TECHNICAL FIELD

[0001] The present invention is directed to novel salts of belumosudil and crystalline forms thereof, processes for the preparation thereof, pharmaceutical compositions containing these forms, and their use for the treatment of chronic graft-versus-host disease in a subject suffering therefrom.

BACKGROUND

[0002] Belumosudil (1 ), or 2-{3-[4-(1/-/-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-/\/ - (propan-2-yl)acetamide, in the form of its methanesulfonate (mesylate) salt (1 :1), is the active pharmaceutical ingredient (API) in branded pharmaceutical REZUROCK®, a drug indicated for the treatment of adult and pediatric patients 12 years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.

[0003] Belumosudil trifluoroacetate salt is disclosed in WO 2006/105081 A2, which discloses a family of compounds that are stated to be useful as inhibitors of Rho kinase (ROCK). Further salts of belumosudil, including the methanesulfonate (mesylate), benzenesulfonate (besylate), and p-toluenesulfonate (tosylate) salts, and crystalline forms thereof, are reported in WO 2022/020850 A1 . i [0004] According to the review published by the U.S. Center for Drug Evaluation and Research (CDER) in connection with the approval of REZUROCK® (NDA 214783), the drug substance belumosudil mesylate has low solubility and low permeability, placing it in Class IV of the Biopharmaceutics Classification System (BCS). Of the four BCS Classes, Class IV drug substances present the most challenges to achieving adequate bioavailability.

[0005] The solubility of individual salt and crystalline forms of a drug substance in an aqueous environment often correlates with their relative bioavailability, since the manner in which the salt or crystalline form dissolves can correspond to the amount of the drug substance that is available to be absorbed into the body to provide the intended therapeutic effect. One measure of solubility is intrinsic dissolution rate (IDR), which is defined as the dissolution rate of a substance under constant surface area conditions. For low solubility substances, higher IDR values can correlate with higher bioavailability following administration. Prediction of the solubility and IDR of a yet undiscovered salt and/or crystalline form of a substance is currently not possible.

[0006] Different salt and/or crystalline forms of the same compound may have different crystal packing, thermodynamic, spectroscopic, kinetic, surface, and mechanical properties. For example, different salt and/or crystalline forms may have different stability properties such that a particular crystalline form may be less sensitive to heat, relative humidity (RH), and/or light. Different salts and/or crystalline forms of a compound may also be more susceptible to moisture uptake, resulting in a potential alteration of physical characteristics of the form such as flowability, density, or compressibility, which can lead to problems during formulation/tabletting and/or to changes in dissolution rate of the formulated drug product. For example, unintended absorption of moisture by a hygroscopic salt and/or crystalline form of a drug substance can alter its compressibility during tabletting, resulting in a softer tablet having a faster dissolution rate following administration. A particular salt and/or crystalline form may provide more favourable compressibility and/or density properties, thereby providing more desirable characteristics for formulation and/or product manufacturing. Particular salts and/or crystalline forms may also have different solubilities, thereby providing different pharmacokinetic parameters, which allow for specific crystalline forms to be used in order to achieve specific pharmacokinetic targets. Differences in solubility between salts and/or crystalline forms are particularly relevant for compounds exhibiting low aqueous solubility, such as BCS Class IV drug substances, where even a modest increase in solubility can provide a beneficial enhancement in bioavailability.

[0007] There exists a need for novel salts and crystalline forms of belumosudil having improved properties for use in providing drug products containing belumosudil, and commercially amenable processes for their manufacture.

SUMMARY OF THE INVENTION

[0008] The present invention provides salts comprising belumosudil and a polycarboxylic acid selected from the group consisting of fumaric acid, maleic acid, L- malic acid, malonic acid, citric acid, and L-tartaric acid. Further provided by the present invention are salts comprising belumosudil and an acid having a sulfonyl group in the form of a sulfamate ester (acesulfame) or an organic sulfonic acid selected from the group consisting of 1 ,2-ethanedisulfonic acid and 2-hydroxyethanesulfonic acid. The polycarboxylic acids and sulfonic acids used in the present invention are pharmaceutically acceptable acids. Acesulfame, in the form of acesulfamate potassium, is used as a sweetener in the food industry and as an inactive ingredient in drug products. Accordingly, it is expected that acesulfame can safely be used in materials intended for use in the preparation of pharmaceutical compositions intended for administration to humans.

[0009] Embodiments of the belumosudil salts and crystalline forms of the present invention exhibit form stability at high temperature and high humidity.

[0010] Accordingly, in a first aspect of the present invention, there is provided an L- malate salt of belumosudil. In a preferred embodiment of the first aspect, the molar ratio of belumosudil to L-malic acid is approximately 1 :1. In a more preferred embodiment of the first aspect, the salt is characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 6.4°, 7.6°, and 16.2°. More preferably, the salt of the first aspect is characterized by a PXRD diffractogram further comprising at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 10.5°, 12.4°, 12.9°, 15.2°, 19.7°, and 21.1 °. In a further preferred embodiment of the first aspect, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 10.5°, 12.4°, 12.9°, 15.2°, 19.7°, and 21.1 °. Preferably, the salt of the first aspect of the invention provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 20) as those shown in Figure 1.

[0011 ] In a second aspect of the present invention, there is provided an acesulfamate salt of belumosudil. In a preferred embodiment of the second aspect, the molar ratio of belumosudil to acesulfame is approximately 1 :1. In a more preferred embodiment of the second aspect, the salt is characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 4.8°, 6.5°, and 25.7°. More preferably, the salt of the second aspect is characterized by a PXRD diffractogram further comprising at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 10.3°, 11.5°, 14.6°, 16.2°, 19.6°, and 20.7°. In a further preferred embodiment of the second aspect, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 10.3°, 11.5°, 14.6°, 16.2°, 19.6°, and 20.7°. Preferably, the salt of the second aspect of the invention provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 20) as those shown in Figure 2.

[0012] In a third aspect of the present invention, there is provided a fumarate salt of belumosudil. In a preferred embodiment of the third aspect, the molar ratio of belumosudil to fumaric acid is approximately 1 :1. In a more preferred embodiment of the third aspect, the salt is characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 7.2°, 7.9°, and 21.1 °. More preferably, the salt of the third aspect is characterized by a PXRD diffractogram further comprising at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 12.7°, 13.6°, 18.7°, 20.1 °, 21 .7°, and 23.8°. In a further preferred embodiment of the third aspect, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 12.7°, 13.6°, 18.7°, 20.1 °, 21.7°, and 23.8°. Preferably, the salt of the third aspect of the invention provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 20) as those shown in Figure 3.

[0013] In a fourth aspect of the present invention, there is provided a maleate salt of belumosudil. In a preferred embodiment of the fourth aspect, the molar ratio of belumosudil to maleic acid is approximately 1 :1. In a more preferred embodiment of the fourth aspect, the salt is characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 5.3°, 6.9°, and 10.8°. More preferably, the salt of the fourth aspect is characterized by a PXRD diffractogram further comprising at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 12.2°, 15.0°, 17.3°, 18.3°, 22.7°, and 24.1 °. In a further preferred embodiment of the fourth aspect, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 12.2°, 15.0°, 17.3°, 18.3°, 22.7°, and 24.1 °. Preferably, the salt of the fourth aspect of the invention provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 20) as those shown in Figure 4.

[0014] In a fifth aspect of the present invention, there is provided an isethionate salt of belumosudil. In a preferred embodiment of the fifth aspect, the molar ratio of belumosudil to 2-hydroxyethanesulfonic acid is approximately 1 :1. In a more preferred embodiment of the fifth aspect, the salt is characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 6.4°, 10.1 °, and 12.7°. More preferably, the salt of the fifth aspect is characterized by a PXRD diffractogram further comprising at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 7.8°, 15.7°, 19.2°, 20.3°, and 25.7°. In a further preferred embodiment of the fifth aspect, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 7.8°, 15.7°, 19.2°, 20.3°, and 25.7°. Preferably, the salt of the fifth aspect of the invention provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 20) as those shown in Figure 5.

[0015] In a sixth aspect of the present invention, there is provided a malonate salt of belumosudil. In a preferred embodiment of the sixth aspect, the molar ratio of belumosudil to malonic acid is approximately 1 :1. In a more preferred embodiment of the sixth aspect, the salt is characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 6.3°, 9.8°, and 12.6°. More preferably, the salt of the sixth aspect is characterized by a PXRD diffractogram further comprising at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 8.1 °, 15.2°, 16.3°, 19.0°, and 21.0°. In a further preferred embodiment of the sixth aspect, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 8.1 °, 15.2°, 16.3°, 19.0°, and 21.0°. Preferably, the salt of the sixth aspect of the invention provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 20) as those shown in Figure 6.

[0016] In a seventh aspect of the present invention, there is provided an edisylate salt of belumosudil. In a preferred embodiment of the seventh aspect, the molar ratio of belumosudil to 1 ,2-ethanedisulfonic acid is approximately 2:1. In a more preferred embodiment of the seventh aspect, the salt is characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 6.7°, 7.7°, and 9.7°. More preferably, the salt of the seventh aspect is characterized by a PXRD diffractogram further comprising at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 5.8°, 8.4°, 12.4°, 13.9°, 15.1 °, and 20.3°. In a further preferred embodiment of the seventh aspect, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 5.8°, 8.4°, 12.4°, 13.9°, 15.1 °, and 20.3°. Preferably, the salt of the seventh aspect of the invention provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 20) as those shown in Figure 7.

[0017] In an eighth aspect of the present invention, there is provided a citrate salt of belumosudil. In a preferred embodiment of the eighth aspect, the molar ratio of belumosudil to citric acid is approximately 1 :1. In a first more preferred embodiment of the eighth aspect, the salt is characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 6.7°, 10.3°, and 11.7°. More preferably, the salt of the eighth aspect is characterized by a PXRD diffractogram further comprising at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 7.3°, 12.5°, 14.6°, 16.4°, 19.1 °, and 19.8°. In a further preferred embodiment of the eighth aspect, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 7.3°, 12.5°, 14.6°, 16.4°, 19.1 °, and 19.8°. Preferably, the salt of the eighth aspect of the invention provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 20) as those shown in Figure 8. In a second more preferred embodiment of the eighth aspect, the salt is characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 5.6°, 6.6°, and 17.7°. More preferably, the salt of the eighth aspect is characterized by a PXRD diffractogram further comprising at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 7.1 °, 11.2°, 12.6°, 15.4°, 15.9°, and 16.8°. In a further preferred embodiment of the eighth aspect, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 7.1 °, 11.2°, 12.6°, 15.4°, 15.9°, and 16.8°. Preferably, the salt of the eighth aspect of the invention provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 20) as those shown in Figure 9.

[0018] In a ninth aspect of the present invention, there is provided an L-tartrate salt of belumosudil. In a preferred embodiment of the ninth aspect, the molar ratio of belumosudil to L-tartaric acid is approximately 1 :1. In a more preferred embodiment of the ninth aspect, the salt is characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 6.5°, 7.6°, and 16.3°. More preferably, the salt of the ninth aspect is characterized by a PXRD diffractogram further comprising at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 10.6°, 12.5°, 15.3°, 18.4°, 19.5°, and 22.5°. In a further preferred embodiment of the ninth aspect, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 10.6°, 12.5°, 15.3°, 18.4°, 19.5°, and 22.5°. Preferably, the salt of the ninth aspect of the invention provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 20) as those shown in Figure 10.

[0019] In a tenth aspect of the present invention, there is provided a pharmaceutical composition comprising a salt of belumosudil according to the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth aspects of the invention, and one or more pharmaceutically acceptable excipients. Preferably, the pharmaceutical composition is in the form of a solid oral dosage form. Most preferably, the pharmaceutical composition is a capsule or a tablet. Preferably, the pharmaceutical composition of the tenth aspect comprises an amount of the belumosudil salt of the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth aspects that is equivalent to 200 mg of belumosudil free base.

[0020] In an eleventh aspect of the present invention, there is provided the use of a salt of belumosudil according to the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth aspects of the invention, or the pharmaceutical compositions of the tenth aspect of the invention, in the treatment of chronic graft-versus-host disease.

[0021 ] Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Embodiments of the present invention are described, by way of example only, with reference to the attached Figures.

[0023] Figure 1 is a representative PXRD diffractogram of belumosudil L-malate Form APO-I as prepared in Example 1.

[0024] Figure 2 is a representative PXRD diffractogram of belumosudil acesulfamate Form APO-I as prepared in Example 2.

[0025] Figure 3 is a representative PXRD diffractogram of belumosudil fumarate Form APO-I as prepared in Example 3.

[0026] Figure 4 is a representative PXRD diffractogram of belumosudil maleate Form APO-I as prepared in Example 4.

[0027] Figure 5 is a representative PXRD diffractogram of belumosudil isethionate Form APO-I as prepared in Example 5.

[0028] Figure 6 is a representative PXRD diffractogram of belumosudil malonate Form APO-I as prepared in Example 6.

[0029] Figure 7 is a representative PXRD diffractogram of belumosudil edisylate Form APO-I as prepared in Example 7. [0030] Figure 8 is a representative PXRD diffractogram of belumosudil citrate Form APO-I as prepared in Example 8.

[0031] Figure 9 is a representative PXRD diffractogram of belumosudil citrate Form APO-I I as prepared in Example 9.

[0032] Figure 10 is a representative PXRD diffractogram of belumosudil L-tartrate Form APO-I as prepared in Example 10.

DETAILED DESCRIPTION

[0033] The present invention provides novel salts of belumosudil and crystalline forms thereof providing improved properties over known salts of belumosudil.

[0034] The belumosudil salts and crystalline forms of the present invention exhibit differences in properties when compared to known salts of belumosudil. Depending on the specific salts and crystalline forms of the invention used, properties that differ between the invention and known salts of belumosudil include crystal packing properties such as molar volume, density, and hygroscopicity; thermodynamic properties such as melting point and solubility; kinetic properties such as dissolution rate and chemical/polymorphic stability; surface properties such as crystal habit/particle morphology; and/or mechanical properties such as hardness, tensile strength, compactibility, tabletting, handling, flow, and blending. The improved properties provided by the salts and crystalline forms of the present invention provide practical advantages over known forms of belumosudil that can be exploited to meet specific needs in the manufacture and formulation of belumosudil.

[0035] Depending on the manner in which the crystalline forms of the present invention are prepared, and the methodology and instrument used for PXRD analysis, the intensity of a given peak observed in a PXRD diffractogram of a crystalline form may vary when compared to the same peak in the representative PXRD diffractograms provided in Figures 1 to 10. Thus, differences in relative peak intensities between peaks in a PXRD diffractogram for a given crystalline form may be observed when compared to the relative peak intensities of the peaks in the representative PXRD diffractograms of Figures 1 to 10. Any such differences may be due, in part, to the preferred orientation of the sample and its deviation from the ideal random sample orientation, the preparation of the sample for analysis, and the methodology applied for the analysis. Such variations are known and understood by a person of skill in the art, and any such variations do not depart from the invention disclosed herein.

[0036] In addition to the differences in relative peak intensities that may be observed in comparison to the representative PXRD diffractograms provided in Figures 1 to 10, it is understood that individual peak positions may vary between ±0.2° 29 from the values observed in the representative PXRD diffractograms provided in Figures 1 to 10 for the crystalline form of the invention, or listed in Tables 1 to 10. Such variations are known and understood by a person of skill in the art, and any such variations do not depart from the invention disclosed herein.

[0037] Further, depending on the instrument used for X-ray analysis and its calibration, uniform offsets in the peak position of each peak in a PXRD diffractogram of greater that 0.2° 26 may be observed when compared to the representative PXRD diffractograms provided in Figures 1 to 10. Thus, PXRD diffractograms of the crystalline forms of the present invention may, in some circumstances, display the same relative peak positions as observed in the representative PXRD diffractograms provided in Figures 1 to 10, with the exception that each peak is offset in the same direction, and by approximately the same amount, such that the overall PXRD diffractogram is substantially the same in appearance as the PXRD diffractograms of Figures 1 to 10, with the exception of the uniform offset in peak positions. The observation of any such uniform peak shift in a PXRD diffractogram does not depart from the invention disclosed herein given that the relative peak positions of the individual peaks within the PXRD diffractogram remain consistent with the relative peak positions observed in the PXRD diffractograms of Figures 1 to 10.

[0038] As used herein, the term ‘crystalline form’ refers to a substance, particularly a belumosudil salt, having a particular arrangement of its components in the crystal lattice, and which may be identified by physical characterization methods such as PXRD and/or DSC. [0039] As used herein, the term “room temperature” refers to a temperature in the range of 20 °C to 25 °C.

[0040] When describing the embodiments of the present invention there may be a common variance to a given temperature or time that would be understood or expected by the person skilled in the art to provide substantially the same result. For example, when reference is made to a particular temperature, it is to be understood by the person skilled in the art that there is an allowable variance of ±5 °C associated with that temperature. When reference is made to a particular time, it is to be understood that there is an allowable variance of ±10 minutes when the time is one or two hours, and ±1 hour when longer periods of time are referenced.

[0041 ] In a first embodiment of the present invention, there is provided a new salt of belumosudil, belumosudil L-malate Form APO-I, wherein the molar ratio of belumosudil to L-malic acid is approximately 1 :1.

[0042] Belumosudil L-malate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 29 (± 0.2°), at 6.4°, 7.6°, and 16.2°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of 10.5°, 12.4°, 12.9°, 15.2°, 19.7°, and 21.1 °. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 26 (± 0.2°), at 10.5°, 12.4°, 12.9°, 15.2°, 19.7°, and 21.1 °. PXRD studies of uncapped samples of belumosudil L-malate Form APO-I maintained in a 40 °C/75% RH stability chamber for at least 4 weeks showed that no change in the crystalline form occurred.

[0043] An illustrative PXRD diffractogram of belumosudil L-malate Form APO-I, as prepared in Example 1 , is shown in Figure 1. A peak listing, comprising representative peaks from the PXRD diffractogram in Figure 1 , and their relative intensities, is provided in Table 1. Although illustrative of the PXRD diffractogram that is provided for the belumosudil L-malate Form APO-I of the present invention, the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.

[0044] In a second embodiment of the present invention, there is provided a new salt of belumosudil, belumosudil acesulfamate Form APO-I, wherein the molar ratio of belumosudil to acesulfame is approximately 1 :1.

[0045] Belumosudil acesulfamate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 29 (± 0.2°), at 4.8°, 6.5°, and 25.7°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of 10.3°, 11.5°, 14.6°, 16.2°, 19.6°, and 20.7°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 26 (± 0.2°), at 10.3°, 11.5°, 14.6°, 16.2°, 19.6°, and 20.7°. PXRD studies of uncapped samples of belumosudil acesulfamate Form APO-I maintained in a 40 °C/75% RH stability chamber for at least 4 weeks showed that no change in the crystalline form occurred. [0046] An illustrative PXRD diffractogram of belumosudil acesulfamate Form APO-I, as prepared in Example 2, is shown in Figure 2. A peak listing, comprising representative peaks from the PXRD diffractogram in Figure 2, and their relative intensities, is provided in Table 2. Although illustrative of the PXRD diffractogram that is provided for the belumosudil acesulfamate Form APO-I of the present invention, the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.

[0047] In a third embodiment of the present invention, there is provided a new salt of belumosudil, belumosudil fumarate Form APO-I, wherein the molar ratio of belumosudil to fumaric acid is approximately 1 :1.

[0048] Belumosudil fumarate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 29 (± 0.2°), at 7.2°, 7.9°, and 21.1 °. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of 12.7°, 13.6°, 18.7°, 20.1 °, 21.7°, and 23.8°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 12.7°, 13.6°, 18.7°, 20.1 °, 21.7°, and 23.8°. PXRD studies of uncapped samples of belumosudil fumarate Form APO-I maintained in a 40 °C/75% RH stability chamber for at least 4 weeks showed that no change in the crystalline form occurred. [0049] An illustrative PXRD diffractogram of belumosudil fumarate Form APO-I, as prepared in Example 3, is shown in Figure 3. A peak listing, comprising representative peaks from the PXRD diffractogram in Figure 3, and their relative intensities, is provided in Table 3. Although illustrative of the PXRD diffractogram that is provided for the belumosudil fumarate Form APO-I of the present invention, the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.

[0050] In a fourth embodiment of the present invention, there is provided a new salt of belumosudil, belumosudil maleate Form APO-I, wherein the molar ratio of belumosudil to maleic acid is approximately 1 :1 .

[0051 ] Belumosudil maleate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 5.3°, 6.9°, and 10.8°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of 12.2°, 15.0°, 17.3°, 18.3°, 22.7°, and 24.1 °. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 12.2°, 15.0°, 17.3°, 18.3°, 22.7°, and 24.1 °. PXRD studies of uncapped samples of belumosudil maleate Form APO-

I maintained in a 40 °C/75% RH stability chamber for at least 4 weeks showed that no change in the crystalline form occurred.

[0052] An illustrative PXRD diffractogram of belumosudil maleate Form APO-I, as prepared in Example 4, is shown in Figure 4. A peak listing, comprising representative peaks from the PXRD diffractogram in Figure 4, and their relative intensities, is provided in Table 4. Although illustrative of the PXRD diffractogram that is provided for the belumosudil maleate Form APO-I of the present invention, the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.

[0053] In a fifth embodiment of the present invention, there is provided a new salt of belumosudil, belumosudil isethionate Form APO-I, wherein the molar ratio of belumosudil to 2-hydroxyethanesulfonic acid is approximately 1 :1. [0054] Belumosudil isethionate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 6.4°, 10.1 °, and 12.7°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of 7.8°, 15.7°, 19.2°, 20.3°, and 25.7°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 7.8°, 15.7°, 19.2°, 20.3°, and 25.7°. PXRD studies of uncapped samples of belumosudil isethionate Form APO-I maintained in a 40 °C/75% RH stability chamber for at least 4 weeks showed that no change in the crystalline form occurred. [0055] An illustrative PXRD diffractogram of belumosudil isethionate Form APO-I, as prepared in Example 5, is shown in Figure 5. A peak listing, comprising representative peaks from the PXRD diffractogram in Figure 5, and their relative intensities, is provided in Table 5. Although illustrative of the PXRD diffractogram that is provided for the belumosudil isethionate Form APO-I of the present invention, the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing. [0056] In a sixth embodiment of the present invention, there is provided a new salt of belumosudil, belumosudil malonate Form APO-I, wherein the molar ratio of belumosudil to malonic acid is approximately 1 :1.

[0057] Belumosudil malonate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 29 (± 0.2°), at 6.3°, 9.8°, and 12.6°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of 8.1 °, 15.2°, 16.3°, 19.0°, and 21.0°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 26 (± 0.2°), at 8.1 °, 15.2°, 16.3°, 19.0°, and 21.0°. PXRD studies of uncapped samples of belumosudil malonate Form APO-I maintained in a 40 °C/75% RH stability chamber for at least 4 weeks showed that no change in the crystalline form occurred.

[0058] An illustrative PXRD diffractogram of belumosudil malonate Form APO-I, as prepared in Example 6, is shown in Figure 6. A peak listing, comprising representative peaks from the PXRD diffractogram in Figure 6, and their relative intensities, is provided in Table 6. Although illustrative of the PXRD diffractogram that is provided for the belumosudil malonate Form APO-I of the present invention, the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.

[0059] In a seventh embodiment of the present invention, there is provided a new salt of belumosudil, belumosudil edisylate Form APO-I, wherein the molar ratio of belumosudil to 1 ,2-ethanedisulfonic acid is approximately 2:1.

[0060] Belumosudil edisylate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 29 (± 0.2°), at 6.7°, 7.7°, and 9.7°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of 5.8°, 8.4°, 12.4°, 13.9°, 15.1 °, and 20.3°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 26 (± 0.2°), at 5.8°, 8.4°, 12.4°, 13.9°, 15.1 °, and 20.3°. PXRD studies of uncapped samples of belumosudil edisylate Form APO-I maintained in a 40 °C/75% RH stability chamber for at least 4 weeks showed that no change in the crystalline form occurred.

[0061 ] An illustrative PXRD diffractogram of belumosudil edisylate Form APO-I, as prepared in Example 7, is shown in Figure 7. A peak listing, comprising representative peaks from the PXRD diffractogram in Figure 7, and their relative intensities, is provided in Table 7. Although illustrative of the PXRD diffractogram that is provided for the belumosudil edisylate Form APO-I of the present invention, the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.

[0062] In an eighth embodiment of the present invention, there is provided a new salt of belumosudil, belumosudil citrate Form APO-I, wherein the molar ratio of belumosudil to citric acid is approximately 1 :1.

[0063] Belumosudil citrate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 29 (± 0.2°), at 6.7°, 10.3°, and 11.7°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of 7.3°, 12.5°, 14.6°, 16.4°, 19.1 °, and 19.8°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 29 (± 0.2°), at 7.3°, 12.5°, 14.6°, 16.4°, 19.1 °, and 19.8°. PXRD studies of uncapped samples of belumosudil citrate Form APO-I maintained in a 40 °C/75% RH stability chamber for at least 4 weeks showed that no change in the crystalline form occurred.

[0064] An illustrative PXRD diffractogram of belumosudil citrate Form APO-I, as prepared in Example 8, is shown in Figure 8. A peak listing, comprising representative peaks from the PXRD in Figure 8, and their relative intensities, is provided in Table 8. Although illustrative of the PXRD diffractogram that is provided for the belumosudil citrate Form APO-I of the present invention, the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.

[0065] In a ninth embodiment of the present invention, there is provided a new salt of belumosudil, belumosudil citrate Form APO-II, wherein the molar ratio of belumosudil to citric acid is approximately 1 :1.

[0066] Belumosudil citrate Form APO-II can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 29 (± 0.2°), at 5.6°, 6.6°, and 17.7°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of 7.1 °, 11.2°, 12.6°, 15.4°, 15.9°, and 16.8°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 26 (± 0.2°), at 7.1 °, 11.2°, 12.6°, 15.4°, 15.9°, and 16.8°.

[0067] An illustrative PXRD diffractogram of belumosudil citrate Form APO-II, as prepared in Example 9, is shown in Figure 9. A peak listing, comprising representative peaks from the PXRD in Figure 9, and their relative intensities, is provided in Table 9. Although illustrative of the PXRD diffractogram that is provided for the belumosudil citrate Form APO-II of the present invention, the relative intensities of the peaks are variable.

Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.

[0068] In a tenth embodiment of the present invention, there is provided a new salt of belumosudil, belumosudil L-tartrate Form APO-I, wherein the molar ratio of belumosudil to L-tartaric acid is approximately 1 :1.

[0069] Belumosudil L-tartrate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 29 (± 0.2°), at 6.5°, 7.6°, and 16.3°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of 10.6°, 12.5°, 15.3°, 18.4°, 19.5°, and 22.5°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 26 (± 0.2°), at 10.6°, 12.5°, 15.3°, 18.4°, 19.5°, and 22.5°.

[0070] An illustrative PXRD diffractogram of belumosudil L-tartrate Form APO-I, as prepared in Example 10, is shown in Figure 10. A peak listing, comprising representative peaks from the PXRD in Figure 10, and their relative intensities, is provided in Table 10. Although illustrative of the PXRD diffractogram that is provided for the belumosudil L- tartrate Form APO-I of the present invention, the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing. [0071 ] In an eleventh embodiment of the invention, there is provided a pharmaceutical composition comprising one or more belumosudil salt(s) selected from the group consisting of belumosudil L-malate, belumosudil acesulfamate, belumosudil fumarate, belumosudil maleate, belumosudil isethionate, belumosudil malonate, belumosudil edisylate, belumosudil citrate, belumosudil L-tartrate, and combinations thereof, with one or more pharmaceutically acceptable excipients. Preferably, the pharmaceutical composition comprises one or more crystalline form(s) of a belumosudil salt selected from the group consisting of belumosudil L-malate Form APO-I, belumosudil acesulfamate Form APO-I, belumosudil fumarate Form APO-I, belumosudil maleate Form APO-I, belumosudil isethionate Form APO-I, belumosudil malonate Form APO-I, belumosudil edisylate Form APO-I, belumosudil citrate Form APO-I, belumosudil citrate Form APO-II, belumosudil L-tartrate Form APO-I, and combinations thereof, with one or more pharmaceutically acceptable excipients. Preferably, the pharmaceutical composition is a solid dosage form suitable for oral administration, such as a capsule, tablet, pill, powder or granulate. Most preferably, the pharmaceutical composition is a tablet. Preferably, the pharmaceutical composition provides a dose of one or more belumosudil salt(s) selected from the group consisting of belumosudil L-malate, belumosudil acesulfamate, belumosudil fumarate, belumosudil maleate, belumosudil isethionate, belumosudil malonate, belumosudil edisylate, belumosudil citrate, belumosudil L-tartrate, such that the total is equivalent to the 200 mg of belumosudil free base found in REZUROCK® drug products.

[0072] Suitable pharmaceutically acceptable excipients are preferably inert with respect to the belumosudil salts of the present invention, and may include, for example, one or more excipients selected from binders such as lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copovidone, gelatine, polyvinylpyrrolidone (PVP), and sodium alginate; fillers or diluents such as lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g., microcrystalline cellulose, cellulose), calcium sulphate, xylitol, and lactitol; disintegrants such as croscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycollate, com starch, microcrystalline cellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; lubricants such as magnesium stearate, magnesium lauryl stearate, sodium stearyl fumarate, stearic acid, calcium stearate, zinc stearate, potassium benzoate, sodium benzoate, myristic acid, palmitic acid, mineral oil, hydrogenated castor oil, medium-chain triglycerides, poloxamer, polyethylene glycol, and talc; and dispersants or solubility enhancing agents, such cyclodextrins, glyceryl monostearate, hypromellose, meglumine, poloxamer, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, polyoxylglycerides, povidone, and stearic acid. Other excipients including preservatives, stabilisers, anti-oxidants, silica flow conditioners, antiadherents, or glidants may be added as required. Other suitable excipients and the preparation of solid oral dosage forms are well known to person of skill in the art, and is described generally, for example, in Remington The Science and Practice of Pharmacy 21 ^st Edition (Lippincott Williams & Wilkins: Philadelphia; 2006; Chapter 45).

[0073] Optionally, when the pharmaceutical compositions are solid dosage forms, the solid dosage forms may be prepared with coatings, such as enteric coatings and extended-release coatings, using standard pharmaceutical coatings. Such coatings, and their application, are well known to persons skilled in the art, and are described, for example, in Remington The Science and Practice of Pharmacy 21 ^st Edition (Lippincott Williams & Wilkins: Philadelphia; 2006; Chapter 46).

EXAMPLES

[0074] The following non-limiting examples are illustrative of some of the aspects and embodiments of the invention described herein.

[0075] The belumosudil free base used as a starting material in the following examples was commercially available and in the form of N1 as described in WO 2021/129589 A1. Acesulfame used as starting material in the following examples was obtained by stirring an ethyl acetate suspension of acesulfame potassium and a stoichiometric amount of 85 % phosphoric acid for about 3 hours, filtering the organic layer and concentrating the solution to dryness.

PXRD Analysis:

[0076] PXRD diffractograms were recorded on a Broker D8 Discover powder X-ray diffractometer (Broker AXS LLC, Karlsruhe, Germany). The generator was a Incoatec Microfocus Source (IpS) Cu tube (A = 1 .54060 A) with a voltage of 50 kV and current of 1 .00 mA, using a divergence slit of 0.1 mm and collimator of 2.0 mm. For each sample, two frames were collected using a still scan with a PILATUS3 R 100K-A detector at the distance of 294.2 mm from the sample. Raw data were evaluated using the program DIFFRAC. EVA (Broker AXS LLC, Karlsruhe, Germany). Example 1 : Preparation of belumosudil L-malate Form APO-I

[0077] To a suspension of belumosudil free base (100 mg) in a mixture of isopropanol (2.7 mL) and water (0.3 mL) at 60 °C was added solid L-malic acid (52 mg), and the resulting suspension was stirred at that temperature for one hour. The suspension was allowed to cool and stirring was continued at room temperature for approximately 16 hours, after which the solids were collected by filtration, washed with acetone (2 x 1 mL), and dried at room temperature in vacuo to afford belumosudil L-malate Form APO-I as a yellow solid (129 mg). The PXRD of the sample is shown in Figure 1 .

[0078] ¹ H NMR (500 MHz, DMSO-d ₆ ): 13.09 (br s, 1 H), 12.42 (br s, 2H), 9.97 (s, 1 H), 8.60 (d, J = 8.2 Hz, 1 H), 8.32 (s, 1 H), 8.16 (s, 1 H), 8.06 (br s, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7.95 (d, J = 7.9 Hz, 1 H), 7.83-7.90 (m, 3H), 7.65 (d, J = 8.7 Hz, overlapping another signal, 2H), 7.42 (t, J = 7.9 Hz, 1 H), 7.08 ( br d, J = 8.2 Hz, 1 H), 4.52 (s, 2H), 4.26 (m, 1 H), 3.99 (m, 1 H), 2.62 (dd, J = 15.7, 4.8 Hz, 1 H), 2.44 (dd, J = 15.7, 7.8 Hz, 1 H), 1.12 (d, J = 6.6 Hz, 6H).

Example 2: Preparation of belumosudil acesulfamate Form APO-I

[0079] To a suspension of belumosudil free base (100 mg) in a mixture of isopropanol (2.7 mL) and water (0.3 mL) at 60 °C was added solid acesulfame (52 mg), and the resulting suspension was stirred at that temperature for one hour. The suspension was allowed to cool and stirring was continued at room temperature for approximately 16 hours, after which the solids were collected by filtration, washed with acetone (2 x 1 mL), and dried at room temperature in vacuo to afford belumosudil acesulfamate Form APO-I as a yellow solid (140 mg). The PXRD of the sample is shown in Figure 2.

[0080] ¹ H NMR (500 MHz, DMSO-d ₆ ): 13.22 (br s, 1 H), 11.00 (br s, 1 H), 8.70 (d, J = 8.3 Hz, 1 H), 8.22 (s, 1 H), 8.20 (d, J = 0.4 Hz, 1 H), 8.04 (t, J = 7.3 Hz, 1 H), 7.99 (d, J = 8.2 Hz, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.90 (br s, overlapping another signal, 2H), 7.79 (dd, J = 8.9, 1 .8 Hz, overlapping another signal, 2H), 7.70 (d, J = 8.9 Hz, 1 H), 7.52 (t, J = 7.9 Hz, 1 H), 7.22 ( br d, J = 7.2 Hz, 1 H), 5.56 (s, 1 H), 4.54 (s, 2H), 3.96 (m, 1 H), 2.01 (d, J = 0.7 Hz, 3H), 1 .09 (d, J = 6.6 Hz, 6H). Example 3: Preparation of belumosudil fumarate Form APO-I

[0081 ] To a suspension of belumosudil free base (100 mg) in a mixture of isopropanol (2.7 mL) and water (0.3 mL) at 60 °C was added solid fumaric acid (51 mg), and the resulting suspension was stirred at that temperature for one hour. The suspension was allowed to cool and stirring was continued at room temperature for approximately 16 hours, after which the solids were collected by filtration, washed with acetone (2 x 1 mL), and dried at room temperature in vacuo to afford belumosudil fumarate Form APO-I as a yellow solid (119 mg). The PXRD of the sample is shown in Figure 3.

[0082] ¹ H NMR (500 MHz, DMSO-d ₆ ): 13.14 (s, 3H), 9.97 (s, 1 H), 8.60 (d, J = 8.3 Hz,

1 H), 8.32 (s, 1 H), 8.16 (s, 1 H), 8.06 (br s, 1 H), 8.05 (d, J = 7.8 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 1 H), 7.83-7.90 (m, 3H), 7.65 (d, J = 9.0 Hz, overlapping another signal, 2H), 7.42 (t, J = 7.9 Hz, 1 H), 7.08 ( br d, J = 8.0 Hz, 1 H), 6.64 (s, 2H), 4.53 (s, 2H), 3.99 (m, 1 H), 1 .11 (d, J = 6.6 Hz, 6H).

Example 4: Preparation of belumosudil maleate Form APO-I

[0083] To a suspension of belumosudil free base (100 mg) in a mixture of isopropanol (2.7 mL) and water (0.3 mL) at 60 °C was added solid maleic acid (59 mg), and the resulting suspension was stirred at that temperature for one hour. The suspension was allowed to cool and stirring was continued at room temperature for approximately 16 hours, after which the solids were collected by filtration, washed with acetone (2 x 1 mL), and dried at room temperature in vacuo to afford belumosudil maleate Form APO-I as a yellow solid (118 mg). The PXRD of the sample is shown in Figure 4.

[0084] ¹ H NMR (500 MHz, DMSO-d ₆ ): 13.14 (s, 2H), 10.22 (s, 1 H), 8.62 (d, J = 8.3 Hz,

1 H), 8.30 (s, 1 H), 8.18 (s, 1 H), 8.02 (br s, 1 H), 8.00 (d, J = 7.9 Hz, 1 H), 7.88-7.96 (m, 3H), 7.83 (d, J = 8.9 Hz, 1 H), 7.66 (d, J = 8.6 Hz, overlapping another signal, 2H), 7.45 (t, J = 7.9 Hz, 1 H), 7.12 ( br d, J = 8.0 Hz, 1 H), 6.24 (s, 2H), 4.53 (s, 2H), 3.99 (m, 1 H), 1.11 (d, J = 6.6 Hz, 6H). Example 5: Preparation of belumosudil isethionate Form APO-I

[0085] To a suspension of belumosudil free base (100 mg) in a mixture of isopropanol (3 mL) and water (1 mL) was added 2-hydroxyethanesulfonic acid (50 pL), and the resulting suspension was stirred at room temperature for approximately 16 hours, after which the solids were collected by filtration, washed with acetone (1 mL), and dried at room temperature in vacuo to afford belumosudil isethionate Form APO-I as a yellow solid (119 mg). The PXRD diffractogram of the sample is shown in Figure 5.

[0086] ¹ H NMR (500 MHz, DMSO-d ₆ ): 13.27 (br s, 1 H), 11 .38 (br s, 1 H), 8.74 (d, J =

8.2 Hz, 1 H), 8.22 (s, 1 H), 8.19 (s, 1 H), 8.10 (t, J =7.2 Hz, 1 H), 8.05 (d, J = 7.9 Hz, 1 H), 7.95 (d, J = 7.9 Hz, 1 H), 7.86 (br s overlapping another signal, 3H), 7.77 (d, J = 8.9 Hz, 1 H), 7.72 (d, J = 8.9 Hz, 1 H), 7.56 (t, J = 7.9 Hz, 1 H), 7.27 ( br d, J = 7.8 Hz, 1 H), 4.55 (s, 2H), 3.96 (m, 1 H), 3.63 (t, J = 6.8 Hz, 2H), 2.62 (t, J = 6.8 Hz, 2H), 1.09 (d, J = 6.6 Hz, 6H).

Example 6: Preparation of belumosudil malonate Form APO-I

[0087] To a suspension of belumosudil free base (100 mg) in a mixture of isopropanol (3 mL) and water (1 mL) was added solid malonic acid (54 mg), and the resulting suspension was stirred at room temperature for approximately 16 hours, after which the solids were collected by filtration, washed with acetone (1 mL), and dried at room temperature in vacuo to afford belumosudil malonate Form APO-I as a yellow solid (101 mg). The PXRD diffractogram of the sample is shown in Figure 6.

[0088] ¹ H NMR (500 MHz, DMSO-d ₆ ): 13.09 (br s, 1 H), 12.71 (br s, 2H), 9.98 (s, 1 H), 8.60 (d, J = 8.2 Hz, 1 H), 8.32 (s, 1 H), 8.16 (s, 1 H), 8.06 (br s, 1 H), 8.03 (d, J = 7.7 Hz, 1 H), 7.94 (d, J = 7.9 Hz, 1 H), 7.83-7.90 (m, 3H), 7.65 (d, J = 8.6 Hz, overlapping another signal, 2H), 7.42 (t, J = 7.9 Hz, 1 H), 7.09 ( br d, J = 8.3 Hz, 1 H), 4.52 (s, 2H), 3.99 (m, 1 H), 3.24 (s, 2H), 1 .12 (d, J = 6.5 Hz, 6H).

Example 7: Preparation of belumosudil edisylate Form APO-I

[0089] To a suspension of belumosudil free base (100 mg) in a mixture of isopropanol (3 mL) and water (1 mL) was added solid 1 ,2-ethanedisulfonic acid dihydrate (25 mg), and the resulting suspension was stirred at room temperature for approximately 16 hours, after which the solids were collected by filtration, washed with acetone (1 mL), and dried at room temperature in vacuo to afford belumosudil edisylate Form APO-I as a yellow solid (98 mg). The PXRD diffractogram of the sample is shown in Figure 7.

[0090] ¹ H NMR (500 MHz, DMSO-d ₆ ): 13.24 (br s, 1 H), 11 .24 (br s, 1 H), 8.72 (d, J =

7.7 Hz, 1 H), 8.21 (s, 1 H), 8.07 (br m, 1 H), 8.03 (br m, 1 H), 7.95 (d, J = 8.0 Hz, 1 H), 7.89 (br s, overlapping another signal, 2H), 7.82 (br m, 1 H), 7.79 (d, J = 9.0 Hz, 1 H), 7.71 (d, J = 8.9 Hz, 1 H), 7.54 (t, J = 7.6 Hz, 1 H), 7.24 ( br d, J = 7.1 Hz, 1 H), 4.54 (s, 2H), 3.96 (m, 1 H), 2.64 (s, 2H), 1.10 (d, J = 6.5 Hz, 6H).

Example 8: Preparation of belumosudil citrate Form APO-I

[0091 ] To a suspension of belumosudil free base (100 mg) in acetone (3 mL) was added solid citric acid (42 mg), and the resulting suspension was stirred at room temperature for approximately 16 hours, after which the solids were collected by filtration, washed with acetone (2 x 1 mL), and dried at room temperature in vacuo to afford belumosudil citrate Form APO-I as a yellow solid (120 mg). The PXRD diffractogram of the sample is shown in Figure 8.

[0092] ¹ H NMR (500 MHz, DMSO-de): 13.09 (br s, 1 H), 12.33 (br s, 2H), 9.99 (s, 1 H), 8.60 (d, J = 8.3 Hz, 1 H), 8.32 (s, 1 H), 8.16 (s, 1 H), 8.06 (s, 1 H), 8.03 (d, J = 7.8 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 1 H), 7.83-7.90 (m, 3H), 7.65 (d, J = 8.7 Hz, overlapping another signal, 2H), 7.42 (t, J = 7.9 Hz, 1 H), 7.09 ( br d, J = 7.8 Hz, 1 H), 5.21 (br s, 1 H), 4.52 (s, 2H), 3.99 (m, 1 H), 2.76 (d, J = 15.4 Hz, 2H), 2.66 (d, J = 15.4 Hz, 2H), 1 .12 (d, J = 6.6 Hz, 6H).

Example 9: Preparation of belumosudil citrate Form APO-

[0093] To a suspension of belumosudil free base (100 mg) in a mixture of acetone (3 mL) and water (1 mL) was added solid citric acid (86 mg), with complete dissolution of all solids being observed. After 12 days at room temperature, a brown, pasty and unstirrable precipitate had formed. The supernatant was decanted and acetone (3 mL) was added, converting the pasty precipitate into a free-flowing powder. The solids were collected by filtration, washed with acetone (2 x 1 mL), and dried at room temperature in vacuo to afford belumosudil citrate Form APO-II as a yellow solid (136 mg). The PXRD diffractogram of the sample is shown in Figure 9.

Example 10: Preparation of belumosudil L-tartrate Form APO-I

[0094] To a belumosudil free base (100 mg) suspension in methanol (4 mL) was added solid L-tartaric acid (33 mg), and the resulting suspension was stirred at room temperature for approximately 4 hours, after which the solids were collected by filtration, washed with methanol (0.5 mL), and dried at room temperature in vacuo to afford belumosudil L-tartrate Form APO-I as a yellow solid (70 mg). The PXRD diffractogram of the sample is shown in Figure 10. [0095] ¹ H NMR (500 MHz, DMSO-d ₆ ): 12.87 (br s, 3H), 9.97 (s, 1 H), 8.60 (d, J = 8.3

Hz, 1 H), 8.32 (d, J = 1 .2 Hz, 1 H), 8.16 (s, 1 H), 8.06 (br s, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.86-7.90 (m, 2H), 7.85 (dd, J = 1 .8, 8.8 Hz, 1 H), 7.65 (d, J = 8.8 Hz, overlapping another signal, 2H), 7.42 (t, J = 7.9 Hz, 1 H), 7.09 (dd, J = 2.2, 8.1 Hz, 1 H), 5.11 (br s, 2H), 4.53 (s, 2H), 4.32 (s, 2H), 3.99 (m, 1 H), 1 .12 (d, J = 6.6 Hz, 6H).