Kα radiation measurements, the amorphous form exhibits XRPD diffraction patterns as shown in Figure 1E.

[0114] In one specific example, using a heating rate of 10°C / min, the amorphous form exhibits an initial temperature 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, in differential scanning calorimetry (DSC). In one specific example, using a heating rate of 10°C / min, the amorphous form exhibits an initial temperature of 215°C in differential scanning calorimetry (DSC).

[0115] In one specific example, using a heating rate of 10°C / min, the amorphous material exhibits peak temperatures 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, such as 223°C, in differential scanning calorimetry (DSC).

[0116] In one specific example, using a heating rate of 10°C / min, the amorphous form exhibited a peak temperature of 223°C in differential scanning calorimetry (DSC). This relates to the metastable form of SCO-101.

[0117] In one specific example, a metastable form of SCO-101 is provided: (SCO-101), which is converted into crystal form I under storage or by means of a process as defined herein for preparing crystal form I; wherein the metastable form is not crystal form II of SCO-101 that exhibits peak maximum values ​​at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diffraction pattern when measured using Cu K α radiation: 18.8±0.2, 23.2±0.2 and 20.5±0.2.

[0118] In one specific instance, "storage" means storage at room temperature, such as 20°C-25°C. In one specific instance, "storage" means storage at 35°C to 50°C. In one specific instance, "storage" means storage at 2°C to 8°C.

[0119] In one specific instance, "storage" refers to storage for one month after the manufacture of the metastable form. In one specific instance, "storage" refers to storage for one month or longer after the manufacture of the metastable form, such as two months or longer, such as three months or longer, such as four months or longer, such as five months or longer, such as six months or longer. Preparation of Crystal Form I Crystal Form I: Preparation

[0120] SCO-101 can be prepared using the method described in Example 1. The SCO-101 product obtained using the method of Example 1 is crystal form II, which can be converted to crystal form I, for example, using the method described in Example 4 or the method described in Example 7. In one specific example, the SCO-101 used to prepare crystal form I is dried as needed before step a), and is dried in a vacuum as needed.

[0121] In one specific example, a process is provided for preparing crystal form I of SCO-101 as defined herein, the process comprising the following sequential steps: a) dissolving SCO-101 in one or more polar aprotic solvents at a first predefined temperature; b) adding one or more polar protic solvents to the one or more polar aprotic solvents over a first predefined period to provide crystal form I of SCO-101; and c) separating crystal form I of SCO-101.

[0122] In one specific example, a process is provided for preparing crystal form I of SCO-101 as defined herein, the process comprising the following sequential steps: a) dissolving SCO-101 in one or more polar protic solvents at a first predefined temperature; b) adding one or more polar aprotic solvents to the one or more polar protic solvents over a first predefined period to provide crystal form I of SCO-101; and c) separating crystal form I of SCO-101.

[0123] In one specific example, a process is provided for preparing crystal form I of SCO-101 as defined herein, the process comprising the following sequential steps: a) dissolving SCO-101 in one or more polar aprotic solvents at a first predefined temperature; b) adding one or more nonpolar solvents to the one or more polar aprotic solvents over a first predefined period to provide crystal form I of SCO-101; and c) separating crystal form I of SCO-101.

[0124] In one specific example, the process further includes a prior crystallization step prior to step a), wherein the prior crystallization step comprises: i) mixing a composition containing SCO-101 and one or more impurities with 2-propanol to provide a mixture; ii) heating the mixture to a second predefined temperature above the first predefined temperature, or heating at a second predefined temperature above the first predefined temperature; iii) adding water to the mixture over a second predefined period; iv) cooling the mixture to a third predefined temperature below the second predefined temperature to provide SCO-101 in solid form, further separating the solid by filtration if necessary. Solvent

[0125] In one specific example, one or more polar aprotic solvents are selected from the group consisting of: acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropyleneurea, dimethyl sulfoxide, ethyl acetate, 2-MeTHF, and tetrahydrofuran. In one specific example, the polar aprotic solvent is acetone.

[0126] In one specific instance, one or more polar protic solvents are selected from the group consisting of: water, methanol, ethanol, isopropanol, and acetic acid. In one specific instance, the polar protic solvent is water.

[0127] In one specific instance, one or more nonpolar solvents are selected from the group consisting of: pentane, heptane, cyclohexane, and methylcyclohexane. Temperature

[0128] In a specific instance, the first predefined temperature is 0°C to 20°C, such as 10 ± 5°C.

[0129] In one specific instance, the second predefined 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.

[0130] In a specific instance, the third predefined 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. Time

[0131] In a specific instance, the first predefined time period is 10 to 360 minutes, such as 70 to 90 minutes.

[0132] In one specific instance, the second predefined time period is 1 to 120 minutes, such as 1 to 10 minutes, such as 10 to 20 minutes, such as 20 to 30 minutes, such as 30 to 40 minutes, such as 40 to 50 minutes, such as 50 to 60 minutes, such as 60 to 70 minutes, such as 70 to 80 minutes, such as 80 to 90 minutes, such as 90 to 100 minutes, such as 100 to 110 minutes, such as 110 to 120 minutes. In one specific instance, the second predefined time period is 30 minutes. Impurities

[0133] In one specific example, 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. One or more, or all, of these impurities can be effectively removed by the processes disclosed herein, for example as demonstrated in Example 4. Seed propagation

[0134] In one specific example, the process disclosed herein includes adding one or more seed crystals of SCO-101 crystal form I. One or more seed crystals may be added before, during or after any step of the process disclosed herein for preparing SCO-101 crystal form I. In one specific example, one or more seed crystals are added before step a) of the process disclosed herein.

[0135] In one specific example, a process without adding seed crystals is provided. Crystal form I is prepared from a metastable form.

[0136] The slurry experiment in Example 7 showed that the crystalline nonsolvent-based polycrystalline form I of SCO-101 is a thermally stable allomorphous material. Furthermore, these methods / processes can be used to transform metastable forms into crystalline form I.

[0137] In one specific example, a process is provided for preparing crystalline form I of SCO-101 as defined herein from a metastable form, comprising: a) providing a metastable form, which is a crystalline or amorphous form of SCO-101; 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 nonpolar solvents; c) stirring the solvent mixture at a sixth predefined temperature for at least 1 hour to provide crystalline form I of SCO-101.

[0138] In one specific example, the solvent mixture in step c) is stirred for 6 hours or longer, such as 12 hours or longer, such as 1 day or longer, such as 2 days or longer, such as 3 days or longer, such as 4 days or longer, such as 5 days or longer, such as 6 days or longer, such as 7 days or longer.

[0139] In one specific example, the SCO-101 crystal form I obtained in step c) is separated from the solvent mixture, which may be done by filtration if necessary. Metastable form

[0140] In a specific instance, the metastable form of SCO-101 is selected from the group consisting of: i) SCO-101 crystal form II: (SCO-101) exhibiting peak maxima at at least the following 2θ angles in an X-ray powder diffraction (XRPD) pattern when measured using Cu Kα radiation: 18.8 ± 0.2, 23.2 ± 0.2, and 20.5 ± 0.2; ii) SCO-101 crystal form III as defined herein; iii) SCO-101 crystal form IV as defined herein; and iv) SCO-101 crystal form V as defined herein. Temperature

[0141] In a specific instance, the sixth predefined temperature is 30°C to 60°C, such as 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.

[0142] In a specific instance, the sixth predefined 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, such as 40°C.

[0143] In one specific example, the solvent mixture in step c) is stirred for 6 hours or longer, such as 12 hours or longer, such as 1 day or longer, such as 2 days or longer, such as 3 days or longer, such as 4 days or longer, such as 5 days or longer, such as 6 days or longer, such as 7 days or longer. Solvent

[0144] In one specific instance, one or more polar aprotic solvents are selected from the group consisting of: acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropylurea, dimethyl methacrylate, ethyl acetate, 2-MeTHF and tetrahydrofuran.

[0145] In one specific instance, one or more polar protic solvents are selected from the group consisting of water, methanol, ethanol, isopropanol and acetic acid.

[0146] In one specific instance, one or more nonpolar solvents are selected from the group consisting of heptane, hexane, pentane, cyclohexane, toluene, and diethyl ether.

[0147] In one specific example, the polar aprotic solvent is acetone and the polar protic solvent is water. In another specific example, the polar aprotic solvent is acetone and the nonpolar solvent is heptane.

[0148] In one specific example, crystal form I of SCO-101 is provided: (SCO-101), which can be obtained by means of a process for preparing crystal form I of SCO-101 as defined herein. Crystal form III: Preparation

[0149] In one specific example, a process is provided for preparing crystalline form III of SCO-101 as defined herein, the process comprising the following sequential steps: 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 cycles between a fourth predefined temperature and a fifth predefined temperature, wherein the fourth predefined temperature is higher than the fifth predefined temperature; c) separating crystalline form III of SCO-101 as defined herein from the mixture.

[0150] In a specific instance, SCO-101 in step a) is an amorphous form of SCO-101 as defined herein. Temperature cycling

[0151] In a specific instance, 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. Temperature

[0152] In a specific instance, the fourth predefined 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.

[0153] In one specific instance, the fifth predefined temperature is 15°C to 30°C, such as 15°C to 20°C, such as 20°C to 25°C, such as 25°C to 30°C. Drying

[0154] In one specific example, SCO-101 is dried before step c), and dried in a vacuum if necessary. In another specific example, SCO-101 is dried after step c), and dried in a vacuum if necessary.

[0155] In one specific example, prior to step c), SCO-101 is dried in a vacuum at 30°C to 60°C for at least 6 hours, if necessary. In one specific example, after step c), SCO-101 is dried in a vacuum at 30°C to 60°C for at least 6 hours, if necessary.

[0156] In one specific example, prior to step c), SCO-101 is dried in a vacuum at 30°C to 60°C for 6 to 72 hours, if necessary. In one specific example, after step c), SCO-101 is dried in a vacuum at 30°C to 60°C for 6 to 72 hours, if necessary. Crystal Form IV: Preparation

[0157] In one specific example, a process is provided for preparing crystalline form IV of SCO-101 as defined herein, the process comprising the following sequential steps: a) providing crystalline form III of SCO-101 as defined herein; b) storing crystalline form III of SCO-101 at 30°C to 60°C for at least 24 hours, thereby preparing crystalline form IV of SCO-101.

[0158] In one specific instance, SCO-101 in crystal form III is stored for 1 day or longer, such as 2 days or longer, such as 3 days or longer, such as 4 days or longer, such as 5 days or longer, such as 6 days or longer, such as 7 days or longer. Crystal form V: Preparation

[0159] Crystal form V can be provided as an intermediate crystal form of crystal form I. Specifically, the first part of the method described in Example 4 can be used to provide crystal form V before solvent synthesis of SCO-101 in acetone. Crystal form V can be further converted into the modified form crystal form I using the methods described herein and especially illustrated in Example 4. As illustrated in Example 7, crystal form V can also be converted into crystal form I.

[0160] In one specific example, a process is provided for preparing crystalline form V of SCO-101 as defined herein, the process comprising the following sequential steps: a) mixing a composition containing SCO-101 with isopropanol to provide a mixture; b) heating the mixture to a seventh predefined temperature or heating at a seventh predefined temperature; c) adding water to the mixture over a third predefined time period; d) adjusting the temperature of the mixture to an eighth predefined temperature over a fourth predefined time period to provide a solid composition; e) separating the solid composition and, if necessary, drying the solid composition to provide crystalline form V of SCO-101. Temperature

[0161] In a specific instance, the seventh predefined temperature is 30°C to 82°C, such as 31°C to 80°C, such as 32°C to 78°C, such as 33°C to 76°C, such as 34°C to 74°C, such as 35°C to 72°C, such as 36°C to 70°C, such as 38°C to 68°C, such as 39°C to 66°C, such as 40°C to 64°C, such as 41°C to 62°C, such as 42°C to 60°C, such as 43°C to 58°C, such as 44°C to 56°C, such as 45°C to 55°C, such as 46°C to 54°C, such as 47°C to 52°C, such as 48°C to 52°C, such as 49°C to 51°C, for example, 50°C.

[0162] In a specific instance, the eighth predefined 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. Time

[0163] In a specific instance, the third predefined time period is within 1 hour, such as within 50 minutes, such as within 40 minutes, such as within 30 minutes.

[0164] In a specific instance, the third predefined time period is from 1 minute to 60 minutes, such as 5 minutes to 55 minutes, such as 10 minutes to 50 minutes, such as 15 minutes to 45 minutes, such as 20 minutes to 40 minutes, such as 25 minutes to 35 minutes, such as 30 minutes.

[0165] In a specific instance, the fourth predefined time period is 1 minute or longer, such as 10 minutes or longer, such as 20 minutes or longer, such as 30 minutes or longer, such as 40 minutes or longer, such as 50 minutes or longer, such as 60 minutes or longer.

[0166] In a specific instance, the fourth predefined time period is from 1 minute to 12 hours, such as 5 minutes to 10 hours, such as 10 minutes to 8 hours, such as 20 minutes to 6 hours, such as 20 minutes to 4 hours, such as 30 minutes to 2 hours, for example, 1 hour. Amorphous SCO-101: Preparation

[0167] In one specific example, a process is provided for preparing an amorphous form of SCO-101 as defined herein, the process comprising the following sequential steps: a) mixing a composition containing SCO-101 with one or more polar aprotic solvents to obtain a clear solution having no visible solid material, indicating that the composition is completely dissolved; b) evaporating the one or more polar aprotic solvents in a vacuum at a ninth predefined temperature, if necessary, to provide a solid composition; c) further drying the solid composition, if necessary, to provide the amorphous form of SCO-101. Solvent

[0168] In one specific example, one or more polar aprotic solvents are selected from the group consisting of: acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropylurea, dimethylsulfoxide, ethyl acetate, 2-MeTHF, and tetrahydrofuran. In one specific example, the polar aprotic solvent is acetone. Temperature

[0169] In a specific instance, the ninth predefined temperature is at the boiling point of one or more polar aprotic solvents.

[0170] In one specific instance, the ninth predefined temperature is between 30°C and 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. Pharmaceutical composition

[0171] A specific example provides a pharmaceutical composition as disclosed herein, wherein the pharmaceutical composition is formulated for oral administration. Such compositions may be in the form of tablets or capsules.

[0172] In one specific example, a pharmaceutical composition is provided which comprises any of the crystalline or amorphous forms of SCO-101 as defined herein; and one or more pharmaceutically acceptable adjuvants, excipients, carriers, buffers and / or diluents.

[0173] In one specific example, a pharmaceutical composition is provided comprising any of the crystalline or amorphous forms of SCO-101 as defined herein, wherein the crystalline form is not crystalline form II of SCO-101; and one or more pharmaceutically acceptable adjuvants, excipients, carriers, buffers and / or diluents.

[0174] In one specific example, a pharmaceutical composition is provided comprising any one of the crystalline I, III, IV, V or amorphous forms of SCO-101 as defined herein; and one or more pharmaceutically acceptable adjuvants, excipients, carriers, buffers and / or diluents.

[0175] In one specific example, a pharmaceutical composition is provided comprising crystalline form I of SCO-101 as defined herein; and one or more pharmaceutically acceptable adjuvants, excipients, carriers, buffers, and / or diluents. Crystalline form I in cancer treatment.

[0176] In one specific example, a method for treating a patient with cancer is provided, comprising administering to the patient a pharmaceutical composition as defined herein; and one or more anticancer agents. The therapeutic effect can be achieved by administering a combination of any crystalline or amorphous pharmaceutical composition comprising SCO-101 with one or more anticancer agents disclosed herein.

[0177] In one specific example, a method for treating a patient with cancer is provided, 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 anticancer agents.

[0178] In one specific instance, a patient is given daily crystalline form I of SCO-101 as defined herein or a pharmaceutical composition as defined herein.

[0179] In one specific example, the present invention provides crystalline form I of SCO-101 as defined herein for the treatment of cancer, wherein crystalline form I of SCO-101 is administered in combination with one or more anticancer agents.

[0180] In one specific example, the present invention provides the use of SCO-101 crystal form I as defined herein for the preparation of a medicament for treating cancer, wherein SCO-101 crystal form I is administered in combination with one or more anticancer agents.

[0181] One or more anticancer agents may be administered simultaneously, sequentially or separately from SCO-101.

[0182] In one specific instance, one or more anticancer agents are selected from the group consisting of: topoisomerase inhibitors, antihormonal agents, alkylating agents, mitotic inhibitors, antimetabolites, antitumor antibiotics, corticosteroids, targeted anticancer therapies, differentiation agents, and immunotherapies. Topoisomerase inhibitors

[0183] In one specific instance, the anticancer agent is a topoisomerase I inhibitor or a topoisomerase II inhibitor.

[0184] In one specific example, the anticancer agent is a topoisomerase I inhibitor selected from the group consisting of irinotecan, its active metabolite SN-38, and toponotecan. Antihormonal agents

[0185] In one specific instance, the anticancer agent is an antihormonal agent, which is: a. an antiestrogen selected from the group consisting of fulvestrant, tamoxifen, toremifene, and clomifene, or b. an antiprogestin selected from the group consisting of mifepristone, ulipristal acetate, aglepristone, lilopristone, and onapristone.

[0186] In one specific instance, the anti-estrogen is fulvestrant or tamoxifen.

[0187] In one specific instance, the anti-progestin is onasone. Alkylating agent

[0188] In one specific instance, the anticancer agent is an alkylating agent, which 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. Choose three from the group consisting of: dacarbazine (DTIC) and temozolomide, or e. Choose three from the group consisting of: thiotepa and hexamethylenetetramine (hexamethylene melamine).

[0189] In one specific example, the alkylating agent is temozolomide. Antimetabolite

[0190] In one specific instance, the anticancer agent is an antimetabolite selected from the group consisting of: 5-fluorouracil, 6-mercaptopurine, capecitabine, cytarabine, fluorouridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, and pemetrexed.

[0191] In one specific instance, the antimetabolite is 5-fluorouracil or gemcitabine. Mitosis inhibitors

[0192] In one specific instance, the anticancer agent is a mitotic inhibitor, which is: a. taxanes selected from the group consisting of paclitaxel and docetaxel; b. ixabepilone; c. vinca alkaloids selected from the group consisting of vinblastine, vincristine and vinorelbine; or d. estramustine.

[0193] In one specific instance, the mitotic inhibitor is paclitaxel or docetaxel. Other anticancer agents

[0194] In one specific instance, the anticancer agent is administered in combination with one or more other anticancer agents.

[0195] In one specific instance, the anticancer agent was administered in combination with another anticancer agent, namely 5-fluorouracil. In one specific instance, the anticancer agent was administered in combination with 5-fluorouracil and folate. In one specific instance, the anticancer agent was irinotecan and administered in combination with 5-fluorouracil and folate. Immunotherapy

[0196] In one specific instance, the anticancer agent is an immunotherapy agent. Immunotherapy drugs are given to people with cancer to help their immune system recognize and attack cancer cells.

[0197] Different types of immunotherapy exist. Active immunotherapy stimulates the body's own immune system to fight disease. Passive immunotherapy does not rely on the body to attack disease; it consists of immune system components (such as antibodies) produced outside the body and administered to fight cancer.

[0198] Examples of active immunotherapy include: • Monoclonal antibody therapies, such as rituximab (Rituxan®) and alemtuzumab (Campath®) • Non-specific immunotherapies and adjuvants (other substances or cells that enhance the immune response), such as BCG, interleukin-2 (IL-2), and interferon-α • Immunomodulatory drugs, such as thalidomide and lenalidomide (Revlimid®)

[0199] In one specific instance, the anticancer agent is a PD-1 or PD-L1 inhibitor, such as an antibody that can inhibit PD-1 or PD-L1.

[0200] Cancer vaccines are a type of active, specific immunotherapy. Cancer

[0201] In a specific instance, the cancer is a solid tumor or leukemia.

[0202] In a specific instance, cancer is a solid tumor, such as a solid tumor selected from sarcoma, carcinoma and lymphoma.

[0203] In a specific instance, cancers are 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 carcinoma, squamous cell carcinoma, liver cancer, pancreatic cancer, prostate cancer, anal cancer, cervical cancer, bladder cancer, endometrial cancer, ovarian cancer, gallbladder cancer, sarcoma, leukemia (myeloid and lymphoid), lymphoma, myeloma, and bile duct cancer.

[0204] In one specific instance, the cancer is metastatic cancer. In one specific instance, the cancer is colorectal cancer, such as metastatic colorectal cancer. In one specific instance, the cancer is pancreatic cancer, such as metastatic pancreatic cancer. In one specific instance, the cancer is breast cancer, such as metastatic breast cancer.

[0205] In a specific instance, the leukemia is acute myeloid leukemia (AML).

[0206] In one specific instance, the cancer is a resistant cancer that is resistant to the anticancer agent administered alone. In one specific instance, the resistance is primary resistance or acquired resistance. Example Example 1: Preparation of SCO-101 crude material (Form II)

[0207] The following materials were used: 4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)aniline was manufactured internally, and 3,5-bis(trifluoromethyl)-phenyl isocyanate was purchased from DONA FINE CHEMICALS SJ. Method

[0208] 3,5-bis(trifluoromethyl)-phenyl isocyanate (3.5 kg) was added to a stirred solution of 3.2 kg of 4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)aniline in toluene (62 L). The tube used for adding 3,5-bis(trifluoromethyl)-phenyl isocyanate was washed with toluene (3.8 L) 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 the starting material, and the reaction mixture was cooled to 23°C after 2.5 hours. The resulting suspension was filtered, the filter cake was washed with toluene (17 L), and dried at 45°C for 16 hours to provide the solids composition. Results

[0209] 6.5 kg of SCO-101 was obtained in crystalline form, analyzed by XRPD (Fig. 1B), DVS (Fig. 3B), and DSC-TGA (Fig. 2B). The obtained crystal form is metastable, form II. Conclusion

[0210] SCO-101 can be prepared in metastable form, form II, using the method described in this embodiment. Form II is not the most stable crystalline form of SCO-101 and absorbs water to form hydrates at increased relative humidity (RH), such as at 70% RH and above. From a clinical development point of view, this makes form II of SCO-101 inferior to the thermally stable form, form I. Example 2: Preparation of amorphous SCO-101 material

[0211] The following materials were used. SCO-101 Form I was manufactured on a 3 L scale using the process described in Example 4. A batch of 268 g was obtained. Method

[0212] Dissolve 3 g of SCO-101 Form I in 30 mL of acetone using sonication to aid dissolution. Filter the clarified solution into a 50 mL round-bottom flask using a syringe, and remove the solvent by rotary evaporation in a 40°C water bath. Allow the solution to stand on the rotary evaporator for one hour to ensure complete drying. Obtain the solid. Decant the solid into a crystallizing dish, cover with thin paper, and dry in a vacuum oven at 40°C overnight (approximately 17 hours). XRPD analysis of the dried solid confirmed successful amorphization (see Figure 1E). Results

[0213] Amorphous SCO-101 can be prepared using this example. Example 3: Screening method A for homomorphic SCO-101: Solubility test and evaporation

[0214] Add an aliquot of the listed solvent to approximately 10 mg of amorphous SCO-101 until dissolution is observed, thus obtaining a clear solution (continue in method A2), or 1 mL has been added to form a slurry (continue in method A1). Stir the sample manually and heat it to approximately 40°C between aliquots in a block connected to a water batch.

[0215] Method A1: Store the slurry at room temperature overnight and then centrifuge and filter it.

[0216] Method A2: The clear solution is left uncovered and allowed to evaporate at room temperature.

[0217] Analysis of any solids obtained from slurry (Method A1) or evaporation (Method A2) by XRPD. Method B: Solvent drop milling

[0218] Add 10 µl of an appropriate saturated solution (if available) or solvent along with 2 steel grinding balls to 20 mg of amorphous SCO-101 in a 2 mL ball mill vial.

[0219] Ball mill the vial using the following procedure: ● Speed: 6000 rpm ● Cycle: 40 x 90 s ● Pause: 10 s Method C: Temperature Cycling

[0220] Amorphous SCO-101 slurry was prepared in vials. All vials were capped, sealed with sealing film, and cyclically incubated in a shaker between room temperature and 40°C for 4 hours with stirring. After 3 days, all slurry and wet solids were centrifuged and filtered, and analyzed by XRPD. Results

[0221] Starting from amorphous SCO-101, depending on the solvent and crystallization technique used, the following crystal forms are obtained, see Table 1. entry form model solvent technology describe 1 I 1 Isopropyl acetate Method A2 Anhydrous nonsolvents 2 2 1,4-Diane Method A1 Single solvate 3 3 1-Propanol Method A1 Single solvate 4 V 5 2-Propanol Method A1 Single solvate 5 10 MEK Method A1 Single solvate 6 13 1-Butanol Method A1 Single solvate 7 14 DMSO Method A1 Single solvate 8 16 DMA Method A1 solvates 9 17 DMF Method A1 solvates 10 twenty two ethanol Method C solvates 11 twenty three acetone Method C Single solvate 12 III twenty four methanol Method C Anhydrous nonsolvents 13 IV 29 DCM Method B Anhydrous nonsolvents 14 36 NMP Method A2 solvates Table 1: Overview of different solvent systems and crystallization techniques, and the resulting crystal forms of SCO-101. Conclusion

[0222] The anhydrous nonsolvent crystal forms of SCO-101 can be prepared using the conditions of items 1, 13 and 14 in Table 1 to provide forms I, III and IV, respectively.

[0223] Furthermore, this embodiment demonstrates the ability to form a wide range of solvates, thereby producing different crystal forms (modes) of SCO-101. The desired crystal form can be obtained by selecting the conditions described in Table 1. Example 4: Preparation of Crystal Form I Material

[0224] The crude SCO-101 material was manufactured using the method described in Example 1. Method

[0225] Crude SCO-101 (50 g, 1.0 equivalent, 101 mmol) was dissolved in 2-propanol (257 g) in a 1 L reactor. The reaction mixture was heated at 50 °C until a clear solution was obtained. Water (326 g) was added fractionally to the solution over a 30-minute period. After cooling the resulting slurry to 20 °C over a 1-hour period, the crude SCO-101 was separated 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. Water (195 g) was then added to the solution over a period of 70 to 90 minutes. Crystallized SCO-101 was separated 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 reduced pressure. Results

[0226] The SCO-101 Form I prepared by the above method has been analyzed by XRPD (Figure 1A), TG / DSC (Figure 2A), and DVS (Figure 3A), and has undergone the competitive slurry experiment further described in Example 7. Conclusion

[0227] SCO-101 Form I has been shown to be non-hygroscopic and is the most thermally stable allomorph of SCO-101. Furthermore, Form I has exhibited superior properties compared to other non-solvable and solvable forms of SCO-101. Form I has the highest melting point, and together with results from competing slurry experiments, it can be inferred that Form I is the most thermally stable allomorph of SCO-101. In addition, DVS analysis of Form I and Form II has shown that Form I is substantially non-hygroscopic, while Form II absorbs approximately 6% (w / w) at 90% RH. Example 5: Preparation of Crystal Form III (Model 24) Material

[0228] Amorphous SCO-101 was prepared as described in Example 2. Method

[0229] A slurry of amorphous SCO-101 in methanol was prepared in a scintillation bottle. The bottle was capped, sealed with sealing film, and cyclically heated between room temperature and 40°C in an incubator shaker for 4 hours.

[0230] After 24 hours, wet sample display pattern 38 was formed. The solid was recovered by centrifugation and dried at 40°C for 24 hours. Results

[0231] XRPD analysis of the solid confirmed the formation of pattern 24 (Fig. 1C). TG / DSC analysis (Fig. 2C) confirmed the formation of the nonsolvent crystal form of SCO-101. DSC analysis showed an exothermic event initiating at 162°C. VT-XRPD confirmed that the exothermic event was caused by the transformation to pattern 29 (form IV). Conclusion

[0232] The solvate crystalline form of SCO-101 (Form III, Mode 24) can be obtained by temperature cycling of amorphous SCO-101 in a slurry of methanol. Example 6: Preparation of Crystalline Form IV (Mode 29) Material

[0233] Form III SCO-101 was prepared as described in Example 5. Method

[0234] 200 mg SCO-101, Form III (Mode 24) was placed in an open vial covered with tissue paper at 40°C / 75% RH for 3 days. Results

[0235] Three days later, XRPD analysis of the solid confirmed the formation of mode 29 (form IV) (Figure 1D). TG / DSC analysis (Figure 2D) confirmed the formation of the solvate crystalline form of SCO-101. Conclusion

[0236] The solvate-free crystalline form of SCO-101 (Form IV, Mode 29) can be obtained by storing Form III in an open vial for 3 days at 40°C / 75% relative humidity (RH). Example 7: Transformation of the metastable crystalline form into a thermostable form, Form I material

[0237] The following materials have been used in competitive slurry experiments to provide thermally stable homomorphic products of SCO-101: Non-solvents: Form I (Example 1), Form II (Example 1), Form III (Example 5), and Form IV (Example 6). Solvents: Mode 5, Mode 22, and Mode 23 (Example 3). Method

[0238] 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 at 40°C for 15 minutes, followed by filtration of the slurry into a preheated vial using a preheated syringe. For each experiment, the relevant form / pattern of SCO-101 listed in Table 2 was added to the specified volume of saturated solution to form a slurry. The slurry was stirred at 40°C for 3 days. After 3 days, the solids were centrifuged, filtered, and analyzed by XRPD. Results

[0239] The results of the competitive slurry experiment are listed in Table 2: serial number enter Solvent system Form / pattern after 3 days of pulping 1 Form I (20 mg) Form II (20 mg) Acetone:water (1.5 mL) Form I 2 Acetone: Heptane (1.5 mL) Form I 3 Form I (10 mg) Mode 5 (10 mg) Acetone:water (0.5 mL) Form I 4 Acetone: Heptane (0.5 mL) Form I 5 Form I (10 mg) Mode 22 (10 mg) Acetone:water (0.5 mL) Form I 6 Acetone: Heptane (0.5 mL) Form I 7 Form I (10 mg) Mode 23 (10 mg) Acetone:water (0.5 mL) Form I 8 Acetone: Heptane (0.5 mL) Form I 9 Form I (10 mg) Form III (10 mg) Acetone:water (0.5 mL) Form I 10 Acetone: Heptane (0.5 mL) Form I 11 Form I (10 mg) Form IV (10 mg) Acetone:water (0.5 mL) Form I 12 Acetone: Heptane (0.5 mL) Form I Table 2. Overview of the results of the competitive paste experiments. All forms / modes described in Table 2 can be successfully converted to Form I. Mode 5 is also described as Form V in this paper. Conclusion

[0240] Slurry experiments showed that SCO-101's crystalline non-solvent composite form I is a thermally stable homocrystalline material. All experiments in the solvent testing system induced the formation of form I. Example 8: Analytical Method X-ray Powder Diffraction (XRPD)

[0241] XRPD analysis was performed on a PANalytical X'pert pro with a PIXcel detector (128 channels), scanning the sample between 3 and 50° 2θ. The material was gently ground to release any agglomerates and loaded onto a porous disk supported by a Mylar polymer film. The porous disk was then placed in a diffractometer and analyzed using Cu K radiation (α1λ=1.54060 Å; α2=1.54443 Å; β=1.39225 Å; α1:α2 ratio=0.5) operating in transmission mode (step size 0.0130° 2θ, step time 18.87 s). The data were visualized and images generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017). Polarized Light Microscopy (PLM)

[0242] The presence of crystallinity (birefringence) was determined using an Olympus BX53 microscope equipped with a cross-polarizing lens and a Motic camera. Images were captured using Motic Images Plus 3.0. Unless otherwise stated, all images were recorded using a 20× objective lens. Thermogravimetric analysis / differential scanning calorimetry (TGA / DSC)

[0243] Approximately 5-10 mg of material was added to a pre-weighed open aluminum dish and loaded into a TA Instruments Discovery SDT 650 Auto-Simultaneous DSC, which was kept 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 sample weight change and thermal flow response (DSC) were recorded. Nitrogen gas was used as the sample purging gas at a flow rate of 200 cm³ / min. Differential Scanning Calorimetry (DSC)

[0244] Weigh approximately 1-5 mg of material into an aluminum DSC pan and seal it loosely with an aluminum cap. Then load the sample pan into a TA Instruments Discovery DSC 2500 differential scanning calorimeter equipped with an RC90 cooler. Heat the sample and reference material to 200°C at a scan rate of 10°C / min and monitor the resulting heat flow response. Cool the sample to -80°C and then reheat it to 200°C at 10°C / min. Use nitrogen gas at a flow rate of 50 cm³ / min as the purging gas. Infrared spectroscopy (IR)

[0245] Infrared spectroscopy was performed on a Bruker ALPHA P spectrometer. Sufficient material was placed at the center of the spectrometer disk, and the following parameters were used to obtain the spectrum: Resolution: 4 cm⁻¹; Background scan time: 16 scans; Sample scan time: 16 scans; Data collection: 4000 to 400 cm⁻¹; Result spectrum: Transmittance; Software: OPUS version 6 Nuclear Magnetic Resonance (NMR)

[0246] NMR experiments were performed on a Bruker AVIIIHD spectrometer equipped with a PRODIGY cryogenic probe operating at 500.23 MHz for protons, or on a Bruker AVIIIHD spectrometer equipped with a DCH cryogenic probe operating at 500.12 MHz for protons. Experiments were conducted in dimethyl deuteride and each sample was prepared at a concentration of approximately 10 mM. Dynamic vapor adsorption (DVS) was used.

[0247] Place approximately 10–20 mg of sample in the mesh tray of a vapor adsorption balance, mounted on a Surface Measurement Systems DVS Intrinsic or Advantage dynamic vapor adsorption balance. The sample is subjected to a gradual change in relative humidity (RH) from 40% to 90% in 10% increments, maintaining the sample at 25°C until a steady weight is achieved (dm / dt 0.004%, minimum step 30 min, maximum step 120 min). After the adsorption cycle is complete, the sample is dried to 0% RH using the same procedure and then restored to 40% RH using a second adsorption cycle. Two cycles are performed. The weight change during the adsorption / desorption cycles is plotted to determine the hygroscopic properties of the sample. Any solids retained are then analyzed by XRPD. [Simplified Explanation of the Diagram]

[0018] [Figure 1A]: This figure shows the XRPD diffraction pattern of the isomorphous form I of compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101).

[0019] [Figure 1B]: This figure shows the XRPD diffraction pattern of the isomorphous form II of compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101).

[0020] [Figure 1C]: This figure shows the XRPD diffraction pattern of the isomorphous form III of compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101).

[0021] [Figure 1D]: This figure shows the XRPD diffraction pattern of the isomorphous form IV of compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101).

[0022] [Figure 1E]: This figure shows the XRPD diffraction pattern of the amorphous 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). No 2θ peak was observed in the amorphous compound.

[0023] [Figure 1F]: This figure shows the XRPD diffraction pattern 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), which is called form V or mode 5 (equivalently used).

[0024] [Figure 2A]: This figure shows the TG / DSC thermal analysis of allomorphic form I of compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101). Secondary mass losses were observed in the TG trace: a 48 wt.% mass loss (C9H7F6N) between 211°C and 250°C, and a 16 wt.% mass loss (CH2N4) between 250°C and 300°C. Since no further mass loss was observed, form I is inferred to be a solvated and anhydrous allomorphic compound. In the DSC trace, an endothermic event initiating at 221°C (melting point) was observed simultaneously with the 48 wt.% mass loss, followed by an exothermic degradation event initiating at 270°C simultaneously with the 16 wt.% mass loss. (a) Enthalpy (normalized): 121.68 J / g; Peak temperature: 228.92℃; Initial temperature: 221.30℃. (b) Enthalpy (normalized): 238.68 J / g; Peak temperature: 278.42℃; Initial temperature: 269.84℃.

[0025] [Figure 2B]: This figure shows the TG / DSC thermal analysis of the isomorphous form II of compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101). Secondary mass losses 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, form II is inferred to be an anhydrous and non-solvent-bound isomorphous compound. In the DSC trace, an endothermic event initiating at 214 °C (melting point) was observed simultaneously with the 54 wt.% mass loss, followed by an exothermic degradation event initiating at 273 °C, simultaneously with the 20 wt.% mass loss. (a) Enthalpy (normalized): 67.701 J / g; Peak temperature: 222.81℃; Initial temperature: 213.99℃. (b) Enthalpy (normalized): 333.24 J / g; Peak temperature: 283.20℃; Initial temperature: 272.94℃.

[0026] [Figure 2C]: This figure shows the TG / DSC thermal analysis of the isomorphous form III of 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 second-order mass loss attributable to API decomposition was observed, namely a 52.0 wt.% mass loss between 185 °C and 250 °C and a 17.4 wt.% mass loss between 250 °C and 300 °C. No additional mass loss was observed. In the DSC trace, an additional exothermic event, absent in form I, was observed, initiating at 162 °C. Further analysis using variable temperature XRPD (VT-XRPD) revealed that this exothermic event was caused by the conversion of form III to form IV, exhibiting a mixture of forms III and IV at 150 °C and a complete conversion to form IV at 155 °C. Subsequently, an endothermic event initiated at 223 °C (melting point), attributed to API decomposition, was followed by an exothermic event initiating at 272 °C. (a) Enthalpy (normalized): 15.517 J / g; Peak temperature: 171.12 °C; Initiation temperature: 161.86 °C. (b) Enthalpy (normalized): 71.642 J / g; Peak temperature: 229.90 °C; Initiation temperature: 223.10 °C. (c) Enthalpy (normalized): 162.97 J / g; Peak temperature: 280.15 °C; Initiation temperature: 271.68 °C.

[0027] [Figure 2D]: This figure shows the TG / DSC thermal analysis of the isomorphous form IV of compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101). No mass loss was observed in the TG trace prior to the second-order mass loss attributed to API decomposition. This mass loss was 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, form IV is inferred to be an anhydrous and non-solvable isomorphous compound. An endothermic event initiating at 225 °C, attributed to API decomposition, was observed, followed by an exothermic event initiating at 271 °C. (a) Enthalpy (normalized): 68.722 J / g; Peak temperature: 231.40℃; Initial temperature: 225.20℃. (b) Enthalpy (normalized): 116.26 J / g; Peak temperature: 278.52℃; Initial temperature: 270.65℃.

[0028] [Figure 2E]: This figure shows the TG / DSC thermal analysis of the amorphous 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). 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. Subsequent mass losses were secondary mass losses attributable to API decomposition, namely a 49 wt.% mass loss between 180 °C and 247 °C, and an 18 wt.% mass loss between 247 °C and 305 °C. In the DSC trace, a small exothermic event initiating at 141 °C was observed concurrent with the acetone mass loss. Additionally, an endothermic event initiating at 215 °C was observed concurrent with the mass loss from decomposition, followed by an exothermic event initiating at 273 °C. (a) Enthalpy (normalized): 16.389 J / g; Peak temperature: 147.62 °C; Initiation temperature: 141.31 °C. (b) Enthalpy (normalized): 46.123 J / g; Peak temperature: 223.34 °C; Initiation temperature: 215.33 °C. (c) Enthalpy (normalized): 192.48 J / g; Peak temperature: 280.08 °C; Initiation temperature: 273.03 °C.

[0029] [Figure 2F]: This figure shows the TG / DSC thermal analysis of compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101) in its 2-propanol (isopropanol) solvate form, i.e., form V. A first-order mass loss, absent in the received material, was observed in the TG trace. This resulted in a mass loss of 11.2 wt.% (1.0 equivalent of 2-propanol or 3.5 equivalent of water) between 100°C and 150°C. Subsequent mass losses were attributed to API decomposition, namely a 46.6 wt.% mass loss between 180°C and 250°C, and a 15.6 wt.% mass loss between 250°C and 305°C. In the DSC trace, an additional endothermic event, absent in Form I, was observed, initiating at 124 °C, coinciding with the mass loss of 2-propanol. This was followed by an endothermic event initiating at 220 °C, attributed to API decomposition, and then an exothermic event initiating at 271 °C. These data support the isopropanol solvate of Form V as described in this invention. (a) Enthalpy (normalized): 81.609 J / g; Peak temperature: 132.09 °C; Initiation temperature: 123.79 °C. (b) Enthalpy (normalized): 67.328 J / g; Peak temperature: 228.55 °C; Initiation temperature: 220.37 °C. (c) Enthalpy (normalized): 175.03 J / g; Peak temperature: 278.52 °C; Initiation temperature: 270.72 °C.

[0030] [Figure 3A]: This figure shows the dynamic vapor adsorption (DVS) diagram of the isomorphous form I of compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101). This figure shows that form I is non-hygroscopic because no increase in the mass of the sample of form I was observed when the relative humidity increased to 90%.

[0031] [Figure 3B]: This figure shows the DVS diagram of the isomorphous form II of compound N-[4-bromo-2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea (SCO-101). An increase in mass of approximately 6% was observed at 90% relative humidity. The 3% weight increase as RH increases from 70% to 80% corresponds to the formation of the monohydrate, and the total 6% weight increase corresponds to the dihydrate. This figure shows that form II is hygroscopic.

Claims

1. A crystal form I of SCO-101 (SCO-101), which, when measured using Cu Kα radiation, exhibits peak maximum values ​​at at least the following 2θ angles in an X-ray powder diffraction (XRPD) pattern: 19.0±0.2, 21.2±0.2, and 23.4±0.

2.

2. Crystal form I as requested in claim 1, wherein, when measured using Cu Kα radiation, crystal form I exhibits peak maximum values ​​at at least the following 2θ angles in the X-ray powder diffraction (XRPD) diagram: 13.9±0.2, 19.0±0.2, 19.9±0.2 and 21.2±0.

2.

3. Crystal form I as claimed in claim 1, wherein, when measured using Cu Kα radiation, crystal form I exhibits peak maximum values ​​at at least the following 2θ angles in the X-ray powder diffraction (XRPD) pattern: 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.

4. Crystal form I as in request item 1, wherein: a) When measured using Cu Kα radiation, crystal form I exhibits the XRPD diffraction pattern according to Figure 1A; b) Using a heating rate of 10 °C / min, crystal form I exhibits an initial temperature of 218 °C to 226 °C in differential scanning calorimetry (DSC); and / or c) Using a heating rate of 10 °C / min, crystal form I exhibits a peak temperature of 224 °C to 234 °C in differential scanning calorimetry (DSC).

5. A crystal form III of SCO-101 (SCO-101), which, when measured using Cu Kα radiation, exhibits peak maximum values ​​at at least the following 2θ angles in an X-ray powder diffraction (XRPD) pattern: 11.1±0.2, 21.7±0.2, and 23.3±0.

2.

6. Crystal form III as claimed in claim 5, wherein: a) When measured using Cu Kα radiation, crystal form III exhibits the XRPD diffraction pattern according to Figure 1C; b) Using a heating rate of 10 °C / min, crystal form III exhibits an initial temperature of 220 °C to 228 °C in differential scanning calorimetry (DSC); and / or c) Using a heating rate of 10 °C / min, crystal form III exhibits a peak temperature of 225 °C to 235 °C in differential scanning calorimetry (DSC).

7. A crystalline form IV of SCO-101 (SCO-101), which, when measured using Cu Kα radiation, exhibits peak maximum values ​​at at least the following 2θ angles in an X-ray powder diffraction (XRPD) pattern: 22.6±0.2, 23.4±0.2, and 23.7±0.

2.

8. Crystal form IV as claimed in claim 7, wherein: a) When measured using Cu Kα radiation, crystal form IV exhibits the XRPD diffraction pattern according to Figure 1D; b) When heated at a rate of 10 °C / min, crystal form IV exhibits an initial temperature of 222 °C to 230 °C in differential scanning calorimetry (DSC); and / or c) When heated at a rate of 10 °C / min, crystal form IV exhibits a peak temperature of 226 °C to 236 °C in differential scanning calorimetry (DSC).

9. An amorphous form of SCO-101, (SCO-101), which, when measured using Cu Kα radiation, does not exhibit a peak maximum at an angle of 2θ between 0 and 40° in an X-ray powder diffraction (XRPD) pattern.

10. As in the amorphous form of claim 9, wherein: a) When measured using Cu Kα radiation, the amorphous form exhibits the XRPD diffraction pattern according to Figure 1E; b) Using a heating rate of 10 °C / min, the amorphous form exhibits an initial temperature of 211 °C to 219 °C in differential scanning calorimetry (DSC); and / or c) Using a heating rate of 10 °C / min, the amorphous form exhibits a peak temperature of 218 °C to 228 °C in differential scanning calorimetry (DSC).

11. A crystal form of SCO-101 isopropanol solvate, V, isopropanol (SCO-101 isopropanol solvate), which, when measured using Cu Kα radiation, exhibits peak maximum values ​​at at least the following 2θ angles in an X-ray powder diffraction (XRPD) pattern: 9.4±0.2, 21.1±0.2, and 22.2±0.

2.

12. Crystal form V as in claim 11, wherein: a) When measured using Cu Kα radiation, crystal form V exhibits the XRPD diffraction pattern according to Figure 1F; b) Using a heating rate of 10 °C / min, crystal form V exhibits an initial temperature of 216 °C to 224 °C in differential scanning calorimetry (DSC); and / or c) Using a heating rate of 10 °C / min, crystal form V exhibits a peak temperature of 224 °C to 234 °C in differential scanning calorimetry (DSC).

13. A method for preparing crystalline form I of SCO-101 as defined in any one of claims 1 to 4, the method comprising the following sequential steps: a) dissolving SCO-101 in one or more polar aprotic solvents selected from the group consisting of acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropyleneurea, dimethyl sulfoxide, ethyl acetate, 2-MeTHF, and tetrahydrofuran at a first predefined temperature of 0°C to 20°C; b) adding one or more polar protic solvents selected from the group consisting of acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropyleneurea, dimethyl sulfoxide, ethyl acetate, 2-MeTHF, and tetrahydrofuran to the one or more polar aprotic solvents for a first predefined period of 10 to 360 minutes to provide crystalline form I of SCO-101: water, methanol, ethanol, isopropanol, and acetic acid; and c) separating crystalline form I of SCO-101.

14. The method of claim 13, further comprising a prior crystallization step prior to step a), wherein the prior crystallization step comprises: i) mixing a composition comprising SCO-101 and one or more impurities with 2-propanol to provide a mixture; ii) heating the mixture to a second predefined temperature, or heating the mixture at the second predefined temperature, the second predefined temperature being between 31°C and 80°C and above the first predefined temperature; iii) adding water to the mixture over a second predefined period; and iv) cooling the mixture to a third predefined temperature to provide SCO-101 in solid form, wherein the third predefined temperature is below the second predefined temperature.

15. A method for preparing crystalline form I of SCO-101 as defined in any one of claims 1 to 4 from a metastable form, comprising: a) providing a metastable form, which is a crystalline or amorphous form of SCO-101; b) mixing the metastable form with crystalline form I of SCO-101 as defined in any one of claims 1 to 4 in a solvent mixture of: i) one or more polar aprotic solvents selected from the group consisting of acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropylurea, dimethyl sulfoxide, ethyl acetate, 2-MeTHF and tetrahydrofuran, and ii) one or more polar protic solvents selected from the group consisting of water, methanol, ethanol, isopropanol and acetic acid, or one or more nonpolar solvents selected from the group consisting of heptane, hexane, pentane, cyclohexane, toluene and diethyl ether; c) Stirring the solvent mixture at 30°C to 60°C for at least 1 hour to provide crystal form I of SCO-101; wherein the crystal form of SCO-101 is selected from the group consisting of: i) crystal form II of SCO-101: (SCO-101) exhibiting peak maximum values ​​at at least the following 2θ angles in an X-ray powder diffraction (XRPD) pattern when measured using Cu Kα radiation: 18.8±0.2, 23.2±0.2 and 20.5±0.2; ii) crystal form III of SCO-101 as defined in any one of claims 5 to 6; iii) crystal form IV of SCO-101 as defined in any one of claims 7 to 8; and iv) crystal form V of SCO-101 as defined in any one of claims 11 to 12, and wherein the amorphous form of SCO-101 is as defined in any one of claims 9 to 10.

16. A pharmaceutical composition comprising crystalline form I of SCO-101 as defined in any one of claims 1 to 4; and one or more pharmaceutically acceptable adjuvants, excipients, carriers, buffers and / or diluents.

17. SCO-101 in crystal form I as defined in any one of claims 1 to 4, which is used in combination with one or more anticancer agents to treat cancer.

18. Use of SCO-101 in crystal form I as defined in any one of claims 1 to 4 for manufacturing a pharmaceutical for treating cancer, wherein the pharmaceutical is used in combination with one or more anticancer agents.

19. Use of a pharmaceutical composition as defined in claim 16 for manufacturing a pharmaceutical product for treating cancer, wherein the pharmaceutical product is used in combination with one or more anticancer agents.

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