Solid state forms of BELUMOSUDIL and BELUMOSUDIL salts

Abstract

The present application relates to a solid state form of a BELUMOSUDIL and a BELUMOSUDIL salt. The present disclosure includes solid state forms of Belumosubl, in embodiments, crystalline polymorphs of Belumosubl or a salt thereof, processes for their preparation, and pharmaceutical compositions thereof.

Description

[0001] This application is a divisional application of an application filed on July 22, 2021, with application number 202180053875.6, and invention name “Solid forms of BELUMOSUDIL and BELUMOSUDIL salts”. FIELD OF THE DISCLOSURE

[0002] The present disclosure includes solid state forms of Belumosudil, in embodiments including crystalline polymorphs of Belumosudil or a salt thereof, processes for their preparation, and pharmaceutical compositions thereof. BACKGROUND OF THE DISCLOSURE

[0003] Belumosudil, 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide, has the following chemical structure:

[0004] 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 cutaneous systemic sclerosis; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis and systemic sclerosis.

[0005] This compound is described in International Publication No. WO 2006 / 105081. A crystalline form of Belumosudil is disclosed in International Publication No. WO 2021 / 129589.

[0006] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. Individual molecules can be produced with different crystal structures and physical properties such as melting points, thermal behavior (e.g., as measured by thermogravimetric analysis ("TGA") or differential scanning calorimetry ("DSC")), X-ray diffraction (XRD) patterns, infrared absorption fingerprints, and solid-state ( 13 C) NMR spectroscopy of multiple polymorphs. One or more of these techniques can be used to distinguish between different polymorphic forms of a compound.

[0007] Different salts and solid forms (including solvated forms) of active pharmaceutical ingredients can have different properties. Such changes in the properties of different salts and solid forms and solvates can provide a basis for improving preparations, for example, by promoting better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorphs and chemical stability) and shelf life. These changes in the properties of different salts and solid forms can also provide improvements to the final dosage form, for example, if they are used to improve bioavailability. Different salts and solid forms and solvates of active pharmaceutical ingredients can also produce multiple polymorphs or crystalline forms, which can provide additional opportunities to evaluate the properties of solid active pharmaceutical ingredients and the changes in characteristics.

[0008] The new solid-state form and solvate of discovery drug product can produce and have desirable processing property such as easy to handle, easy to process, storage stability and be easy to purify or as the material of desirable intermediate crystal form that promotes conversion into other polymorphic forms.The new solid-state form of pharmaceutically useful compound can also provide the opportunity of improving the performance characteristics of drug product.It has expanded the reservoir of material that formulation scientist can be used for formulation optimization, for example, by providing products with different properties, including different crystal habits, higher crystallinity or polymorphic stability, this can provide better processing or handling characteristics, improved dissolution profile or improved shelf life (chemical / physical stability).For at least these reasons, there is demand for other solid-state form (comprising solvated form) of Belumosudil and Belumosudil salt. Summary of the Disclosure

[0009] The present disclosure provides crystalline polymorphs of Belumosudil and its salts (including Belumosudil mesylate, Belumosudil tosylate and / or Belumosudil benzenesulfonate), preparation processes and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other solid forms of Belumosudil, Belumosudil salts and solid forms thereof.

[0010] The present disclosure also provides the use of the solid state forms of API or its salts (including Belumosudil mesylate, Belumosudil tosylate and / or Belumosudil besylate) in the preparation of other solid state forms of Belumosudil or its salts.

[0011] The present disclosure provides crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil tosylate and Belumosudil besylate) for use in medicine, including for the treatment of graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse cutaneous systemic sclerosis; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; systemic scleroderma. In particular, the present disclosure provides crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil tosylate and Belumosudil besylate) for use in medicine, including for the treatment of chronic graft-versus-host disease and / or systemic sclerosis.

[0012] The present disclosure also includes the use of the crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil tosylate and Belumosudil besylate) of the present disclosure for preparing pharmaceutical compositions and / or formulations.

[0013] In another aspect, the present disclosure provides a pharmaceutical composition comprising a crystalline polymorph of Belumosudil or a salt thereof according to the present disclosure, including Belumosudil mesylate, Belumosudil tosylate, and Belumosudil besylate.

[0014] The present disclosure includes a process for preparing the pharmaceutical composition mentioned above. The process includes combining any one or combination of crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil tosylate and Belumosudil besylate) with at least one pharmaceutically acceptable excipient.

[0015] Crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil tosylate and Belumosudil besylate) as defined herein, and pharmaceutical compositions or pharmaceutical formulations of crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil tosylate and Belumosudil besylate) can be used as medicaments, such as for the treatment of graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse cutaneous systemic sclerosis; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; systemic scleroderma. In particular, the crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil tosylate and Belumosudil besylate) as defined herein, and the pharmaceutical compositions or pharmaceutical preparations of the crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil tosylate and / or Belumosudil besylate) can be used as medicaments for the treatment of chronic graft-versus-host disease and / or systemic sclerosis.

[0016] The present disclosure also provides methods for treating graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse cutaneous systemic sclerosis; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; systemic scleroderma, by administering to a subject a therapeutically effective amount of any one or combination of crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil tosylate and Belumosudil besylate) of the present disclosure, or at least one of the above-mentioned pharmaceutical compositions, wherein the subject suffers from graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse cutaneous systemic sclerosis; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; systemic scleroderma or the patient is otherwise in need of treatment. In particular, the present disclosure provides methods for treating chronic graft-versus-host disease and / or systemic sclerosis by administering a therapeutically effective amount of any one or combination of crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil tosylate and Belumosudil besylate) of the present disclosure, or at least one of the above-mentioned pharmaceutical compositions, to a subject suffering from chronic graft-versus-host disease and / or systemic sclerosis or otherwise in need of treatment.

[0017] The present disclosure also provides the use of at least one of the crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil tosylate and / or Belumosudil besylate) of the present disclosure or the above-mentioned pharmaceutical compositions for the manufacture of a medicament for treating: for example, graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse cutaneous systemic sclerosis; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; systemic sclerosis; and in particular for the treatment of chronic graft-versus-host disease and / or systemic sclerosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Shown is the X-ray powder diffraction pattern (XRPD) of amorphous Belumosudil.

[0019] Figure 2 The characteristic X-ray powder diffraction pattern (XRPD) of Belumosudil Form Bl is shown.

[0020] Figure 3 The characteristic X-ray powder diffraction pattern (XRPD) of Belumosudil Form B2 is shown.

[0021] Figure 4 The characteristic X-ray powder diffraction pattern (XRPD) of Belumosudil Form B3 is shown.

[0022] Figure 5 The characteristic X-ray powder diffraction pattern (XRPD) of Belumosudil mesylate Form M1 is shown.

[0023] Figure 6 The characteristic X-ray powder diffraction pattern (XRPD) of Belumosudil Form B4 is shown.

[0024] Figure 7 The characteristic X-ray powder diffraction pattern (XRPD) of Belumosudil mesylate salt Form M2 is shown.

[0025] Figure 8 The characteristic X-ray powder diffraction pattern (XRPD) of Belumosudil mesylate salt Form M3 is shown.

[0026] Fig. 9 The characteristic X-ray powder diffraction pattern (XRPD) of Belumosudil Form B5 is shown.

[0027] Fig.10The characteristic X-ray powder diffraction pattern (XRPD) of amorphous Belumosudil mesylate is shown.

[0028] Fig.11 The characteristic X-ray powder diffraction pattern (XRPD) of Belumosudil mesylate salt Form M4 is shown.

[0029] Fig.12 The characteristic X-ray powder diffraction pattern (XRPD) of Belumosudil mesylate salt Form M5 is shown.

[0030] Fig.13 The characteristic X-ray powder diffraction pattern (XRPD) of Belumosudil besylate salt form BS1 is shown.

[0031] Fig.14 The characteristic X-ray powder diffraction pattern (XRPD) of Belumosudil Tosylate Form T1 is shown.

[0032] Fig.15 The characteristic X-ray powder diffraction pattern (XRPD) of Belumosudil Tosylate Form T2 is shown.

[0033] Fig.16 The characteristic solid state of Form M1 of Belumosudil mesylate is shown 13 C NMR spectrum (full range 200 ppm-0 ppm).

[0034] Fig.17 The characteristic solid state of Form M1 of Belumosudil mesylate is shown 13 C NMR spectrum (200 ppm-100 ppm).

[0035] Fig.18 The characteristic solid state of Form M1 of Belumosudil mesylate is shown 13 C NMR spectrum (100 ppm-0 ppm).

[0036] Fig.19 Characteristic solid state diagram of Form M2 of Belumosudil mesylate is shown. 13 C NMR spectrum (full range 200 ppm-0 ppm).

[0037] Fig. 20 Characteristic solid state diagram of Form M2 of Belumosudil mesylate is shown. 13 C NMR spectrum (200 ppm-100 ppm).

[0038] Fig.21Characteristic solid state diagram of Form M2 of Belumosudil mesylate is shown. 13 C NMR spectrum (100 ppm-0 ppm).

[0039] Fig. 22 Characteristic solid state diagram of Belumosudil besylate form BS1 is shown 13 C NMR spectrum (full range 200 ppm-0 ppm).

[0040] Fig.23 Characteristic solid state diagram of Belumosudil besylate form BS1 is shown 13 C NMR spectrum (200 ppm-100 ppm).

[0041] Fig.24 Characteristic solid state diagram of Belumosudil besylate form BS1 is shown 13 C NMR spectrum (100 ppm-0 ppm).

[0042] Fig.25 Shown is a scanning electron microscopy (SEM) image of particles of belumosudil besylate form BS1.

[0043] Fig.26 Characteristic solid state diagram of Form T1 of Belumosudil Tosylate 13 C NMR spectrum (full range 200 ppm-0 ppm).

[0044] Fig. 27 Characteristic solid state diagram of Form T1 of Belumosudil Tosylate 13 C NMR spectrum (200 ppm-100 ppm).

[0045] Fig.28 Characteristic solid state diagram of Form T1 of Belumosudil Tosylate 13 C NMR spectrum (100 ppm-0 ppm).

[0046] Fig.29 Shown is a scanning electron microscopy (SEM) image of particles of Form T1 of belumosudil tosylate.

[0047] Fig.30 Characteristic solid state diagram of Form T2 of Belumosudil Tosylate 13 C NMR spectrum (full range 200 ppm-0 ppm).

[0048] Fig.31 Characteristic solid state diagram of Form T2 of Belumosudil Tosylate 13 C NMR spectrum (200 ppm-100 ppm).

[0049] Fig.32 Characteristic solid state diagram of Form T2 of Belumosudil Tosylate 13 C NMR spectrum (100 ppm-0 ppm).

[0050] Fig.33 Shown is a scanning electron microscopy (SEM) image of particles of Form T2 of Belumosudil Tosylate.

[0051] Detailed Description of the Disclosure The present disclosure includes solid state forms of Belumosudil and its salts (including Belumosudil mesylate, Belumosudil tosylate and / or Belumosudil besylate), including crystalline polymorphs of Belumosudil and its salts, processes for their preparation and pharmaceutical compositions thereof.

[0052] The solid state properties of Belumosudil, Belumosudil salts and crystalline polymorphs thereof can be influenced by controlling the conditions under which Belumosudil and Belumosudil salts and crystalline polymorphs thereof are obtained in solid form.

[0053] Solid-state form (or polymorph) can be referred to herein as polymorph-pure or substantially free of any other solid-state (or polymorph) form. As used herein, the statement "substantially free of any other form" will be understood to mean that the solid-state form comprises 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 the subject compound of any other form, as measured by XRPD, for example. Therefore, the crystalline polymorph of Belumosudil or Belumosudil salt described herein as being substantially free of any other solid-state form will be understood to comprise greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w) or about 100% of the subject crystalline polymorph of Belumosudil or Belumosudil salt. In some embodiments of the present disclosure, the described crystalline polymorph of Belumosudil or a Belumosudil salt may contain 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) of one or more other crystalline polymorphs of the same Belumosudil or a Belumosudil salt. Similarly, a crystalline polymorph of a belumosudil salt (e.g., belumosudil mesylate, belumosudil tosylate, or belumosudil besylate) described herein as being substantially free of any other solid state form will be understood to comprise greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the subject crystalline polymorph of a belumosudil salt (e.g., belumosudil mesylate, belumosudil tosylate, or belumosudil besylate).In some embodiments of the present disclosure, the described crystalline polymorph of a Belumosudil salt (e.g., Belumosudil mesylate, Belumosudil tosylate, or Belumosudil besylate) may contain 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) of one or more other crystalline polymorphs of the same Belumosudil salt (e.g., Belumosudil mesylate, Belumosudil tosylate, or Belumosudil besylate).

[0054] Depending on the other crystalline polymorphs to which they are compared, the crystalline polymorphs of Belumosudil and Belumosudil salts (e.g., Belumosudil mesylate, Belumosudil tosylate, or Belumosudil besylate) of the present disclosure may have advantageous properties selected from at least one of chemical purity, fluidity, solubility, dissolution rate, morphology or crystal habit, stability such as chemical stability and thermal and mechanical stability with respect to polymorphic conversion, dehydration stability and / or storage stability, low content of residual solvents, a lower degree of hygroscopicity, fluidity, and advantageous processing and handling characteristics such as compressibility and bulk density.

[0055] A solid state form, such as a crystalline form or an amorphous form, may be referred to herein as being characterized by graphical data "as depicted in the figure" or "substantially as depicted in the figure." Such data include, for example, powder X-ray diffraction patterns and solid state NMR spectra. As is well known in the art, graphical data potentially provide additional technical information to further define the corresponding solid state form (a so-called "fingerprint") that is not necessarily described solely by reference values ​​or peak positions. In any case, the skilled person will understand that such graphical representations of the data may undergo small changes, such as small changes in peak relative intensities and peak positions, due to certain factors well known to the skilled person, such as, but not limited to, changes in instrument response and changes in sample concentration and purity. Nonetheless, the skilled person will be able to readily compare the graphical data in the figures herein with graphical data generated for an unknown crystalline form and confirm whether the two sets of graphical data characterize the same crystalline form or two different crystalline forms. Thus, crystalline forms of Belumosudil or a salt of Belumosudil referred to herein as being characterized by graphical data "as depicted in the Figure" or "substantially as depicted in the Figure" will be understood to include any crystalline form of Belumosudil or a salt of Belumosudil characterized by the graphical data with such minor variations from the Figure as are well known to the skilled artisan.

[0056] As used herein and unless otherwise indicated, the term "anhydrous" with respect to the crystalline forms of Belumosudil, Belumosudil mesylate, Belumosudil tosylate and / or Belumosudil benzenesulfonate relates to a crystalline form of Belumosudil or a Belumosudil salt that does not include any definite stoichiometric amount of water of crystallization (or other solvent) within the crystal. In addition, the "anhydrous" form will typically not contain greater than 1% (w / w) water or organic solvents, as measured, for example, by TGA.

[0057] As used herein and unless otherwise indicated, the term "solvate" refers to a crystalline form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in the solvate can be present in stoichiometric amounts or in non-stoichiometric amounts.

[0058] As used herein, the term "isolated" with respect to a crystalline polymorph of Belumosudil or a Belumosudil salt (e.g., Belumosudil mesylate, Belumosudil tosylate and / or Belumosudil besylate) of the present disclosure corresponds to a crystalline polymorph of Belumosudil or a Belumosudil salt that is physically separated from the reaction mixture from which it is formed.

[0059] As used herein, unless otherwise stated, XRPD measurements are performed using copper Kα radiation wavelength 1.5418 Å. XRPD peaks reported herein are measured using Cu Kα radiation, λ = 1.5418 Å, typically at a temperature of 25°C ± 3°C.

[0060] As used herein, 13 C NMR spectra are preferably measured at 125 MHz with a magic angle spinning (MAS) frequency ωr / 2π=11 kHz.

[0061] As used herein, unless otherwise stated, TGA analysis is preferably performed at a heating rate of 10°C / min to 250°C, preferably with a nitrogen flow rate of 40 ml / min.

[0062] A substance, such as a reaction mixture, may be characterized herein as being at or allowed to reach "room temperature" or "ambient temperature," which is often abbreviated as "RT." This means that the temperature of the substance is close to or the same as the temperature of the space, such as a room or fume hood, in which the substance is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0063] The amount of the solvent used in a chemical process such as a reaction or crystallization can be referred to as the quantity of "volume" or "vol" or "V" in this article. For example, a material can be referred to as being suspended in 10 volumes (or 10 vol or 10V) of solvent. In this context, this expression will be understood to mean the milliliters of solvent per gram of suspended material, so that 5 grams of material is suspended in 10 volumes of solvent means that the solvent is used with the amount of 10 milliliters of solvent per gram of suspended material, or in this example, with the amount of 50 mL of solvent. In another case, the term "v / v" can be used to indicate the quantity of the volume of the 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 reaction mixture will indicate the addition of 150 mL of solvent X.

[0064] A process or step may be referred to herein as being performed "overnight." This refers, for example, to a time interval for a process or step that spans the nighttime hours when the process or step may not be actively observed. The time interval is from about 8 hours to about 20 hours or about 10 hours to 18 hours, and in some cases about 16 hours.

[0065] As used herein, the term "reduced pressure" refers to a pressure lower than atmospheric pressure. For example, the reduced pressure is about 10 mbar to about 50 mbar.

[0066] As used herein and unless otherwise indicated, the term "ambient conditions" refers to atmospheric pressure and a temperature of 22°C-24°C.

[0067] The present disclosure includes a crystalline polymorph of belumosudil designated as Form B1. Crystalline Form B1 of belumosudil can be characterized by one or more data selected from the following: substantially as Figure 2 an X-ray powder diffraction pattern depicted in ; an X-ray powder diffraction pattern having peaks at 3.5 degrees 2θ±0.2 degrees 2θ, 6.9 degrees 2θ±0.2 degrees 2θ, 10.5 degrees 2θ±0.2 degrees 2θ, 24.9 degrees 2θ±0.2 degrees 2θ, and 25.7 degrees 2θ±0.2 degrees 2θ; and combinations of these data.

[0068] The crystalline Form B1 of belumosudil may be further characterized by an X-ray powder diffraction pattern having peaks at 3.5 degrees 2θ±0.2 degrees 2θ, 6.9 degrees 2θ±0.2 degrees 2θ, 10.5 degrees 2θ±0.2 degrees 2θ, 24.9 degrees 2θ±0.2 degrees 2θ, and 25.7 degrees 2θ±0.2 degrees 2θ, and further having any one, two, three, four or five additional peaks selected from 9.4 degrees 2θ±0.2 degrees 2θ, 12.5 degrees 2θ±0.2 degrees 2θ, 15.7 degrees 2θ±0.2 degrees 2θ, 18.9 degrees 2θ±0.2 degrees 2θ, and 19.7 degrees 2θ±0.2 degrees 2θ.

[0069] The crystalline Form B1 of belumosudil may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 3.5 degrees 2θ±0.2 degrees 2θ, 6.9 degrees 2θ±0.2 degrees 2θ, 9.4 degrees 2θ±0.2 degrees 2θ, 10.5 degrees 2θ±0.2 degrees 2θ, 12.5 degrees 2θ±0.2 degrees 2θ, 15.7 degrees 2θ±0.2 degrees 2θ, 18.9 degrees 2θ±0.2 degrees 2θ, 19.7 degrees 2θ±0.2 degrees 2θ, 24.9 degrees 2θ±0.2 degrees 2θ, and 25.7 degrees 2θ±0.2 degrees 2θ.

[0070] In one embodiment of the present disclosure, crystalline Form Bl of Belumosudil is isolated.

[0071] Crystalline Form B1 of belumosudil may be characterized by each of the above characteristics individually and / or by all possible combinations, for example, an XRPD pattern having peaks at 3.5 degrees 2θ ± 0.2 degrees 2θ, 6.9 degrees 2θ ± 0.2 degrees 2θ, 10.5 degrees 2θ ± 0.2 degrees 2θ, 24.9 degrees 2θ ± 0.2 degrees 2θ, and 25.7 degrees 2θ ± 0.2 degrees 2θ; Figure 2 The XRPD patterns depicted in and combinations thereof.

[0072] The present disclosure includes a crystalline polymorph of belumosudil designated as Form B2. Crystalline Form B2 of belumosudil can be characterized by one or more data selected from the following: substantially as Figure 3 an X-ray powder diffraction pattern depicted in ; an X-ray powder diffraction pattern having peaks at 3.8 degrees 2θ±0.2 degrees 2θ, 5.7 degrees 2θ±0.2 degrees 2θ, 7.6 degrees 2θ±0.2 degrees 2θ, 9.6 degrees 2θ±0.2 degrees 2θ, and 25.9 degrees 2θ±0.2 degrees 2θ; and combinations of these data.

[0073] The crystalline Form B2 of belumosudil may be further characterized by an X-ray powder diffraction pattern having peaks at 3.8 degrees 2θ±0.2 degrees 2θ, 5.7 degrees 2θ±0.2 degrees 2θ, 7.6 degrees 2θ±0.2 degrees 2θ, 9.6 degrees 2θ±0.2 degrees 2θ, and 25.9 degrees 2θ±0.2 degrees 2θ, and further having any one, two, three, four or five additional peaks selected from 10.7 degrees 2θ±0.2 degrees 2θ, 15.4 degrees 2θ±0.2 degrees 2θ, 16.6 degrees 2θ±0.2 degrees 2θ, 17.8 degrees 2θ±0.2 degrees 2θ, and 19.3 degrees 2θ±0.2 degrees 2θ.

[0074] The crystalline Form B2 of belumosudil may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 3.8 degrees 2θ±0.2 degrees 2θ, 5.7 degrees 2θ±0.2 degrees 2θ, 7.6 degrees 2θ±0.2 degrees 2θ, 9.6 degrees 2θ±0.2 degrees 2θ, 10.7 degrees 2θ±0.2 degrees 2θ, 15.4 degrees 2θ±0.2 degrees 2θ, 16.6 degrees 2θ±0.2 degrees 2θ, 17.8 degrees 2θ±0.2 degrees 2θ, 19.3 degrees 2θ±0.2 degrees 2θ, and 25.9 degrees 2θ±0.2 degrees 2θ.

[0075] In one embodiment of the present disclosure, crystalline Form B2 of Belumosudil is isolated.

[0076] The crystalline form B2 of belumosudil may be characterized by each of the above characteristics individually and / or by all possible combinations, for example, an XRPD pattern having peaks at 3.8 degrees 2θ ± 0.2 degrees 2θ, 5.7 degrees 2θ ± 0.2 degrees 2θ, 7.6 degrees 2θ ± 0.2 degrees 2θ, 9.6 degrees 2θ ± 0.2 degrees 2θ, and 25.9 degrees 2θ ± 0.2 degrees 2θ; Figure 3 The XRPD patterns depicted in and combinations thereof.

[0077] The present disclosure includes a crystalline polymorph of belumosudil designated as Form B3. Crystalline Form B3 of belumosudil can be characterized by one or more data selected from the following: substantially as Figure 4 an X-ray powder diffraction pattern depicted in ; an X-ray powder diffraction pattern having peaks at 6.5 degrees 2θ±0.2 degrees 2θ, 8.4 degrees 2θ±0.2 degrees 2θ, 12.2 degrees 2θ±0.2 degrees 2θ, 19.6 degrees 2θ±0.2 degrees 2θ, and 26.3 degrees 2θ±0.2 degrees 2θ; and combinations of these data.

[0078] The crystalline Form B3 of belumosudil may be further characterized by an X-ray powder diffraction pattern having peaks at 6.5 degrees 2θ±0.2 degrees 2θ, 8.4 degrees 2θ±0.2 degrees 2θ, 12.2 degrees 2θ±0.2 degrees 2θ, 19.6 degrees 2θ±0.2 degrees 2θ, and 26.3 degrees 2θ±0.2 degrees 2θ, and further having any one, two, three, four or five additional peaks selected from 14.7 degrees 2θ±0.2 degrees 2θ, 15.4 degrees 2θ±0.2 degrees 2θ, 16.4 degrees 2θ±0.2 degrees 2θ, 18.8 degrees 2θ±0.2 degrees 2θ, and 22.5 degrees 2θ±0.2 degrees 2θ.

[0079] The crystalline Form B3 of belumosudil may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 6.5 degrees 2θ±0.2 degrees 2θ, 8.4 degrees 2θ±0.2 degrees 2θ, 12.2 degrees 2θ±0.2 degrees 2θ, 14.7 degrees 2θ±0.2 degrees 2θ, 15.4 degrees 2θ±0.2 degrees 2θ, 16.4 degrees 2θ±0.2 degrees 2θ, 18.8 degrees 2θ±0.2 degrees 2θ, 19.6 degrees 2θ±0.2 degrees 2θ, 22.5 degrees 2θ±0.2 degrees 2θ, and 26.3 degrees 2θ±0.2 degrees 2θ.

[0080] In one embodiment of the present disclosure, crystalline Form B3 of Belumosudil is isolated.

[0081] Crystalline Form B3 of belumosudil may be characterized by each of the above characteristics individually and / or by all possible combinations, for example, an XRPD pattern having peaks at 6.5 degrees 2θ ± 0.2 degrees 2θ, 8.4 degrees 2θ ± 0.2 degrees 2θ, 12.2 degrees 2θ ± 0.2 degrees 2θ, 19.6 degrees 2θ ± 0.2 degrees 2θ, and 26.3 degrees 2θ ± 0.2 degrees 2θ; Figure 4 The XRPD patterns depicted in and combinations thereof.

[0082] The present disclosure includes a crystalline polymorph of belumosudil designated as Form B4. Crystalline Form B4 of belumosudil can be characterized by one or more data selected from the following: substantially as Figure 6 an X-ray powder diffraction pattern depicted in ; an X-ray powder diffraction pattern having peaks at 8.3 degrees 2θ±0.2 degrees 2θ, 9.3 degrees 2θ±0.2 degrees 2θ, 11.9 degrees 2θ±0.2 degrees 2θ, 16.7 degrees 2θ±0.2 degrees 2θ, and 17.2 degrees 2θ±0.2 degrees 2θ; and combinations of these data.

[0083] The crystalline Form B4 of belumosudil may be further characterized by an X-ray powder diffraction pattern having peaks at 8.3 degrees 2θ±0.2 degrees 2θ, 9.3 degrees 2θ±0.2 degrees 2θ, 11.9 degrees 2θ±0.2 degrees 2θ, 16.7 degrees 2θ±0.2 degrees 2θ, and 17.2 degrees 2θ±0.2 degrees 2θ, and further having any one, two, three, four or five additional peaks selected from 15.2 degrees 2θ±0.2 degrees 2θ, 18.7 degrees 2θ±0.2 degrees 2θ, 24.1 degrees 2θ±0.2 degrees 2θ, 25.6 degrees 2θ±0.2 degrees 2θ, and 26.2 degrees 2θ±0.2 degrees 2θ.

[0084] The crystalline Form B4 of belumosudil may be further characterized by an X-ray powder diffraction pattern having peaks at 8.3 degrees 2θ±0.2 degrees 2θ, 9.3 degrees 2θ±0.2 degrees 2θ, 11.9 degrees 2θ±0.2 degrees 2θ, 16.7 degrees 2θ±0.2 degrees 2θ, and 17.2 degrees 2θ±0.2 degrees 2θ, and further having any one, two, three, four or five additional peaks selected from 15.2 degrees 2θ±0.2 degrees 2θ, 18.7 degrees 2θ±0.2 degrees 2θ, 24.1 degrees 2θ±0.2 degrees 2θ, 25.6 degrees 2θ±0.2 degrees 2θ, and 26.2 degrees 2θ±0.2 degrees 2θ.

[0085] The crystalline Form B4 of belumosudil may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 8.3 degrees 2θ±0.2 degrees 2θ, 9.3 degrees 2θ±0.2 degrees 2θ, 11.9 degrees 2θ±0.2 degrees 2θ, 15.2 degrees 2θ±0.2 degrees 2θ, 16.7 degrees 2θ±0.2 degrees 2θ, 17.2 degrees 2θ±0.2 degrees 2θ, 18.7 degrees 2θ±0.2 degrees 2θ, 24.1 degrees 2θ±0.2 degrees 2θ, 25.6 degrees 2θ±0.2 degrees 2θ, and 26.2 degrees 2θ±0.2 degrees 2θ.

[0086] In one embodiment of the present disclosure, crystalline Form B4 of Belumosudil is isolated.

[0087] Crystalline Form B4 of belumosudil may be characterized by each of the above characteristics individually and / or by all possible combinations, for example, an XRPD pattern having peaks at 8.3 degrees 2θ ± 0.2 degrees 2θ, 9.3 degrees 2θ ± 0.2 degrees 2θ, 11.9 degrees 2θ ± 0.2 degrees 2θ, 16.7 degrees 2θ ± 0.2 degrees 2θ, and 17.2 degrees 2θ ± 0.2 degrees 2θ; Figure 6 The XRPD patterns depicted in and combinations thereof.

[0088] The present disclosure includes a crystalline polymorph of belumosudil designated as Form B5. Crystalline Form B5 of belumosudil can be characterized by one or more data selected from the following: substantially as Fig. 9 an X-ray powder diffraction pattern depicted in ; an X-ray powder diffraction pattern having peaks at 6.1 degrees 2θ±0.2 degrees 2θ, 12.9 degrees 2θ±0.2 degrees 2θ, 16.2 degrees 2θ±0.2 degrees 2θ, 16.8 degrees 2θ±0.2 degrees 2θ, and 19.2 degrees 2θ±0.2 degrees 2θ; and combinations of these data.

[0089] The crystalline Form B5 of belumosudil may be further characterized by an X-ray powder diffraction pattern having peaks at 6.1 degrees 2θ±0.2 degrees 2θ, 12.9 degrees 2θ±0.2 degrees 2θ, 16.2 degrees 2θ±0.2 degrees 2θ, 16.8 degrees 2θ±0.2 degrees 2θ, and 19.2 degrees 2θ±0.2 degrees 2θ, and further having any one, two, three, four or five additional peaks selected from 3.7 degrees 2θ±0.2 degrees 2θ, 9.4 degrees 2θ±0.2 degrees 2θ, 9.8 degrees 2θ±0.2 degrees 2θ, 12.4 degrees 2θ±0.2 degrees 2θ, and 18.4 degrees 2θ±0.2 degrees 2θ.

[0090] The crystalline Form B5 of belumosudil may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 3.7 degrees 2θ±0.2 degrees 2θ, 6.1 degrees 2θ±0.2 degrees 2θ, 9.4 degrees 2θ±0.2 degrees 2θ, 9.8 degrees 2θ±0.2 degrees 2θ, 12.4 degrees 2θ±0.2 degrees 2θ, 12.9 degrees 2θ±0.2 degrees 2θ, 16.2 degrees 2θ±0.2 degrees 2θ, 16.8 degrees 2θ±0.2 degrees 2θ, 18.4 degrees 2θ±0.2 degrees 2θ, and 19.2 degrees 2θ±0.2 degrees 2θ.

[0091] In one embodiment of the present disclosure, crystalline Form B5 of Belumosudil is isolated.

[0092] Crystalline Form B5 of belumosudil may be characterized by each of the above characteristics individually and / or by all possible combinations, for example, an XRPD pattern having peaks at 6.1 degrees 2θ ± 0.2 degrees 2θ, 12.9 degrees 2θ ± 0.2 degrees 2θ, 16.2 degrees 2θ ± 0.2 degrees 2θ, 16.8 degrees 2θ ± 0.2 degrees 2θ, and 19.2 degrees 2θ ± 0.2 degrees 2θ; Fig. 9 The XRPD patterns depicted in and combinations thereof.

[0093] The present disclosure includes a crystalline polymorph of belumosudil mesylate designated as Form M1. Crystalline Form M1 of belumosudil mesylate can be characterized by one or more of the following data: substantially as Figure 5 an X-ray powder diffraction pattern depicted in ; an X-ray powder diffraction pattern having peaks at 7.1 degrees 2θ±0.2 degrees 2θ, 17.2 degrees 2θ±0.2 degrees 2θ, 20.3 degrees 2θ±0.2 degrees 2θ, 21.5 degrees 2θ±0.2 degrees 2θ, and 25.5 degrees 2θ±0.2 degrees 2θ; a solid 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; solid with the following absolute differences in chemical shifts compared to the reference peak at 167.2 ppm ± 1 ppm 13 C NMR spectrum: 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; generally the same Fig.16 , Fig.17 and Fig.18 The solid state depicted in any of 13 C NMR spectra; and combinations of these data.

[0094] The crystalline Form M1 of belumosudil mesylate may be further characterized by an X-ray powder diffraction pattern having peaks at 7.1 degrees 2θ±0.2 degrees 2θ, 17.2 degrees 2θ±0.2 degrees 2θ, 20.3 degrees 2θ±0.2 degrees 2θ, 21.5 degrees 2θ±0.2 degrees 2θ, and 25.5 degrees 2θ±0.2 degrees 2θ, and further having any one, two, three, four or five additional peaks selected from 8.4 degrees 2θ±0.2 degrees 2θ, 15.5 degrees 2θ±0.2 degrees 2θ, 16.8 degrees 2θ±0.2 degrees 2θ, 19.5 degrees 2θ±0.2 degrees 2θ, and 22.1 degrees 2θ±0.2 degrees 2θ.

[0095] The crystalline Form M1 of belumosudil mesylate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 7.1 degrees 2θ±0.2 degrees 2θ, 8.4 degrees 2θ±0.2 degrees 2θ, 15.5 degrees 2θ±0.2 degrees 2θ, 16.8 degrees 2θ±0.2 degrees 2θ, 17.2 degrees 2θ±0.2 degrees 2θ, 19.5 degrees 2θ±0.2 degrees 2θ, 20.3 degrees 2θ±0.2 degrees 2θ, 21.5 degrees 2θ±0.2 degrees 2θ, 22.1 degrees 2θ±0.2 degrees 2θ, and 25.5 degrees 2θ±0.2 degrees 2θ.

[0096] According to any aspect or embodiment as described herein, the crystalline form M1 of belumosudil mesylate may be in anhydrous form, as can be determined by TGA. According to any aspect or embodiment as described herein, the crystalline form M1 of belumosudil mesylate 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 (particularly C 1-4 In some embodiments, the present invention provides a crystalline form M1 of Belumosudil mesylate according to any aspect or embodiment of the present disclosure, wherein the crystalline form M1 comprises 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 mesylate according to any aspect or embodiment of the present disclosure may comprise 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less of ethanol, or 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less of a mixture of ethanol and DMSO.

[0097] In one embodiment of the present disclosure, the crystalline Form M1 of Belumosudil mesylate is isolated. In particular, the crystalline Form M1 of Belumosudil mesylate according to any aspect or embodiment of the present disclosure may be isolated.

[0098] According to any aspect or embodiment of the present disclosure, the crystalline Form M1 of belumosudil mesylate is non-hygroscopic. In particular, Form M1 of belumosudil mesylate according to any aspect or embodiment is polymorphically stable at room temperature at a relative humidity of up to 100% for at least 7 days.

[0099] The crystalline form M1 of belumosudil mesylate may be characterized by each of the above characteristics individually and / or by all possible combinations, for example, an XRPD pattern having peaks at 7.1 degrees 2θ ± 0.2 degrees 2θ, 17.2 degrees 2θ ± 0.2 degrees 2θ, 20.3 degrees 2θ ± 0.2 degrees 2θ, 21.5 degrees 2θ ± 0.2 degrees 2θ, and 25.5 degrees 2θ ± 0.2 degrees 2θ; Figure 5 The XRPD patterns depicted in and combinations thereof.

[0100] Crystalline Form M1 of belumosudil mesylate can be prepared by crystallization from a mixture comprising belumosudil mesylate 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 the present disclosure for preparing Form M1, the process may include:

[0101] (a) providing a mixture of belumosudil mesylate in at least one polar solvent, optionally heated; (b) optionally stirring the mixture, optionally stirring the mixture at an elevated temperature; (c) optionally cooling the mixture, preferably to room temperature; (d) optionally stirring the cooled mixture; and (e) optionally isolating the crystalline Form M1 of Belumosudil mesylate from the mixture.

[0102] The mixture in step (a) can be prepared by: (i) providing a mixture of Belumosudil free base in a polar solvent; (ii) combining the mixture with methanesulfonic acid; (iii) optionally heating the mixture; and (iv) optionally adding further polar solvent.

[0103] Preferably, the process for preparing Form M1 of Belumosudil mesylate according to any embodiment described herein is carried out in the absence or substantial absence of water, in particular 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.

[0104] According to any embodiment of the process for preparing form M1, the solvent in step (i) is preferably an organic solvent, in particular comprising an alcohol, a halogenated solvent or a mixture thereof. Preferably, the solvent is selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, n-butanol and dichloromethane or a mixture thereof, and in particular ethanol, isopropanol, 1-propanol, n-butanol.

[0105] 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.

[0106] In the step (ii) of the process for preparing form M1, the combination of methanesulfonic acid and Belumosudil can be in any order. Preferably, methanesulfonic acid can be added to the mixture of Belumosudil in a solvent. Addition can be carried out in batches or dropwise. Methanesulfonic acid is optionally added in the following amount: relative to Belumosudil 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. Preferably, step (ii) includes adding methanesulfonic acid to a mixture of Belumosudil and a solvent.

[0107] In step (iii) of the process for preparing Form M1, the mixture may optionally be heated. Heating may be to 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.

[0108] In step (iv), additional polar solvent can be added to the reaction mixture. Additional solvent can be any solvent that is a poor solvent for Belumosudil mesylate, that is, Belumosudil mesylate has a solvent with low solubility therein. Additional polar solvent can be the same solvent as the solvent used in step (i), or can be different. Additional solvent is preferably selected from the group consisting of: methanol, ethanol, isopropanol, 1-propanol, n-butanol and methylene chloride or its mixture. 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. Additional polar solvent in step (iv) can be added in any suitable amount. Preferably, the v / v ratio of the additional polar solvent to the solvent in step (i) may 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.

[0109] Alternatively, according to any embodiment of the process for preparing Form M1, the mixture in step (a) may be prepared by: (ia) combining Belumosudil mesylate with a polar solvent, optionally with heating, to form a solution; and optionally (ii-a) Adding an organic antisolvent.

[0110] 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 a mixture thereof. In particular, the solvent is selected from the group consisting of TFE and DMSO. In step (ia), the ratio of solvent to Belumosudil mesylate can be: from about 5 ml to about 50 ml, from about 7 ml to about 40 ml, from about 9 ml to about 35 ml or from about 10 ml to about 30 ml per gram of Belumosudil mesylate.

[0111] The organic antisolvent in step (ii-a) can be any organic solvent in which Belumosudil mesylate 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.

[0112] 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 the form of a slurry. The mixture in step (a) can be at room temperature, or can be heated. The heating can 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. Alternatively, the mixture can be at room temperature.

[0113] In any embodiment of the process for preparing Form M1, step (b) is preferably carried out by stirring at 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. Alternatively, step (b) can be carried out at room temperature. Stirring can be carried out for any suitable time. 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.

[0114] In any embodiment of the process for preparing Form M1, step (c) is performed. Preferably, cooling reaches 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 continued 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.

[0115] In any embodiment of the process, step (e) may be performed by any suitable method, for example by filtration, decantation or by a centrifuge. Separation of the solids is preferably by filtration or by a centrifuge, and more preferably by a centrifuge.

[0116] In any embodiment, the process may also include washing and / or drying steps.

[0117] The present disclosure includes a crystalline polymorph of belumosudil mesylate designated as Form M2. Crystalline Form M2 of belumosudil mesylate can be characterized by one or more of the following data: substantially as Figure 7 an X-ray powder diffraction pattern depicted in ; an X-ray powder diffraction pattern having peaks at 6.3 degrees 2θ±0.2 degrees 2θ, 12.8 degrees 2θ±0.2 degrees 2θ, 15.8 degrees 2θ±0.2 degrees 2θ, 19.3 degrees 2θ±0.2 degrees 2θ, and 26.5 degrees 2θ±0.2 degrees 2θ; a solid 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 ppm13 C NMR spectrum; solid with the following absolute differences in chemical shifts compared to the reference peak at 166.9 ppm ± 1 ppm 13 C NMR spectrum: 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; generally the same Fig.19 , Fig. 20 and Fig.21 The solid state depicted in any of 13 C NMR spectra; and combinations of these data.

[0118] The crystalline Form M2 of belumosudil mesylate may be further characterized by an X-ray powder diffraction pattern having peaks at 6.3 degrees 2θ ± 0.2 degrees 2θ, 12.8 degrees 2θ ± 0.2 degrees 2θ, 15.8 degrees 2θ ± 0.2 degrees 2θ, 19.3 degrees 2θ ± 0.2 degrees 2θ, and 26.5 degrees 2θ ± 0.2 degrees 2θ, and further having any one, two, three, four or five additional peaks selected from 7.8 degrees 2θ ± 0.2 degrees 2θ, 20.4 degrees 2θ ± 0.2 degrees 2θ, 23.7 degrees 2θ ± 0.2 degrees 2θ, 25.1 degrees 2θ ± 0.2 degrees 2θ, and 27.4 degrees 2θ ± 0.2 degrees 2θ.

[0119] The crystalline Form M2 of belumosudil mesylate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 6.3 degrees 2θ±0.2 degrees 2θ, 7.8 degrees 2θ±0.2 degrees 2θ, 12.8 degrees 2θ±0.2 degrees 2θ, 15.8 degrees 2θ±0.2 degrees 2θ, 19.3 degrees 2θ±0.2 degrees 2θ, 20.4 degrees 2θ±0.2 degrees 2θ, 23.7 degrees 2θ±0.2 degrees 2θ, 25.1 degrees 2θ±0.2 degrees 2θ, 26.5 degrees 2θ±0.2 degrees 2θ, and 27.4 degrees 2θ±0.2 degrees 2θ.

[0120] According to any aspect or embodiment of the present disclosure, the crystalline form M2 of belumosudil mesylate may be a hydrate, preferably a dihydrate. Alternatively, according to any aspect or embodiment of the present disclosure, the crystalline form M2 of belumosudil mesylate may contain from about 1% to about 7% water by weight, preferably from about 1.5% to about 6.1% water.

[0121] In one embodiment of the present disclosure, the crystalline Form M2 of Belumosudil mesylate is isolated. In particular, the crystalline Form M2 of Belumosudil mesylate according to any aspect or embodiment of the present disclosure may be isolated.

[0122] According to any aspect or embodiment of the present disclosure, the crystalline Form M2 of Belumosudil mesylate is non-hygroscopic. In particular, Form M2 of Belumosudil mesylate according to any aspect or embodiment is polymorphically stable at room temperature at a relative humidity of up to 100% for at least 7 days.

[0123] The crystalline form M2 of belumosudil mesylate may be characterized by each of the above characteristics individually and / or by all possible combinations, for example, an XRPD pattern having peaks at 6.3 degrees 2θ ± 0.2 degrees 2θ, 12.8 degrees 2θ ± 0.2 degrees 2θ, 15.8 degrees 2θ ± 0.2 degrees 2θ, 19.3 degrees 2θ ± 0.2 degrees 2θ, and 26.5 degrees 2θ ± 0.2 degrees 2θ; Figure 7 The XRPD patterns depicted in and combinations thereof.

[0124] Crystalline form M2 of belumosudil mesylate can be prepared by crystallization from a mixture comprising belumosudil mesylate and water and optionally one or more polar organic solvents (preferably alcohol or a mixture thereof). Examples of suitable solvents include, but are not limited to, methanol, isopropanol, 1-propanol, n-butanol. Water can be present in the following amount: about 1 ml to about 60 ml per mmol of Belumosudil. In any embodiment, the process comprises:

[0125] (a) providing a mixture of belumosudil mesylate in water and optionally one or more polar organic solvents, optionally with heating, (b) optionally stirring the mixture, optionally stirring the mixture at an elevated temperature; (c) optionally cooling the mixture; (d) optionally stirring the cooled mixture; and (e) optionally isolating the crystalline Form M2 of Belumosudil mesylate from the mixture.

[0126] In any embodiment of the process, the mixture in step (a) can be prepared by: (i) providing a mixture of Belumosudil free base in water or a mixture of water and at least one polar organic solvent; (ii) combining the mixture with methanesulfonic acid; and (iii) optionally heating the mixture.

[0127] According to any embodiment of the process for preparing Form M2 of Belumosudil mesylate, the polar organic solvent in step (i) may preferably include 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.

[0128] According to any embodiment of the process for preparing Form M2 of Belumosudil mesylate, the ratio of solvent to Belumosudil in step (i) 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 in step (i) can be a solution or a slurry.

[0129] According to any embodiment of the process of form M2 for preparing Belumosudil mesylate, in step (ii), the combination of methanesulfonic acid and Belumosudil can be in any order. Preferably, methanesulfonic acid can be added to the mixture of Belumosudil in a solvent. Addition can be carried out in batches or dropwise. Methanesulfonic acid is optionally added in the following amount: relative to Belumosudil about 0.7 molar equivalent to about 1.5 molar equivalents, about 0.9 molar equivalent to about 1.3 molar equivalents, about 1.0 molar equivalent to about 1.2 molar equivalents or about 1.1 molar equivalents. Preferably, step (ii) includes adding methanesulfonic acid to the mixture of Belumosudil and a solvent.

[0130] In step (iii) of the process for preparing Belumosudil Form M2, the mixture may be optionally heated. The heating may be to 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. The heating may be performed for any suitable period of time to form a solution of Belumosudil mesylate.

[0131] Alternatively, in the process for preparing Belumosudil form M2 according to any aspect or embodiment of the present invention, the mixture in step (a) may be prepared by a process comprising: (ib) combining belumosudil mesylate with a polar organic solvent, optionally with heating, to produce a solution; and (ii-b) Adding water as an antisolvent.

[0132] According to any embodiment of the process for preparing Form M2 of Belumosudil mesylate, the polar organic solvent in step (ib) is preferably selected from the group consisting of TFE, DMSO and / or a mixture thereof. In particular, the solvent is selected from the group consisting of TFE and DMSO. The ratio of the polar organic solvent in step (ib) is preferably about 5 ml 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 mesylate.

[0133] Alternatively, in the process for preparing Belumosudil form M2 according to any aspect or embodiment of the present invention, the mixture in step (a) can be prepared by a process comprising: (ic) combining Belumosudil mesylate with water to produce a slurry. Preferably, Belumosudil mesylate is form M1 described according to any aspect or embodiment of the present invention. Preferably, the proportion of water in step (ic) is preferably about 10 ml to 60 ml, about 20 ml to about 50 ml, about 30 ml to about 45 ml or about 40 ml per gram of Belumosudil mesylate.

[0134] In any embodiment of the process, step (b) is performed. Step (b) is preferably performed under heating, preferably at a temperature of 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. Agitation may be performed for any suitable period of time.

[0135] In any embodiment of the process for preparing Form M2, step (c) is performed.Step (c) preferably comprises cooling the mixture to room temperature.

[0136] In any embodiment of the process for preparing Form M2, step (d) may be performed. Agitation may be continued for any suitable time to prepare Form M2.

[0137] In any embodiment of the process for preparing crystalline Belumosudil mesylate Form M2, step (e) can be performed by any suitable method, such as by filtration, decantation or by centrifuge. The separation of the solid is preferably by filtration or by centrifuge, and more preferably by centrifuge.

[0138] In any embodiment, the process may also include washing and / or drying steps.

[0139] The present disclosure includes a crystalline polymorph of belumosudil mesylate designated as Form M3. Crystalline Form M3 of belumosudil mesylate can be characterized by one or more of the following data: substantially as Figure 8 an X-ray powder diffraction pattern depicted in ; an X-ray powder diffraction pattern having peaks at 7.3 degrees 2θ±0.2 degrees 2θ, 14.6 degrees 2θ±0.2 degrees 2θ, 16.6 degrees 2θ±0.2 degrees 2θ, 17.5 degrees 2θ±0.2 degrees 2θ, and 19.6 degrees 2θ±0.2 degrees 2θ; and combinations of these data.

[0140] The crystalline Form M3 of belumosudil mesylate may be further characterized by an X-ray powder diffraction pattern having peaks at 7.3 degrees 2θ±0.2 degrees 2θ, 14.6 degrees 2θ±0.2 degrees 2θ, 16.6 degrees 2θ±0.2 degrees 2θ, 17.5 degrees 2θ±0.2 degrees 2θ, and 19.6 degrees 2θ±0.2 degrees 2θ, and further having any one, two, three, four or five additional peaks selected from 12.9 degrees 2θ±0.2 degrees 2θ, 13.7 degrees 2θ±0.2 degrees 2θ, 19.0 degrees 2θ±0.2 degrees 2θ, 20.6 degrees 2θ±0.2 degrees 2θ, and 26.0 degrees 2θ±0.2 degrees 2θ.

[0141] The crystalline Form M3 of belumosudil mesylate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 7.3 degrees 2θ±0.2 degrees 2θ, 12.9 degrees 2θ±0.2 degrees 2θ, 13.7 degrees 2θ±0.2 degrees 2θ, 14.6 degrees 2θ±0.2 degrees 2θ, 16.6 degrees 2θ±0.2 degrees 2θ, 17.5 degrees 2θ±0.2 degrees 2θ, 19.0 degrees 2θ±0.2 degrees 2θ, 19.6 degrees 2θ±0.2 degrees 2θ, 20.6 degrees 2θ±0.2 degrees 2θ, and 26.0 degrees 2θ±0.2 degrees 2θ.

[0142] In one embodiment of the present disclosure, crystalline Form M3 of Belumosudil mesylate is isolated.

[0143] The crystalline form M3 of belumosudil mesylate may be characterized by each of the above characteristics individually and / or by all possible combinations, for example, an XRPD pattern having peaks at 7.3 degrees 2θ ± 0.2 degrees 2θ, 14.6 degrees 2θ ± 0.2 degrees 2θ, 16.6 degrees 2θ ± 0.2 degrees 2θ, 17.5 degrees 2θ ± 0.2 degrees 2θ, and 19.6 degrees 2θ ± 0.2 degrees 2θ; Figure 8 The XRPD patterns depicted in and combinations thereof.

[0144] The present disclosure includes a crystalline polymorph of belumosudil mesylate designated as Form M4. Crystalline Form M4 of belumosudil mesylate can be characterized by one or more of the following data: substantially as Fig.11 an X-ray powder diffraction pattern depicted in ; an X-ray powder diffraction pattern having peaks at 7.5 degrees 2θ±0.2 degrees 2θ, 15.0 degrees 2θ±0.2 degrees 2θ, 17.9 degrees 2θ±0.2 degrees 2θ, 21.8 degrees 2θ±0.2 degrees 2θ, and 22.6 degrees 2θ±0.2 degrees 2θ; and combinations of these data.

[0145] The crystalline Form M4 of belumosudil mesylate may be further characterized by an X-ray powder diffraction pattern having peaks at 7.5 degrees 2θ±0.2 degrees 2θ, 15.0 degrees 2θ±0.2 degrees 2θ, 17.9 degrees 2θ±0.2 degrees 2θ, 21.8 degrees 2θ±0.2 degrees 2θ, and 22.6 degrees 2θ±0.2 degrees 2θ, and further having any one, two, three, four or five additional peaks selected from 11.3 degrees 2θ±0.2 degrees 2θ, 17.4 degrees 2θ±0.2 degrees 2θ, 20.9 degrees 2θ±0.2 degrees 2θ, 24.2 degrees 2θ±0.2 degrees 2θ, and 29.2 degrees 2θ±0.2 degrees 2θ.

[0146] The crystalline Form M4 of belumosudil mesylate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 7.5 degrees 2θ±0.2 degrees 2θ, 11.3 degrees 2θ±0.2 degrees 2θ, 15.0 degrees 2θ±0.2 degrees 2θ, 17.4 degrees 2θ±0.2 degrees 2θ, 17.9 degrees 2θ±0.2 degrees 2θ, 20.9 degrees 2θ±0.2 degrees 2θ, 21.8 degrees 2θ±0.2 degrees 2θ, 22.6 degrees 2θ±0.2 degrees 2θ, 24.2 degrees 2θ±0.2 degrees 2θ, and 29.2 degrees 2θ±0.2 degrees 2θ.

[0147] In one embodiment of the present disclosure, crystalline Form M4 of Belumosudil mesylate is isolated.

[0148] Crystalline Form M4 of belumosudil mesylate may be characterized by each of the above characteristics individually and / or by all possible combinations, for example, an XRPD pattern having peaks at 7.5 degrees 2θ ± 0.2 degrees 2θ, 15.0 degrees 2θ ± 0.2 degrees 2θ, 17.9 degrees 2θ ± 0.2 degrees 2θ, 21.8 degrees 2θ ± 0.2 degrees 2θ, and 22.6 degrees 2θ ± 0.2 degrees 2θ; Fig.11 The XRPD patterns depicted in and combinations thereof.

[0149] The present disclosure includes a crystalline polymorph of belumosudil mesylate designated as Form M5. Crystalline Form M5 of belumosudil mesylate can be characterized by one or more data selected from the following: substantially as Fig.12 an X-ray powder diffraction pattern depicted in ; an X-ray powder diffraction pattern having peaks at 6.2 degrees 2θ±0.2 degrees 2θ, 15.7 degrees 2θ±0.2 degrees 2θ, 18.4 degrees 2θ±0.2 degrees 2θ, 19.2 degrees 2θ±0.2 degrees 2θ, and 25.1 degrees 2θ±0.2 degrees 2θ; and combinations of these data.

[0150] The crystalline Form M5 of belumosudil mesylate can be further characterized by an X-ray powder diffraction pattern having peaks at 6.2 degrees 2θ ± 0.2 degrees 2θ, 15.7 degrees 2θ ± 0.2 degrees 2θ, 18.4 degrees 2θ ± 0.2 degrees 2θ, 19.2 degrees 2θ ± 0.2 degrees 2θ, and 25.1 degrees 2θ ± 0.2 degrees 2θ, and further having any one, two, three, four or five additional peaks selected from 17.8 degrees 2θ ± 0.2 degrees 2θ, 21.6 degrees 2θ ± 0.2 degrees 2θ, 21.9 degrees 2θ ± 0.2 degrees 2θ, 24.7 degrees 2θ ± 0.2 degrees 2θ, 25.9 degrees 2θ ± 0.2 degrees 2θ.

[0151] The crystalline Form M5 of belumosudil mesylate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 6.2 degrees 2θ±0.2 degrees 2θ, 15.7 degrees 2θ±0.2 degrees 2θ, 17.8 degrees 2θ±0.2 degrees 2θ, 18.4 degrees 2θ±0.2 degrees 2θ, 19.2 degrees 2θ±0.2 degrees 2θ, 21.6 degrees 2θ±0.2 degrees 2θ, 21.9 degrees 2θ±0.2 degrees 2θ, 24.7 degrees 2θ±0.2 degrees 2θ, 25.1 degrees 2θ±0.2 degrees 2θ, and 25.9 degrees 2θ±0.2 degrees 2θ.

[0152] In one embodiment of the present disclosure, crystalline Form M5 of Belumosudil mesylate is isolated.

[0153] Crystalline Form M5 of belumosudil mesylate may be characterized by each of the above characteristics individually and / or by all possible combinations, for example, an XRPD pattern having peaks at 6.2 degrees 2θ ± 0.2 degrees 2θ, 15.7 degrees 2θ ± 0.2 degrees 2θ, 18.4 degrees 2θ ± 0.2 degrees 2θ, 19.2 degrees 2θ ± 0.2 degrees 2θ, and 25.1 degrees 2θ ± 0.2 degrees 2θ; Fig.12 The XRPD patterns depicted in and combinations thereof.

[0154] The present disclosure includes a crystalline polymorph of belumosudil besylate designated as Form BS1. Crystalline Form BS1 of belumosudil besylate can be characterized by one or more of the following data: substantially as Fig.13 an X-ray powder diffraction pattern depicted in ; an X-ray powder diffraction pattern having peaks at 6.6 degrees 2θ±0.2 degrees 2θ, 12.5 degrees 2θ±0.2 degrees 2θ, 14.9 degrees 2θ±0.2 degrees 2θ, 17.0 degrees 2θ±0.2 degrees 2θ, and 20.1 degrees 2θ±0.2 degrees 2θ; a solid 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; solid with the following absolute differences in chemical shifts compared to the reference peak at 169.6 ppm ± 1 ppm 13 C NMR spectrum: 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; generally the same Fig. 22 , Fig.23 and Fig.24 The solid state depicted in any of 13 C NMR spectra; and combinations of these data.

[0155] The crystalline Form BS1 of belumosudil besylate can be further characterized by an X-ray powder diffraction pattern having peaks at 6.6 degrees 2θ±0.2 degrees 2θ, 12.5 degrees 2θ±0.2 degrees 2θ, 14.9 degrees 2θ±0.2 degrees 2θ, 17.0 degrees 2θ±0.2 degrees 2θ, and 20.1 degrees 2θ±0.2 degrees 2θ, and further having any one, two, three, four or five additional peaks selected from 11.6 degrees 2θ±0.2 degrees 2θ, 17.6 degrees 2θ±0.2 degrees 2θ, 18.2 degrees 2θ±0.2 degrees 2θ, 21.7 degrees 2θ±0.2 degrees 2θ, and 25.1 degrees 2θ±0.2 degrees 2θ.

[0156] The crystalline Form BS1 of belumosudil besylate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 6.6 degrees 2θ±0.2 degrees 2θ, 11.6 degrees 2θ±0.2 degrees 2θ, 12.5 degrees 2θ±0.2 degrees 2θ, 14.9 degrees 2θ±0.2 degrees 2θ, 17.0 degrees 2θ±0.2 degrees 2θ, 17.6 degrees 2θ±0.2 degrees 2θ, 18.2 degrees 2θ±0.2 degrees 2θ, 20.1 degrees 2θ±0.2 degrees 2θ, 21.7 degrees 2θ±0.2 degrees 2θ, and 25.1 degrees 2θ±0.2 degrees 2θ.

[0157] The crystalline form BS1 of belumosudil besylate can be in anhydrous form, as can be determined by TGA. In certain embodiments, the present disclosure includes crystalline form BS1 of belumosudil besylate having 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less of total residual solvent. According to any aspect or embodiment as described herein, the crystalline form BS1 of belumosudil besylate can 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 can be one or more polar solvents, preferably water, alcohol (particularly C 1-4 The residual organic solvent may be ethanol. In particular, the crystalline form BS1 of Belumosudil besylate according to any aspect or embodiment of the present disclosure may contain 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less of ethanol.

[0158] In one embodiment of the present disclosure, the crystalline Form BS1 of Belumosudil besylate is isolated. In particular, the crystalline Form BS1 of Belumosudil besylate according to any aspect or embodiment of the present disclosure may be isolated.

[0159] In any aspect or embodiment of the present disclosure, the crystalline Form BS1 of belumosudil mesylate is non-hygroscopic. In particular, Form BS1 of belumosudil mesylate according to any aspect or embodiment is polymorphically stable at room temperature at a relative humidity of up to 100% for at least 7 days.

[0160] Crystalline Form BS1 of belumosudil besylate may be characterized by each of the above characteristics individually and / or by all possible combinations, for example, an XRPD pattern having peaks at 6.6 degrees 2θ ± 0.2 degrees 2θ, 12.5 degrees 2θ ± 0.2 degrees 2θ, 14.9 degrees 2θ ± 0.2 degrees 2θ, 17.0 degrees 2θ ± 0.2 degrees 2θ, and 20.1 degrees 2θ ± 0.2 degrees 2θ; Fig.13 The XRPD patterns depicted in and combinations thereof.

[0161] The crystalline form BS1 of belumosudil besylate can be prepared by crystallization from a mixture comprising belumosudil besylate and a polar solvent such as ethanol. In any aspect or embodiment, the process comprises:

[0162] (a) providing a mixture of belumosudil besylate in one or more polar solvents; (b) optionally stirring the mixture, optionally stirring the mixture at an elevated temperature; (c) optionally cooling the mixture; and (d) optionally isolating the crystalline Form BS1 of Belumosudil besylate from the mixture.

[0163] In any embodiment of the process for preparing Form BS1, the mixture in step (a) may be prepared by: (i) providing a mixture of Belumosudil free base (preferably Form B1 as described herein) in a polar solvent; and (ii) combining the mixture with benzenesulfonic acid.

[0164] In any embodiment of the process for preparing form BS1, the polar solvent in step (i) is preferably an alcohol (especially C 1-4 Preferably, the polar solvent comprises 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.

[0165] 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 the mixture of Belumosudil in a solvent. Addition can be carried out in batches or dropwise. Benzenesulfonic acid is optionally added in the following amount: relative to Belumosudil 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. Preferably, step (ii) includes adding benzenesulfonic acid to a mixture of Belumosudil and a polar solvent.

[0166] Alternatively, in any embodiment of the process for preparing Form BS1, the mixture in step (a) may be prepared by combining Belumosudil besylate with a polar solvent. Preferably, the polar solvent is an alcohol (particularly C 1-4 Alcohol, in particular ethanol, methanol, isopropanol, 1-propanol or n-butanol), and most preferably, the polar solvent is ethanol.

[0167] 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 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. Preferably, stirring is carried out at a certain temperature. Stirring can be carried out for any suitable time to form Belumosudil besylate salt form BS1. Typically, stirring can be carried out in a time period of about 10 minutes to about 2 hours, about 20 minutes to about 1 hour or about 45 minutes.

[0168] In any embodiment of the process for preparing form BS1, step (c) is performed, preferably wherein cooling is to room temperature.

[0169] In any embodiment of the process for preparing form BS1, step (d) may be performed by any suitable method, for example by filtration, decantation or by a centrifuge. Separation of the solid is preferably by filtration or by a centrifuge, and more preferably by a centrifuge.

[0170] In any embodiment, the process for preparing Form BS1 may further comprise a washing and / or drying step.

[0171] The present disclosure includes a crystalline polymorph of belumosudil tosylate designated as Form T1. Crystalline Form T1 of belumosudil tosylate can be characterized by one or more data selected from the following: substantially as Fig.14an X-ray powder diffraction pattern depicted in ; an X-ray powder diffraction pattern having peaks at 6.2 degrees 2θ±0.2 degrees 2θ, 12.3 degrees 2θ±0.2 degrees 2θ, 14.1 degrees 2θ±0.2 degrees 2θ, 17.7 degrees 2θ±0.2 degrees 2θ, and 18.4 degrees 2θ±0.2 degrees 2θ; a solid having characteristic peaks at 152.6 ppm±0.2 ppm, 143.4 ppm±0.2 ppm, 132.3 ppm±0.2 ppm, 125.3ppm±0.2 ppm, and 119.8 ppm±0.2 ppm 13 C NMR spectrum; solid with the following absolute differences in chemical shifts compared to the reference peak at 168.6 ppm ± 1 ppm 13 C NMR spectrum: 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; generally the same Fig.26 , Fig. 27 and Fig.28 The solid state depicted in any of 13 C NMR spectra; and combinations of these data.

[0172] The crystalline Form T1 of belumosudil tosylate may be further characterized by an X-ray powder diffraction pattern having peaks at 6.2 degrees 2θ±0.2 degrees 2θ, 12.3 degrees 2θ±0.2 degrees 2θ, 14.1 degrees 2θ±0.2 degrees 2θ, 17.7 degrees 2θ±0.2 degrees 2θ, and 18.4 degrees 2θ±0.2 degrees 2θ, and further having any one, two, three, four or five additional peaks selected from 9.9 degrees 2θ±0.2 degrees 2θ, 14.5 degrees 2θ±0.2 degrees 2θ, 16.7 degrees 2θ±0.2 degrees 2θ, 21.5 degrees 2θ±0.2 degrees 2θ, and 24.6 degrees 2θ±0.2 degrees 2θ.

[0173] The crystalline Form T1 of belumosudil tosylate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 6.2 degrees 2θ±0.2 degrees 2θ, 9.9 degrees 2θ±0.2 degrees 2θ, 12.3 degrees 2θ±0.2 degrees 2θ, 14.1 degrees 2θ±0.2 degrees 2θ, 14.5 degrees 2θ±0.2 degrees 2θ, 16.7 degrees 2θ±0.2 degrees 2θ, 17.7 degrees 2θ±0.2 degrees 2θ, 18.4 degrees 2θ±0.2 degrees 2θ, 21.5 degrees 2θ±0.2 degrees 2θ, and 24.6 degrees 2θ±0.2 degrees 2θ.

[0174] The crystalline Form T1 of belumosudil tosylate can be in an anhydrous form, as can be determined by TGA. In certain embodiments, the present disclosure includes crystalline Form T1 of belumosudil tosylate having 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 can be one or more polar solvents, preferably water and / or alcohol (particularly C 1-4 The residual organic solvent may be an alcohol, in particular 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 the present disclosure may contain 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less of methanol.

[0175] In one embodiment of the present 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 the present disclosure may be isolated.

[0176] In any aspect or embodiment of the present disclosure, the crystalline Form T1 of belumosudil tosylate is non-hygroscopic. In particular, Form T1 of belumosudil tosylate according to any aspect or embodiment is polymorphically stable at room temperature at a relative humidity of up to 100% for at least 7 days.

[0177] The crystalline Form T1 of belumosudil tosylate may be characterized by each of the above characteristics individually and / or by all possible combinations, for example, an XRPD pattern having peaks at 6.2 degrees 2θ ± 0.2 degrees 2θ, 12.3 degrees 2θ ± 0.2 degrees 2θ, 14.1 degrees 2θ ± 0.2 degrees 2θ, 17.7 degrees 2θ ± 0.2 degrees 2θ, and 18.4 degrees 2θ ± 0.2 degrees 2θ; Fig.14 The XRPD patterns depicted in and combinations thereof.

[0178] Crystalline Form T1 of belumosudil tosylate can be prepared by crystallization from a mixture comprising belumosudil tosylate and one or more polar solvents such as alcohols. Preferably, the solvent is methanol. In any embodiment, the process comprises:

[0179] (a) providing a mixture of Belumosudil tosylate in one or more polar solvents (preferably including methanol); (b) optionally stirring the mixture, optionally stirring the mixture at an elevated temperature; (c) optionally cooling the mixture; and (d) optionally isolating the crystalline Form T1 of Belumosudil tosylate from the mixture.

[0180] In any embodiment of the process, the mixture in step (a) can be prepared by: (i) providing a mixture of Belumosudil free base in a polar solvent; and (ii) combining the mixture with toluenesulfonic acid.

[0181] Preferably, the process for preparing Form T1 of belumosudil tosylate according to any embodiment described herein is carried out in the absence or substantial absence of water, in particular 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.

[0182] In any aspect or embodiment of the process for preparing Form T1, the polar solvent is preferably an alcohol (particularly C 1-4 Preferably, the polar solvent is methanol. 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 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 may be a solution or a slurry.

[0183] In step (ii), the combination of toluenesulfonic acid and Belumosudil can be in any order. Preferably, toluenesulfonic acid can be added to a mixture of Belumosudil in a solvent. Addition can be carried out in batches or dropwise. Toluenesulfonic acid is optionally added in the following amount: 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.

[0184] Alternatively, in any embodiment of the process for preparing Form T1, the mixture in step (a) can be prepared by combining Belumosudil tosylate with a polar solvent. Preferably, the polar solvent is an alcohol (particularly C1-4 Alcohols, in particular ethanol, methanol, isopropanol, 1-propanol or n-butanol), and most preferably, the polar solvent is methanol.

[0185] In any embodiment of the process for preparing Form T1, step (b) is preferably performed with stirring at 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. The stirring may be performed for any suitable time.

[0186] In any embodiment of the process for preparing Form T1, step (c) is performed, preferably wherein cooling is to room temperature.

[0187] In any embodiment of the process for preparing Form T1, step (d) may be performed by any suitable method, for example by filtration, decantation or by a centrifuge. Separation of the solid is preferably by filtration or by a centrifuge, and more preferably by a centrifuge.

[0188] In any embodiment of the process for preparing Form T1, the process may further comprise a washing and / or drying step.

[0189] The present disclosure includes a crystalline polymorph of belumosudil tosylate designated as Form T2. Crystalline Form T2 of belumosudil tosylate can be characterized by one or more of the following data: substantially as Fig.15 an X-ray powder diffraction pattern depicted in ; an X-ray powder diffraction pattern having peaks at 5.1 degrees 2θ±0.2 degrees 2θ, 15.7 degrees 2θ±0.2 degrees 2θ, 16.4 degrees 2θ±0.2 degrees 2θ, 19.7 degrees 2θ±0.2 degrees 2θ, and 23.7 degrees 2θ±0.2 degrees 2θ; a solid 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; solid with the following absolute differences in chemical shifts compared to the reference peak at 166.3 ppm ± 1 ppm 13 C NMR spectrum: 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; generally the same Fig.30 , Fig.31 and Fig.32 The solid state depicted in any of 13 C NMR spectra; and combinations of these data.

[0190] The crystalline Form T2 of belumosudil tosylate may be further characterized by an X-ray powder diffraction pattern having peaks at 5.1 degrees 2θ ± 0.2 degrees 2θ, 15.7 degrees 2θ ± 0.2 degrees 2θ, 16.4 degrees 2θ ± 0.2 degrees 2θ, 19.7 degrees 2θ ± 0.2 degrees 2θ, and 23.7 degrees 2θ ± 0.2 degrees 2θ, and further having any one, two, three, four or five additional peaks selected from 13.7 degrees 2θ ± 0.2 degrees 2θ, 14.2 degrees 2θ ± 0.2 degrees 2θ, 14.6 degrees 2θ ± 0.2 degrees 2θ, 19.1 degrees 2θ ± 0.2 degrees 2θ, and 23.0 degrees 2θ ± 0.2 degrees 2θ.

[0191] The crystalline Form T2 of belumosudil tosylate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 5.1 degrees 2θ±0.2 degrees 2θ, 13.7 degrees 2θ±0.2 degrees 2θ, 14.2 degrees 2θ±0.2 degrees 2θ, 14.6 degrees 2θ±0.2 degrees 2θ, 15.7 degrees 2θ±0.2 degrees 2θ, 16.4 degrees 2θ±0.2 degrees 2θ, 19.1 degrees 2θ±0.2 degrees 2θ, 19.7 degrees 2θ±0.2 degrees 2θ, 23.0 degrees 2θ±0.2 degrees 2θ, and 23.7 degrees 2θ±0.2 degrees 2θ.

[0192] The crystalline Form T2 of belumosudil tosylate can be in an anhydrous form, as can be determined by TGA. In certain embodiments, the present disclosure includes crystalline Form T2 of belumosudil tosylate having 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 of total residual solvent. The residual solvent can be one or more polar solvents, preferably water or an alcohol (particularly C 1-4 In one embodiment of the present disclosure, the crystalline form T2 of Belumosudil tosylate is separated. In another embodiment of the present disclosure, the crystalline form T2 of Belumosudil tosylate is separated. In another embodiment of the present disclosure, the crystalline form T2 of Belumosudil tosylate is separated. In another embodiment of the present disclosure, the crystalline form T2 of Belumosudil tosylate is separated. In another embodiment of the present disclosure, the crystalline form T2 of Belumosudil tosylate is separated. In another embodiment of the present disclosure, the crystalline form T2 of Belumosudil tosylate can be separated.

[0193] In any aspect or embodiment of the present disclosure, the crystalline Form T2 of belumosudil mesylate is non-hygroscopic. In particular, Form T2 of belumosudil mesylate according to any aspect or embodiment is polymorphically stable at room temperature at a relative humidity of up to 100% for at least 7 days.

[0194] The crystalline Form T2 of belumosudil tosylate may be characterized by each of the above characteristics individually and / or by all possible combinations, for example, an XRPD pattern having peaks at 5.1 degrees 2θ ± 0.2 degrees 2θ, 15.7 degrees 2θ ± 0.2 degrees 2θ, 16.4 degrees 2θ ± 0.2 degrees 2θ, 19.7 degrees 2θ ± 0.2 degrees 2θ, and 23.7 degrees 2θ ± 0.2 degrees 2θ; Fig.15 The XRPD patterns depicted in and combinations thereof.

[0195] The crystalline form T2 of belumosudil tosylate can be prepared by crystallization from a mixture comprising belumosudil tosylate and one or more polar solvents such as water. In any embodiment, the process comprises:

[0196] (a) providing a mixture of belumosudil tosylate in one or more polar solvents; (b) optionally stirring the mixture, optionally stirring the mixture at an elevated temperature; (c) optionally cooling to room temperature; and (d) optionally isolating the crystalline Form T2 of Belumosudil tosylate from the mixture.

[0197] In any embodiment of the process for preparing Form T2, the mixture in step (a) can be prepared by: (i) providing a mixture of Belumosudil free base (preferably Form B1 as described herein) in a polar solvent, preferably comprising water and / or ethanol; and (ii) combining the mixture with toluenesulfonic acid, optionally at an elevated temperature; and (iii) Optionally adding a polar solvent.

[0198] In any aspect or embodiment of the process for preparing Form T2, the polar solvent in step (i) preferably includes 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.

[0199] 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 the mixture of Belumosudil in a solvent. Addition can be carried out in batches or dropwise. Toluenesulfonic acid is optionally added in the following amount: relative to Belumosudil 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. Preferably, step (ii) includes adding toluenesulfonic acid to a mixture of Belumosudil and a solvent.

[0200] 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.

[0201] Alternatively, in any embodiment of the process for preparing Form T2, the mixture in step (a) can be prepared by combining Belumosudil tosylate with one or more polar solvents. Preferably, the polar solvent is water and / or an alcohol (particularly C 1-4 Alcohols, in particular ethanol, methanol, isopropanol, 1-propanol or n-butanol). Preferably, the polar solvents are water and ethanol.

[0202] In any embodiment of the process for preparing Form T2, step (b) is preferably carried out by stirring at 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. Stirring can be carried out for any suitable time. 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 50 minutes.

[0203] In any embodiment of the process for preparing form T2, the mixture can be cooled, preferably cooled to room temperature, and step (d) can be carried out by any suitable method, such as by filtering, decanting or by centrifuge. The separation of the solid is preferably by filtering or by centrifuge, and more preferably by centrifuge.

[0204] In any embodiment, the process may also include washing and / or drying steps.

[0205] The above-mentioned crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil tosylate and / or Belumosudil besylate) can be used to prepare other crystalline polymorphs of Belumosudil, Belumosudil salts and solid-state forms thereof.

[0206] The present disclosure encompasses processes for preparing other solid forms of Belumosudil, Belumosudil salts and solid forms thereof. The process includes preparing any solid form of Belumosudil or its salt by the process of the present disclosure, and converting the salt into the other Belumosudil salt. For example, the conversion can be accomplished by a process comprising alkalizing any one or combination of the salts described above such as Belumosudil mesylate, Belumosudil tosylate and / or Belumosudil benzenesulfonate and / or its solid forms, and reacting the obtained Belumosudil base with an appropriate acid to obtain the corresponding salt. Alternatively, the conversion can be accomplished by salt switching, i.e., reacting the Belumosudil acid addition salt with an acid having a pKa lower than the pKa of the acid of the first Belumosudil acid addition salt.

[0207] The present disclosure provides crystalline polymorphs of Belumosudil or its salts (including Belumosudil mesylate, Belumosudil tosylate and / or Belumosudil besylate) described above for use in preparing pharmaceutical compositions comprising Belumosudil, its salts and / or its crystalline polymorphs.

[0208] The present disclosure also encompasses the use of crystalline polymorphs of Belumosudil or a salt thereof, such as crystalline forms of Belumosudil mesylate, Belumosudil tosylate and / or Belumosudil besylate of the present disclosure, for the preparation of a pharmaceutical composition comprising a crystalline polymorph of Belumosudil or a salt thereof, such as a crystalline polymorph of Belumosudil mesylate, Belumosudil tosylate and / or Belumosudil besylate and / or a crystalline polymorph thereof.

[0209] In any aspect or embodiment of the present disclosure, any solid state form of Belumosudil, Belumosudil mesylate, Belumosudil tosylate and / or Belumosudil besylate described herein may be polymorphically pure, or may be substantially free of any other solid state form of the subject compound (i.e., Belumosudil, Belumosudil mesylate, Belumosudil tosylate and / or Belumosudil besylate, respectively). In any aspect or embodiment of the present disclosure, any solid state form of Belumosudil, Belumosudil mesylate, Belumosudil tosylate and / or Belumosudil besylate may contain: 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 state form of the subject compound, preferably as measured by XRPD. Thus, any disclosed crystalline form of Belumosudil, Belumosudil mesylate, Belumosudil tosylate, and / or Belumosudil besylate described herein may be substantially free of any other solid state form of the subject compound, and may comprise greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the solid state form of Belumosudil, Belumosudil mesylate, Belumosudil tosylate, and / or Belumosudil besylate.

[0210] The present disclosure includes a process for preparing the pharmaceutical composition mentioned above. The process includes combining any one or a combination of crystalline polymorphs of Belumosudil or a salt thereof of the present disclosure with at least one pharmaceutically acceptable excipient.

[0211] The pharmaceutical composition or pharmaceutical preparation of the present disclosure comprises any one or combination of the solid form of Belumosudil or its salt of the present disclosure. In addition to the active ingredient, the pharmaceutical preparation of the present disclosure may comprise one or more excipients. For various purposes, excipients are added to the preparation. Preferably, the pharmaceutical composition or pharmaceutical preparation according to any aspect or embodiment of the present disclosure is in the form of a tablet or capsule, more preferably in the form of a tablet.

[0212] Diluents increase the volume of solid pharmaceutical compositions and can make pharmaceutical dosage forms comprising the compositions easier for patients and caregivers to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfine cellulose (microfine cellulose), lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, calcium hydrogen phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talcum powder.

[0213] Solid pharmaceutical compositions compacted into dosage forms such as tablets may include excipients whose function includes helping to bind active ingredients and other excipients together after compression. Adhesives for solid pharmaceutical compositions include gum arabic, alginic acid, carbomer (e.g., carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oils, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), hydroxypropylmethylcellulose (e.g., Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, polyvidone (e.g., Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0214] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by adding a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, cross-linked polyvinylpyrrolidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[0215] Glidants may be added to improve the flowability of non-compacted solid compositions and to improve the accuracy of administration. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tricalcium phosphate.

[0216] When preparing dosage forms such as tablets by compacting powdery compositions, compositions experience pressure from punch and die.Some excipients and active ingredients have a tendency to adhere to the surface of punch and die, which may cause the product to have depressions (pitting) and other surface irregularities. Lubricants can be added to compositions to reduce adhesion and make the product easily released from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, palmitic acid stearyl glyceride, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talcum powder and zinc stearate.

[0217] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the compositions of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0218] Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and / or facilitate patient identification of the product and unit dosage level.

[0219] In the liquid pharmaceutical composition 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.

[0220] Liquid pharmaceutical compositions may include emulsifiers to evenly disperse active ingredients or other excipients that are insoluble in the 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, gum tragacanth, carrageenan, pectin, methylcellulose, carbomer, cetearyl alcohol, and cetyl alcohol.

[0221] The liquid pharmaceutical composition of the present invention may also contain a viscosity enhancer to improve the mouthfeel of the product and / or coat the inner layer of the gastrointestinal tract. Such agents include gum arabic, alginic acid, bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetearyl alcohol, methylcellulose, ethylcellulose, gelatin, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch, tragacanth gum, xanthan gum, and combinations thereof.

[0222] Sweeteners such as sorbitol, saccharin, saccharin sodium, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.

[0223] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improve storage stability.

[0224] According to the present disclosure, the liquid composition may also include a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate. The choice of excipient and the amount used may be readily determined by a formulation scientist based on experience and consideration of standard procedures and references in the art.

[0225] Solid compositions of the present disclosure include powders, granules, aggregates and compacted compositions. Dosage includes dosages suitable for oral administration, buccal administration, rectal administration, parenteral (including subcutaneous, intramuscular and intravenous) administration, inhalation administration and ocular administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition treated, in embodiments, route of administration is oral. Dosage can be conveniently presented in unit dosage form and prepared by any method known in the pharmaceutical field.

[0226] Dosage forms include solid dosage forms, such as tablets, powders, capsules, suppositories, sachets, troches and lozenges, and liquid syrups, suspensions and elixirs.

[0227] The dosage form of the present disclosure can be a capsule containing a composition, such as a powdered solid composition or a granular solid composition of the present disclosure in a hard or soft shell. The shell can be made of gelatin and optionally contain a plasticizer such as glycerol and / or sorbitol, an opacifier and / or a coloring agent.

[0228] The active ingredients and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0229] Compositions for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients in powder form are blended with excipients, 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 a desired particle size. The granules can then be tableted, or other excipients, such as glidants and / or lubricants, are added before tableting.

[0230] Tableting compositions can be conventionally prepared by dry blending. For example, the blended composition of the active substance and excipients can be compacted into blocks or tablets and then pulverized into compacted granules. The compacted granules can then be compressed into tablets.

[0231] As an alternative to dry granulation, direct compression techniques can be used to compress the blended composition directly 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 silicon dioxide. The proper use of these and other excipients in direct compression tableting is known to those skilled in the art who have experience and skills in the specific formulation challenges of direct compression tableting.

[0232] The capsule fills of the present disclosure may include any of the above-mentioned blends and granules described with respect to tableting, but they do not undergo a final tableting step.

[0233] Pharmaceutical formulations of Belumosudil can be administered. Belumosudil can be formulated for administration to mammals by injection, in embodiments to humans. Belumosudil can, for example, be formulated as a viscous liquid solution or suspension for injection, such as a clear solution. The formulation can include one or more solvents. Suitable solvents can be selected by considering the physical and chemical stability of the solvent at multiple pH levels, the viscosity of the solvent (which will allow injectability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and castor oil USP. Additional substances, such as buffers, solubilizers, and antioxidants and other substances can be added to the formulation. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition.

[0234] In embodiments for treating: graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse cutaneous systemic sclerosis; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; systemic scleroderma; and in particular chronic graft-versus-host disease and / or systemic sclerosis, the crystalline polymorphs of Belumosudil and the pharmaceutical compositions and / or pharmaceutical formulations of Belumosudil of the present disclosure may be used as medicaments.

[0235] The present disclosure also provides methods for treating graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse cutaneous systemic sclerosis; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; systemic scleroderma; and in particular chronic graft-versus-host disease and / or systemic sclerosis, by administering to a subject in need of treatment a therapeutically effective amount of any one or combination of the crystalline polymorphs of Belumosudil of the present disclosure, or at least one of the above-mentioned pharmaceutical compositions and / or pharmaceutical formulations.

[0236] The present disclosure has thus been described with reference to specific preferred embodiments and illustrative examples, and those skilled in the art will appreciate modifications to the present disclosure as described and illustrated without departing from the spirit and scope of the present disclosure as disclosed in this specification. The examples are set forth to aid in understanding the present disclosure, but are not intended and should not be construed as limiting the scope of the present disclosure in any way.

[0237] X-ray powder diffraction ("XRPD") method For Examples 1-9 and Examples 12-15: XRPD analysis was performed on an ARL (SCINTAG) powder X-ray diffractometer model X'TRA 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 was 3 degrees / min.

[0238] For Example 10 and Example 11: XRPD analysis was performed on a Bruker powder X-ray diffractometer model D8 ADVANCE 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°.

[0239] The position of the peak is corrected to correspond to the theoretical peak of silicon at 28.45 degrees 2Θ.

[0240] Solid State 13 C-NMR method Solid-state spectroscopy was recorded using a BRUKER Avance II+ spectrometer operating at 125 MHz and a controlled temperature of 0 °C with variable amplitude cross-polarization, magic angle spinning, and high-power proton decoupling. 13 C NMR spectroscopy. A probe using a 4 mm od zirconium oxide rotor was employed. The operating conditions were: contact time: 2 ms; recycle delay: 5 s; 1024 scans and a rotation rate of 11 kHz. Chemical shifts were referenced via substitution samples of glycine (the carboxyl carbon chemical shift was assigned to 176.03 ppm relative to the signal of tetramethylsilane).

[0241] TGA Method Thermogravimetric analysis was performed using a Mettler Toledo TGA / DSC with the following scan parameters: Heat between 25°C-250°C.

[0242] Heating rate: 10°C / min.

[0243] Purge with 40 ml / min N2 flow.

[0244] Sample weight: 7 mg-15 mg.

[0245] Crucible: 150 µL alumina crucible with standard aluminum lid.

[0246] SEM Method SEM micrographs were taken on a Phenom Pro scanning microscope at 10 kV, low current. The samples were sputtered with gold by a DentonDesk V sputter coater. Example

[0247] Preparation of starting materials Belumosudil can be prepared according to methods known from the literature, for example according to International Publication No. WO 2006 / 105081.

[0248] Example 1: Preparation of Amorphous Belumosudil Program A Methanol (90 ml, 90 V) was added to Belumosudil (1 gram, 2.21 mmol) to give a slurry. The slurry was stirred magnetically at 62 ° C for 15 minutes to obtain a clear solution, followed by mechanical filtration. The solution was cooled to room temperature and then heated to 40 ° C for 2 hours. 入 =140℃ (T 出 =78°C) in a spray dryer. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern was Figure 1 Presented in.

[0249] Procedure B Methanol (3.5 ml, 70 V) is added to Belumosudil (50 mg, 0.11 mmol) to give a slurry. The slurry is stirred magnetically at 60 ° C for 15 minutes to obtain a clear solution, followed by mechanical filtration. The obtained clarified mother liquor is evaporated at 50 ° C / 300-35 mbar to give a solid. The obtained solid is characterized as amorphous Belumosudil by X-ray powder diffraction.

[0250] Example 2: Preparation of Crystalline Form B1 of Belumosudil Program A Acetone (7.5 ml, 250 V) was added to Belumosudil (30 mg, 0.066 mmol) to obtain a clear solution. The solution was then mechanically filtered at room temperature and allowed to evaporate slowly over a period of 6 days at this temperature. The obtained solid was analyzed by X-ray powder diffraction, and Belumosudil crystalline form B1 was obtained. The XRPD pattern is shown in FIG. Figure 2 Presented in.

[0251] Procedure B Ethanol (0.6 ml, 20V) is added to amorphous Belumosudil (30 mg, 0.066 mmol) to give a slurry. The slurry is magnetically stirred at 50 ° C through a time period of 5 hours. The solid is separated by a centrifuge and dried in a vacuum oven at 45 ° C through a time period of 20 hours to provide an off-white solid, which is identified as Belumosudil crystalline form B1.

[0252] Example 3: Preparation of Crystalline Form B2 of Belumosudil Program A At 80°C, acetonitrile (12 ml, 400 V) was added to amorphous Belumosudil (30 mg, 0.066 mmol) to obtain a clear solution. The solution was then mechanically filtered at room temperature and allowed to evaporate slowly over a period of 5 days at this temperature. The solid obtained was analyzed by XRPD and characterized as Belumosudil crystalline form B2. The XRPD pattern is shown in Figure 3 Presented in.

[0253] Procedure B Amorphous Belumosudil (30 mg, 0.066 mmol) was heated to 160° C. by TGA over a period of 0.5 hours. The solid obtained was analyzed by X-ray powder diffraction and identified as Belumosudil crystalline form B2.

[0254] Program C Methanol (12 ml, 400V) is added to amorphous Belumosudil (30 mg, 0.066 mmol) at room temperature to give a slurry. The slurry is magnetically stirred at 50°C through a time period of 5 hours. The solid is separated by a centrifuge and dried in a vacuum oven at 45°C through a time period of 20 hours. The off-white solid obtained is analyzed by X-ray powder diffraction, and is characterized as Belumosudil crystalline form B2 by X-ray powder diffraction.

[0255] Example 4: Preparation of Crystalline Form B3 of Belumosudil Tetrahydrofuran (5 ml, 50V) was added to Belumosudil (100 mg, 0.22 mmol) at 40°C and stirred for 10 minutes to obtain a clear solution. The solution was then mechanically filtered, cooled to room temperature, and stirred over a period of 14 hours to provide a wet solid. The solid was separated by a centrifuge. The wet solid obtained was analyzed by XRPD and characterized as Belumosudil crystalline form B3. The XRPD pattern is shown in Figure 4 Presented in.

[0256] Example 5: Preparation of Crystalline Form M1 of Belumosudil Mesylate Program A Ethanol (4 ml, 20V) was added to Belumosudil (200 mg, 0.44 mmol) at room temperature to obtain a slurry. Next, methanesulfonic acid (31 μL, 1.1 equivalents) was added dropwise to give a clear solution. The solution was heated to 50 ° C and precipitation was observed. Ethanol (3 ml, 15V) was added to the obtained block precipitate, followed by magnetic stirring at 50 ° C for 30 minutes. Next, the precipitate was cooled to room temperature naturally. The solid was separated by a centrifuge. The obtained solid was washed twice with ethanol (400 μL, 2V) 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 Belumosudil mesylate crystalline form M1. The XRPD figure is at Figure 5 Presented in.

[0257] Procedure B Belumosudil mesylate (30 mg, 0.06 mmol) is added to DMSO (0.9 ml, 30V) to give slurry. The slurry is heated to 50 ° C for 10 minutes to obtain complete dissolution, followed by thermomechanical filtration. Next, dropwise add ethanol (2.7 ml, 100V) as an antisolvent to obtain solid precipitate. Next, the slurry is stirred magnetically at room temperature during 40 hours. Then, solid is separated by centrifuge. The wet solid obtained is analyzed by X-ray powder diffraction, and is accredited as Belumosudil mesylate crystalline form M1.

[0258] Program C Isopropyl alcohol (2 ml, 20V) is added to Belumosudil (100 mg, 0.2 mmol) at room temperature to obtain a slurry. Next, methanesulfonic acid (161 μL, 1.1 equivalents) is added dropwise to give a clear solution. The solution is heated to 50 ° C and precipitation is observed, and magnetic stirring is performed at 50 ° C for 30 minutes. Next, the precipitate is cooled to room temperature naturally. The solid is separated by a centrifuge. The obtained solid is washed twice with IPA (200 μL, 2V), to provide a yellow solid. The obtained solid is analyzed by X-ray powder diffraction, and is identified as Belumosudil mesylate crystalline form M1.

[0259] Program D At room temperature, n-butanol (2 ml, 20V) is added to Belumosudil (100 mg, 0.2 mmol) to obtain a slurry. Next, methanesulfonic acid (161 μL, 1.1 equivalents) is added dropwise to give a clear solution. The solution is heated to 50 ° C and precipitation is observed, and magnetic stirring is performed at 50 ° C for 30 minutes. Next, the precipitate is cooled to room temperature naturally. The solid is separated by a centrifuge. The solid obtained is washed twice with n-butanol (200 μL, 2V), to provide a yellow solid. The solid obtained is analyzed by X-ray powder diffraction, and is identified as Belumosudil mesylate crystalline form M1.

[0260] Program E 1-propanol (2 ml, 20V) is added to Belumosudil (100 mg, 0.2 mmol) at room temperature to obtain slurry. Next, methanesulfonic acid (161 μL, 1.1 equivalents) is added dropwise to give a clear solution. The solution is heated to 50 ° C and precipitation is observed, and magnetic stirring is performed at 50 ° C for 30 minutes. Next, the precipitate is cooled to room temperature naturally. The solid is separated by a centrifuge. The obtained solid is washed twice with 1-propanol (200 μL, 2V), to provide a yellow solid. The obtained solid is analyzed by X-ray powder diffraction, and is identified as Belumosudil mesylate crystalline form M1.

[0261] Procedure F 2,2,2-trifluoroethanol (0.3 ml, 10V) is added to Belumosudil mesylate (30 mg, 0.06mmol) to give slurry. The slurry is heated to 60 ° C for 10 minutes to obtain complete dissolution, followed by thermomechanical filtration. Next, ethanol (1.2 ml, 40V) as an antisolvent is added dropwise to obtain a solid precipitate. Next, the slurry is magnetically stirred at room temperature during 17 hours. Then, the solid is separated by a centrifuge. The wet solid obtained is analyzed by X-ray powder diffraction, and is identified as Belumosudil mesylate crystalline form M1.

[0262] Example 6: Preparation of Crystalline Form B4 of Belumosudil Program A Methanol (0.6 ml, 20V) was added to Belumosudil Form B1 (30 mg, 0.066 mmol) to obtain a slurry. The slurry was then stirred magnetically at 50 °C for 5 hours. The slurry was then cooled to room temperature and stirred magnetically for 16 hours. The solid was then separated by a centrifuge at room temperature. The obtained wet solid was dried in a vacuum oven at 45 °C over a period of 18 hours to provide an off-white solid characterized by X-ray powder diffraction and the XRPD pattern was 0.404. Figure 6 Presented in.

[0263] Procedure B Acetonitrile: MeOH (0.75 ml, 25V, 1: 1 equivalent) was added to B1 (50 mg, 0.11 mmol) to give a slurry. The slurry was stirred magnetically at room temperature for a period of 1 week. The solid was then separated by a centrifuge at room temperature. The wet solid obtained was characterized as Belumosudil crystalline form B4 by X-ray powder diffraction.

[0264] Example 7: Preparation of Crystalline Form M2 of Belumosudil Mesylate Program A 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 equivalents) was added dropwise to give a slurry. The slurry was heated to 50°C over a period of 45 minutes to obtain a clear solution. Next, the solution was cooled to room temperature naturally, 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 over a period of 18 hours to provide a yellow solid. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern was Figure 7 Presented in.

[0265] Procedure B Water: ethanol (2 ml, 20V, 1: 3) mixture is added to form B1 (100 mg, 0.22 mmol) at room temperature to obtain slurry. Next, methanesulfonic acid (16 μL, 1.1 equivalents) is added dropwise to give slurry. The slurry is heated to 50 ° C over a period of 45 minutes to obtain a clear solution. Next, the solution is cooled to room temperature naturally, and a precipitate is observed. The solid obtained is separated using a centrifuge. The separated solid is washed twice with water: ethanol (2.2 ml, 22V, 1: 3), and dried in a vacuum oven at 45 ° C over a period of 18 hours to provide a yellow solid. The solid obtained is analyzed by X-ray powder diffraction, and is identified as Belumosudil mesylate crystalline form M2.

[0266] Program C Water (2 ml, 40V) is added to Belumosudil mesylate form M1 (50 mg, 0.11 mmol) to give slurry. The slurry is magnetically stirred at 60 ° C through a time period of 1 week. Then, the solid is separated by a centrifuge at room temperature. The wet solid obtained is analyzed by X-ray powder diffraction, and is identified as Belumosudil mesylate crystalline form M2.

[0267] Program D DMSO (2 ml, 40V) is added to Belumosudil mesylate form M1 (50 mg, 0.11 mmol) to give slurry. The slurry is heated to 50 ° C for 10 minutes to obtain complete dissolution, followed by thermomechanical filtration. The solution is naturally cooled to room temperature and magnetic stirring continues for 5 days. Next, cold water (5 ml, 100V, 4 ° C) as an antisolvent is added dropwise to obtain solid precipitate. Next, the slurry is magnetically stirred during 18 hours at room temperature. Then, solid is separated by centrifuge. The wet solid obtained is analyzed by X-ray powder diffraction, and is accredited as Belumosudil mesylate crystalline form M2.

[0268] Program E 2,2,2-trifluoroethanol (0.3 ml, 10V) is added to Belumosudil mesylate (30 mg, 0.06mmol) to give slurry. The slurry is heated to 60 ° C for 10 minutes to obtain complete dissolution, followed by thermomechanical filtration. Next, water (1.2 ml, 40V) as an antisolvent is added dropwise to obtain a solid precipitate. Next, the slurry is magnetically stirred at room temperature during 17 hours. Then, the solid is separated by a centrifuge. The wet solid obtained is analyzed by X-ray powder diffraction, and is identified as Belumosudil mesylate crystalline form M2.

[0269] Example 8: Preparation of Crystalline Form M3 of Belumosudil Mesylate Program A Belumosudil mesylate Form M2 (prepared according to Procedure C of Example 7) was dried in a vacuum oven at 200°C over a period of 4 hours to provide a yellow solid. The obtained solid was characterized by X-ray powder diffraction as Belumosudil mesylate crystalline Form M3.

[0270] Example 9: Preparation of Crystalline Form B5 of Belumosudil Program A 2,2,2-Trifluoroethanol (TFE) (0.6 ml, 50V) was added to Belumosudil (12.5 mg, 0.03mmol) to obtain a clear solution. The solution was then stirred magnetically at 70°C for 1 hour. The solution was then cooled to 4°C at a rate of 20°C per 10 minutes, and a blocky precipitate was observed. Additional TFE (0.1 ml, 10V) was added to give a slurry. Next, the solid was separated using a centrifuge. Next, the mother liquor was placed at 4°C for slow crystallization for 20 days. The wet solid obtained was filtered through a Buchner filter, and the solid was characterized as Belumosudil crystalline form B5 by X-ray powder diffraction, and the XRPD pattern was Fig. 9 Presented in.

[0271] Example 10: Preparation of Amorphous Belumosudil Methanesulfonate Program A Methanol (286 ml, 220 V) was added to Belumosudil mesylate Form M1 (1.3 grams, 2.4 mmol) to give a slurry. The slurry was magnetically stirred at 62 ° C for 45 minutes to obtain a clear solution, followed by mechanical filtration. The solution was cooled to room temperature and then at T 入 =140℃ (T 出= 63 ° C) in a spray dryer. The obtained solid was analyzed by X-ray powder diffraction and identified as amorphous Belumosudi mesylate, and the XRPD pattern was Fig.10 Presented in.

[0272] Example 11: Preparation of Form M4 of Belumosudil Mesylate Program A 2,2,2-trifluoroethanol (TFE) (0.7 ml, 7V) was added to Belumosudil mesylate 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) precooled to 4 ° C to obtain two phases. The solution was stirred at 4 ° C for 4 days. Then, the mixture was inoculated with Belumosudil mesylate form M3 (about 1 wt%), and after stirring for 1 day, a solid precipitate was obtained. Next, the precipitate was separated by a centrifuge and dried in a vacuum oven at 45 ° C over a period of 18 hours to provide a yellow solid. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern was Fig.11 Presented in.

[0273] Procedure B Belumosudil mesylate form M1 (100 mg, 0.2 mmol) is added to TFE (0.7 ml, 7V) to obtain a clear solution. The clear solution is mechanically filtered, and is added to the heptane (0.8 ml, 8V) precooled to 4 ° C, to obtain two phases. Then, the mixture is inoculated with Belumosudil mesylate form M4 (about 1 wt%), and after stirring for 1 day, a solid precipitate is obtained. Next, the precipitate is separated by a centrifuge, and in a vacuum oven at 45 ° C, dried through the time period of 18 hours, to provide a yellow solid. The solid obtained is analyzed by X-ray powder diffraction, and is accredited as Belumosudil mesylate crystalline form M4.

[0274] Program C Belumosudil mesylate form M1 (100 mg, 0.2 mmol) is added to TFE (0.7 ml, 7V) to obtain a clear solution. The clear solution is mechanically filtered, and is added to the cyclopentyl methyl ether (0.8 ml, 8V) precooled to 4 ° C. Then, the mixture is inoculated with Belumosudil mesylate form M4 (about 1 wt%), and after stirring for 18 hours, a solid precipitate is obtained. Next, the precipitate is separated by a centrifuge, and in a vacuum drying oven at 45 ° C, a yellow solid is provided through the time period of 18 hours. The solid obtained is analyzed by X-ray powder diffraction, and is accredited as Belumosudil mesylate crystalline form M4.

[0275] Program D TFE (0.7 ml, 7V) is added to Belumosudil mesylate form M1 (100 mg, 0.2 mmol) to obtain a clear solution. Clear solution is added to cyclopentyl methyl ether (0.8 ml, 8V) precooled to 4 ° C, and a block slurry is obtained. Next, cyclopentyl methyl ether (0.4 ml, 4V) is added to obtain a slurry. Then, the mixture is inoculated with NaCl (about 1 wt%), and stirring is continued for 1 hour before obtaining a precipitate. Next, the precipitate is separated by a centrifuge, and in a vacuum oven at 45 ° C, dried over a period of 18 hours, to provide a yellow solid. The solid obtained is analyzed by X-ray powder diffraction, and is accredited as Belumosudil mesylate crystalline form M4.

[0276] Example 12: Preparation of Form M5 of Belumosudil Mesylate Program A DMSO (9 ml, 30V) is added to Belumosudil mesylate form M1 (300 mg, 0.6 mmol) to obtain a clear solution. Next, the clear solution is added to cyclopentyl methyl ether (9 ml, 30V) precooled to about 4 ° C, the cyclopentyl methyl ether comprises the seed crystals (about 1 wt%) of Belumosudil mesylate form M4, then other cyclopentyl methyl ether (18 ml, 60V) and the seed crystals (about 1 wt%) of Belumosudil mesylate form M4 are added, and some precipitates are observed after 10 minutes. The mixture is stirred for a period of 18 hours at about 4 ° C, and a block precipitate is obtained. Next, the precipitate is separated by a centrifuge, and dried in a vacuum oven at 45 ° C over a period of 18 hours to provide a yellow solid. The solid obtained is analyzed by X-ray powder diffraction, and the XRPD pattern is Fig.12 Presented in.

[0277] Example 13: Preparation of Belumosudil Besylate Form BS1 Program A Ethanol (10 ml, 20V) 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 equivalents) was added, and the slurry was heated to 50 ° C over a period of 45 minutes with stirring. Next, the slurry was naturally cooled to room temperature, and the obtained solid was separated using a centrifuge. The separated solid was dried in a vacuum oven at 45 ° C over a period of 18 hours to provide a yellow solid. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern was Fig.13 Presented in.

[0278] Example 14: Preparation of Form T1 of Belumosudil Tosylate Program A 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 equiv) was added and a clear solution was obtained. After stirring at 50°C for 10 minutes, a precipitation was observed. The solution was stirred at 50°C for a period of 45 minutes. Next, the solution was cooled to room temperature naturally and a blocky precipitate was observed. The obtained solid was separated using a centrifuge and washed once with methanol (200µL, 2V). The solid was dried in a vacuum oven at 45°C for a period of 18 hours to provide a yellow solid. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern was Fig.14 Presented in.

[0279] Example 15: Preparation of Form T2 of Belumosudil Tosylate Program A 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 equivalents) was added, and the viscous slurry was stirred at 50°C for a period of 20 minutes. Then, ethanol (250 μl, 5V) was added to obtain a slurry. The slurry was stirred at 50°C for a period of 50 minutes. Next, the slurry was cooled to room temperature naturally, and the obtained 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 a period of 18 hours to provide a yellow solid. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern was Fig.15 Presented in.

[0280] The present disclosure also provides the following aspects: 1. A crystalline form of belumosudil mesylate designated Form M1, said crystalline form being characterized by data selected from one or more of the following: (a) an XRPD pattern having peaks at 7.1 degrees 2θ±0.2 degrees 2θ, 17.2 degrees 2θ±0.2 degrees 2θ, 20.3 degrees 2θ±0.2 degrees 2θ, 21.5 degrees 2θ±0.2 degrees 2θ, and 25.5 degrees 2θ±0.2 degrees 2θ; (b) Generally based on Figure 5 The XRPD pattern depicted in; (c) an XRPD pattern having peaks at 7.1 degrees 2θ±0.2 degrees 2θ, 17.2 degrees 2θ±0.2 degrees 2θ, 20.3 degrees 2θ±0.2 degrees 2θ, 21.5 degrees 2θ±0.2 degrees 2θ, and 25.5 degrees 2θ±0.2 degrees 2θ and further having any one, two, three, four or five additional peaks selected from 8.4 degrees 2θ±0.2 degrees 2θ, 15.5 degrees 2θ±0.2 degrees 2θ, 16.8 degrees 2θ±0.2 degrees 2θ, 19.5 degrees 2θ±0.2 degrees 2θ, and 22.1 degrees 2θ±0.2 degrees 2θ; (d) an X-ray powder diffraction pattern having peaks at 7.1 degrees 2θ±0.2 degrees 2θ, 8.4 degrees 2θ±0.2 degrees 2θ, 15.5 degrees 2θ±0.2 degrees 2θ, 16.8 degrees 2θ±0.2 degrees 2θ, 17.2 degrees 2θ±0.2 degrees 2θ, 19.5 degrees 2θ±0.2 degrees 2θ, 20.3 degrees 2θ±0.2 degrees 2θ, 21.5 degrees 2θ±0.2 degrees 2θ, 22.1 degrees 2θ±0.2 degrees 2θ, and 25.5 degrees 2θ±0.2 degrees 2θ; (e) a solid 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 spectroscopy; (f) Solids having the following absolute differences in chemical shift compared to the reference peak at 167.2 ppm ± 1 ppm 13 CNMR spectrum: 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; (g) Generally based on Fig.16 , Fig.17 or Fig.18 The solid state depicted in 13 C NMR spectroscopy; and (h) Combination of these data.

[0281] 2. The crystalline form according to aspect 1, wherein the crystalline form is an anhydrous form.

[0282] 3. The crystalline form according to any one of aspects 1-2, comprising no greater than about 20%, no greater than about 10%, no greater than about 5%, no greater than about 2%, no greater than about 1%, or about 0% of any other crystalline form of belumosudil mesylate.

[0283] 4. The crystalline form of any one of aspects 1-3, comprising no greater than about 20%, no greater than about 10%, no greater than about 5%, no greater than about 2%, no greater than about 1%, or about 0% amorphous belumosudil mesylate.

[0284] 5. A crystalline form of belumosudil mesylate designated Form M2, said crystalline form being characterized by data selected from one or more of the following: (a) an XRPD pattern having peaks at 6.3 degrees 2θ±0.2 degrees 2θ, 12.8 degrees 2θ±0.2 degrees 2θ, 15.8 degrees 2θ±0.2 degrees 2θ, 19.3 degrees 2θ±0.2 degrees 2θ, and 26.5 degrees 2θ±0.2 degrees 2θ; (b) Generally based on Figure 7 The XRPD pattern depicted in; (c) an XRPD pattern having peaks at 6.3 degrees 2θ±0.2 degrees 2θ, 12.8 degrees 2θ±0.2 degrees 2θ, 15.8 degrees 2θ±0.2 degrees 2θ, 19.3 degrees 2θ±0.2 degrees 2θ, and 26.5 degrees 2θ±0.2 degrees 2θ and further having any one, two, three, four or five additional peaks selected from 7.8 degrees 2θ±0.2 degrees 2θ, 20.4 degrees 2θ±0.2 degrees 2θ, 23.7 degrees 2θ±0.2 degrees 2θ, 25.1 degrees 2θ±0.2 degrees 2θ, and 27.4 degrees 2θ±0.2 degrees 2θ; (d) an X-ray powder diffraction pattern having peaks at 6.3 degrees 2θ±0.2 degrees 2θ, 7.8 degrees 2θ±0.2 degrees 2θ, 12.8 degrees 2θ±0.2 degrees 2θ, 15.8 degrees 2θ±0.2 degrees 2θ, 19.3 degrees 2θ±0.2 degrees 2θ, 20.4 degrees 2θ±0.2 degrees 2θ, 23.7 degrees 2θ±0.2 degrees 2θ, 25.1 degrees 2θ±0.2 degrees 2θ, 26.5 degrees 2θ±0.2 degrees 2θ, and 27.4 degrees 2θ±0.2 degrees 2θ; (e) a solid 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 spectroscopy; (f) Solids having the following absolute differences in chemical shift compared to the reference peak at 166.9 ppm ± 1 ppm 13 CNMR spectrum: 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; (g) Generally based on Fig.19 , Fig. 20 or Fig.21 The solid state depicted in 13 C NMR spectroscopy; and (h) Combination of these data.

[0285] 6. The crystalline form of aspect 5, wherein the crystalline form is a hydrate.

[0286] 7. The crystalline form according to any one of aspects 5-6, wherein the crystalline form comprises from about 1% to about 7% by weight water, preferably from about 1.5% to about 6.1% by weight water.

[0287] 8. The crystalline form according to any one of aspects 5-7, comprising no greater than about 20%, no greater than about 10%, no greater than about 5%, no greater than about 2%, no greater than about 1%, or about 0% of any other crystalline form of belumosudil mesylate.

[0288] 9. The crystalline form of any one of aspects 5-8, comprising no greater than about 20%, no greater than about 10%, no greater than about 5%, no greater than about 2%, no greater than about 1%, or about 0% amorphous belumosudil mesylate.

[0289] 10. A crystalline form of belumosudil besylate designated Form BS1, said crystalline form being characterized by data selected from one or more of the following: (a) an XRPD pattern having peaks at 6.6 degrees 2θ±0.2 degrees 2θ, 12.5 degrees 2θ±0.2 degrees 2θ, 14.9 degrees 2θ±0.2 degrees 2θ, 17.0 degrees 2θ±0.2 degrees 2θ, and 20.1 degrees 2θ±0.2 degrees 2θ; (b) Generally based on Fig.13 The XRPD pattern depicted in; (c) an XRPD pattern having peaks at 6.6 degrees 2θ±0.2 degrees 2θ, 12.5 degrees 2θ±0.2 degrees 2θ, 14.9 degrees 2θ±0.2 degrees 2θ, 17.0 degrees 2θ±0.2 degrees 2θ, and 20.1 degrees 2θ±0.2 degrees 2θ and further having any one, two, three, four or five additional peaks selected from 11.6 degrees 2θ±0.2 degrees 2θ, 17.6 degrees 2θ±0.2 degrees 2θ, 18.2 degrees 2θ±0.2 degrees 2θ, 21.7 degrees 2θ±0.2 degrees 2θ, and 25.1 degrees 2θ±0.2 degrees 2θ; (d) an X-ray powder diffraction pattern having peaks at 11.6 degrees 2θ±0.2 degrees 2θ, 12.5 degrees 2θ±0.2 degrees 2θ, 14.9 degrees 2θ±0.2 degrees 2θ, 17.0 degrees 2θ±0.2 degrees 2θ, 17.6 degrees 2θ±0.2 degrees 2θ, 18.2 degrees 2θ±0.2 degrees 2θ, 20.1 degrees 2θ±0.2 degrees 2θ, 21.7 degrees 2θ±0.2 degrees 2θ, and 25.1 degrees 2θ±0.2 degrees 2θ; (e) a solid 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 spectroscopy; (f) Solids having the following absolute differences in chemical shift compared to the reference peak at 169.6 ppm ± 1 ppm 13 CNMR spectrum: 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; (g) Generally based on Fig. 22 , Fig.23 or Fig.24 The solid state depicted in 13 C NMR spectroscopy; and (h) Combination of these data.

[0290] 11. The crystalline form according to aspect 10, wherein the crystalline form is an anhydrous form.

[0291] 12. The crystalline form according to any one of aspects 10-11, comprising no greater than about 20%, no greater than about 10%, no greater than about 5%, no greater than about 2%, no greater than about 1%, or about 0% of any other crystalline form of belumosudil besylate.

[0292] 13. The crystalline form according to any one of aspects 10-12, comprising no greater than about 20%, no greater than about 10%, no greater than about 5%, no greater than about 2%, no greater than about 1%, or about 0% amorphous Belumosudil besylate.

[0293] 14. A crystalline form of belumosudil tosylate designated Form T1, said crystalline form being characterized by data selected from one or more of the following: (a) an XRPD pattern having peaks at 6.2 degrees 2θ±0.2 degrees 2θ, 12.3 degrees 2θ±0.2 degrees 2θ, 14.1 degrees 2θ±0.2 degrees 2θ, 17.7 degrees 2θ±0.2 degrees 2θ, and 18.4 degrees 2θ±0.2 degrees 2θ; (b) Generally based on Fig.14 The XRPD pattern depicted in; (c) an XRPD pattern having peaks at 6.2 degrees 2θ±0.2 degrees 2θ, 12.3 degrees 2θ±0.2 degrees 2θ, 14.1 degrees 2θ±0.2 degrees 2θ, 17.7 degrees 2θ±0.2 degrees 2θ, and 18.4 degrees 2θ±0.2 degrees 2θ and further having any one, two, three, four or five additional peaks selected from 9.9 degrees 2θ±0.2 degrees 2θ, 14.5 degrees 2θ±0.2 degrees 2θ, 16.7 degrees 2θ±0.2 degrees 2θ, 21.5 degrees 2θ±0.2 degrees 2θ, and 24.6 degrees 2θ±0.2 degrees 2θ; (d) an X-ray powder diffraction pattern having peaks at 6.2 degrees 2θ±0.2 degrees 2θ, 9.9 degrees 2θ±0.2 degrees 2θ, 12.3 degrees 2θ±0.2 degrees 2θ, 14.1 degrees 2θ±0.2 degrees 2θ, 14.5 degrees 2θ±0.2 degrees 2θ, 16.7 degrees 2θ±0.2 degrees 2θ, 17.7 degrees 2θ±0.2 degrees 2θ, 18.4 degrees 2θ±0.2 degrees 2θ, 21.5 degrees 2θ±0.2 degrees 2θ, and 24.6 degrees 2θ±0.2 degrees 2θ; (e) a solid 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 spectroscopy; (f) Solids having the following absolute differences in chemical shift compared to the reference peak at 168.6 ppm ± 1 ppm 13 CNMR spectrum: 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; (g) Generally based on Fig.26 , Fig. 27 or Fig.28 The solid state depicted in 13 C NMR spectroscopy; and (h) Combination of these data.

[0294] 15. The crystalline form according to aspect 14, wherein the crystalline form is an anhydrous form.

[0295] 16. The crystalline form according to any one of aspects 14-15, comprising no greater than about 20%, no greater than about 10%, no greater than about 5%, no greater than about 2%, no greater than about 1%, or about 0% of any other crystalline form of belumosudil tosylate.

[0296] 17. The crystalline form according to any one of aspects 14-16, comprising no greater than about 20%, no greater than about 10%, no greater than about 5%, no greater than about 2%, no greater than about 1%, or about 0% amorphous Belumosudil Tosylate.

[0297] 18. A crystalline form of belumosudil tosylate designated Form T2, said crystalline form being characterized by data selected from one or more of the following: (a) an XRPD pattern having peaks at 5.1 degrees 2θ±0.2 degrees 2θ, 15.7 degrees 2θ±0.2 degrees 2θ, 16.4 degrees 2θ±0.2 degrees 2θ, 19.7 degrees 2θ±0.2 degrees 2θ, and 23.7 degrees 2θ±0.2 degrees 2θ; (b) Generally based on Fig.15 The XRPD pattern depicted in; (c) an XRPD pattern having peaks at 5.1 degrees 2θ±0.2 degrees 2θ, 15.7 degrees 2θ±0.2 degrees 2θ, 16.4 degrees 2θ±0.2 degrees 2θ, 19.7 degrees 2θ±0.2 degrees 2θ, and 23.7 degrees 2θ±0.2 degrees 2θ and further having any one, two, three, four or five additional peaks selected from 13.7 degrees 2θ±0.2 degrees 2θ, 14.2 degrees 2θ±0.2 degrees 2θ, 14.6 degrees 2θ±0.2 degrees 2θ, 19.1 degrees 2θ±0.2 degrees 2θ, and 23.0 degrees 2θ±0.2 degrees 2θ; (d) an X-ray powder diffraction pattern having peaks at 5.1 degrees 2θ±0.2 degrees 2θ, 13.7 degrees 2θ±0.2 degrees 2θ, 14.2 degrees 2θ±0.2 degrees 2θ, 14.6 degrees 2θ±0.2 degrees 2θ, 15.7 degrees 2θ±0.2 degrees 2θ, 16.4 degrees 2θ±0.2 degrees 2θ, 19.1 degrees 2θ±0.2 degrees 2θ, 19.7 degrees 2θ±0.2 degrees 2θ, 23.0 degrees 2θ±0.2 degrees 2θ, and 23.7 degrees 2θ±0.2 degrees 2θ; (e) a solid 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 spectroscopy; (f) Solids having the following absolute differences in chemical shift compared to the reference peak at 166.3 ppm ± 1 ppm 13CNMR spectrum: 24.6 ppm±0.1 ppm, 26.1 ppm±0.1 ppm, 35.2 ppm±0.1 ppm, 40.4 ppm±0.1ppm and 42.1 ppm±0.1 ppm; (g) Generally based on Fig.30 , Fig.31 or Fig.32 The solid state depicted in 13 C NMR spectroscopy; and (h) Combination of these data.

[0298] 19. The crystalline form according to aspect 18, wherein the crystalline form is an anhydrous form.

[0299] 20. The crystalline form according to any one of aspects 18-19, comprising no greater than about 20%, no greater than about 10%, no greater than about 5%, no greater than about 2%, no greater than about 1%, or about 0% of any other crystalline form of belumosudil tosylate.

[0300] 21. The crystalline form according to any one of aspects 18-20, comprising no greater than about 20%, no greater than about 10%, no greater than about 5%, no greater than about 2%, no greater than about 1%, or about 0% amorphous Belumosudil Tosylate.

[0301] 22. The crystalline form according to any preceding aspect, which is non-hygroscopic, preferably, wherein the crystalline form is polymorphically stable at room temperature at a relative humidity of up to 100% for at least 7 days.

[0302] 23. Use of the crystalline form according to any one of aspects 1 to 22 for the preparation of a pharmaceutical composition.

[0303] 24. A pharmaceutical composition comprising the crystalline form according to any one of aspects 1 to 22 and at least one pharmaceutically acceptable excipient.

[0304] 25. A process for preparing a pharmaceutical composition according to aspect 24, comprising combining the crystalline form according to any one of aspects 1 to 22 with at least one pharmaceutically acceptable excipient.

[0305] 26. The crystalline form according to any one of aspects 1 to 22 or the pharmaceutical composition according to aspect 24, for use as a medicament.

[0306] 27. The crystalline form according to any one of aspects 1 to 22, or the pharmaceutical composition according to aspect 24, for use in the treatment of graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse cutaneous systemic sclerosis; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; systemic sclerosis; and in particular chronic graft-versus-host disease and systemic sclerosis.

[0307] 28. A method of treating: graft-versus-host disease, including chronic graft-versus-host disease; systemic sclerosis, including diffuse cutaneous systemic sclerosis; fibrosis, including idiopathic pulmonary fibrosis; plaque psoriasis; systemic scleroderma; and in particular chronic graft-versus-host disease and systemic sclerosis, the method comprising administering to a subject in need of treatment a therapeutically effective amount of a crystalline form according to any one of aspects 1 to 22 or a pharmaceutical composition according to aspect 24.

[0308] 29. Use of the crystalline form according to any one of aspects 1 to 22 for the preparation of another solid state form of Belumosudil or another salt of Belumosudil or a solid state form thereof.

[0309] 30. A process for preparing a belumosudil salt or a solid form thereof, comprising preparing the crystalline form of 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 Form M2, said crystalline form being characterized by data selected from one or more of the following: (a) an XRPD pattern having peaks at 6.3 degrees 2θ±0.2 degrees 2θ, 12.8 degrees 2θ±0.2 degrees 2θ, 15.8 degrees 2θ±0.2 degrees 2θ, 19.3 degrees 2θ±0.2 degrees 2θ, and 26.5 degrees 2θ±0.2 degrees 2θ; (b) an XRPD pattern substantially in accordance with that depicted in Figure 7; (c) an XRPD pattern having peaks at 6.3 degrees 2θ±0.2 degrees 2θ, 12.8 degrees 2θ±0.2 degrees 2θ, 15.8 degrees 2θ±0.2 degrees 2θ, 19.3 degrees 2θ±0.2 degrees 2θ, and 26.5 degrees 2θ±0.2 degrees 2θ and further having any one, two, three, four or five additional peaks selected from 7.8 degrees 2θ±0.2 degrees 2θ, 20.4 degrees 2θ±0.2 degrees 2θ, 23.7 degrees 2θ±0.2 degrees 2θ, 25.1 degrees 2θ±0.2 degrees 2θ, and 27.4 degrees 2θ±0.2 degrees 2θ; (d) an X-ray powder diffraction pattern having peaks at 6.3 degrees 2θ±0.2 degrees 2θ, 7.8 degrees 2θ±0.2 degrees 2θ, 12.8 degrees 2θ±0.2 degrees 2θ, 15.8 degrees 2θ±0.2 degrees 2θ, 19.3 degrees 2θ±0.2 degrees 2θ, 20.4 degrees 2θ±0.2 degrees 2θ, 23.7 degrees 2θ±0.2 degrees 2θ, 25.1 degrees 2θ±0.2 degrees 2θ, 26.5 degrees 2θ±0.2 degrees 2θ, and 27.4 degrees 2θ±0.2 degrees 2θ; (e) a solid 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 spectroscopy; (f) Solids having the following absolute differences in chemical shift compared to the reference peak at 166.9 ppm ± 1 ppm 13 C NMR spectrum: 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; (g) a solid state device substantially according to the solid state device depicted in FIG. 19, FIG. 20 or FIG. 21 13 C NMR spectroscopy; and (h) Combination of these data.

2. The crystalline form of claim 1, wherein the crystalline form is a hydrate.

3. The crystalline form of claim 1, wherein the form comprises from about 1% to about 7% water by weight.

4. The crystalline form of claim 1, comprising no greater than about 20% of any other crystalline form of belumosudil mesylate.

5. The crystalline form of claim 1, comprising no greater than about 20% amorphous Belumosudil mesylate.

6. A pharmaceutical composition comprising the crystalline form according to claim 1 and at least one pharmaceutically acceptable excipient.

7. A process for preparing a pharmaceutical composition comprising combining the crystalline form according to claim 1 with at least one pharmaceutically acceptable excipient.

8. A method of treating graft-versus-host disease, systemic sclerosis, fibrosis, plaque psoriasis or systemic scleroderma, the method comprising administering to a subject in need of treatment a therapeutically effective amount of the crystalline form of claim 1.

9. The method of claim 8, wherein the graft-versus-host disease is chronic graft-versus-host disease.

10. The method of claim 8, wherein the systemic sclerosis is diffuse cutaneous systemic sclerosis.

11. The method of claim 8, wherein the fibrosis is idiopathic pulmonary fibrosis.

12. The crystalline form of claim 1, comprising no greater than about 10% of any other crystalline form of belumosudil mesylate.

13. The crystalline form of claim 1, comprising no greater than about 5% of any other crystalline form of belumosudil mesylate.

14. The crystalline form of claim 1, comprising no greater than about 1% of any other crystalline form of belumosudil mesylate.

15. The crystalline form of claim 1, comprising no greater than about 10% amorphous Belumosudil mesylate.

16. The crystalline form of claim 1, comprising no greater than about 5% amorphous Belumosudil mesylate.

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