BELUMOSUDIL and BELUMOSUDIL salt in solid form

Abstract

This application relates to the solid forms of BELUMOSUDIL and BELUMOSUDIL salts. This disclosure includes the solid forms of BELUMOSUDIL, including crystalline polymorphs of BELUMOSUDIL or its salts in embodiments, their preparation processes, and pharmaceutical compositions thereof.

Description

[0001] This application is a divisional application of the application filed on July 22, 2021, with application number 202180053875.6 and invention title "BELUMOSUDIL and solid form of BELUMOSUDIL salt".

[0002] The scope of this disclosure

[0003] This disclosure includes the solid form of Belumosudil, including, in embodiments, crystalline polymorphs of Belumosudil or its salts, its preparation process, and pharmaceutical compositions thereof.

[0004] Background of this public disclosure

[0005] Belumosudil, 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide, has the following chemical structure:

[0006]

[0007] Belumosudil is a ROCK2 inhibitor and is being developed for the treatment of graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse systemic sclerosis cutanea; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; and systemic scleroderma.

[0008] This compound is described in International Publication No. 2006 / 105081. The crystalline form of Belumosudil is disclosed in International Publication No. 2021 / 129589.

[0009] Polymorphism, the appearance of different crystalline forms, is a property of some molecules and molecular complexes. Individual molecules can produce different crystal structures and physical properties such as melting point, thermal behavior (e.g., measured by thermogravimetric analysis (“TGA”) or differential scanning calorimetry (“DSC”), X-ray diffraction (XRD) patterns, infrared absorption fingerprints, and solid-state properties. 13 C) Multiple polymorphs of NMR spectra. One or more of these techniques can be used to distinguish different polymorphic forms of compounds.

[0010] Different salts and solid forms (including solvated forms) of active pharmaceutical ingredients can possess different properties. Such variations in the properties of different salts and solid forms, as well as solvates, can provide a basis for improving formulations, for example, by facilitating better processing or handling characteristics, altering the solubility profile in a favorable direction, or improving stability (polymorphism and chemical stability) and shelf life. These variations in the properties of different salts and solid forms can also provide improvements to the final dosage form, for example, if they are intended to improve bioavailability. Different salts and solid forms of active pharmaceutical ingredients, as well as solvates, can also produce multiple polymorphs or crystalline forms, which in turn provides additional opportunities to evaluate variations in the properties and characteristics of solid active pharmaceutical ingredients.

[0011] Discovering new solid forms and solvates of pharmaceutical products can yield materials with desirable processing properties such as ease of handling, processability, storage stability, and ease of purification, or serve as desirable intermediate crystalline forms that facilitate conversion to other polymorphic forms. New solid forms of pharmaceutically useful compounds can also provide opportunities to improve the performance properties of pharmaceutical products. This expands the pool of materials available to formulation scientists for formulation optimization, for example, by providing products with different properties, including different crystal habits, higher crystallinity, or polymorphic stability, which can provide better processing or handling characteristics, improved solubility profiles, or improved shelf life (chemical / physical stability). For at least these reasons, there is a need for additional solid forms (including solvated forms) of Belumosudil and Belumosudil salts.

[0012] Overview of this disclosure

[0013] This disclosure provides crystalline polymorphs of Belumosudil and its salts (including Belumosudil methanesulfonate, Belumosudil toluenesulfonate, and / or Belumosudil benzenesulfonate), their preparation processes, and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other solid forms of Belumosudil, Belumosudil salts, and their solid forms.

[0014] This disclosure also provides the use of the solid form of the API or its salts (including Beluosudil methanesulfonate, Beluosudil toluenesulfonate and / or Beluosudil benzenesulfonate) in the preparation of other solid forms of Beluosudil or its salts.

[0015] This disclosure provides crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil tosylate, and Belumosudil benzylsulfonate) for medical use, including for the treatment of graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse systemic sclerosis cutanea; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; and systemic scleroderma. In particular, this disclosure provides crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil tosylate, and Belumosudil benzylsulfonate) for medical use, including for the treatment of chronic graft-versus-host disease and / or systemic sclerosis.

[0016] This disclosure also includes the use of the crystalline polymorphs of Belmosudil or its salts (including Belmosudil mesylate, Belmosudil toluenesulfonate and Belmosudil benzenesulfonate) in the preparation of pharmaceutical compositions and / or formulations.

[0017] In another aspect, this disclosure provides pharmaceutical compositions comprising crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil toluenesulfonate and Belumosudil benzenesulfonate) according to this disclosure.

[0018] This disclosure includes a process for preparing the pharmaceutical compositions mentioned above. The process includes combining any or a combination of crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil toluenesulfonate, and Belumosudil benzenesulfonate) with at least one pharmaceutically acceptable excipient.

[0019] Crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil toluenesulfonate, and Belumosudil benzenesulfonate) as defined herein, and pharmaceutical compositions or formulations thereof, may be used as medicines, such as for the treatment of graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse systemic sclerosis of the cutaneous body; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; and systemic scleroderma. In particular, pharmaceutical compositions or pharmaceutical preparations of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil toluenesulfonate and Belumosudil benzenesulfonate) as defined herein, and of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil toluenesulfonate and / or Belumosudil benzenesulfonate), may be used as pharmaceuticals for the treatment of chronic graft-versus-host disease and / or systemic sclerosis.

[0020] This disclosure also provides methods for treating the following: graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse systemic scleroderma; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; systemic scleroderma, said treatment being performed by administering to a subject a therapeutically effective amount of any or a combination of crystalline polymorphs of Belumosudil of the present disclosure or its salts (including Belumosudil mesylate, Belumosudil tosylate, and Belumosudil benzenesulfonate), or at least one of the above pharmaceutical compositions, said subject having graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse systemic scleroderma; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; systemic scleroderma, or said patient requiring treatment in other ways. In particular, this disclosure provides a method for treating chronic graft-versus-host disease and / or systemic sclerosis, said treatment being performed by administering a therapeutically effective amount of any or a combination of crystalline polymorphs of Belumosudil of the present disclosure or its salts (including Belumosudil mesylate, Belumosudil toluenesulfonate, and Belumosudil benzenesulfonate), or at least one of the aforementioned pharmaceutical compositions, to a subject suffering from chronic graft-versus-host disease and / or systemic sclerosis or otherwise requiring treatment.

[0021] This disclosure also provides for the use of crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil toluenesulfonate, and / or Belumosudil benzenesulfonate) or at least one of the above pharmaceutical compositions in the manufacture of a medicament for treating:, for example, graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse systemic sclerosis of the cutaneous body; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; systemic scleroderma; and particularly for the treatment of chronic graft-versus-host disease and / or systemic sclerosis. Brief description of the attached diagram

[0023] Figure 1 The X-ray powder diffraction (XRPD) pattern of amorphous Belumosudil is shown.

[0024] Figure 2 The characteristic X-ray powder diffraction (XRPD) pattern of Belumosudil form B1 is shown.

[0025] Figure 3 The characteristic X-ray powder diffraction (XRPD) pattern of Belumosudil form B2 is shown.

[0026] Figure 4 The characteristic X-ray powder diffraction (XRPD) pattern of Belumosudil form B3 is shown.

[0027] Figure 5 The characteristic X-ray powder diffraction (XRPD) pattern of Belumosudil methanesulfonate form M1 is shown.

[0028] Figure 6 The characteristic X-ray powder diffraction (XRPD) pattern of Belumosudil form B4 is shown.

[0029] Figure 7 The characteristic X-ray powder diffraction (XRPD) pattern of Belumosudil methanesulfonate form M2 is shown.

[0030] Figure 8 The characteristic X-ray powder diffraction (XRPD) pattern of Belumosudil methanesulfonate form M3 is shown.

[0031] Figure 9 The characteristic X-ray powder diffraction (XRPD) pattern of Belumosudil form B5 is shown.

[0032] Figure 10The characteristic X-ray powder diffraction (XRPD) pattern of amorphous Belumosudil methanesulfonate is shown.

[0033] Figure 11 The characteristic X-ray powder diffraction (XRPD) pattern of Belumosudil methanesulfonate form M4 is shown.

[0034] Figure 12 The characteristic X-ray powder diffraction (XRPD) pattern of Belumosudil methanesulfonate form M5 is shown.

[0035] Figure 13 The characteristic X-ray powder diffraction (XRPD) pattern of Belumosudil benzenesulfonate form BS1 is shown.

[0036] Figure 14 The characteristic X-ray powder diffraction (XRPD) pattern of Belumosudil toluenesulfonate form T1 is shown.

[0037] Figure 15 The characteristic X-ray powder diffraction (XRPD) pattern of Belumosudil toluenesulfonate form T2 is shown.

[0038] Figure 16 The characteristic solid state of Belumosudil methanesulfonate M1 is shown. 13 C10 NMR spectrum (full range 200ppm-0ppm).

[0039] Figure 17 The characteristic solid state of Belumosudil methanesulfonate M1 is shown. 13 C NMR spectrum (200 ppm-100 ppm).

[0040] Figure 18 The characteristic solid state of Belumosudil methanesulfonate M1 is shown. 13 C NMR spectrum (100 ppm-0 ppm).

[0041] Figure 19 The characteristic solid state of Belumosudil methanesulfonate M2 is shown. 13 C10 NMR spectrum (full range 200ppm-0ppm).

[0042] Figure 20 The characteristic solid state of Belumosudil methanesulfonate M2 is shown. 13 C NMR spectrum (200 ppm-100 ppm).

[0043] Figure 21The characteristic solid state of Belumosudil methanesulfonate M2 is shown. 13 C NMR spectrum (100 ppm-0 ppm).

[0044] Figure 22 The characteristic solid state of Belumosudil benzenesulfonate BS1 is shown. 13 C10 NMR spectrum (full range 200ppm-0ppm).

[0045] Figure 23 The characteristic solid state of Belumosudil benzenesulfonate BS1 is shown. 13 C NMR spectrum (200 ppm-100 ppm).

[0046] Figure 24 The characteristic solid state of Belumosudil benzenesulfonate BS1 is shown. 13 C NMR spectrum (100 ppm-0 ppm).

[0047] Figure 25 A scanning electron microscope (SEM) image of particles of Belumosudil benzenesulfonate BS1 is shown.

[0048] Figure 26 The characteristic solid state of Belumosudil toluenesulfonate T1 is shown. 13 C10 NMR spectrum (full range 200ppm-0ppm).

[0049] Figure 27 The characteristic solid state of Belumosudil toluenesulfonate T1 is shown. 13 C NMR spectrum (200 ppm-100 ppm).

[0050] Figure 28 The characteristic solid state of Belumosudil toluenesulfonate T1 is shown. 13 C NMR spectrum (100 ppm-0 ppm).

[0051] Figure 29 A scanning electron microscopy (SEM) image of particles of Belumosudil tosylate in the form of T1 is shown.

[0052] Figure 30 The characteristic solid state of Belumosudil toluenesulfonate T2 is shown. 13 C10 NMR spectrum (full range 200ppm-0ppm).

[0053] Figure 31 The characteristic solid state of Belumosudil toluenesulfonate T2 is shown. 13 C NMR spectrum (200 ppm-100 ppm).

[0054] Figure 32 The characteristic solid state of Belumosudil toluenesulfonate T2 is shown. 13 C NMR spectrum (100 ppm-0 ppm).

[0055] Figure 33 A scanning electron microscopy (SEM) image of particles of Belumosudil tosylate in the form of T2 is shown.

[0056] Detailed description of this disclosure

[0057] This disclosure includes the solid form of Belumosudil and its salts (including Belumosudil mesylate, Belumosudil toluenesulfonate and / or Belumosudil benzenesulfonate), including crystalline polymorphs of Belumosudil and its salts, their preparation processes, and pharmaceutical compositions thereof.

[0058] The solid-state properties of Belumosudil, Belumosudil salt, and their crystalline polymorphs can be influenced by controlling the conditions under which Belumosudil and Belumosudil salts and their crystalline polymorphs are obtained in solid form.

[0059] Solid form (or polymorph) may be referred to herein as polymorphically pure or substantially free of any other solid (or polymorph) form. As used in the context herein, the expression “substantially free of any other form” will be understood to mean that the solid form contains about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other form of the subject compound, as measured, for example, by XRPD. Therefore, a crystalline polymorph of Belumosudil or Belumosudil salt described herein as substantially free of any other solid form will be understood to contain more than about 80% (w / w), more than about 90% (w / w), more than about 95% (w / w), more than about 98% (w / w), more than about 99% (w / w), or about 100% of the subject crystalline polymorph of Belumosudil or Belumosudil salt. In some embodiments of this disclosure, the crystalline polymorphs of the described Belumosudil or Belumosudil salt may comprise one or more other crystalline polymorphs of the same Belumosudil or Belumosudil salt, ranging from about 1% (w / w) to about 20% (w / w), from about 5% (w / w) to about 20% (w / w), or from about 5% (w / w) to about 10% (w / w). Similarly, a crystalline polymorph described herein as substantially free of any other solid form of Belumosudil salt (e.g., Belumosudil methanesulfonate, Belumosudil toluenesulfonate, or Belumosudil benzenesulfonate) shall be understood as a subject crystalline polymorph containing more than about 80% (w / w), more than about 90% (w / w), more than about 95% (w / w), more than about 98% (w / w), more than about 99% (w / w), or about 100% of Belumosudil salt (e.g., Belumosudil methanesulfonate, Belumosudil toluenesulfonate, or Belumosudil benzenesulfonate).In some embodiments of this disclosure, the crystalline polymorphs of the described Belumosudil salt (e.g., Belumosudil methanesulfonate, Belumosudil toluenesulfonate, or Belumosudil benzenesulfonate) may comprise one or more other crystalline polymorphs of the same Belumosudil salt (e.g., Belumosudil methanesulfonate, Belumosudil toluenesulfonate, or Belumosudil benzenesulfonate) ranging from about 1% (w / w) to about 20% (w / w), from about 5% (w / w) to about 20% (w / w), or from about 5% (w / w) to about 10% (w / w).

[0060] Depending on other crystalline polymorphs for comparison, the crystalline polymorphs of Belumosudil and Belumosudil salts (e.g., Belumosudil methanesulfonate, Belumosudil toluenesulfonate, or Belumosudil benzenesulfonate) of this disclosure may have advantageous properties selected from at least one of the following: chemical purity, fluidity, solubility, dissolution rate, morphology or crystal habit, stability such as chemical stability and thermal and mechanical stability with respect to polymorphic transformation, dehydration stability and / or storage stability, low residual solvent content, low degree of hygroscopicity, fluidity, and advantageous processing and handling characteristics such as compressibility and bulk density.

[0061] Solid-state forms, such as crystalline or amorphous forms, may herein be characterized by graphical data “as depicted in the figure” or “generally as depicted in the figure.” Such data includes, for example, powder X-ray diffraction patterns and solid-state NMR spectra. As is well known in the art, graphical data potentially provides additional technical information to further define the corresponding solid-state form (the so-called “fingerprint”), which is not necessarily described solely by reference values ​​or peak positions. In any case, those skilled in the art will understand that such graphical representations of the data may undergo small variations, such as small variations in peak relative intensities and peak positions, due to factors well known to them, such as, but not limited to, variations in instrument response and variations in sample concentration and purity. Nevertheless, those skilled in the art will be able to readily compare the graphical data in the figures herein with graphical data generated for unknown crystalline forms and confirm whether the two sets of graphical data characterize the same crystalline form or two different crystalline forms. Therefore, the crystal form of Belumosudil or Belumosudil salt characterized by graphical data “as depicted in the figure” or “generally as depicted in the figure” shall be understood to include any crystal form of Belumosudil or Belumosudil salt characterized by graphical data having such small variations as are well known to those skilled in the art compared to the figure.

[0062] As used herein and unless otherwise stated, the term "anhydrous" with respect to the crystalline forms of Belumosudil, Belumosudil methanesulfonate, Belumosudil toluenesulfonate, and / or Belumosudil benzenesulfonate refers to the crystalline form of Belumosudil or a Belumosudil salt that does not contain any defined stoichiometric amount of water of crystallization (or other solvent) within the crystals. Furthermore, the "anhydrous" form generally does not contain more than 1% (w / w) of water or organic solvents, as measured, for example, by a TGA.

[0063] As used herein and unless otherwise indicated, the term "solvent" refers to a crystalline form incorporating a solvent into its crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate". The solvent in a solvate may be present in stoichiometric or non-stoichiometric amounts.

[0064] As used herein, the term “separate” in relation to crystalline polymorphs of Belumosudil or Belumosudil salts (e.g., Belumosudil methanesulfonate, Belumosudil toluenesulfonate, and / or Belumosudil benzenesulfonate) of this disclosure corresponds to crystalline polymorphs of Belumosudil or Belumosudil salts that are physically separated from the reaction mixtures in which they are formed.

[0065] As used herein, unless otherwise stated, XRPD measurements were performed using copper Kα radiation at a wavelength of 1.5418 Å. The XRPD peaks reported herein were measured using CuKα radiation, λ = 1.5418 Å, typically at a temperature of 25 °C ± 3 °C.

[0066] As used in this article, 13 C NMR spectra are preferably measured at 125 MHz with a magic angle rotation (MAS) frequency ωr / 2π = 11 kHz.

[0067] As used herein, unless otherwise stated, TGA analysis is preferably performed at a heating rate of 10 °C / min up to 250 °C, preferably with a nitrogen flow rate of 40 ml / min.

[0068] A substance, such as a reaction mixture, may be characterized herein as being at or permitted to reach “room temperature” or “ambient temperature,” which is commonly abbreviated as “RT.” This means that the temperature of the substance is close to or the same as the temperature of the space in which the substance is located, such as a room or fume hood. Typically, room temperature is from about 20°C to about 30°C, or from about 22°C to about 27°C, or about 25°C.

[0069] The amount of solvent used in chemical processes such as reactions or crystallization may be referred to herein as a quantity in terms of “vol” or “V”. For example, a material may be described as being suspended in 10 volumes (or 10 vol or 10V) of solvent. In this context, this expression will be understood to mean the number of milliliters of solvent per gram of suspended material, such that suspending 5 grams of material in 10 volumes of solvent means that the solvent is used in an amount of 10 milliliters per gram of suspended material, or in this example, in an amount of 50 mL of solvent. In another case, the term “v / v” may be used to indicate the amount of solvent added to the mixture based on the volume of the liquid mixture. For example, adding solvent X (1.5 v / v) to 100 mL of a reaction mixture would indicate the addition of 150 mL of solvent X.

[0070] The process or step may be referred to herein as “overnight”. This refers, for example, to a time interval for a process or step that spans the night, during which the process or step may not be actively observed. This time interval ranges from about 8 hours to about 20 hours or from about 10 to 18 hours, and in some cases is about 16 hours.

[0071] As used herein, the term "decompression" refers to pressure below atmospheric pressure. For example, decompression is from about 10 millibars to about 50 millibars.

[0072] As used herein and unless otherwise indicated, the term “ambient conditions” means atmospheric pressure and a temperature of 22°C–24°C.

[0073] This disclosure includes crystalline polymorphs of Belumosudil designated as form B1. Crystalline form B1 of Belumosudil can be characterized by one or more of the following data: generally as Figure 2 The X-ray powder diffraction patterns depicted; X-ray powder diffraction patterns with peaks at 3.5°2θ±0.2°2θ, 6.9°2θ±0.2°2θ, 10.5°2θ±0.2°2θ, 24.9°2θ±0.2°2θ, and 25.7°2θ±0.2°2θ; and combinations of these data.

[0074] The crystalline form of Belumosudil, B1, can be further characterized by X-ray powder diffraction patterns having peaks at 3.5°2θ±0.2°2θ, 6.9°2θ±0.2°2θ, 10.5°2θ±0.2°2θ, 24.9°2θ±0.2°2θ, and 25.7°2θ±0.2°2θ, and also having any two, three, four, or five additional peaks selected from 9.4°2θ±0.2°2θ, 12.5°2θ±0.2°2θ, 15.7°2θ±0.2°2θ, 18.9°2θ±0.2°2θ, and 19.7°2θ±0.2°2θ.

[0075] The crystalline form of Belumosudil, B1, can be optionally characterized by X-ray powder diffraction patterns having peaks at 3.5°2θ±0.2°2θ, 6.9°2θ±0.2°2θ, 9.4°2θ±0.2°2θ, 10.5°2θ±0.2°2θ, 12.5°2θ±0.2°2θ, 15.7°2θ±0.2°2θ, 18.9°2θ±0.2°2θ, 19.7°2θ±0.2°2θ, 24.9°2θ±0.2°2θ, and 25.7°2θ±0.2°2θ.

[0076] In one embodiment of this disclosure, the crystalline form B1 of Belumosudil was isolated.

[0077] The crystalline form of Belumosudil, B1, can be characterized individually by each of the above characteristics and / or by all possible combinations thereof, for example, by an XRPD plot having peaks at 3.5°2θ ± 0.2°2θ, 6.9°2θ ± 0.2°2θ, 10.5°2θ ± 0.2°2θ, 24.9°2θ ± 0.2°2θ, and 25.7°2θ ± 0.2°2θ; as Figure 2 The XRPD diagram and its combination depicted in the document.

[0078] This disclosure includes crystalline polymorphs of Belumosudil designated as form B2. Crystalline form B2 of Belumosudil can be characterized by one or more of the following data: generally as Figure 3 The X-ray powder diffraction pattern depicted; the X-ray powder diffraction pattern having peaks at 3.8°2θ±0.2°2θ, 5.7°2θ±0.2°2θ, 7.6°2θ±0.2°2θ, 9.6°2θ±0.2°2θ and 25.9°2θ±0.2°2θ; and combinations of these data.

[0079] The crystalline form of Belumosudil, B2, can be further characterized by X-ray powder diffraction patterns having peaks at 3.8°2θ±0.2°2θ, 5.7°2θ±0.2°2θ, 7.6°2θ±0.2°2θ, 9.6°2θ±0.2°2θ, and 25.9°2θ±0.2°2θ, and also having any two, three, four, or five additional peaks selected from 10.7°2θ±0.2°2θ, 15.4°2θ±0.2°2θ, 16.6°2θ±0.2°2θ, 17.8°2θ±0.2°2θ, and 19.3°2θ±0.2°2θ.

[0080] The crystalline form of Belumosudil, B2, can be optionally characterized by X-ray powder diffraction patterns having peaks at 3.8°2θ±0.2°2θ, 5.7°2θ±0.2°2θ, 7.6°2θ±0.2°2θ, 9.6°2θ±0.2°2θ, 10.7°2θ±0.2°2θ, 15.4°2θ±0.2°2θ, 16.6°2θ±0.2°2θ, 17.8°2θ±0.2°2θ, 19.3°2θ±0.2°2θ, and 25.9°2θ±0.2°2θ.

[0081] In one embodiment of this disclosure, the crystalline form B2 of Belumosudil was isolated.

[0082] The crystalline form of Belumosudil, B2, can be characterized individually by each of the above characteristics and / or by all possible combinations thereof, for example, by an XRPD plot showing peaks at 3.8°2θ ± 0.2°2θ, 5.7°2θ ± 0.2°2θ, 7.6°2θ ± 0.2°2θ, 9.6°2θ ± 0.2°2θ, and 25.9°2θ ± 0.2°2θ; as shown. Figure 3 The XRPD diagram and its combination depicted in the document.

[0083] This disclosure includes crystalline polymorphs of Belumosudil designated as form B3. Crystalline form B3 of Belumosudil can be characterized by one or more of the following data: generally as Figure 4 The X-ray powder diffraction pattern depicted; the X-ray powder diffraction pattern having peaks at 6.5° 2θ ± 0.2° 2θ, 8.4° 2θ ± 0.2° 2θ, 12.2° 2θ ± 0.2° 2θ, 19.6° 2θ ± 0.2° 2θ and 26.3° 2θ ± 0.2° 2θ; and combinations of these data.

[0084] The crystalline form of Belumosudil, B3, can be further characterized by X-ray powder diffraction patterns having peaks at 6.5°2θ±0.2°2θ, 8.4°2θ±0.2°2θ, 12.2°2θ±0.2°2θ, 19.6°2θ±0.2°2θ, and 26.3°2θ±0.2°2θ, and also having any two, three, four, or five additional peaks selected from 14.7°2θ±0.2°2θ, 15.4°2θ±0.2°2θ, 16.4°2θ±0.2°2θ, 18.8°2θ±0.2°2θ, and 22.5°2θ±0.2°2θ.

[0085] The crystalline form of Belumosudil, B3, can be optionally characterized by X-ray powder diffraction patterns having peaks at 6.5°2θ±0.2°2θ, 8.4°2θ±0.2°2θ, 12.2°2θ±0.2°2θ, 14.7°2θ±0.2°2θ, 15.4°2θ±0.2°2θ, 16.4°2θ±0.2°2θ, 18.8°2θ±0.2°2θ, 19.6°2θ±0.2°2θ, 22.5°2θ±0.2°2θ, and 26.3°2θ±0.2°2θ.

[0086] In one embodiment of this disclosure, the crystalline form B3 of Belumosudil was isolated.

[0087] The crystalline form of Belumosudil, B3, can be characterized individually by each of the above characteristics and / or by all possible combinations thereof, for example, by an XRPD plot having peaks at 6.5°2θ ± 0.2°2θ, 8.4°2θ ± 0.2°2θ, 12.2°2θ ± 0.2°2θ, 19.6°2θ ± 0.2°2θ, and 26.3°2θ ± 0.2°2θ; as Figure 4 The XRPD diagram and its combination depicted in the document.

[0088] This disclosure includes crystalline polymorphs of Belumosudil designated as form B4. Crystalline form B4 of Belumosudil can be characterized by one or more of the following data: substantially as Figure 6 The X-ray powder diffraction patterns depicted; X-ray powder diffraction patterns with peaks at 8.3°2θ±0.2°2θ, 9.3°2θ±0.2°2θ, 11.9°2θ±0.2°2θ, 16.7°2θ±0.2°2θ, and 17.2°2θ±0.2°2θ; and combinations of these data.

[0089] The crystalline form of Belumosudil, B4, can be further characterized by X-ray powder diffraction patterns having peaks at 8.3°2θ±0.2°2θ, 9.3°2θ±0.2°2θ, 11.9°2θ±0.2°2θ, 16.7°2θ±0.2°2θ, and 17.2°2θ±0.2°2θ, and also having any two, three, four, or five additional peaks selected from 15.2°2θ±0.2°2θ, 18.7°2θ±0.2°2θ, 24.1°2θ±0.2°2θ, 25.6°2θ±0.2°2θ, and 26.2°2θ±0.2°2θ.

[0090] The crystalline form of Belumosudil, B4, can be further characterized by X-ray powder diffraction patterns having peaks at 8.3°2θ±0.2°2θ, 9.3°2θ±0.2°2θ, 11.9°2θ±0.2°2θ, 16.7°2θ±0.2°2θ, and 17.2°2θ±0.2°2θ, and also having any two, three, four, or five additional peaks selected from 15.2°2θ±0.2°2θ, 18.7°2θ±0.2°2θ, 24.1°2θ±0.2°2θ, 25.6°2θ±0.2°2θ, and 26.2°2θ±0.2°2θ.

[0091] The crystalline form of Belumosudil, B4, can be optionally characterized by X-ray powder diffraction patterns having peaks at 8.3°2θ±0.2°2θ, 9.3°2θ±0.2°2θ, 11.9°2θ±0.2°2θ, 15.2°2θ±0.2°2θ, 16.7°2θ±0.2°2θ, 17.2°2θ±0.2°2θ, 18.7°2θ±0.2°2θ, 24.1°2θ±0.2°2θ, 25.6°2θ±0.2°2θ, and 26.2°2θ±0.2°2θ.

[0092] In one embodiment of this disclosure, the crystalline form of Belumosudil, B4, was isolated.

[0093] The crystalline form of Belumosudil, B4, can be characterized individually by each of the above characteristics and / or by all possible combinations thereof, for example, by an XRPD plot showing peaks at 8.3°2θ ± 0.2°2θ, 9.3°2θ ± 0.2°2θ, 11.9°2θ ± 0.2°2θ, 16.7°2θ ± 0.2°2θ, and 17.2°2θ ± 0.2°2θ; as shown. Figure 6 The XRPD diagram and its combination depicted in the document.

[0094] This disclosure includes crystalline polymorphs of Belumosudil designated as form B5. Crystalline form B5 of Belumosudil can be characterized by one or more of the following data: generally as Figure 9 The X-ray powder diffraction pattern depicted; the X-ray powder diffraction pattern having peaks at 6.1°2θ±0.2°2θ, 12.9°2θ±0.2°2θ, 16.2°2θ±0.2°2θ, 16.8°2θ±0.2°2θ and 19.2°2θ±0.2°2θ; and combinations of these data.

[0095] The crystalline form of Belumosudil, B5, can be further characterized by X-ray powder diffraction patterns having peaks at 6.1°2θ±0.2°2θ, 12.9°2θ±0.2°2θ, 16.2°2θ±0.2°2θ, 16.8°2θ±0.2°2θ, and 19.2°2θ±0.2°2θ, and also having any two, three, four, or five additional peaks selected from 3.7°2θ±0.2°2θ, 9.4°2θ±0.2°2θ, 9.8°2θ±0.2°2θ, 12.4°2θ±0.2°2θ, and 18.4°2θ±0.2°2θ.

[0096] The crystalline form of Belumosudil, B5, can be optionally characterized by X-ray powder diffraction patterns having peaks at 3.7°2θ±0.2°2θ, 6.1°2θ±0.2°2θ, 9.4°2θ±0.2°2θ, 9.8°2θ±0.2°2θ, 12.4°2θ±0.2°2θ, 12.9°2θ±0.2°2θ, 16.2°2θ±0.2°2θ, 16.8°2θ±0.2°2θ, 18.4°2θ±0.2°2θ, and 19.2°2θ±0.2°2θ.

[0097] In one embodiment of this disclosure, the crystalline form B5 of Belumosudil was isolated.

[0098] The crystalline form of Belumosudil, B5, can be characterized individually by each of the above characteristics and / or by all possible combinations thereof, for example, by an XRPD plot having peaks at 6.1°2θ ± 0.2°2θ, 12.9°2θ ± 0.2°2θ, 16.2°2θ ± 0.2°2θ, 16.8°2θ ± 0.2°2θ, and 19.2°2θ ± 0.2°2θ; as Figure 9 The XRPD diagram and its combination depicted in the document.

[0099] This disclosure includes crystalline polymorphs of Belumosudil methanesulfonate designated as form M1. The crystalline form M1 of Belumosudil methanesulfonate can be characterized by one or more of the following data: substantially as Figure 5 The X-ray powder diffraction pattern depicted; the X-ray powder diffraction pattern with peaks at 7.1°2θ±0.2°2θ, 17.2°2θ±0.2°2θ, 20.3°2θ±0.2°2θ, 21.5°2θ±0.2°2θ, and 25.5°2θ±0.2°2θ; the solid-state X-ray powder diffraction pattern with characteristic peaks at 137.8 ppm±0.2 ppm, 133.8 ppm±0.2 ppm, 122.5 ppm±0.2 ppm, 118.3 ppm±0.2 ppm, and 111.6 ppm±0.2 ppm. 13 C NMR spectrum; solid-state with the following absolute difference in chemical shift compared to the reference peak at 167.2 ppm ± 1 ppm. 13 C NMR spectra: 29.4 ppm ± 0.1 ppm, 33.4 ppm ± 0.1 ppm, 44.7 ppm ± 0.1 ppm, 48.9 ppm ± 0.1 ppm and 55.6 ppm ± 0.1 ppm; roughly as Figure 16 , Figure 17 and Figure 18 The solid state described in any one of them 13 C NMR spectra; and combinations of these data.

[0100] The crystalline form M1 of Belumosudil methanesulfonate can be further characterized by an X-ray powder diffraction pattern having peaks at 7.1°2θ±0.2°2θ, 17.2°2θ±0.2°2θ, 20.3°2θ±0.2°2θ, 21.5°2θ±0.2°2θ, and 25.5°2θ±0.2°2θ, and also having any two, three, four, or five additional peaks selected from 8.4°2θ±0.2°2θ, 15.5°2θ±0.2°2θ, 16.8°2θ±0.2°2θ, 19.5°2θ±0.2°2θ, and 22.1°2θ±0.2°2θ.

[0101] The crystalline form M1 of Belumosudil methanesulfonate can be optionally characterized by X-ray powder diffraction patterns having peaks at 7.1°2θ±0.2°2θ, 8.4°2θ±0.2°2θ, 15.5°2θ±0.2°2θ, 16.8°2θ±0.2°2θ, 17.2°2θ±0.2°2θ, 19.5°2θ±0.2°2θ, 20.3°2θ±0.2°2θ, 21.5°2θ±0.2°2θ, 22.1°2θ±0.2°2θ, and 25.5°2θ±0.2°2θ.

[0102] According to any aspect or embodiment described herein, the crystalline form M1 of Belumosudil methanesulfonate may be an anhydrous form, as determined by TGA. According to any aspect or embodiment described herein, the crystalline form M1 of Belumosudil methanesulfonate may contain 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less of total residual solvent. The residual solvent may be one or more polar solvents, preferably water, alcohol (especially C...). 1-4 Alcohols, particularly methanol, ethanol, isopropanol, 1-propanol, or n-butanol, or halogenated solvents (particularly 2,2,2-trifluoroethanol or dichloromethane), or DMSO, or mixtures thereof. Specifically, the crystalline form M1 of Belumosudil methanesulfonate according to any aspect or embodiment of this disclosure may contain 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less of total residual solvent, wherein the residual solvent is: ethanol, water, or DMSO, or a combination of ethanol, water, and DMSO, or a combination of ethanol and DMSO. Alternatively, the crystalline form M1 of Belumosudil methanesulfonate according to any aspect or embodiment of this disclosure may contain 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less of ethanol, or a mixture of 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less of ethanol and DMSO.

[0103] In one embodiment of this disclosure, the crystalline form M1 of Belumosudil methanesulfonate is isolated. In particular, the crystalline form M1 of Belumosudil methanesulfonate according to any aspect or embodiment of this disclosure can be isolated.

[0104] According to any aspect or embodiment of this disclosure, the crystalline form M1 of Belumosudil methanesulfonate is non-hygroscopic. In particular, the Belumosudil methanesulfonate form M1 according to any aspect or embodiment is polymorphically stable at room temperature and at relative humidity up to 100% for at least 7 days.

[0105] The crystalline form M1 of Belumosudil methanesulfonate can be characterized individually by each of the above characteristics and / or by all possible combinations thereof, for example, by an XRPD plot having peaks at 7.1°2θ ± 0.2°2θ, 17.2°2θ ± 0.2°2θ, 20.3°2θ ± 0.2°2θ, 21.5°2θ ± 0.2°2θ, and 25.5°2θ ± 0.2°2θ; as Figure 5 The XRPD diagram and its combination depicted in the document.

[0106] The crystalline form M1 of Belumosudil methanesulfonate can be prepared by crystallization from a mixture comprising Belumosudil methanesulfonate and one or more polar solvents (preferably polar organic solvents, and particularly wherein the polar solvent is an alcohol or a halogenated solvent or a mixture thereof). Examples of suitable solvents include, but are not limited to, methanol, ethanol, isopropanol, 1-propanol, n-butanol, dichloromethane, and combinations thereof; and preferably ethanol, isopropanol, n-butanol, or 1-propanol. In any aspect or embodiment of this disclosure for the preparation of form M1, the process may include:

[0107] (a) Provide a mixture of Belumosudil methanesulfonate in at least one polar solvent, optionally heated;

[0108] (b) Optionally, the mixture is stirred, optionally at an elevated temperature;

[0109] (c) Optionally, the mixture is cooled, preferably to room temperature;

[0110] (d) Optionally, stir the cooled mixture; and

[0111] (e) Optionally, the crystalline form M1 of Belumosudil methanesulfonate is separated from the mixture.

[0112] The mixture in step (a) can be prepared by the following:

[0113] (i) Provide a mixture of Belumosudil free base in a polar solvent;

[0114] (ii) Combine the mixture with methanesulfonic acid;

[0115] (iii) Optionally, heat the mixture; and

[0116] (iv) Optionally add another polar solvent.

[0117] Preferably, the process for preparing Belumosudil mesylate form M1 according to any embodiment described herein is carried out in the absence of water or substantially in the absence of water, particularly 2 wt% or less, 1 wt% or less, 0.5 wt% or less, 0.2 wt% or less, or 0.1 wt% or less of water.

[0118] According to any embodiment of the process for preparing form M1, the solvent in step (i) is preferably an organic solvent, particularly including alcohols, halogenated solvents, or mixtures thereof. Preferably, the solvent is selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, n-butanol, and dichloromethane, or mixtures thereof, and particularly ethanol, isopropanol, 1-propanol, and n-butanol.

[0119] In step (i), the ratio of solvent to Belumosudil may be: about 10 ml to about 40 ml per gram of Belumosudil, about 14 ml to about 35 ml per gram of Belumosudil, or about 16 ml to about 32 ml per gram of Belumosudil, or about 18 ml to about 24 ml per gram of Belumosudil, and optionally about 20 ml per gram of Belumosudil. The mixture in step (i) may be a solution or a slurry.

[0120] In step (ii) of the process for preparing form M1, the combination of mesylic acid and Belumosudil can be in any order. Preferably, mesylic acid can be added to the mixture of Belumosudil in a solvent. The addition can be done in batches or dropwise. Optionally, mesylic acid is added in amounts of about 0.7 molar equivalents to about 1.5 molar equivalents, about 0.9 molar equivalents to about 1.3 molar equivalents, about 1.0 molar equivalents to about 1.2 molar equivalents, or about 1.1 molar equivalents relative to Belumosudil. Preferably, step (ii) includes adding mesylic acid to the mixture of Belumosudil and a solvent.

[0121] In step (iii) of the process for preparing form M1, the mixture may optionally be heated. The heating may reach a temperature of about 30°C to about 70°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 50°C.

[0122] In step (iv), an additional polar solvent may be added to the reaction mixture. The additional solvent may be any solvent that is poor for Belumosudil methanesulfonate, i.e., a solvent in which Belumosudil methanesulfonate has low solubility. The additional polar solvent may be the same solvent used in step (i), or it may be different. The additional solvent is preferably selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, n-butanol, and dichloromethane, or mixtures thereof. Preferably, the additional polar solvent in step (iv) is selected from methanol, ethanol, isopropanol, 1-propanol, and n-butanol. More preferably, the additional polar solvent in step (iv) is ethanol. The additional polar solvent in step (iv) may be added in any suitable amount. Preferably, the v / v ratio of the additional polar solvent to the solvent in step (i) can be from about 5:1 to about 1:5, or about 2:1 to about 1:2, or about 1.5:1 to about 1:1.5, or about 1.3:1 to about 1:1.3, and preferably about 1:1.3.

[0123] Alternatively, depending on any embodiment of the process used to prepare form M1, the mixture in step (a) can be prepared by:

[0124] (ia) Combining Belumosudil methanesulfonate with a polar solvent, optionally heating to form a solution; and optionally...

[0125] (ii-a) Add organic antisolvents.

[0126] The polar solvent in step (ia) is preferably an organic solvent, more preferably selected from the group consisting of 2,2,2-trifluoroethanol (TFE) and DMSO or mixtures thereof. Specifically, the solvent is selected from the group consisting of TFE and DMSO. In step (ia), the ratio of solvent to Belumosudil methanesulfonate can be: from about 5 ml to about 50 ml, about 7 ml to about 40 ml, about 9 ml to about 35 ml, or about 10 ml to about 30 ml per gram of Belumosudil methanesulfonate.

[0127] The organic antisolvent in step (ii-a) can be any organic solvent in which Belumosudil methanesulfonate is poorly soluble. Preferably, the organic antisolvent in step (ii-a) is selected from the group consisting of acetonitrile, dioxane, methyl ethyl ketone, methyl tert-butyl ketone, ethanol, isopropanol, 1-propanol, n-butanol, and more particularly, ethanol.

[0128] In any embodiment of the process for preparing form M1, the mixture in step (a) can be a solution or a slurry. The mixture in step (a) is preferably in slurry form. The mixture in step (a) can be at room temperature or can be heated. Heating can reach temperatures of about 30°C to about 70°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 50°C. Alternatively, the mixture can be at room temperature.

[0129] In any embodiment of the process for preparing form M1, step (b) is preferably carried out by stirring at the following temperatures: about 30°C to about 70°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 50°C. Alternatively, step (b) can be carried out at room temperature. Stirring can be carried out for any suitable duration. Typically, stirring can be carried out over a period of about 10 minutes to about 2 hours, about 20 minutes to about 1 hour, or about 45 minutes.

[0130] In any embodiment of the process for preparing form M1, step (c) is performed. Preferably, cooling is carried out to room temperature. After cooling, step (d) can be performed, preferably by stirring the cooled mixture for a suitable time to prepare Belumosudil mesylate form M1. Stirring can be carried out for any suitable time, preferably for about 6 hours to about 96 hours, about 20 hours to about 80 hours, about 30 hours to about 50 hours, or about 40 hours.

[0131] In any embodiment of this process, step (e) can be carried out by any suitable method, such as by filtration, decantation, or centrifugation. Separation of solids is preferably by filtration or centrifugation, and more preferably by centrifugation.

[0132] In any implementation, the process may also include washing and / or drying steps.

[0133] This disclosure includes crystalline polymorphs of Belumosudil methanesulfonate designated as form M2. The crystalline form M2 of Belumosudil methanesulfonate can be characterized by one or more of the following data: substantially as Figure 7 The X-ray powder diffraction pattern depicted; the X-ray powder diffraction pattern with peaks at 6.3°2θ±0.2°2θ, 12.8°2θ±0.2°2θ, 15.8°2θ±0.2°2θ, 19.3°2θ±0.2°2θ, and 26.5°2θ±0.2°2θ; the solid-state X-ray powder diffraction pattern with characteristic peaks at 156.1 ppm±0.2 ppm, 132.7 ppm±0.2 ppm, 135.5 ppm±0.2 ppm, 119.8 ppm±0.2 ppm, and 110.9 ppm±0.2 ppm.13 C NMR spectrum; solid-state with the following absolute difference in chemical shift compared to the reference peak at 166.9 ppm ± 1 ppm. 13 C NMR spectra: 10.8 ppm ± 0.1 ppm, 34.2 ppm ± 0.1 ppm, 36.4 ppm ± 0.1 ppm, 47.1 ppm ± 0.1 ppm, and 56.0 ppm ± 0.1 ppm; roughly as follows Figure 19 , Figure 20 and Figure 21 The solid state described in any one of them 13 C NMR spectra; and combinations of these data.

[0134] The crystalline form M2 of Belumosudil methanesulfonate can be further characterized by an X-ray powder diffraction pattern having peaks at 6.3°2θ±0.2°2θ, 12.8°2θ±0.2°2θ, 15.8°2θ±0.2°2θ, 19.3°2θ±0.2°2θ, and 26.5°2θ±0.2°2θ, and also having any two, three, four, or five additional peaks selected from 7.8°2θ±0.2°2θ, 20.4°2θ±0.2°2θ, 23.7°2θ±0.2°2θ, 25.1°2θ±0.2°2θ, and 27.4°2θ±0.2°2θ.

[0135] The crystalline form M2 of Belumosudil methanesulfonate can be optionally characterized by X-ray powder diffraction patterns having peaks at 6.3°2θ±0.2°2θ, 7.8°2θ±0.2°2θ, 12.8°2θ±0.2°2θ, 15.8°2θ±0.2°2θ, 19.3°2θ±0.2°2θ, 20.4°2θ±0.2°2θ, 23.7°2θ±0.2°2θ, 25.1°2θ±0.2°2θ, 26.5°2θ±0.2°2θ, and 27.4°2θ±0.2°2θ.

[0136] According to any aspect or embodiment of this disclosure, the crystalline form M2 of Belumosudil methanesulfonate can be a hydrate, preferably a dihydrate. Alternatively, according to any aspect or embodiment of this disclosure, the crystalline form M2 of Belumosudil methanesulfonate may contain about 1% to about 7% water by weight, preferably about 1.5% to about 6.1% water.

[0137] In one embodiment of this disclosure, the crystalline form M2 of Belumosudil methanesulfonate is isolated. Specifically, the crystalline form M2 of Belumosudil methanesulfonate according to any aspect or embodiment of this disclosure can be isolated.

[0138] According to any aspect or embodiment of this disclosure, the crystalline form M2 of Belumosudil methanesulfonate is non-hygroscopic. In particular, the Belumosudil methanesulfonate form M2 according to any aspect or embodiment is polymorphically stable at room temperature and at a relative humidity of up to 100% for at least 7 days.

[0139] The crystalline form M2 of Belumosudil methanesulfonate can be characterized individually by each of the above characteristics and / or by all possible combinations thereof, for example, by an XRPD plot having peaks at 6.3°2θ ± 0.2°2θ, 12.8°2θ ± 0.2°2θ, 15.8°2θ ± 0.2°2θ, 19.3°2θ ± 0.2°2θ, and 26.5°2θ ± 0.2°2θ; as Figure 7 The XRPD diagram and its combination depicted in the document.

[0140] The crystalline form M2 of Belumosudil methanesulfonate can be prepared by crystallization from a mixture comprising Belumosudil methanesulfonate and water, and optionally one or more polar organic solvents (preferably alcohols or mixtures thereof). Examples of suitable solvents include, but are not limited to, methanol, isopropanol, 1-propanol, and n-butanol. Water may be present in amounts ranging from about 1 ml to about 60 ml per mmol of Belumosudil. In any embodiment, the process comprises:

[0141] (a) Provide a mixture of Belumosudil methanesulfonate in water and optionally one or more polar organic solvents, optionally heated.

[0142] (b) Optionally, the mixture is stirred, optionally at an elevated temperature;

[0143] (c) Optionally, cool the mixture;

[0144] (d) Optionally, stir the cooled mixture; and

[0145] (e) Optionally, the crystalline form M2 of Belumosudil methanesulfonate is separated from the mixture.

[0146] In any implementation of the process, the mixture in step (a) can be prepared by:

[0147] (i) Provide a mixture of Belumosudil free base in water or a mixture of water and at least one polar organic solvent;

[0148] (ii) combining the mixture with methanesulfonic acid; and

[0149] (iii) Optionally heat the mixture.

[0150] According to any embodiment of the process for preparing Belumosudil methanesulfonate M2, the polar organic solvent in step (i) may preferably comprise an alcohol or a mixture thereof. Preferably, the polar organic solvent in step (i) is selected from methanol, isopropanol, 1-propanol, and n-butanol or a mixture thereof; more preferably, the polar organic solvent in step (i) is methanol, ethanol, isopropanol, 1-propanol, or n-butanol, and most preferably ethanol.

[0151] According to any embodiment of the process for preparing Belumosudil mesylate in form M2, the ratio of solvent to Belumosudil in step (i) may be: about 10 ml to about 40 ml per gram of Belumosudil, about 14 ml to about 35 ml per gram of Belumosudil, or about 16 ml to about 28 ml per gram of Belumosudil, or about 18 ml to about 24 ml per gram of Belumosudil, and optionally about 20 ml per gram of Belumosudil. The mixture in step (i) may be a solution or a slurry.

[0152] According to any embodiment of the process for preparing Belmosudil mesylate form M2, in step (ii), the combination of mesylate and Belmosudil can be in any order. Preferably, mesylate can be added to the mixture of Belmosudil in a solvent. The addition can be done in batches or dropwise. Optionally, mesylate is added in amounts of about 0.7 molar equivalents to about 1.5 molar equivalents, about 0.9 molar equivalents to about 1.3 molar equivalents, about 1.0 molar equivalents to about 1.2 molar equivalents, or about 1.1 molar equivalents relative to Belmosudil. Preferably, step (ii) comprises adding mesylate to the mixture of Belmosudil and a solvent.

[0153] In step (iii) of the process for preparing Belumosudil form M2, the mixture may optionally be heated. Heating may reach temperatures of about 30°C to about 70°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 50°C. Heating may be carried out for any suitable period of time to form a solution of Belumosudil methanesulfonate.

[0154] Alternatively, in any aspect or embodiment of the invention, in the process for preparing Belumosudil form M2, the mixture in step (a) can be prepared by a process comprising:

[0155] (ib) Combining Belumosudil methanesulfonate with a polar organic solvent, optionally heating, to produce a solution; and

[0156] (ii-b) Add water as an antisolvent.

[0157] According to any embodiment of the process for preparing Belumosudil methanesulfonate in form M2, the polar organic solvent in step (ib) is preferably selected from the group consisting of TFE, DMSO, and / or mixtures thereof. In particular, the solvent is selected from the group consisting of TFE and DMSO. The proportion of the polar organic solvent in step (ib) is preferably about 5 to 60 ml, about 7 ml to about 50 ml, or about 10 ml to about 45 ml, or about 10 ml to about 40 ml per gram of Belumosudil methanesulfonate.

[0158] Alternatively, in the process for preparing Belumosudil form M2 according to any aspect or embodiment of the invention, the mixture in step (a) can be prepared by a process comprising: (ic) combining Belumosudil methanesulfonate with water to produce a slurry. Preferably, the Belumosudil methanesulfonate is form M1 as described in any aspect or embodiment herein. Preferably, the proportion of water in step (ic) is preferably from about 10 ml to 60 ml, from about 20 ml to about 50 ml, from about 30 ml to about 45 ml, or about 40 ml per gram of Belumosudil methanesulfonate.

[0159] In any embodiment of this process, step (b) is performed. Step (b) is preferably performed under heating, preferably at the following temperatures: about 30°C to about 80°C, about 40°C to about 75°C, about 45°C to about 70°C, about 45°C to about 65°C, about 48°C to about 62°C, or about 50°C to about 60°C. Stirring can be performed for any suitable period of time.

[0160] In any embodiment of the process for preparing form M2, step (c) is performed. Step (c) preferably includes cooling the mixture to room temperature.

[0161] In any embodiment of the process used to prepare form M2, step (d) may be performed. Stirring may continue for any suitable time to prepare form M2.

[0162] In any embodiment of the process for preparing crystalline Belumosudil methanesulfonate form M2, step (e) can be carried out by any suitable method, such as by filtration, decantation, or centrifugation. Separation of the solids is preferably by filtration or centrifugation, and more preferably by centrifugation.

[0163] In any implementation, the process may also include washing and / or drying steps.

[0164] This disclosure includes crystalline polymorphs of Belumosudil methanesulfonate designated as form M3. The crystalline form M3 of Belumosudil methanesulfonate can be characterized by one or more of the following data: substantially as Figure 8 The X-ray powder diffraction patterns depicted; X-ray powder diffraction patterns with peaks at 7.3°2θ±0.2°2θ, 14.6°2θ±0.2°2θ, 16.6°2θ±0.2°2θ, 17.5°2θ±0.2°2θ, and 19.6°2θ±0.2°2θ; and combinations of these data.

[0165] The crystalline form M3 of Belumosudil methanesulfonate can be further characterized by an X-ray powder diffraction pattern having peaks at 7.3°2θ±0.2°2θ, 14.6°2θ±0.2°2θ, 16.6°2θ±0.2°2θ, 17.5°2θ±0.2°2θ, and 19.6°2θ±0.2°2θ, and also having any two, three, four, or five additional peaks selected from 12.9°2θ±0.2°2θ, 13.7°2θ±0.2°2θ, 19.0°2θ±0.2°2θ, 20.6°2θ±0.2°2θ, and 26.0°2θ±0.2°2θ.

[0166] The crystalline form M3 of Belumosudil methanesulfonate can be optionally characterized by X-ray powder diffraction patterns having peaks at 7.3°2θ±0.2°2θ, 12.9°2θ±0.2°2θ, 13.7°2θ±0.2°2θ, 14.6°2θ±0.2°2θ, 16.6°2θ±0.2°2θ, 17.5°2θ±0.2°2θ, 19.0°2θ±0.2°2θ, 19.6°2θ±0.2°2θ, 20.6°2θ±0.2°2θ, and 26.0°2θ±0.2°2θ.

[0167] In one embodiment of this disclosure, the crystalline form M3 of Belumosudil methanesulfonate was isolated.

[0168] The crystalline form M3 of Belumosudil methanesulfonate can be characterized individually by each of the above characteristics and / or by all possible combinations thereof, for example, by an XRPD plot having peaks at 7.3°2θ ± 0.2°2θ, 14.6°2θ ± 0.2°2θ, 16.6°2θ ± 0.2°2θ, 17.5°2θ ± 0.2°2θ, and 19.6°2θ ± 0.2°2θ; as Figure 8 The XRPD diagram and its combination depicted in the document.

[0169] This disclosure includes crystalline polymorphs of Belumosudil methanesulfonate designated as form M4. The crystalline form M4 of Belumosudil methanesulfonate can be characterized by one or more of the following data: substantially as Figure 11 The X-ray powder diffraction pattern depicted; the X-ray powder diffraction pattern having peaks at 7.5°2θ±0.2°2θ, 15.0°2θ±0.2°2θ, 17.9°2θ±0.2°2θ, 21.8°2θ±0.2°2θ, and 22.6°2θ±0.2°2θ; and combinations of these data.

[0170] The crystalline form M4 of Belumosudil methanesulfonate can be further characterized by an X-ray powder diffraction pattern having peaks at 7.5°2θ±0.2°2θ, 15.0°2θ±0.2°2θ, 17.9°2θ±0.2°2θ, 21.8°2θ±0.2°2θ, and 22.6°2θ±0.2°2θ, and also having any two, three, four, or five additional peaks selected from 11.3°2θ±0.2°2θ, 17.4°2θ±0.2°2θ, 20.9°2θ±0.2°2θ, 24.2°2θ±0.2°2θ, and 29.2°2θ±0.2°2θ.

[0171] The crystalline form M4 of Belumosudil methanesulfonate can be optionally characterized by X-ray powder diffraction patterns having peaks at 7.5°2θ±0.2°2θ, 11.3°2θ±0.2°2θ, 15.0°2θ±0.2°2θ, 17.4°2θ±0.2°2θ, 17.9°2θ±0.2°2θ, 20.9°2θ±0.2°2θ, 21.8°2θ±0.2°2θ, 22.6°2θ±0.2°2θ, 24.2°2θ±0.2°2θ, and 29.2°2θ±0.2°2θ.

[0172] In one embodiment of this disclosure, the crystalline form M4 of Belumosudil methanesulfonate was isolated.

[0173] The crystalline form M4 of Belumosudil methanesulfonate can be characterized individually by each of the above characteristics and / or by all possible combinations thereof, for example, by an XRPD plot having peaks at 7.5°2θ ± 0.2°2θ, 15.0°2θ ± 0.2°2θ, 17.9°2θ ± 0.2°2θ, 21.8°2θ ± 0.2°2θ, and 22.6°2θ ± 0.2°2θ; as Figure 11 The XRPD diagram and its combination depicted in the document.

[0174] This disclosure includes crystalline polymorphs of Belumosudil methanesulfonate designated as form M5. The crystalline form M5 of Belumosudil methanesulfonate can be characterized by one or more of the following data: substantially as Figure 12 The X-ray powder diffraction pattern depicted; the X-ray powder diffraction pattern having peaks at 6.2°2θ±0.2°2θ, 15.7°2θ±0.2°2θ, 18.4°2θ±0.2°2θ, 19.2°2θ±0.2°2θ and 25.1°2θ±0.2°2θ; and combinations of these data.

[0175] The crystalline form M5 of Belumosudil methanesulfonate can be further characterized by an X-ray powder diffraction pattern having peaks at 6.2°2θ±0.2°2θ, 15.7°2θ±0.2°2θ, 18.4°2θ±0.2°2θ, 19.2°2θ±0.2°2θ, and 25.1°2θ±0.2°2θ, and also having any two, three, four, or five additional peaks selected from 17.8°2θ±0.2°2θ, 21.6°2θ±0.2°2θ, 21.9°2θ±0.2°2θ, 24.7°2θ±0.2°2θ, and 25.9°2θ±0.2°2θ.

[0176] The crystalline form M5 of Belumosudil methanesulfonate can be optionally characterized by X-ray powder diffraction patterns having peaks at 6.2° ± 0.2° 2θ, 15.7° ± 0.2° 2θ, 17.8° ± 0.2° 2θ, 18.4° ± 0.2° 2θ, 19.2° ± 0.2° 2θ, 21.6° ± 0.2° 2θ, 21.9° ± 0.2° 2θ, 24.7° ± 0.2° 2θ, 25.1° ± 0.2° 2θ, and 25.9° ± 0.2° 2θ.

[0177] In one embodiment of this disclosure, the crystalline form M5 of Belumosudil methanesulfonate was isolated.

[0178] The crystalline form M5 of Belumosudil methanesulfonate can be characterized individually by each of the above characteristics and / or by all possible combinations thereof, for example, by an XRPD plot having peaks at 6.2° ± 0.2°, 15.7° ± 0.2°, 18.4° ± 0.2°, 19.2° ± 0.2°, and 25.1° ± 0.2°; as Figure 12 The XRPD diagram and its combination depicted in the document.

[0179] This disclosure includes crystalline polymorphs of Belumosudil benzenesulfonate designated as form BS1. The crystalline form BS1 of Belumosudil benzenesulfonate can be characterized by one or more of the following data: substantially as Figure 13 The X-ray powder diffraction pattern depicted; the X-ray powder diffraction pattern with peaks at 6.6°2θ±0.2°2θ, 12.5°2θ±0.2°2θ, 14.9°2θ±0.2°2θ, 17.0°2θ±0.2°2θ, and 20.1°2θ±0.2°2θ; the solid-state X-ray powder diffraction pattern with characteristic peaks at 158.9 ppm±0.2 ppm, 146.8 ppm±0.2 ppm, 134.3 ppm±0.2 ppm, 121.3 ppm±0.2 ppm, and 117.6 ppm±0.2 ppm. 13 C NMR spectrum; solid-state sample with the following absolute chemical shift difference compared to the reference peak at 169.6 ppm ± 1 ppm. 13 C NMR spectra: 10.7 ppm ± 0.1 ppm, 22.8 ppm ± 0.1 ppm, 35.3 ppm ± 0.1 ppm, 48.3 ppm ± 0.1 ppm and 52.0 ppm ± 0.1 ppm; roughly as Figure 22 , Figure 23 and Figure 24 The solid state described in any one of them 13 C NMR spectra; and combinations of these data.

[0180] The crystalline form of belumosudil benzenesulfonate, BS1, can be further characterized by an X-ray powder diffraction pattern having peaks at 6.6°2θ±0.2°2θ, 12.5°2θ±0.2°2θ, 14.9°2θ±0.2°2θ, 17.0°2θ±0.2°2θ, and 20.1°2θ±0.2°2θ, and also having any two, three, four, or five additional peaks selected from 11.6°2θ±0.2°2θ, 17.6°2θ±0.2°2θ, 18.2°2θ±0.2°2θ, 21.7°2θ±0.2°2θ, and 25.1°2θ±0.2°2θ.

[0181] The crystalline form of belumosudil benzenesulfonate, BS1, can be optionally characterized by X-ray powder diffraction patterns having peaks at 6.6°2θ±0.2°2θ, 11.6°2θ±0.2°2θ, 12.5°2θ±0.2°2θ, 14.9°2θ±0.2°2θ, 17.0°2θ±0.2°2θ, 17.6°2θ±0.2°2θ, 18.2°2θ±0.2°2θ, 20.1°2θ±0.2°2θ, 21.7°2θ±0.2°2θ, and 25.1°2θ±0.2°2θ.

[0182] The crystalline form of Belumosudil benzenesulfonate, BS1, can be in an anhydrous form, as can be determined by TGA. In some embodiments, this disclosure includes the crystalline form of Belumosudil benzenesulfonate, BS1, having a total residual solvent of 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less. According to any aspect or embodiment described herein, the crystalline form of Belumosudil benzenesulfonate, BS1, may contain 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less of total residual solvent. The residual organic solvent may be one or more polar solvents, preferably water, alcohol (especially C...). 1-4 The solvent may contain alcohols, particularly ethanol, methanol, isopropanol, 1-propanol, or n-butanol, and most preferably, the residual organic solvent may be ethanol. In particular, the crystalline form BS1 of Belumosudil benzenesulfonate according to any aspect or embodiment of this disclosure may contain 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less of ethanol.

[0183] In one embodiment of this disclosure, the crystalline form BS1 of Belumosudil benzenesulfonate is isolated. Specifically, the crystalline form BS1 of Belumosudil benzenesulfonate according to any aspect or embodiment of this disclosure can be isolated.

[0184] In any aspect or embodiment of this disclosure, the crystalline form of Belumosudil methanesulfonate, BS1, is non-hygroscopic. In particular, the Belumosudil methanesulfonate form BS1 according to any aspect or embodiment is polymorphically stable at room temperature and at relative humidity up to 100% for at least 7 days.

[0185] The crystalline form of belumosudil benzenesulfonate, BS1, can be characterized individually by each of the above characteristics and / or by all possible combinations thereof, for example, by an XRPD plot having peaks at 6.6°2θ ± 0.2°2θ, 12.5°2θ ± 0.2°2θ, 14.9°2θ ± 0.2°2θ, 17.0°2θ ± 0.2°2θ, and 20.1°2θ ± 0.2°2θ; as shown Figure 13 The XRPD diagram and its combination depicted in the document.

[0186] The crystalline form of Belumosudil benzenesulfonate, BS1, can be prepared by crystallization from a mixture comprising Belumosudil benzenesulfonate and a polar solvent such as ethanol. In any aspect or embodiment, the process includes:

[0187] (a) Providing a mixture of Belumosudil benzenesulfonate in one or more polar solvents;

[0188] (b) Optionally, the mixture is stirred, optionally at an elevated temperature;

[0189] (c) Optionally, cool the mixture; and

[0190] (d) Optionally, the crystalline form of Belumosudil benzenesulfonate BS1 is separated from the mixture.

[0191] In any embodiment of the process used to prepare form BS1, the mixture in step (a) can be prepared by:

[0192] (i) Providing a mixture of Belumosudil free base (preferably in form B1 as described herein) in a polar solvent; and

[0193] (ii) Combine the mixture with benzenesulfonic acid.

[0194] In any embodiment of the process for preparing form BS1, the polar solvent in step (i) is preferably an alcohol (especially C14). 1-4 Alcohols, especially ethanol, methanol, isopropanol, 1-propanol, or n-butanol. Preferably, the polar solvent includes ethanol or isopropanol, and more preferably, the polar solvent is ethanol. In step (i), the ratio of solvent to Belumosudil can be: about 10 ml to about 40 ml per gram of Belumosudil, about 14 ml to about 35 ml per gram of Belumosudil, or about 16 ml to about 28 ml per gram of Belumosudil, or about 18 ml to about 24 ml per gram of Belumosudil, and optionally about 20 ml per gram of Belumosudil. The mixture can be a solution or a slurry.

[0195] In any aspect or embodiment of the process for preparing form BS1, step (ii) includes combining benzenesulfonic acid with Belumosudil. The combination can be in any order. Preferably, benzenesulfonic acid can be added to a mixture of Belumosudil in a solvent. The addition can be done in batches or dropwise. Benzenesulfonic acid is optionally added in amounts of about 0.7 molar equivalents to about 1.5 molar equivalents, about 0.9 molar equivalents to about 1.3 molar equivalents, about 1.0 molar equivalents to about 1.2 molar equivalents, or about 1.1 molar equivalents relative to Belumosudil. Preferably, step (ii) includes adding benzenesulfonic acid to a mixture of Belumosudil and a polar solvent.

[0196] Alternatively, in any embodiment of the process for preparing form BS1, the mixture in step (a) can be prepared by combining Belumosudil benzenesulfonate with a polar solvent. Preferably, the polar solvent is an alcohol (especially C125-4 ... 1-4 Alcohols, especially ethanol, methanol, isopropanol, 1-propanol or n-butanol, and most preferably, the polar solvent is ethanol.

[0197] In any embodiment of the process for preparing form BS1, step (b) is preferably carried out by stirring at room temperature, more preferably by stirring at temperatures of about 30°C to about 70°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 50°C. Preferably, stirring is carried out at a specific temperature. Stirring can be carried out for any suitable time to form the belumosudil benzenesulfonate form BS1. Typically, stirring can be carried out over a time period of about 10 minutes to about 2 hours, about 20 minutes to about 1 hour, or about 45 minutes.

[0198] In any embodiment of the process for preparing form BS1, step (c) is performed, preferably wherein cooling is achieved to room temperature.

[0199] In any embodiment of the process for preparing form BS1, step (d) can be carried out by any suitable method, such as by filtration, decantation, or centrifugation. Separation of the solids is preferably by filtration or centrifugation, and more preferably by centrifugation.

[0200] In any implementation, the process for preparing form BS1 may also include washing and / or drying steps.

[0201] This disclosure includes crystalline polymorphs of Belumosudil toluenesulfonate designated as form T1. The crystalline form T1 of Belumosudil toluenesulfonate can be characterized by one or more of the following data: substantially as Figure 14 The X-ray powder diffraction pattern depicted; the X-ray powder diffraction pattern with peaks at 6.2°2θ±0.2°2θ, 12.3°2θ±0.2°2θ, 14.1°2θ±0.2°2θ, 17.7°2θ±0.2°2θ, and 18.4°2θ±0.2°2θ; the solid-state X-ray powder diffraction pattern with characteristic peaks at 152.6 ppm±0.2 ppm, 143.4 ppm±0.2 ppm, 132.3 ppm±0.2 ppm, 125.3 ppm±0.2 ppm, and 119.8 ppm±0.2 ppm. 13 C NMR spectrum; solid-state sample with the following absolute chemical shift difference compared to the reference peak at 168.6 ppm ± 1 ppm. 13 C NMR spectra: 16.0 ppm ± 0.1 ppm, 25.2 ppm ± 0.1 ppm, 36.3 ppm ± 0.1 ppm, 43.3 ppm ± 0.1 ppm and 48.8 ppm ± 0.1 ppm; roughly as Figure 26 , Figure 27 and Figure 28 The solid state described in any one of them 13 C NMR spectra; and combinations of these data.

[0202] The crystalline form T1 of Belumosudil tosylate can be further characterized by an X-ray powder diffraction pattern having peaks at 6.2°2θ±0.2°2θ, 12.3°2θ±0.2°2θ, 14.1°2θ±0.2°2θ, 17.7°2θ±0.2°2θ, and 18.4°2θ±0.2°2θ, and also having any two, three, four, or five additional peaks selected from 9.9°2θ±0.2°2θ, 14.5°2θ±0.2°2θ, 16.7°2θ±0.2°2θ, 21.5°2θ±0.2°2θ, and 24.6°2θ±0.2°2θ.

[0203] The crystalline form T1 of Belumosudil tosylate can be optionally characterized by X-ray powder diffraction patterns having peaks at 6.2°2θ±0.2°2θ, 9.9°2θ±0.2°2θ, 12.3°2θ±0.2°2θ, 14.1°2θ±0.2°2θ, 14.5°2θ±0.2°2θ, 16.7°2θ±0.2°2θ, 17.7°2θ±0.2°2θ, 18.4°2θ±0.2°2θ, 21.5°2θ±0.2°2θ, and 24.6°2θ±0.2°2θ.

[0204] The crystalline form T1 of Belumosudil toluenesulfonate can be anhydrous, as can be determined by TGA. In some embodiments, this disclosure includes the crystalline form T1 of Belumosudil toluenesulfonate having a total residual solvent of 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less. The residual solvent can be one or more polar solvents, preferably water and / or alcohols (especially C450-4 ... 1-4 The residual organic solvent may be methanol (especially ethanol, methanol, isopropanol, 1-propanol or n-butanol), and most preferably, the residual organic solvent may be methanol. In particular, the crystalline form T1 of Belumosudil tosylate according to any aspect or embodiment of this disclosure may contain 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less methanol.

[0205] In one embodiment of this disclosure, the crystalline form T1 of Belumosudil tosylate is isolated. In particular, the crystalline form T1 of Belumosudil tosylate according to any aspect or embodiment of this disclosure can be isolated.

[0206] In any aspect or embodiment of this disclosure, the crystalline form T1 of Belumosudil toluenesulfonate is non-hygroscopic. In particular, the form T1 of Belumosudil toluenesulfonate according to any aspect or embodiment is polymorphically stable at room temperature and at a relative humidity of up to 100% for at least 7 days.

[0207] The crystalline form T1 of Belumosudil tosylate can be characterized individually by each of the above characteristics and / or by all possible combinations thereof, for example, by an XRPD plot having peaks at 6.2° ± 0.2°, 12.3° ± 0.2°, 14.1° ± 0.2°, 17.7° ± 0.2°, and 18.4° ± 0.2°; as Figure 14 The XRPD diagram and its combination depicted in the document.

[0208] The crystalline form T1 of Belumosudil toluenesulfonate can be prepared by crystallization from a mixture comprising Belumosudil toluenesulfonate and one or more polar solvents such as alcohols. Preferably, the solvent is methanol. In any embodiment, the process includes:

[0209] (a) Providing a mixture of Belumosudil toluenesulfonate in one or more polar solvents (preferably including methanol);

[0210] (b) Optionally, the mixture is stirred, optionally at an elevated temperature;

[0211] (c) Optionally, cool the mixture; and

[0212] (d) Optionally, the crystalline form T1 of Belumosudil toluenesulfonate is separated from the mixture.

[0213] In any implementation of the process, the mixture in step (a) can be prepared by:

[0214] (i) Provide a mixture of Belumosudil free base in a polar solvent; and

[0215] (ii) Combine the mixture with toluenesulfonic acid.

[0216] Preferably, the process for preparing Belumosudil toluenesulfonate form T1 according to any embodiment described herein is carried out in the absence of water or substantially in the absence of water, particularly 2 wt% or less, 1 wt% or less, 0.5 wt% or less, 0.2 wt% or less, or 0.1 wt% or less of water.

[0217] In any aspect or embodiment of the process used to prepare form T1, the polar solvent is preferably an alcohol (especially C125-240 ...50-240-240-250-240-250-240-250-240-250-240-250-240-250-240-250-240-250-240-250-250-240-250-250-260-250-250-260-250-250-260-250-250-260-25 1-4 The solvent is an alcohol, particularly ethanol, methanol, isopropanol, 1-propanol, or n-butanol, and most preferably, methanol is the polar solvent. In step (i), the ratio of solvent to Belumosudil can be: about 10 ml to about 40 ml per gram of Belumosudil, about 14 ml to about 35 ml per gram of Belumosudil, or about 16 ml to about 28 ml per gram of Belumosudil, or about 18 ml to about 24 ml per gram of Belumosudil, and optionally about 20 ml per gram of Belumosudil. The mixture can be a solution or a slurry.

[0218] In step (ii), the combination of toluenesulfonic acid and Belumosudil can be in any order. Preferably, toluenesulfonic acid can be added to the mixture of Belumosudil and solvent. The addition can be done in batches or dropwise. Toluenesulfonic acid is optionally added in amounts of about 0.7 molar equivalents to about 1.5 molar equivalents, about 0.9 molar equivalents to about 1.3 molar equivalents, about 1.0 molar equivalents to about 1.2 molar equivalents, or about 1.1 molar equivalents relative to Belumosudil. Preferably, step (ii) comprises adding toluenesulfonic acid to the mixture of Belumosudil and solvent.

[0219] Alternatively, in any embodiment of the process for preparing form T1, the mixture in step (a) can be prepared by combining Belumosudil toluenesulfonate with a polar solvent. Preferably, the polar solvent is an alcohol (especially C125-240 ...50-240-240-240-250-240-240-250-240-240-250-240-240-250-240-250-240-250-240-250-240-250-240-250-240-250-240-250-240-250-240-250-240-250-240-250-240-250-240-250-240-250-240-250-240-250-240-250-240-250-240-250-24 1-4 Alcohols, especially ethanol, methanol, isopropanol, 1-propanol or n-butanol, and most preferably, the polar solvent is methanol.

[0220] In any embodiment of the process for preparing form T1, step (b) is preferably carried out by stirring at the following temperatures: about 30°C to about 70°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 50°C. Stirring can be carried out for any suitable time.

[0221] In any embodiment of the process for preparing form T1, step (c) is performed, preferably wherein cooling is achieved to room temperature.

[0222] In any embodiment of the process for preparing form T1, step (d) can be carried out by any suitable method, such as by filtration, decantation, or centrifugation. Separation of the solids is preferably by filtration or centrifugation, and more preferably by centrifugation.

[0223] In any embodiment of the process for preparing form T1, the process may also include washing and / or drying steps.

[0224] This disclosure includes crystalline polymorphs of Belumosudil toluenesulfonate, designated as form T2. The crystalline form T2 of Belumosudil toluenesulfonate can be characterized by one or more of the following data: substantially as Figure 15 The X-ray powder diffraction pattern depicted; the X-ray powder diffraction pattern with peaks at 5.1°2θ±0.2°2θ, 15.7°2θ±0.2°2θ, 16.4°2θ±0.2°2θ, 19.7°2θ±0.2°2θ, and 23.7°2θ±0.2°2θ; the solid-state X-ray powder diffraction pattern with characteristic peaks at 141.7 ppm±0.2 ppm, 140.2 ppm±0.2 ppm, 131.1 ppm±0.2 ppm, 125.9 ppm±0.2 ppm, and 124.2 ppm±0.2 ppm. 13 C NMR spectrum; solid-state sample with the following absolute chemical shift difference compared to the reference peak at 166.3 ppm ± 1 ppm. 13 C NMR spectra: 24.6 ppm ± 0.1 ppm, 26.1 ppm ± 0.1 ppm, 35.2 ppm ± 0.1 ppm, 40.4 ppm ± 0.1 ppm, and 42.1 ppm ± 0.1 ppm; roughly as follows Figure 30 , Figure 31 and Figure 32 The solid state described in any one of them 13 C NMR spectra; and combinations of these data.

[0225] The crystalline form T2 of Belumosudil tosylate can be further characterized by an X-ray powder diffraction pattern having peaks at 5.1°2θ±0.2°2θ, 15.7°2θ±0.2°2θ, 16.4°2θ±0.2°2θ, 19.7°2θ±0.2°2θ, and 23.7°2θ±0.2°2θ, and also having any two, three, four, or five additional peaks selected from 13.7°2θ±0.2°2θ, 14.2°2θ±0.2°2θ, 14.6°2θ±0.2°2θ, 19.1°2θ±0.2°2θ, and 23.0°2θ±0.2°2θ.

[0226] The crystalline form T2 of Belumosudil tosylate can be optionally characterized by X-ray powder diffraction patterns having peaks at 5.1°2θ±0.2°2θ, 13.7°2θ±0.2°2θ, 14.2°2θ±0.2°2θ, 14.6°2θ±0.2°2θ, 15.7°2θ±0.2°2θ, 16.4°2θ±0.2°2θ, 19.1°2θ±0.2°2θ, 19.7°2θ±0.2°2θ, 23.0°2θ±0.2°2θ, and 23.7°2θ±0.2°2θ.

[0227] The crystalline form T2 of Belumosudil toluenesulfonate can be anhydrous, as can be determined by TGA. In some embodiments, this disclosure includes the crystalline form T2 of Belumosudil toluenesulfonate having a total residual solvent of 1% w / w or less, or 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less. The residual solvent can be one or more polar solvents, preferably water or alcohol (especially C445). 1-4 The residual organic solvent may be water and / or ethanol (especially ethanol, methanol, isopropanol, 1-propanol, or n-butanol). Specifically, the crystalline form T2 of Belmosudil tosylate according to any aspect or embodiment of this disclosure may contain 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less ethanol. In one embodiment of this disclosure, the crystalline form T2 of Belmosudil tosylate is isolated. Specifically, the crystalline form T2 of Belmosudil tosylate according to any aspect or embodiment of this disclosure can be isolated.

[0228] In any aspect or embodiment of this disclosure, the crystalline form T2 of Belumosudil methanesulfonate is non-hygroscopic. In particular, the form T2 of Belumosudil methanesulfonate according to any aspect or embodiment is polymorphically stable at room temperature and at a relative humidity of up to 100% for at least 7 days.

[0229] The crystalline form T2 of Belumosudil tosylate can be characterized individually by each of the above characteristics and / or by all possible combinations thereof, for example, by an XRPD plot having peaks at 5.1°2θ ± 0.2°2θ, 15.7°2θ ± 0.2°2θ, 16.4°2θ ± 0.2°2θ, 19.7°2θ ± 0.2°2θ, and 23.7°2θ ± 0.2°2θ; as Figure 15 The XRPD diagram and its combination depicted in the document.

[0230] The crystalline form T2 of Belumosudil toluenesulfonate can be prepared by crystallization from a mixture comprising Belumosudil toluenesulfonate and one or more polar solvents such as water. In any embodiment, the process includes:

[0231] (a) Providing a mixture of Belumosudil toluenesulfonate in one or more polar solvents;

[0232] (b) Optionally, the mixture is stirred, optionally at an elevated temperature;

[0233] (c) Optionally cool to room temperature; and

[0234] (d) Optionally, the crystalline form T2 of Belumosudil toluenesulfonate is separated from the mixture.

[0235] In any embodiment of the process used to prepare form T2, the mixture in step (a) can be prepared by:

[0236] (i) Providing a mixture of Belumosudil free base (preferably in form B1 as described herein) in a polar solvent, said polar solvent preferably comprising water and / or ethanol; and

[0237] (ii) Combining the mixture with toluenesulfonic acid, optionally combining the mixture with toluenesulfonic acid at an elevated temperature; and

[0238] (iii) Optionally add a polar solvent.

[0239] In any aspect or embodiment of the process for preparing form T2, the polar solvent in step (i) preferably comprises water, and more preferably, the polar solvent in step (i) is water. In step (i), the ratio of solvent to Belumosudil can be: about 10 ml to about 40 ml per gram of Belumosudil, about 14 ml to about 35 ml per gram of Belumosudil, or about 16 ml to about 28 ml per gram of Belumosudil, or about 18 ml to about 24 ml per gram of Belumosudil, about 20 ml to about 30 ml per gram of Belumosudil, and optionally about 20 ml per gram of Belumosudil. The mixture can be a solution or a slurry.

[0240] In any aspect or embodiment of the process for preparing form T2, step (ii) includes combining toluenesulfonic acid with Belumosudil in any order. Preferably, toluenesulfonic acid can be added to a mixture of Belumosudil in a solvent. The addition can be done in batches or dropwise. Toluenesulfonic acid is optionally added in amounts of about 0.7 molar equivalents to about 1.5 molar equivalents, about 0.9 molar equivalents to about 1.3 molar equivalents, about 1.0 molar equivalents to about 1.2 molar equivalents, or about 1.1 molar equivalents relative to Belumosudil. Preferably, step (ii) includes adding toluenesulfonic acid to a mixture of Belumosudil and a solvent.

[0241] In any aspect or embodiment of the process for preparing form T2, in step (iii), the polar solvent is preferably selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, and n-butanol. More preferably, the polar solvent in step (iii) is ethanol. In step (iii), the ratio of total solvent to Belumosudil can be from about 20 ml to about 50 ml, about 20 ml to about 40 ml, about 22 ml to about 35 ml, or about 25 ml per gram of Belumosudil.

[0242] Alternatively, in any embodiment of the process for preparing form T2, the mixture in step (a) can be prepared by combining Belumosudil toluenesulfonate with one or more polar solvents. Preferably, the polar solvent is water and / or an alcohol (especially C42-2 ... 1-4 Alcohols, especially ethanol, methanol, isopropanol, 1-propanol, or n-butanol. Preferably, the polar solvents are water and ethanol.

[0243] In any embodiment of the process for preparing form T2, step (b) is preferably carried out by stirring at the following temperatures: about 30°C to about 70°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 50°C. Stirring can be carried out for any suitable duration. Typically, stirring can be carried out over a time period of about 10 minutes to about 2 hours, about 20 minutes to about 1 hour, or about 50 minutes.

[0244] In any embodiment of the process for preparing form T2, the mixture may be cooled, preferably to room temperature, and step (d) may be carried out by any suitable method, such as by filtration, decantation, or centrifugation. Separation of solids is preferably by filtration or centrifugation, and more preferably by centrifugation.

[0245] In any implementation, the process may also include washing and / or drying steps.

[0246] The aforementioned crystalline polymorphs of Belumosudil or its salts (including Belumosudil methanesulfonate, Belumosudil toluenesulfonate and / or Belumosudil benzenesulfonate) can be used to prepare other crystalline polymorphs of Belumosudil, Belumosudil salts and their solid forms.

[0247] This disclosure covers processes for preparing other solid forms of Belmosudil, Belmosudil salts, and solid forms thereof. The process includes preparing any solid form of Belmosudil or a salt thereof using the process of this disclosure, and converting the salt into the other Belmosudil salt. For example, the conversion can be accomplished by a process comprising: basifying any or a combination of the salts described above, such as Belmosudil methanesulfonate, Belmosudil toluenesulfonate, and / or Belmosudil benzenesulfonate, and / or their solid forms, and reacting the resulting Belmosudil base with a suitable acid to obtain the corresponding salt. Alternatively, the conversion can be accomplished by salt switching, i.e., reacting a Belmosudil acid addition salt with an acid whose pKa is lower than that of the first Belmosudil acid addition salt.

[0248] This disclosure provides crystalline polymorphs of Beluosudil or its salts (including Beluosudil mesylate, Beluosudil toluenesulfonate and / or Beluosudil benzenesulfonate) as described above for use in preparing pharmaceutical compositions comprising Beluosudil, its salts and / or its crystalline polymorphs.

[0249] This disclosure also covers the use of crystalline polymorphs of Beluosudil or its salts (such as the crystalline forms of Beluosudil mesylate, Beluosudil tosylate, and / or Beluosudil benzenesulfonate of this disclosure) for the preparation of pharmaceutical compositions comprising crystalline polymorphs of Beluosudil or its salts (such as Beluosudil mesylate, Beluosudil tosylate, and / or Beluosudil benzenesulfonate and / or its crystalline polymorphs).

[0250] In any aspect or embodiment of this disclosure, any solid form of Belumosudil, Belumosudil methanesulfonate, Belumosudil toluenesulfonate and / or Belumosudil benzenesulfonate described herein may be polymorphically pure or may be any other solid form substantially free of the subject compound (i.e., Belumosudil, Belumosudil methanesulfonate, Belumosudil toluenesulfonate and / or Belumosudil benzenesulfonate, respectively). In any aspect or embodiment of this disclosure, any solid form of Belumosudil, Belumosudil mesylate, Belumosudil toluenesulfonate and / or Belumosudil benzenesulfonate may comprise: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, about 0.5% (w / w) or less, about 0.2% (w / w) or less, about 0.1% (w / w) or less, or about 0% of any other solid form of the subject compound, preferably as measured by XRPD. Therefore, any disclosed crystalline form of Belumosudil, Belumosudil methanesulfonate, Belumosudil toluenesulfonate and / or Belumosudil benzenesulfonate described herein may be substantially free of any other solid form of the subject compound and may contain more than about 80% (w / w), more than about 90% (w / w), more than about 95% (w / w), more than about 98% (w / w), more than about 99% (w / w) or about 100% of Belumosudil, Belumosudil methanesulfonate, Belumosudil toluenesulfonate and / or Belumosudil benzenesulfonate in solid form.

[0251] This disclosure includes a process for preparing the pharmaceutical compositions mentioned above. The process includes combining any or a combination of crystalline polymorphs of Belumosudil or its salts thereof with at least one pharmaceutically acceptable excipient.

[0252] The pharmaceutical compositions or pharmaceutical formulations of this disclosure comprise any or a combination of Belumosudil or its salts in solid form as disclosed herein. In addition to the active ingredient, the pharmaceutical formulations of this disclosure may comprise one or more excipients. Excipients are added to the formulation for a variety of purposes. Preferably, the pharmaceutical compositions or pharmaceutical formulations according to any aspect or embodiment of this disclosure are in the form of tablets or capsules, more preferably in the form of tablets.

[0253] Diluents increase the volume of solid pharmaceutical compositions and make the dosage form containing the composition easier for patients and caregivers to handle. Diluents used for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrate, dextrin, dextran, calcium hydrogen phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethyl methacrylate (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0254] Solid pharmaceutical compositions compacted into dosage forms such as tablets may contain excipients that function to help bind the active ingredient and other excipients together after compression. Binders used in solid pharmaceutical compositions include gum arabic, alginate, carbomer (e.g., carbopol), sodium carboxymethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel®), hydroxypropyl methylcellulose (e.g., Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methyl cellulose, polymethyl methacrylate, povidone (e.g., Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0255] Adding a disintegrant to the composition can improve the dissolution rate of compacted solid pharmaceutical compositions in a patient's stomach. Disintegrants include alginate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose (e.g., Ac-Di-Sol®, Primellose®), colloidal silica, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium glycolate starch (e.g., Explotab®), and starch.

[0256] Gliding agents can be added to improve the flowability of uncompacted solid compositions and to improve the accuracy of drug administration. Excipients that can act as gliding agents include colloidal silica, magnesium trisilicate, powdered cellulose, starch, talc, and tricalcium phosphate.

[0257] When preparing dosage forms such as tablets by compacting powdered compositions, the composition undergoes pressure from the punch and die. Some excipients and active ingredients tend to adhere to the surfaces of the punch and die, which can result in pitting and other surface irregularities in the product. Lubricants can be added to the composition to reduce adhesion and facilitate product release from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitate stearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[0258] Flavoring agents and flavor enhancers make dosage forms more palatable to patients. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the compositions disclosed herein include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0259] Solid and liquid compositions can also be stained with any pharmaceutically acceptable colorant to improve their appearance and / or facilitate patient identification of the product and unit dose level.

[0260] In the liquid pharmaceutical compositions of the present invention, Belumosudil and any other solid excipients may be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0261] Liquid pharmaceutical compositions may contain emulsifiers to uniformly disperse active ingredients or other excipients insoluble in a liquid carrier throughout the composition. Emulsifiers that can be used in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, gum arabic, tragacanth, carrageenan, pectin, methylcellulose, carbomer, cetearyl alcohol, and cetyl alcohol.

[0262] The liquid pharmaceutical compositions of the present invention may further comprise viscosity enhancers to improve the palatability of the product and / or coat the inner lining of the gastrointestinal tract. Such enhancers include gum arabic, alginate, bentonite, carbomer, calcium or sodium carboxymethyl cellulose, cetearyl alcohol, methylcellulose, ethylcellulose, gelatin, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium glycolic acid starch, starch, tragacanth gum, xanthan gum, and combinations thereof.

[0263] Sweeteners such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the flavor.

[0264] Preservatives and chelating agents can be added at levels that are safe for ingestion to improve storage stability. These preservatives and chelating agents include alcohols, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid.

[0265] According to this disclosure, the liquid composition may also contain a buffer, such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate. The selection of excipients and the amount used can be readily determined by the formulation scientist based on experience and consideration of standard procedures, as well as references in the art.

[0266] The solid compositions disclosed herein include powders, granules, aggregates, and compacted compositions. Dosages include those suitable for oral administration, sublingual administration, rectal administration, parenteral (including subcutaneous, intramuscular, and intravenous) administration, inhalation administration, and ocular administration. Although the most appropriate administration in any given situation will depend on the nature and severity of the condition being treated, in embodiments, the route of administration is oral. Dosages can be conveniently presented in unit dosage forms and prepared by any method well known in the pharmaceutical industry.

[0267] Dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, lozenges, and tablets, as well as liquid syrups, suspensions, and elixirs.

[0268] The dosage form of this disclosure may be a capsule containing the composition, such as a powdered or granular solid composition of this disclosure within a hard or soft shell. The shell may be made of gelatin and optionally contain plasticizers such as glycerin and / or sorbitol, opacifiers, and / or colorants.

[0269] The active ingredients and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0270] Compositions for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredient and excipients in powder form are blended and then further mixed in the presence of a liquid (usually water), which causes the powder to agglomerate into granules. The granules are sieved and / or milled, dried, and then sieved and / or milled to the desired particle size. The granules can then be tableted, or other excipients, such as glidants and / or lubricants, can be added before tableting.

[0271] Tableting compositions can be conventionally prepared by dry mixing. For example, a composition of blends of active ingredients and excipients can be compacted into blocks or tablets and then pulverized into compacted granules. The compacted granules can then be compressed into tablets.

[0272] As an alternative to dry granulation, direct compression technology can be used to directly compress the blended composition into a compacted dosage form. Direct compression produces more uniform tablets without granules. Excipients particularly suitable for direct compression tableting include microcrystalline cellulose, spray-dried lactose, calcium hydrogen phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those skilled in the art with experience and skill in the specific formulation challenges of direct compression tableting.

[0273] The capsule fillers in this disclosure may include any blends and granules mentioned above in relation to the tableting description, but they do not undergo the final tableting step.

[0274] Pharmaceutical formulations of Belumosudil are available. Belumosudil can be formulated for administration to mammals by injection, and in some embodiments, for administration to humans. Belumosudil can be formulated, for example, as a viscous liquid solution or suspension for injection, such as a clear solution. Formulations may contain one or more solvents. Suitable solvents can be selected by considering their physical and chemical stability at various pH levels, their viscosity (which will allow for injectability), flowability, boiling point, miscibility, and purity. Suitable solvents include alcohols (USP), benzyl alcohol (NF), benzyl benzoate (USP), and castor oil (USP). Additional substances, such as buffers, solubilizers, antioxidants, and other substances, can be added to the formulation. (Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition.)

[0275] In treating the following embodiments: graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse systemic sclerosis of the cutaneous body; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; systemic scleroderma; and particularly chronic graft-versus-host disease and / or systemic sclerosis, the crystalline polymorphs of Belumosudil and pharmaceutical compositions and / or pharmaceutical formulations of Belumosudil of this disclosure may be used as medicines.

[0276] This disclosure also provides methods for treating the following: graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse systemic sclerosis of the cutaneous body; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; systemic scleroderma; and particularly chronic graft-versus-host disease and / or systemic sclerosis, said treatment by administering to a subject in need of treatment a therapeutically effective amount of any or a combination of crystalline polymorphs of Belumosudil of this disclosure, or at least one of the above pharmaceutical compositions and / or pharmaceutical preparations.

[0277] Therefore, this disclosure has been described with reference to specific preferred embodiments and illustrative examples. Those skilled in the art will understand that modifications to the described and illustrated disclosure will not depart from the spirit and scope of the disclosure as disclosed herein. The examples are set forth to aid in understanding this disclosure, but are not intended and should not be construed as limiting the scope of this disclosure in any way.

[0278] Powder X-ray diffraction ("XRPD") method

[0279] For Examples 1-9 and 12-15: XRPD analysis was performed on an ARL (SCINTAG) X'TRA powder X-ray diffractometer equipped with a solid-state detector. Copper radiation of 1.5418 Å was used. Scan parameters: range: 2–40 degrees 2θ; scan mode: continuous scan; step size: 0.05°, and rate: 3 degrees / min.

[0280] For Examples 10 and 11: XRPD analysis was performed on a Bruker D8 ADVANCE powder X-ray diffractometer equipped with a solid-state detector. Copper radiation of 1.54060 Å was used. Scan parameters: range: 2–40 degrees 2θ; scan mode; step size: 0.05°.

[0281] This corresponds to the position of the theoretical peak correction peak of silicon at 28.45 degrees 2θ.

[0282] solid state 13 C-NMR method

[0283] Solid-state recordings were performed using a BRUKER Avance II+ spectrometer at a controlled temperature of 125 MHz and 0 °C, employing variable amplitude cross-polarization, magic angle rotation, and high-power proton decoupling. 13 C10 NMR spectroscopy. A probe using a 4 mm od zirconia rotor was employed. Operating conditions were: contact time: 2 ms; recirculation delay: 5 s; 1024 scans and a rotation rate of 11 kHz. Chemical shifts were referenced via a replacement sample of glycine (the carboxyl carbon chemical shift was specified as 176.03 ppm relative to the signal from tetramethylsilane).

[0284] TGA method

[0285] Thermogravimetric analysis was performed using Mettler Toledo TGA / DSC with the following scanning parameters:

[0286] Heating between 25℃ and 250℃.

[0287] Heating rate: 10℃ / min.

[0288] Purge with a 40 ml / min N2 stream.

[0289] Sample weight: 7 mg-15 mg.

[0290] Crucible: 150 µL alumina crucible with a standard aluminum lid.

[0291] SEM method

[0292] SEM micrographs were taken using a Phenom Pro scanning microscope at 10 kV and low current. The samples were sputtered with gold using a Denton Desk V sputtering plater.

[0293] Example

[0294] Preparation of starting materials

[0295] Belumosudil can be prepared according to methods known from the literature, such as according to International Publication No. WO 2006 / 105081.

[0296] Example 1: Preparation of amorphous Belumosudil

[0297] Program A

[0298] Methanol (90 ml, 90V) was added to Belumosudil (1 g, 2.21 mmol) to give a slurry. The slurry was magnetically stirred at 62°C for 15 minutes to obtain a clear solution, which was then mechanically filtered. The solution was cooled to room temperature and then... 入 =140℃ (T 出 The solid was dried in a spray dryer at 78°C. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern was obtained in... Figure 1 Presented in the middle.

[0299] Program B

[0300] Methanol (3.5 ml, 70 V) was added to Belmosudil (50 mg, 0.11 mmol) to give a slurry. The slurry was magnetically stirred at 60 °C for 15 min to obtain a clear solution, which was then mechanically filtered. The resulting clear mother liquor was evaporated at 50 °C / 300-35 mbar to give a solid. The obtained solid was characterized by X-ray powder diffraction as amorphous Belmosudil.

[0301] Example 2: Preparation of crystalline form B1 of Belumosudil

[0302] Program A

[0303] Acetone (7.5 ml, 250 V) was added to Belmosudil (30 mg, 0.066 mmol) to obtain a clear solution. The solution was then mechanically filtered at room temperature and allowed to slowly evaporate over a period of 6 days. The obtained solid was analyzed by X-ray powder diffraction and Belmosudil was identified as crystalline form B1. The XRPD pattern is shown in [image missing]. Figure 2 Presented in the middle.

[0304] Program B

[0305] Ethanol (0.6 ml, 20V) was added to amorphous Belumosudil (30 mg, 0.066 mmol) to give a slurry. The slurry was magnetically stirred at 50°C for 5 hours. The solid was separated by centrifugation and dried in a vacuum oven at 45°C for 20 hours to give an off-white solid, which was identified as crystalline Belumosudil B1.

[0306] Example 3: Preparation of crystalline form B2 of Belumosudil

[0307] Program A

[0308] Acetonitrile (12 ml, 400 V) was added to amorphous Belumosudil (30 mg, 0.066 mmol) at 80 °C to obtain a clear solution. The solution was then mechanically filtered at room temperature and allowed to evaporate slowly at that temperature for 5 days. The obtained solid was analyzed by XRPD and characterized as Belumosudil crystalline form B2. The XRPD plot is shown in [image missing]. Figure 3 Presented in the middle.

[0309] Program B

[0310] Amorphous belumosudil (30 mg, 0.066 mmol) was heated to 160 °C via TGA over a period of 0.5 hours. The resulting solid was analyzed by X-ray powder diffraction and identified as crystalline belumosudil B2.

[0311] Program C

[0312] Methanol (12 ml, 400 V) was added to amorphous belumosudil (30 mg, 0.066 mmol) at room temperature to give a slurry. The slurry was magnetically stirred at 50 °C for 5 hours. The solids were separated by centrifugation and dried in a vacuum oven at 45 °C for 20 hours. The resulting off-white solid was analyzed by X-ray powder diffraction and characterized by X-ray powder diffraction as crystalline belumosudil B2.

[0313] Example 4: Preparation of crystalline form B3 of Belumosudil

[0314] Tetrahydrofuran (5 ml, 50 V) was added to Belumosudil (100 mg, 0.22 mmol) at 40 °C and stirred for 10 min to obtain a clear solution. The solution was then mechanically filtered, cooled to room temperature, and stirred for 14 h to provide a wet solid. The solid was separated by centrifugation. The obtained wet solid was analyzed by XRPD and characterized as Belumosudil crystalline form B3. The XRPD plot is shown in [image missing]. Figure 4 Presented in the middle.

[0315] Example 5: Preparation of crystalline form M1 of Belumosudil methanesulfonate

[0316] Program A

[0317] Ethanol (4 ml, 20 V) was added to Belmosudil (200 mg, 0.44 mmol) at room temperature to obtain a slurry. Next, methanesulfonic acid (31 µL, 1.1 equivalence) was added dropwise to give a clear solution. The solution was heated to 50 °C and precipitation was observed. Ethanol (3 ml, 15 V) was added to the obtained lumpy precipitate, followed by magnetic stirring at 50 °C for 30 minutes. The precipitate was then allowed to cool naturally to room temperature. The solid was separated by centrifugation. The obtained solid was washed twice with ethanol (400 µL, 2 V) and dried in a vacuum oven at 45 °C for 16 hours to provide a yellow solid. The obtained solid was analyzed by X-ray powder diffraction and characterized as Belmosudil methanesulfonate crystal form M1. The XRPD plot is shown in [image missing]. Figure 5 Presented in the middle.

[0318] Program B

[0319] DMSO (0.9 ml, 30 V) was added to Belusudil methanesulfonate (30 mg, 0.06 mmol) to give a slurry. The slurry was heated to 50 °C for 10 minutes to obtain complete dissolution, followed by thermomechanical filtration. Next, ethanol (2.7 ml, 100 V) was added dropwise as an antisolvent to obtain a solid precipitate. The slurry was then magnetically stirred at room temperature for 40 hours. The solid was then separated by centrifugation. The obtained wet solid was analyzed by X-ray powder diffraction and identified as Belusudil methanesulfonate crystalline form M1.

[0320] Program C

[0321] Isopropanol (2 ml, 20 V) was added to Belmosudil (100 mg, 0.2 mmol) at room temperature to obtain a slurry. Next, methanesulfonic acid (161 µL, 1.1 equivalence) was added dropwise to give a clear solution. The solution was heated to 50 °C and a precipitation was observed, and the mixture was magnetically stirred at 50 °C for 30 minutes. The precipitate was then allowed to cool naturally to room temperature. The solid was separated by centrifugation. The obtained solid was washed twice with IPA (200 µL, 2 V) to provide a yellow solid. The obtained solid was analyzed by X-ray powder diffraction and identified as Belmosudil methanesulfonate crystalline form M1.

[0322] Program D

[0323] To obtain a slurry, n-butanol (2 mL, 20 V) was added to Belmosudil (100 mg, 0.2 mmol) at room temperature. Next, methanesulfonic acid (161 µL, 1.1 equivalence) was added dropwise to give a clear solution. The solution was heated to 50 °C and a precipitation was observed, and the mixture was magnetically stirred at 50 °C for 30 minutes. The precipitate was then allowed to cool naturally to room temperature. The solid was separated by centrifugation. The obtained solid was washed twice with n-butanol (200 µL, 2 V) to provide a yellow solid. The obtained solid was analyzed by X-ray powder diffraction and identified as Belmosudil methanesulfonate crystalline form M1.

[0324] Program E

[0325] 1-Propanol (2 ml, 20 V) was added to Belmosudil (100 mg, 0.2 mmol) at room temperature to obtain a slurry. Next, methanesulfonic acid (161 µL, 1.1 equivalence) was added dropwise to give a clear solution. The solution was heated to 50 °C and a precipitation was observed, and the mixture was magnetically stirred at 50 °C for 30 minutes. The precipitate was then allowed to cool naturally to room temperature. The solid was separated by centrifugation. The obtained solid was washed twice with 1-propanol (200 µL, 2 V) to provide a yellow solid. The obtained solid was analyzed by X-ray powder diffraction and identified as Belmosudil methanesulfonate crystalline form M1.

[0326] Program F

[0327] 2,2,2-Trifluoroethanol (0.3 ml, 10 V) was added to Belusudil methanesulfonate (30 mg, 0.06 mmol) to give a slurry. The slurry was heated to 60 °C for 10 minutes to obtain complete dissolution, followed by thermomechanical filtration. Next, ethanol (1.2 ml, 40 V) was added dropwise as an antisolvent to obtain a solid precipitate. The slurry was then magnetically stirred at room temperature for 17 hours. The solid was then separated by centrifugation. The obtained wet solid was analyzed by X-ray powder diffraction and identified as Belusudil methanesulfonate crystalline form M1.

[0328] Example 6: Preparation of Belumosudil crystalline form B4

[0329] Program A

[0330] Methanol (0.6 ml, 20V) was added to Belumosudil form B1 (30 mg, 0.066 mmol) to obtain a slurry. The slurry was then magnetically stirred at 50°C for 5 hours. The slurry was then cooled to room temperature and magnetically stirred for 16 hours. The solid was then separated by centrifugation at room temperature. The obtained wet solid was dried in a vacuum oven at 45°C for 18 hours to provide an off-white solid, which was characterized by X-ray powder diffraction and XRPD pattern. Figure 6 Presented in the middle.

[0331] Program B

[0332] Acetonitrile:MeOH (0.75 ml, 25 V, 1:1 equivalent) was added to B1 (50 mg, 0.11 mmol) to give a slurry. The slurry was magnetically stirred at room temperature for one week. The solids were then separated by centrifugation at room temperature. The obtained wet solid was characterized by X-ray powder diffraction as Belumosudil crystalline form B4.

[0333] Example 7: Preparation of Belumosudil methanesulfonate in crystalline form M2

[0334] Program A

[0335] Water (2 ml, 20V) was added to form B1 (100 mg, 0.22 mmol) at room temperature to obtain a slurry. Next, methanesulfonic acid (16 µL, 1.1 equivalence) was added dropwise to give the slurry. The slurry was heated to 50°C for 45 minutes to obtain a clear solution. The solution was then allowed to cool naturally to room temperature, and a precipitate was observed. The obtained solid was separated using a centrifuge. The separated solid was washed twice with water (0.2 ml, 2V) and dried in a vacuum oven at 45°C for 18 hours to provide a yellow solid. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern was obtained in… Figure 7 Presented in the middle.

[0336] Program B

[0337] A water:ethanol mixture (2 ml, 20V, 1:3) was added to form B1 (100 mg, 0.22 mmol) at room temperature to obtain a slurry. Next, methanesulfonic acid (16 µL, 1.1 equivalents) was added dropwise to give the slurry. The slurry was heated to 50°C for 45 minutes to obtain a clear solution. The solution was then allowed to cool naturally to room temperature, and a precipitate was observed. The obtained solid was separated using a centrifuge. The separated solid was washed twice with water:ethanol (2.2 ml, 22V, 1:3) and dried in a vacuum oven at 45°C for 18 hours to provide a yellow solid. The obtained solid was identified by X-ray powder diffraction analysis as Belumosudil methanesulfonate crystal form M2.

[0338] Program C

[0339] Water (2 ml, 40 V) was added to Belusudil methanesulfonate form M1 (50 mg, 0.11 mmol) to give a slurry. The slurry was magnetically stirred at 60 °C for 1 week. The solids were then separated by centrifugation at room temperature. The obtained wet solid was analyzed by X-ray powder diffraction and identified as Belusudil methanesulfonate crystalline form M2.

[0340] Program D

[0341] DMSO (2 ml, 40 V) was added to Belusudil methanesulfonate form M1 (50 mg, 0.11 mmol) to give a slurry. The slurry was heated to 50 °C for 10 minutes to obtain complete dissolution, followed by thermomechanical filtration. The solution was allowed to cool naturally to room temperature and magnetically stirred for 5 days. Next, cold water (5 ml, 100 V, 4 °C) was added dropwise as an antisolvent to obtain a solid precipitate. The slurry was then magnetically stirred at room temperature for 18 hours. The solid was then separated by centrifugation. The obtained wet solid was analyzed by X-ray powder diffraction and identified as Belusudil methanesulfonate crystalline form M2.

[0342] Program E

[0343] 2,2,2-Trifluoroethanol (0.3 ml, 10 V) was added to Belusudil methanesulfonate (30 mg, 0.06 mmol) to give a slurry. The slurry was heated to 60 °C for 10 minutes to obtain complete dissolution, followed by thermomechanical filtration. Next, water (1.2 ml, 40 V) was added dropwise as an antisolvent to obtain a solid precipitate. The slurry was then magnetically stirred at room temperature for 17 hours. The solid was then separated by centrifugation. The obtained wet solid was analyzed by X-ray powder diffraction and identified as Belusudil methanesulfonate crystalline form M2.

[0344] Example 8: Preparation of Belumosudil methanesulfonate in crystalline form M3

[0345] Program A

[0346] Belumosudil methanesulfonate form M2 (prepared according to procedure C of Example 7) was dried in a vacuum oven at 200°C for 4 hours to provide a yellow solid. The obtained solid was characterized by X-ray powder diffraction as Belumosudil methanesulfonate crystalline form M3.

[0347] Example 9: Preparation of crystalline form B5 of Belumosudil

[0348] Program A

[0349] 2,2,2-Trifluoroethanol (TFE) (0.6 ml, 50 V) was added to Belumosudil (12.5 mg, 0.03 mmol) to obtain a clear solution. The solution was then magnetically stirred at 70 °C for 1 hour. The solution was then cooled to 4 °C at a rate of 20 °C every 10 minutes, and a lumpy precipitate was observed. Additional TFE (0.1 ml, 10 V) was added to give a slurry. The solids were then separated using a centrifuge. The mother liquor was then placed at 4 °C for slow crystallization for 20 days. The obtained wet solid was filtered through a Buchner filter, and the solid was characterized by X-ray powder diffraction as Belumosudil crystalline form B5, and the XRPD pattern was obtained in… Figure 9 Presented in the middle.

[0350] Example 10: Preparation of amorphous Belumosudil methanesulfonate

[0351] Program A

[0352] Methanol (286 ml, 220 V) was added to Belumosudil methanesulfonate form M1 (1.3 g, 2.4 mmol) to give a slurry. The slurry was magnetically stirred at 62 °C for 45 min to obtain a clear solution, which was then mechanically filtered. The solution was cooled to room temperature and then... 入 =140℃ (T 出 The solid was dried in a spray dryer at 63°C. The obtained solid was analyzed by X-ray powder diffraction and identified as amorphous Belumosudi methanesulfonate, and the XRPD pattern was obtained in... Figure 10 Presented in the middle.

[0353] Example 11: Preparation of Belumosudil mesylate form M4

[0354] Program A

[0355] 2,2,2-Trifluoroethanol (TFE) (0.7 ml, 7V) was added to Belumosudil methanesulfonate form M1 (100 mg, 0.2 mmol) to obtain a clear solution. The clear solution was mechanically filtered and added to heptane (0.8 ml, 8V) pre-cooled to 4°C to obtain a two-phase solution. The solution was stirred at 4°C for 4 days. The mixture was then inoculated with Belumosudil methanesulfonate form M3 (approximately 1 wt%) and, after stirring for 1 day, a solid precipitate was obtained. The precipitate was then separated by centrifugation and dried in a vacuum oven at 45°C for 18 hours to provide a yellow solid. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern was obtained in... Figure 11 Presented in the middle.

[0356] Program B

[0357] TFE (0.7 ml, 7V) was added to Belusudil methanesulfonate form M1 (100 mg, 0.2 mmol) to obtain a clear solution. The clear solution was mechanically filtered and added to heptane (0.8 ml, 8V) pre-cooled to 4°C to obtain a two-phase mixture. The mixture was then inoculated with Belusudil methanesulfonate form M4 (approximately 1 wt%) and a solid precipitate was obtained after stirring for 1 day. The precipitate was then separated by centrifugation and dried in a vacuum oven at 45°C for 18 hours to provide a yellow solid. The obtained solid was identified by X-ray powder diffraction analysis as Belusudil methanesulfonate crystalline form M4.

[0358] Program C

[0359] TFE (0.7 ml, 7V) was added to Belumosudil methanesulfonate form M1 (100 mg, 0.2 mmol) to obtain a clear solution. The clear solution was mechanically filtered and added to cyclopentyl methyl ether (0.8 ml, 8V) pre-cooled to 4°C. The mixture was then inoculated with Belumosudil methanesulfonate form M4 (approximately 1 wt%), and a solid precipitate was obtained after stirring for 18 hours. The precipitate was then separated by centrifugation and dried in a vacuum oven at 45°C for 18 hours to provide a yellow solid. The obtained solid was identified by X-ray powder diffraction analysis as Belumosudil methanesulfonate crystalline form M4.

[0360] Program D

[0361] TFE (0.7 ml, 7V) was added to Belumosudil methanesulfonate form M1 (100 mg, 0.2 mmol) to obtain a clear solution. The clear solution was added to cyclopentyl methyl ether (0.8 ml, 8V) pre-cooled to 4°C, and a lumpy slurry was obtained. Next, cyclopentyl methyl ether (0.4 ml, 4V) was added to obtain a slurry. The mixture was then inoculated with NaCl (approximately 1 wt%), and a precipitate was obtained after stirring for 1 hour. The precipitate was then separated by centrifugation and dried in a vacuum oven at 45°C for 18 hours to provide a yellow solid. The obtained solid was analyzed by X-ray powder diffraction and identified as Belumosudil methanesulfonate crystalline form M4.

[0362] Example 12: Preparation of Belumosudil mesylate form M5

[0363] Program A

[0364] DMSO (9 ml, 30 V) was added to Belumosudil methanesulfonate form M1 (300 mg, 0.6 mmol) to obtain a clear solution. Next, the clear solution was added to cyclopentyl methyl ether (9 ml, 30 V) pre-cooled to approximately 4 °C, which contained seed crystals of Belumosudil methanesulfonate form M4 (approximately 1 wt%). Then, additional cyclopentyl methyl ether (18 ml, 60 V) and seed crystals of Belumosudil methanesulfonate form M4 (approximately 1 wt%) were added, and some precipitate was observed after 10 minutes. The mixture was stirred at approximately 4 °C for 18 hours, and a lumpy precipitate was obtained. The precipitate was then separated by centrifugation and dried in a vacuum oven at 45 °C for 18 hours to provide a yellow solid. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern was obtained on... Figure 12 Presented in the middle.

[0365] Example 13: Preparation of Belumosudil benzenesulfonate form BS1

[0366] Program A

[0367] Ethanol (10 ml, 20°C) was added to Belumosudil form B1 (500 mg, 1.1 mmol) at room temperature to obtain a slurry. Next, benzenesulfonic acid (192.3 mg, 1.1 equivalence) was added, and the slurry was heated to 50°C for 45 minutes with stirring. The slurry was then allowed to cool naturally to room temperature, and the resulting solids were separated using a centrifuge. The separated solids were dried in a vacuum oven at 45°C for 18 hours to provide a yellow solid. The obtained solids were analyzed by X-ray powder diffraction, and the XRPD pattern was obtained in… Figure 13 Presented in the middle.

[0368] Example 14: Preparation of Belumosudil tosylate form T1

[0369] Program A

[0370] Methanol (2 ml, 20V) was added to Belumosudil form B1 (100 mg, 0.22 mmol) and heated to 50°C to obtain a slurry. Next, p-toluenesulfonic acid (46.2 mg, 1.1 equivalence) was added, and a clear solution was obtained. After stirring at 50°C for 10 minutes, a precipitate was observed. The solution was stirred at 50°C for 45 minutes. The solution was then allowed to cool naturally to room temperature, and a lumpy precipitate was observed. The obtained solid was separated using a centrifuge and washed once with methanol (200 µL, 2V). The solid was dried in a vacuum oven at 45°C for 18 hours to provide a yellow solid. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern was obtained as follows: Figure 14 Presented in the middle.

[0371] Example 15: Preparation of Belumosudil tosylate form T2

[0372] Program A

[0373] Water (1 ml, 20V) was added to Belumosudil form B1 (50 mg, 0.11 mmol) and heated to 50°C to obtain a slurry. Next, p-toluenesulfonic acid (23.1 mg, 1.1 equivalence) was added, and the viscous slurry was stirred at 50°C for 20 minutes. Then, ethanol (250 µl, 5V) was added to obtain a slurry. The slurry was stirred at 50°C for 50 minutes. The slurry was then allowed to cool naturally to room temperature, and the resulting solid was separated using a centrifuge. The separated solid was washed once with water:ethanol (1 ml, 2V, 4:1) and dried in a vacuum oven at 45°C for 18 hours to provide a yellow solid. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern was obtained as follows: Figure 15 Presented in the middle.

[0374] This disclosure also provides the following:

[0375] 1. A crystalline form of Belumosudil methanesulfonate designated as form M1, said crystalline form being characterized by data selected from one or more of the following:

[0376] (a) XRPD plots showing peaks at 7.1°2θ±0.2°2θ, 17.2°2θ±0.2°2θ, 20.3°2θ±0.2°2θ, 21.5°2θ±0.2°2θ and 25.5°2θ±0.2°2θ;

[0377] (b) Generally speaking Figure 5 The XRPD diagram depicted in the image;

[0378] (c) An XRPD plot having peaks at 7.1°2θ±0.2°2θ, 17.2°2θ±0.2°2θ, 20.3°2θ±0.2°2θ, 21.5°2θ±0.2°2θ, and 25.5°2θ±0.2°2θ and also having any, two, three, four, or five additional peaks selected from 8.4°2θ±0.2°2θ, 15.5°2θ±0.2°2θ, 16.8°2θ±0.2°2θ, 19.5°2θ±0.2°2θ, and 22.1°2θ±0.2°2θ;

[0379] (d) X-ray powder diffraction patterns with peaks at 7.1°2θ±0.2°2θ, 8.4°2θ±0.2°2θ, 15.5°2θ±0.2°2θ, 16.8°2θ±0.2°2θ, 17.2°2θ±0.2°2θ, 19.5°2θ±0.2°2θ, 20.3°2θ±0.2°2θ, 21.5°2θ±0.2°2θ, 22.1°2θ±0.2°2θ, and 25.5°2θ±0.2°2θ;

[0380] (e) Solid state having characteristic peaks at 137.8 ppm ± 0.2 ppm, 133.8 ppm ± 0.2 ppm, 122.5 ppm ± 0.2 ppm, 118.3 ppm ± 0.2 ppm and 111.6 ppm ± 0.2 ppm 13 C NMR spectrum;

[0381] (f) Solid state with the following absolute difference in chemical shift compared to the reference peak at 167.2 ppm ± 1 ppm 13 CNMR spectra: 29.4 ppm ± 0.1 ppm, 33.4 ppm ± 0.1 ppm, 44.7 ppm ± 0.1 ppm, 48.9 ppm ± 0.1 ppm and 55.6 ppm ± 0.1 ppm;

[0382] (g) Generally based on Figure 16 , Figure 17 or Figure 18 The solid state described in 13 C NMR spectrum; and

[0383] (h) The combination of these data.

[0384] 2. The crystalline form according to aspect 1, wherein the crystalline form is anhydrous.

[0385] 3. The crystalline form according to any one of aspects 1-2, wherein the crystalline form comprises no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline form of Belumosudil methanesulfonate.

[0386] 4. The crystalline form according to any one of aspects 1-3, wherein the crystalline form comprises not more than about 20%, not more than about 10%, not more than about 5%, not more than about 2%, not more than about 1% or about 0% of amorphous Belumosudil methanesulfonate.

[0387] 5. A crystalline form of Belumosudil methanesulfonate designated as form M2, said crystalline form being characterized by data selected from one or more of the following:

[0388] (a) XRPD plots showing peaks at 6.3°2θ±0.2°2θ, 12.8°2θ±0.2°2θ, 15.8°2θ±0.2°2θ, 19.3°2θ±0.2°2θ and 26.5°2θ±0.2°2θ;

[0389] (b) Generally speaking Figure 7 The XRPD diagram depicted in the image;

[0390] (c) An XRPD plot having peaks at 6.3°2θ±0.2°2θ, 12.8°2θ±0.2°2θ, 15.8°2θ±0.2°2θ, 19.3°2θ±0.2°2θ, and 26.5°2θ±0.2°2θ, and also having any, two, three, four, or five additional peaks selected from 7.8°2θ±0.2°2θ, 20.4°2θ±0.2°2θ, 23.7°2θ±0.2°2θ, 25.1°2θ±0.2°2θ, and 27.4°2θ±0.2°2θ;

[0391] (d) X-ray powder diffraction pattern with peaks at 6.3°2θ±0.2°2θ, 7.8°2θ±0.2°2θ, 12.8°2θ±0.2°2θ, 15.8°2θ±0.2°2θ, 19.3°2θ±0.2°2θ, 20.4°2θ±0.2°2θ, 23.7°2θ±0.2°2θ, 25.1°2θ±0.2°2θ, 26.5°2θ±0.2°2θ, and 27.4°2θ±0.2°2θ;

[0392] (e) Solid state having characteristic peaks at 156.1 ppm ± 0.2 ppm, 132.7 ppm ± 0.2 ppm, 135.5 ppm ± 0.2 ppm, 119.8 ppm ± 0.2 ppm and 110.9 ppm ± 0.2 ppm 13 C NMR spectrum;

[0393] (f) Solid state with the following absolute difference in chemical shift compared to the reference peak at 166.9 ppm ± 1 ppm 13 CNMR spectra: 10.8 ppm ± 0.1 ppm, 34.2 ppm ± 0.1 ppm, 36.4 ppm ± 0.1 ppm, 47.1 ppm ± 0.1 ppm and 56.0 ppm ± 0.1 ppm;

[0394] (g) Generally based on Figure 19 , Figure 20 or Figure 21 The solid state described in 13 C NMR spectrum; and

[0395] (h) The combination of these data.

[0396] 6. The crystalline form according to aspect 5, wherein the crystalline form is a hydrate.

[0397] 7. The crystalline form according to any one of aspects 5-6, wherein the crystalline form comprises about 1% to about 7% water by weight, preferably about 1.5% to about 6.1% water by weight.

[0398] 8. The crystalline form according to any one of aspects 5-7, wherein the crystalline form comprises no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline form of Belumosudil methanesulfonate.

[0399] 9. The crystalline form according to any one of aspects 5-8, wherein the crystalline form comprises not more than about 20%, not more than about 10%, not more than about 5%, not more than about 2%, not more than about 1% or about 0% of amorphous Belumosudil methanesulfonate.

[0400] 10. A crystalline form of Belumosudil benzenesulfonate designated as form BS1, said crystalline form being characterized by data selected from one or more of the following:

[0401] (a) XRPD plots showing peaks at 6.6°2θ±0.2°2θ, 12.5°2θ±0.2°2θ, 14.9°2θ±0.2°2θ, 17.0°2θ±0.2°2θ and 20.1°2θ±0.2°2θ;

[0402] (b) Generally speaking Figure 13 The XRPD diagram depicted in the image;

[0403] (c) An XRPD plot having peaks at 6.6°2θ±0.2°2θ, 12.5°2θ±0.2°2θ, 14.9°2θ±0.2°2θ, 17.0°2θ±0.2°2θ, and 20.1°2θ±0.2°2θ, and also having any, two, three, four, or five additional peaks selected from 11.6°2θ±0.2°2θ, 17.6°2θ±0.2°2θ, 18.2°2θ±0.2°2θ, 21.7°2θ±0.2°2θ, and 25.1°2θ±0.2°2θ;

[0404] (d) X-ray powder diffraction pattern with peaks at 11.6°2θ±0.2°2θ, 12.5°2θ±0.2°2θ, 14.9°2θ±0.2°2θ, 17.0°2θ±0.2°2θ, 17.6°2θ±0.2°2θ, 18.2°2θ±0.2°2θ, 20.1°2θ±0.2°2θ, 21.7°2θ±0.2°2θ, and 25.1°2θ±0.2°2θ;

[0405] (e) Solid state having characteristic peaks at 158.9 ppm ± 0.2 ppm, 146.8 ppm ± 0.2 ppm, 134.3 ppm ± 0.2 ppm, 121.3 ppm ± 0.2 ppm and 117.6 ppm ± 0.2 ppm 13 C NMR spectrum;

[0406] (f) Solid state with the following absolute difference in chemical shift compared to the reference peak at 169.6 ppm ± 1 ppm 13 CNMR spectra: 10.7 ppm ± 0.1 ppm, 22.8 ppm ± 0.1 ppm, 35.3 ppm ± 0.1 ppm, 48.3 ppm ± 0.1 ppm and 52.0 ppm ± 0.1 ppm;

[0407] (g) Generally based on Figure 22 , Figure 23 or Figure 24 The solid state described in 13 C NMR spectrum; and

[0408] (h) The combination of these data.

[0409] 11. The crystalline form according to aspect 10, wherein the crystalline form is anhydrous.

[0410] 12. The crystalline form according to any one of aspects 10-11, wherein the crystalline form comprises no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline form of Belumosudil benzenesulfonate.

[0411] 13. The crystalline form according to any one of aspects 10-12, wherein the crystalline form comprises not more than about 20%, not more than about 10%, not more than about 5%, not more than about 2%, not more than about 1% or about 0% of amorphous Belumosudil benzenesulfonate.

[0412] 14. A crystalline form of Belumosudil toluenesulfonate designated as form T1, said crystalline form being characterized by data selected from one or more of the following:

[0413] (a) XRPD plots showing peaks at 6.2°2θ±0.2°2θ, 12.3°2θ±0.2°2θ, 14.1°2θ±0.2°2θ, 17.7°2θ±0.2°2θ and 18.4°2θ±0.2°2θ;

[0414] (b) Generally speaking Figure 14 The XRPD diagram depicted in the image;

[0415] (c) An XRPD plot having peaks at 6.2°2θ±0.2°2θ, 12.3°2θ±0.2°2θ, 14.1°2θ±0.2°2θ, 17.7°2θ±0.2°2θ, and 18.4°2θ±0.2°2θ, and also having any, two, three, four, or five additional peaks selected from 9.9°2θ±0.2°2θ, 14.5°2θ±0.2°2θ, 16.7°2θ±0.2°2θ, 21.5°2θ±0.2°2θ, and 24.6°2θ±0.2°2θ;

[0416] (d) X-ray powder diffraction pattern with peaks at 6.2°2θ±0.2°2θ, 9.9°2θ±0.2°2θ, 12.3°2θ±0.2°2θ, 14.1°2θ±0.2°2θ, 14.5°2θ±0.2°2θ, 16.7°2θ±0.2°2θ, 17.7°2θ±0.2°2θ, 18.4°2θ±0.2°2θ, 21.5°2θ±0.2°2θ, and 24.6°2θ±0.2°2θ;

[0417] (e) Solid state having characteristic peaks at 152.6 ppm ± 0.2 ppm, 143.4 ppm ± 0.2 ppm, 132.3 ppm ± 0.2 ppm, 125.3 ppm ± 0.2 ppm and 119.8 ppm ± 0.2 ppm 13 C NMR spectrum;

[0418] (f) Solid state with the following absolute difference in chemical shift compared to the reference peak at 168.6 ppm ± 1 ppm 13 CNMR spectra: 16.0 ppm ± 0.1 ppm, 25.2 ppm ± 0.1 ppm, 36.3 ppm ± 0.1 ppm, 43.3 ppm ± 0.1 ppm and 48.8 ppm ± 0.1 ppm;

[0419] (g) Generally based on Figure 26 , Figure 27 or Figure 28 The solid state described in 13 C NMR spectrum; and

[0420] (h) The combination of these data.

[0421] 15. The crystalline form according to aspect 14, wherein the crystalline form is anhydrous.

[0422] 16. The crystalline form according to any one of aspects 14-15, wherein the crystalline form comprises no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline form of Belumosudil toluenesulfonate.

[0423] 17. The crystalline form according to any one of aspects 14-16, wherein the crystalline form comprises not more than about 20%, not more than about 10%, not more than about 5%, not more than about 2%, not more than about 1% or about 0% of amorphous Belumosudil toluenesulfonate.

[0424] 18. A crystalline form of Belumosudil toluenesulfonate designated as form T2, said crystalline form being characterized by data selected from one or more of the following:

[0425] (a) XRPD plots showing peaks at 5.1°2θ±0.2°2θ, 15.7°2θ±0.2°2θ, 16.4°2θ±0.2°2θ, 19.7°2θ±0.2°2θ and 23.7°2θ±0.2°2θ;

[0426] (b) Generally speaking Figure 15The XRPD diagram depicted in the image;

[0427] (c) An XRPD plot having peaks at 5.1°2θ±0.2°2θ, 15.7°2θ±0.2°2θ, 16.4°2θ±0.2°2θ, 19.7°2θ±0.2°2θ, and 23.7°2θ±0.2°2θ, and also having any, two, three, four, or five additional peaks selected from 13.7°2θ±0.2°2θ, 14.2°2θ±0.2°2θ, 14.6°2θ±0.2°2θ, 19.1°2θ±0.2°2θ, and 23.0°2θ±0.2°2θ;

[0428] (d) X-ray powder diffraction pattern with peaks at 5.1°2θ±0.2°2θ, 13.7°2θ±0.2°2θ, 14.2°2θ±0.2°2θ, 14.6°2θ±0.2°2θ, 15.7°2θ±0.2°2θ, 16.4°2θ±0.2°2θ, 19.1°2θ±0.2°2θ, 19.7°2θ±0.2°2θ, 23.0°2θ±0.2°2θ, and 23.7°2θ±0.2°2θ;

[0429] (e) Solid state having characteristic peaks at 141.7 ppm ± 0.2 ppm, 140.2 ppm ± 0.2 ppm, 131.1 ppm ± 0.2 ppm, 125.9 ppm ± 0.2 ppm and 124.2 ppm ± 0.2 ppm 13 C NMR spectrum;

[0430] (f) Solid state with the following absolute difference in chemical shift compared to the reference peak at 166.3 ppm ± 1 ppm 13 CNMR spectra: 24.6 ppm ± 0.1 ppm, 26.1 ppm ± 0.1 ppm, 35.2 ppm ± 0.1 ppm, 40.4 ppm ± 0.1 ppm and 42.1 ppm ± 0.1 ppm;

[0431] (g) Generally based on Figure 30 , Figure 31 or Figure 32 The solid state described in 13 C NMR spectrum; and

[0432] (h) The combination of these data.

[0433] 19. The crystalline form according to aspect 18, wherein the crystalline form is anhydrous.

[0434] 20. The crystalline form according to any one of aspects 18-19, wherein the crystalline form comprises no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline form of Belumosudil toluenesulfonate.

[0435] 21. The crystalline form according to any one of aspects 18-20, wherein the crystalline form comprises not more than about 20%, not more than about 10%, not more than about 5%, not more than about 2%, not more than about 1% or about 0% of amorphous Belumosudil toluenesulfonate.

[0436] 22. The crystalline form according to any of the foregoing aspects, wherein the crystalline form is non-hygroscopic, preferably wherein the crystalline form is polymorphically stable at room temperature and relative humidity up to 100% for at least 7 days.

[0437] 23. Use of the crystalline form according to any one of aspects 1 to 22 for the preparation of pharmaceutical compositions.

[0438] 24. A pharmaceutical composition comprising a crystalline form according to any one of aspects 1 to 22 and at least one pharmaceutically acceptable excipient.

[0439] 25. A process for preparing a pharmaceutical composition according to aspect 24, comprising combining a crystalline form according to any one of aspects 1 to 22 with at least one pharmaceutically acceptable excipient.

[0440] 26. The crystalline form according to any one of aspects 1 to 22 or the pharmaceutical composition according to aspect 24, used as a medicine.

[0441] 27. The crystalline form according to any one of aspects 1 to 22, or the pharmaceutical composition according to aspect 24, for treating graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse systemic sclerosis of the cutaneous body; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; systemic scleroderma; and particularly chronic graft-versus-host disease and systemic sclerosis.

[0442] 28. A method for treating graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse systemic sclerosis of the cutaneous body; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; systemic scleroderma; and particularly chronic graft-versus-host disease and systemic sclerosis, said method comprising administering to a subject requiring treatment a therapeutically effective amount of the crystalline form according to any one of aspects 1 to 22 or the pharmaceutical composition according to aspect 24.

[0443] 29. Use of the crystalline form according to any one of aspects 1 to 22 in the preparation of another solid form of Belumosudil or another salt of Belumosudil or its solid form.

[0444] 30. A process for preparing a Belumosudil salt or a solid form thereof, comprising preparing the crystalline form as described in any one of aspects 1 to 22, and converting it into another solid form of Belumosudil or another salt of Belumosudil or a solid form thereof.

Claims

1. A crystalline form of Belumosudil mesylate designated as Form M2, which is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 6.3 degrees 2theta ± 0.2 degrees 2theta, 12.8 degrees 2theta ± 0.2 degrees 2theta, 15.8 degrees 2theta ± 0.2 degrees 2theta, 19.3 degrees 2theta ± 0.2 degrees 2theta, and 26.5 degrees 2theta ± 0.2 degrees 2theta.

2. A crystalline form of Belumosudil mesylate designated as Form M2, which is characterized by an XRPD pattern substantially as depicted in Figure 7.

3. A crystalline form of Belumosudil mesylate designated as Form M2, which is characterized by an XRPD pattern having peaks at 6.3 degrees 2theta ± 0.2 degrees 2theta, 12.8 degrees 2theta ± 0.2 degrees 2theta, 15.8 degrees 2theta ± 0.2 degrees 2theta, 19.3 degrees 2theta ± 0.2 degrees 2theta, and 26.5 degrees 2theta ± 0.2 degrees 2theta, and further having any one, two, three, four, or five additional peaks selected from 7.8 degrees 2theta ± 0.2 degrees 2theta, 20.4 degrees 2theta ± 0.2 degrees 2theta, 23.7 degrees 2theta ± 0.2 degrees 2theta, 25.1 degrees 2theta ± 0.2 degrees 2theta, and 27.4 degrees 2theta ± 0.2 degrees 2theta.

4. A crystalline form of Belumosudil mesylate designated as Form M2, which is characterized by an XRPD pattern having peaks at 6.3 degrees 2theta ± 0.2 degrees 2theta, 7.8 degrees 2theta ± 0.2 degrees 2theta, 12.8 degrees 2theta ± 0.2 degrees 2theta, 15.8 degrees 2theta ± 0.2 degrees 2theta, 19.3 degrees 2theta ± 0.2 degrees 2theta, 20.4 degrees 2theta ± 0.2 degrees 2theta, 23.7 degrees 2theta ± 0.2 degrees 2theta, 25.1 degrees 2theta ± 0.2 degrees 2theta, 26.5 degrees 2theta ± 0.2 degrees 2theta, and 27.4 degrees 2theta ± 0.2 degrees 2theta.

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

6. A process for the preparation of a pharmaceutical composition comprising combining the crystalline form according to any one of claims 1-4 and at least one pharmaceutically acceptable excipient.

7. Use of the crystalline form according to any one of claims 1-4 in the manufacture of a medicament for the treatment of chronic graft-versus-host disease and / or systemic sclerosis.

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