Pharmaceutical compound, salts thereof, formulations thereof, and methods of making and using same

Abstract

What is revealed are novel salts, hydrates, and solvates of compound I, as well as methods for their preparation and use and related dosage forms.

Description

Pharmaceutical compounds, their salts, their preparations, and methods of their preparation and use The present invention generally relates to Compound 1, novel salts, hydrates, and solvates described herein, and methods of making and using the same. Specifically, the present invention relates to various salts of Compound 1 (including the tosylate salt), pharmaceutical and diagnostic compositions containing the same, and their pharmaceutical uses, particularly as medicaments for treating and / or preventing disease. Compound I is an orally available small molecule with the following structure: Compound I has therapeutic value in several different indications exhibiting fibrotic pathophysiology, including idiopathic pulmonary fibrosis (IPF). Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology that primarily occurs in middle-aged and elderly patients and is characterized by persistent fibrosis in the lungs, leading to pulmonary insufficiency and death. Because fibrosis has long been considered a clinically irreversible process, conventional treatments have focused on controlling symptoms and complications, with little hope of significantly slowing the progression of the disease. For many years, the primary treatments have typically been anti-inflammatory, immunosuppressive, and antioxidant. These therapies appear to be minimally effective and variable in treating IPF and other fibrotic conditions, and their side effects are often difficult for patients to tolerate. New treatment options have only recently become available. Pirfenidone and nintedanib are both approved for the treatment of IPF. Current research efforts to develop new antifibrotic agents aim to uncover multiple mechanisms underlying molecular mechanisms of action. This evolving landscape offers hope and expectations for the potential of new single-agent therapies or combination therapies targeting alternative pathways. The present invention relates to salts, hydrates, and solvates of Compound 1. In one aspect, the present invention relates to a tosylate salt of Compound 1. Optionally, the salt is a hydrochloride salt other than Compound 1. In another aspect, the present invention relates to a pharmaceutical composition comprising Compound 1 or a salt, hydrate, or solvate thereof and a pharmaceutically acceptable excipient or carrier. Another aspect of the present invention provides a process for preparing a pharmaceutical composition comprising Compound 1 or a salt, hydrate, or solvate thereof into an oral dosage form. Some embodiments of the present invention relate to a method of administering Compound 1 or a salt, hydrate or solvate thereof to treat a patient suffering from a fibrotic disease, an inflammatory disease or an autoimmune disease, comprising administering a pharmaceutically effective amount of Compound 1 or a salt, hydrate or solvate thereof. Some embodiments of the present invention relate to methods of administering Compound 1, or a salt, hydrate, or solvate thereof, to treat a subject suffering from a fibrotic disease, an inflammatory disease, or an autoimmune disease, comprising administering to a subject a pharmaceutically effective amount of Compound 1, or a salt, hydrate, or solvate thereof, wherein the bioavailability of Compound 1 is relative or increased compared to the bioavailability of the same amount of Compound 1 administered as a nanosuspension. Another aspect of the present invention provides a method for synthesizing Compound 1 or a salt, hydrate, or solvate thereof. Another aspect of the present invention provides a method for synthesizing Compound 1 in a methanol-free process. Yet another aspect of the present invention provides a method for synthesizing the tosylate salt of Compound 1 in a methanol-free process. Some other embodiments of the present invention relate to a kit comprising a pharmaceutical composition, prescribing information, and a container, wherein the pharmaceutical composition comprises a pharmaceutically effective amount of Compound I. In any embodiment of the methods or kits described herein, the effective daily amount of Compound 1 is from about 1 mg to about 5000 mg per day, from about 5 mg to about 2500 mg per day, or from about 10 mg to about 2000 mg per day, calculated as the free base. In some other embodiments, the amount of Compound 1 administered is from about 25 mg to about 1600 mg per day, calculated as the free base. In some other embodiments, the amount of Compound 1 administered is from about 25 mg, about 75 mg, about 200 mg, about 275 mg, about 400 mg, about 550 mg, about 575 mg, about 800 mg, about 1150 mg, or about 1600 mg per day, calculated as the free base, or within a range defined by any two of the foregoing values. In any embodiment of the methods described herein, the subject being treated has a disease or disorder described herein, eg, a fibrotic disease, or specifically, idiopathic pulmonary fibrosis (IPF). For the compositions and methods described herein, optional features, including but not limited to components, compositional ranges thereof, substituents, conditions, and steps, are contemplated to be selected from the various aspects, embodiments, and examples provided herein. Other aspects and advantages will be apparent to those skilled in the art upon reading the following detailed description in conjunction with the accompanying drawings. Although the compounds, compositions, and methods are susceptible to various embodiments, the following description includes specific examples, but it should be understood that the present invention is illustrative and is not intended to limit the present invention to the specific embodiments described herein. The details of one or more embodiments of the present invention are set forth in the following description. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are now described. Other features, objects and advantages of the present invention will be apparent from the description. In the specification, unless otherwise expressly provided, the singular also includes the plural. Unless otherwise expressly provided, all technical and scientific terms used herein have the same meaning as understood by a person of ordinary skill in the art to which the invention belongs. In the event of a conflict, the specification will control. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference in their entirety. Unless otherwise stated, it is intended that compounds and methods include embodiments that include any combination of one or more additional optional elements, features and steps further described below (including those shown in the drawings). In jurisdictions that prohibit patenting of methods performed on humans, the meaning of "administering" a composition to a human subject should be limited to specifying the test substance, which the human subject will self-administer by any technique (e.g., oral, inhaled, topical application, injection, insertion, etc.). This is intended to be the broadest reasonable interpretation consistent with the law or regulation defining patentable subject matter. In jurisdictions that do not prohibit patenting of methods performed on humans, "administering" a composition encompasses methods performed on humans and the aforementioned activities. The term wt% as used herein refers to weight percentage based on the total weight. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. The following provides salts of compound I (Formula C 18 H 14 N 5O 2F 3, mass 389.3 g / mol), which has the structure shown below. The salt can be selected from the group consisting of benzenesulfonate, citrate, fumarate, hemi-edisylate, hemi-naphthalenedisulfonate, hydrobromide, maleate, nicotinate, nitrate, oxalate, phosphonate, saccharate, sulfate, L-tartrate, and toluenesulfonate of Compound I. Alternatively, the salt is selected from the group consisting of benzenesulfonate, hemi-edisylate, hemi-naphthalenedisulfonate, hydrobromide, nitrate, phosphonate, sulfate, and toluenesulfonate of Compound I. For example, the salt can be a toluenesulfonate, e.g., a monotoluenesulfonate or a ditoluenesulfonate. In one contemplated embodiment, the salt is the monotoluenesulfonate of Compound I. In another contemplated embodiment, the salt is the dihydrochloride of Compound I. In one class of embodiments, the dihydrochloride salt of Compound 1 is amorphous. In another class of embodiments, the dihydrochloride salt of Compound 1 is crystalline. In another class of embodiments, there is a composition comprising a mixture of amorphous and crystalline dihydrochloride salts of Compound 1. The salt of Compound 1 is characterized by an X-ray diffraction pattern substantially similar to that set forth in any one of Figures 1 to 12. The salt of Compound 1 is further characterized by a melting onset in a range of about 204°C to about 207°C. In some embodiments, the salt of Compound 1 is the monotosylate salt. In some embodiments, the monotosylate salt is characterized by an X-ray diffraction pattern substantially similar to that shown in FIG8 . In some embodiments, the monotosylate salt is characterized by an X-ray diffraction pattern having three or more peaks when irradiated with a Cu-Ka light source, the peaks being selected from those at diffraction angle 2θ values ​​of 10.92°±0.2°, 13.28°±0.2°, 15.36°±0.2°, 16.94°±0.2°, 17.74°±0.2°, 18.20°±0.2°, 20.51°±0.2°, 23.21°±0.2°, 23.86°±0.2°, 24.73°±0.2°, 25.69°±0.2°, 26.68°±0.2°, 27.63°±0.2°, 29.12°±0.2°, and 30.532°±0.2°. In some embodiments, the monotosylate salt is characterized by an X-ray diffraction pattern having three or more peaks when irradiated with a Cu-Ka light source, the peaks being selected from diffraction angle 2θ values ​​of 10.92°±0.2°, 15.36°±0.2°, 16.94°±0.2°, 17.74°±0.2°, 23.21°±0.2°, 23.86°±0.2°, 24.73°±0.2°, 25.69°±0.2°, 27.63°±0.2°, and 29.12°±0.2°. In some embodiments, the monotosylate salt is characterized by an X-ray diffraction pattern having three or more peaks when irradiated with a Cu-Ka light source, the peaks being selected from those at diffraction angle 2θ values ​​of 15.36°±0.2°, 17.74°±0.2°, 23.21°±0.2°, 23.86°±0.2°, and 24.73°±0.2°. Preparation of compounds I and its salts The synthesis of compound I and its tosylate salt is shown in the figure below: 1-Methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c] Pyridin-4-one (5) is synthesized in four steps, including a copper-catalyzed coupling reaction, for example, a Goldberg-Ullmann coupling reaction. In another aspect of the present invention, any transition metal-catalyzed coupling reaction is used to synthesize intermediate (5). Chemists skilled in the art will recognize that intermediate (5) can be synthesized from intermediate (4) and a compound of the following general formula: , wherein the leaving group "LG" includes but is not limited to halogen, tosylate, mesylate, triflate, etc. Compound I is synthesized in 6 steps using a transition metal cross-linking reaction (e.g., a Suzuki reaction). In another aspect of the present invention, any cross-linking reaction is used to synthesize Compound I. Compound I is synthesized from Intermediate 6 containing any leaving group. For example, a chemist skilled in the art would use a compound having the following general formula: , wherein the leaving group "LG" includes but is not limited to halogen, tosylate, mesylate, triflate, etc. Compound I tosylate is synthesized from the free base form of Compound I by treatment with p-toluenesulfonic acid (toluenesulfonic acid). In one aspect of the invention, Compound I is treated with p-toluenesulfonic acid in a solvent. Chemists skilled in the art will appreciate the use of various suitable solvent mixtures to form the Compound I tosylate salt from the free base. In one aspect of the invention, the salt is formed in a solvent mixture, for example, acetone and water. In another aspect, the salt is formed in methanol. In yet another aspect, the salt is formed in a solvent mixture or a solvent mixture without methanol. In one embodiment, the present invention relates to a process for preparing a compound or an intermediate thereof, comprising one or more of the following steps: (1) reacting 2,4-dichloro-3-nitropyridine with methylamine to obtain 2-chloro-N-methyl-3-nitropyridine-4-amine; (2) reducing 2-chloro-N-methyl-3-nitropyridine-4-amine to obtain 2-chloro-N-methyl-3-nitropyridine-4-amine; 4 -methylpyridine-3,4-diamine; (3) condensation of 2-chloro-N 4 -methylpyridine-3,4-diamine to give 1-methyl-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one; (4) coupling 1-methyl-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one and 1-bromo-4-(trifluoromethoxy)benzene to give 1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one; (5) 1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one to give 7-bromo-1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one; and (6) coupling of 7-bromo-1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give compound I. In another embodiment, the present invention relates to a process for preparing compound I or an intermediate thereof, comprising one or more of the following steps: (1) reacting 2,4-dichloro-3-nitropyridine with methylamine to obtain 2-chloro-N-methyl-3-nitropyridine-4-amine; (2) reducing 2-chloro-N-methyl-3-nitropyridine-4-amine to obtain 2-chloro-N-methyl-3-nitropyridine-4-amine; 4 -methylpyridine-3,4-diamine; (3) condensation of 2-chloro-N 4 -methylpyridine-3,4-diamine to give 1-methyl-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one; (4) coupling 1-methyl-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one and 1-bromo-4-(trifluoromethoxy)benzene to give 1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one; (5) 1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one to give 7-bromo-1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one; and (6) coupling of 7-bromo-1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to obtain compound I, and further comprising a step of recrystallizing compound I. In another embodiment, the present invention relates to a process for preparing a tosylate salt of Compound I or an intermediate thereof, comprising one or more of the following steps: (1) reacting 2,4-dichloro-3-nitropyridine with methylamine to obtain 2-chloro-N-methyl-3-nitropyridine-4-amine; (2) reducing 2-chloro-N-methyl-3-nitropyridine-4-amine to obtain 2-chloro-N-methyl-3-nitropyridine-4-amine; 4 -methylpyridine-3,4-diamine; (3) condensation of 2-chloro-N 4 -methylpyridine-3,4-diamine to give 1-methyl-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one; (4) coupling 1-methyl-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one and 1-bromo-4-(trifluoromethoxy)benzene to give 1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one; (5) 1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one to give 7-bromo-1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one; (6) coupling 7-bromo-1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to obtain compound I, (7) recrystallizing compound I in a two-solvent system; and (8) contacting compound I with p-toluenesulfonic acid to obtain compound I tosylate salt. In another embodiment, the present invention relates to a process for preparing a tosylate salt of Compound 1, comprising the steps of contacting Compound 1 with p-toluenesulfonic acid to obtain a tosylate salt of Compound 1. In one embodiment, the tosylate salt of Compound 1 is a ditosylate salt. In another embodiment, the tosylate salt of Compound 1 is a monotosylate salt. In another aspect, the present invention relates to a method for preparing 7-bromo-1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c] A process for preparing pyridin-4-one, comprising the following steps: (1) reacting 2,4-dichloro-3-nitropyridine with methylamine to obtain 2-chloro-N-methyl-3-nitropyridine-4-amine; (2) reducing 2-chloro-N-methyl-3-nitropyridine-4-amine to obtain 2-chloro-N 4 -methylpyridine-3,4-diamine; (3) condensation of 2-chloro-N 4 -methylpyridine-3,4-diamine to give 1-methyl-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one; (4) coupling 1-methyl-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one and 1-bromo-4-(trifluoromethoxy)benzene to give 1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one; and (5) 1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one to give 7-bromo-1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one. In another aspect, the present invention relates to a method for preparing 1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c] A process for preparing pyridin-4-one, comprising the following steps: (1) reacting 2,4-dichloro-3-nitropyridine with methylamine to obtain 2-chloro-N-methyl-3-nitropyridine-4-amine; (2) reducing 2-chloro-N-methyl-3-nitropyridine-4-amine to obtain 2-chloro-N 4 -methylpyridine-3,4-diamine; (3) condensation of 2-chloro-N 4 -methylpyridine-3,4-diamine to give 1-methyl-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one; and (4) coupling of 1-methyl-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one and 1-bromo-4-(trifluoromethoxy)benzene to give 1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one. In another aspect, the present invention relates to a method for preparing 1-methyl-1,5-dihydro-4H-imidazo[4,5- c] A process for preparing pyridin-4-one, comprising the following steps: (1) reacting 2,4-dichloro-3-nitropyridine with methylamine to obtain 2-chloro-N-methyl-3-nitropyridine-4-amine; (2) reducing 2-chloro-N-methyl-3-nitropyridine-4-amine to obtain 2-chloro-N 4 -methylpyridine-3,4-diamine; and (3) condensation of 2-chloro-N 4 -methylpyridine-3,4-diamine to give 1-methyl-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one. In another aspect, the present invention relates to a method for preparing 2-chloro-N 4 The invention relates to a process for preparing 2,4-dichloro-3-nitropyridine-3,4-diamine, which comprises the following steps: (1) reacting 2,4-dichloro-3-nitropyridine with methylamine to obtain 2-chloro-N-methyl-3-nitropyridine-4-amine; and (2) reducing 2-chloro-N-methyl-3-nitropyridine-4-amine to obtain 2-chloro-N-methyl-3-nitropyridine-4-amine. 4 -methylpyridine-3,4-diamine. In another embodiment, the present invention relates to a process for preparing compound I, comprising the steps of: coupling 7-bromo-1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give compound I. In another aspect, the present invention relates to a method for preparing 7-bromo-1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one, comprising the steps of: bromination of 1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one to give 7-bromo-1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one. In another aspect, the present invention relates to a method for preparing 1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one, comprising the steps of: coupling 1-methyl-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one and 1-bromo-4-(trifluoromethoxy)benzene to give 1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one. In another aspect, the present invention relates to a method for preparing 1-methyl-1,5-dihydro-4H-imidazo[4,5- c] a process for preparing pyridin-4-one, comprising the steps of: condensing 2-chloro-N-pyridin-4-one with formic acid; 4 -methylpyridine-3,4-diamine to give 1-methyl-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one. In another aspect, the present invention relates to a method for preparing 2-chloro-N 4 -methylpyridine-3,4-diamine, which comprises the following steps: reducing 2-chloro-N-methyl-3-nitropyridine-4-amine to obtain 2-chloro-N 4 -methylpyridine-3,4-diamine. In another aspect, the present invention relates to a process for preparing 2-chloro-N-methyl-3-nitropyridine-4-amine, comprising the steps of reacting 2,4-dichloro-3-nitropyridine with methylamine to obtain 2-chloro-N-methyl-3-nitropyridine-4-amine. Another synthesis of compound I and its salts is shown in the following scheme: In this synthesis, intermediate (2a) is prepared from 3-nitropyridine-2,4-diol (1a) by treating 3-nitropyridine-2,4-diol with a brominating agent. The brominating agent can be selected from any suitable brominating agent, including those known in the art, such as molecular bromine, N-bromosuccinimide, and the like. Intermediate (3a) is prepared from intermediate (2a) by treating intermediate (3a) with a chlorinating agent. The chlorinating agent can be selected from any suitable chlorinating agent, including those known in the art, such as molecular chlorine, N-chlorosuccinimide, chlorophosphate and its derivatives. Intermediate (8a) is prepared from 3-nitropyridine-2,4-diol (1a) in six steps. Intermediate (8a) is prepared by a transition metal-catalyzed coupling reaction, such as a Chan-Lam coupling reaction. In another embodiment of the present invention, any transition metal-catalyzed coupling reaction is used to synthesize intermediate (8a). Compound I can be synthesized in 7 steps using a transition metal cross-coupling reaction (e.g., a Suzuki reaction). In another aspect of the present invention, any cross-coupling reaction can be used to synthesize Compound I. Compound I can be synthesized from an intermediate (8a) containing any leaving group. For example, a chemist skilled in the art can use a compound having the following general formula: , wherein the leaving group "LG" includes but is not limited to halogen, tosylate, mesylate, triflate, etc. Any process for preparing Compound I may optionally include a step of recrystallizing Compound I, further optionally including recrystallizing in a solvent system having at least two solvents or consisting of two solvents. For example, the solvent system may include or consist of acetic acid and ethanol. One of the solvents in the two-solvent system may be present in excess volume. For example, in a solvent system comprising or consisting of acetic acid and ethanol, the ethanol may be present in excess volume compared to the acetic acid. The solvent ratio may be varied as needed to achieve the desired purity and / or to obtain the recrystallization. For example, a solvent system may contain acetic acid and ethanol, wherein the acetic acid and ethanol are present in a volume ratio of about 1:1 to about 1:15, about 1:1 to about 1:10, about 1:4 to about 1:10, or about 1:6 to about 1:8 acetic acid:ethanol. Compound I hydrochloride salts can be synthesized from the free base form of Compound I by treatment with hydrochloric acid. In one aspect of the invention, Compound I is treated with hydrochloric acid in a solvent. Chemists skilled in the art will appreciate the use of various suitable solvent mixtures to form Compound I hydrochloride salts from the free base. In one aspect of the invention, the salts are formed in a solvent mixture, for example, dioxane and water. In another aspect, the salts are formed in methanol. In yet another aspect, the salts are formed in a solvent mixture or a solvent mixture without methanol. For example, a salt of Compound I can be prepared by milling to obtain a desired particle size. For example, the particle size can range from nanometers to low micrometers, e.g., a volume mean diameter of 500 μm or less, or 100 μm or less. In one class of embodiments, the majority of particles are in the range of 1 μm to 100 μm, or 1 μm to 10 μm. The particle size distribution can be characterized by D10, D50, D90, and D[4,3] values, as known in the art. In one class of embodiments, the particles of the Compound I salt (e.g., the tosylate salt) can have a D50 ranging from about 10 μm to about 60 μm, or from about 10 μm to about 35 μm, or from about 25 μm to about 30 μm. The particles of the Compound I salt (e.g., the tosylate salt) can have a volume mean diameter D[4,3] ranging from about 10 μm to about 60 μm, or from about 25 μm to about 45 μm, or from about 30 μm to about 40 μm. The Compound 1 salt (e.g., tosylate salt) particles may have a D90 ranging from about 50 µm to about 100 µm, or from about 60 µm to about 90 µm. The Compound 1 salt (e.g., tosylate salt) particles may have a D10 ranging from about 1 µm to about 20 µm, or from about 1 µm to about 15 µm, or from about 5 µm to about 10 µm. A salt of Compound 1 can be prepared into a pharmaceutical composition, for example, by adding one or more excipients and performing other processing steps. Standard pharmaceutical formulation techniques can be used, such as those described in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), the entire contents of which are incorporated herein by reference. In addition to Compound 1 salts, embodiments include compositions containing a pharmaceutically acceptable carrier or other excipient. As used herein, the term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler diluents or encapsulating substances that are suitable for administration to a mammal. As used herein, the term "compatible" means that the components of the composition are capable of mixing with the subject Compound 1 salt and with each other, such that, under normal use, there are no interactions that would significantly reduce the efficacy of the composition. Of course, a pharmaceutically acceptable carrier must be of sufficiently high purity and sufficiently low toxicity to make it suitable for administration, preferably to an animal, preferably a mammal to be treated. Suitable excipients are described in the Handbook of Pharmaceutical Excipients (Rowe, Ed., APhA Publications, 2017). Excipients are either intragranular (i.e., incorporated within the granules) or extragranular (i.e., incorporated outside the granules). Some examples of substances that can be used as pharmaceutically acceptable excipients, carriers, or components thereof are dicalcium phosphate, calcium sulfate, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, and methylcellulose; kaolin, powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid, magnesium stearate, and calcium stearate; calcium sulfate; mineral oil; vegetable oils such as hydrogenated vegetable oil, peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa oil; polyols such as propylene glycol, glycerol, sorbitol, inositol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as TWEENS; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers, antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffered solution. The choice of pharmaceutically acceptable carrier for use in conjunction with the subject compounds is essentially determined by the mode of administration of the compound. Compound 1 salts described herein can be provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to an animal, preferably a mammalian subject, in a single dose according to good medical practice. However, the preparation of a single or unit dosage form does not imply that the dosage form is administered once a day or once per course of treatment. It is expected that such dosage forms will be administered once, twice, three times, or more daily and may be administered as an infusion over a period of time (e.g., about 30 minutes to about 2-6 hours), or, although single administration is not specifically excluded, may be administered as a continuous infusion and may be administered more than once during the course of treatment. Those skilled in the art will appreciate that the formulation does not specifically contemplate an entire course of treatment, and that these are determined by those skilled in the art, not the formulation. The useful compositions described above can be in any of a variety of suitable forms for a variety of administration routes, for example, for oral, nasal, rectal, topical (including transdermal), ophthalmic, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular or other parenteral administration routes. Those skilled in the art will appreciate that oral and nasal compositions include compositions administered by inhalation and are prepared using available methods. Depending on the desired individual administration route, various pharmaceutically acceptable carriers known in the art can be used. For example, pharmaceutically acceptable carriers include solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating materials. Optional pharmaceutically active substances that do not substantially interfere with the inhibitory activity of the compound may be included. The amount of carrier used in conjunction with the compound is sufficient to provide the actual amount of material administered per unit dose of the compound. Techniques and compositions for preparing dosage forms for use in the methods described herein are described in the following references, all of which are incorporated herein by reference: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004). A variety of oral dosage forms can be used, including solid forms such as pills, tablets, cores, capsules, caplets, granules, suspensions, nanosuspensions, and bulk powders. Tablets can be compressed, tablet milled, enteric-coated, sugar-coated, film-coated, or multi-compressed, containing suitable binders, fillers, lubricants, diluents, disintegrants, colorants, flavorings, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent dosage forms reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavorings, or any combination thereof. Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art. Tablets generally contain one or more conventional pharmaceutically compatible adjuvants as inert diluents or fillers, such as inorganic salts (e.g., calcium carbonate, calcium phosphate, calcium sulfate, sodium carbonate), sugar alcohols (e.g., xylitol, sorbitol, mannitol, maltitol), sugars (e.g., sucrose, glucose, molasses, lactose), and cellulose, or the like or a combination thereof; binders such as starch, gelatin, sugars (e.g., sucrose, glucose, molasses, lactose), sugar alcohols (e.g., xylitol, sorbitol, mannitol, maltitol), and cellulose, or a combination thereof; ), natural and synthetic gums (acacia, alginic acid, sodium alginate, Irish moss extract, panwort gum, gati gum, cellulose, microcrystalline cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose (HPMC or hydroxypropyl methylcellulose), methylcellulose, ethylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose (croscarmellose sodium), polyvinyl pyrrolidone (PVP), Veegum® (magnesium aluminum silicate), arabinogalactan, proteins, and polymers, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose), tragacanth gum, polyvinyl alcohol, polymethacrylate and polyethylene glycol (PEG), and combinations thereof; disintegrants such as sugars, starches, modified starches, alginic acid, cross-linked polymers, sodium starch glycolate, polyvinyl pyrrolidone and cross-linked carboxymethyl cellulose, or combinations thereof; lubricants such as calcium stearate, magnesium stearate, stearic acid, glyceryl behenate, mineral oil, hydrogenated vegetable oil, polyethylene glycol, sodium lauryl sulfate, glyceryl palmitostearate, sodium benzoate, sodium stearyl fumarate, Silicon dioxide and talc. Glidants such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. Colorants such as FD&C dyes can be added for appearance. Sweeteners and flavorings, such as aspartame, saccharin, menthol, mint, and fruit flavorings, are useful adjuvants for chewable tablets. Capsules typically contain one or more solid diluents of the invention described above. The choice of carrier component depends on secondary considerations such as taste, cost, and storage stability, which are not important and can be prepared by one of ordinary skill in the art. Oral compositions also include liquid solutions, emulsions, suspensions, and the like. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL, RC-591, gum tragacanth, and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more components, such as sweeteners, flavorings, and coloring agents as described above. Such compositions may also be coated by conventional methods, typically using a pH or time-dependent coating, so that the subject compound is released in the gastrointestinal tract near the desired local application, or at different times to prolong the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethylcellulose, Eudragit® (derived from a copolymer of acrylic acid and methacrylate) coating, wax, and shellac. The compositions described herein may optionally contain other secondary pharmaceutically active substances other than salts of Compound 1. Other compositions for achieving systemic delivery of the subject compounds include sublingual, buccal, and nasal dosage forms. These compositions typically contain one or more soluble fillers, such as sucrose, sorbitol, and mannitol, and binders, such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. They may also contain glidants, lubricants, sweeteners, colorants, antioxidants, and flavorings as described above. Liquid compositions can be formulated so that they can be administered topically to the eye. While formulation considerations (e.g., drug stability) may sometimes necessitate less than optimal comfort, comfort should be maximized whenever possible. Where maximization of comfort is not possible, the liquid should be formulated so that it is tolerable for topical ophthalmic use by the patient. Ophthalmologically acceptable liquids should be packaged for single use or contain a preservative to prevent contamination from repeated use. For ophthalmic applications, physiological saline solutions are typically used as the primary carrier to prepare solutions or medications. Ophthalmic solutions should preferably be maintained at a comfortable pH using an appropriate buffer system. Such preparations may also contain conventional pharmaceutically acceptable preservatives, stabilizers, and surfactants. Preservatives that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. For example, a useful surfactant is Tween® 80 (polyoxyethylene (20) sorbitan monooleate). Similarly, various useful carriers can be used in the ophthalmic dosage forms of the present invention. Such carriers include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethylcellulose, strong ethyl cellulose, and purified water. A tonicity adjusting agent may be added as needed or convenient, including, but not limited to, salts, particularly sodium chloride, potassium chloride, mannitol, and glycerol, or any other suitable ophthalmologically acceptable tonicity adjusting agent. Various buffers and means for adjusting pH can be used, so long as the formulation is ophthalmologically acceptable. For many compositions, the pH is between 4 and 9. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases can be used to adjust the pH of these formulations as needed. Similarly, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Other excipient components that may be included in ophthalmic dosage forms are chelating agents. A useful chelating agent is edetate disodium, but other chelating agents may also be used in combination with it. For topical use, creams, ointments, gels, solutions or suspensions containing the salts of Compound I of the present invention are used. Topical formulations may generally include a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system and emollient. For intravenous administration, the compounds and compositions described herein can be dissolved or dispersed in a pharmaceutically acceptable diluent, such as saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sodium sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates, such as glucose, mannitol, and dextran. Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332 describe additional acceptable excipients, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to obtain a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol. Compositions for intravenous administration can be provided to the caregiver as one or more solid forms that are reconstituted in water with a suitable diluent (e.g., sterile water, saline, or dextrose) shortly before administration. In other embodiments, the compositions are provided as solutions ready for parenteral administration. In further embodiments, the compositions are provided as solutions that are further diluted prior to administration. In embodiments comprising administering a combination of a compound described herein and another agent, the combination can be provided to the caregiver as a mixture, or the caregiver can mix the two agents prior to administration, or the two agents can be administered separately. The actual dosage of the active compounds described herein depends on the specific compound and the condition to be treated; selection of the appropriate dosage is well within the knowledge of one of ordinary skill in the art. In any embodiment of the methods or kits described herein, the effective daily amount of a Compound 1 salt is from about 1 mg to about 5000 mg per day, from about 5 mg to about 2500 mg per day, or from about 10 mg to about 2000 mg per day, calculated as the free base. In some other embodiments, the amount of a Compound 1 salt administered is from about 25 mg to about 1600 mg per day, calculated as the free base. In some other embodiments, the amount of a Compound 1 salt administered is from about 25 mg, about 75 mg, about 200 mg, about 275 mg, about 400 mg, about 550 mg, about 575 mg, about 800 mg, about 1150 mg, or about 1600 mg per day, calculated as the free base, or within a range defined by any two of the foregoing values. Solid compositions, including solid dosage forms and oral solid dosage forms, such as tablets and capsules, are particularly contemplated. Such compositions can be made from or include granules containing a salt of Compound 1, for example, by wet granulation, fluidized bed granulation, compression granulation, or extrusion spheronization. Given the hygroscopic nature of Compound 1 salts, dry granulation methods and dry granulated compositions are particularly contemplated. Examples include anhydrous wet granulation (e.g., using ethanol as a binder solvent), anhydrous fluidized bed granulation, and compression granulation (e.g., by using a press or roller compaction). Tablets can also be made by direct compression. The pharmaceutical composition, granule, or dosage form may suitably include a polymerization inhibitor. The polymerization inhibitor includes cellulose acetate phthalate, carbomer, ethylcellulose, Eudragit®, alginic acid, gum arabic, locust bean gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (e.g., Methocel® K15M), hydroxypropylmethylcellulose succinate acetate, hydroxypropylmethylcellulose phthalate, methylcellulose, methyl 2-hydroxyethylcellulose, poly(acrylic acid), polyallylamine hydrochloride, poly(acrylamide-co-acrylic acid), polydiallyldimethylammonium chloride, polyethyleneimine, P-EPE, poly(2-ethyl-2-oxazoline), polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, or any combination thereof. Hydrophobic polymers are contemplated. Celluloses are particularly contemplated, such as cellulose acetate phthalate, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose succinate acetate, hydroxypropylmethylcellulose phthalate, methylcellulose, and methyl 2-hydroxyethylcellulose. Preferred are monohydroxypropylmethylcelluloses having a 2% solution viscosity in the range of about 13,000 to about 25,000 mPa·s at 20°C, such as Methocel® K15M. The polymeric precipitation inhibitor (e.g., HPMC) can be present in an external region of the dosage form, such as in an outer layer, outer coating, or as an extragranular component. The polymeric precipitation inhibitor (e.g., HPMC) is present in an amount effective to inhibit the precipitation of Compound I, compared to a composition omitting the polymeric precipitation inhibitor. For example, the polymeric precipitation inhibitor (e.g., HPMC) can be present in the dosage form in an amount of at least 0.1 wt.%, or at least 0.2 wt.%, or at least 0.5 wt.%, and can be present in an amount of up to 50 wt.%, or 40 wt.%, or 30 wt.%, or 20 wt.%, or 10 wt.%, or 5 wt.%, or 3 wt.%, for example, within the range of 0.5 wt.% to 5 wt.%. In some embodiments, the polymeric precipitation inhibitor (e.g., HPMC) is present in the dosage form in an amount of about 0.5 wt.%. For example, granules containing a salt of Compound I (e.g., toluenesulfonic acid) may contain a binder (e.g., microcrystalline cellulose), a filler (e.g., lactose), and a disintegrant (e.g., croscarmellose sodium). The granules may further contain a lubricant (e.g., magnesium stearate). Tablets or other dosage forms containing such granules may further contain an extragranular polymerization precipitation inhibitor (e.g., hydroxypropyl methylcellulose). The extragranular portion of the dosage form may contain, for example, a binder (e.g., microcrystalline cellulose). The extragranular portion of the dosage form may further contain, for example, a disintegrant (e.g., croscarmellose sodium). The extragranular portion of the dosage form may further contain a lubricant (e.g., magnesium stearate). The extragranular portion of the dosage form may contain a combination of excipients, such as a disintegrant, a lubricant, a binder, or any combination thereof. For example, the extragranular portion of the dosage form may contain a disintegrant and a binder, a lubricant, or an polymerization precipitation inhibitor. The oral dosage form can have any suitable strength, for example, within the range of 1 mg to 2000 mg, or 10 mg to 1000 mg, or 25 mg to 400 mg, or 100 mg to 300 mg of a salt (e.g., a tosylate salt) of Compound 1. In another class of embodiments, the oral dosage form can have a strength defined based on the free base of Compound 1, for example, within the range of 1 mg to 2000 mg, or 10 mg to 1000 mg, or 25 mg to 400 mg, or 100 mg to 300 mg of the free base of Compound 1. The pharmaceutical composition (e.g., granules, tablets, capsules) can include granules having various ratios of Compound 1 salt (e.g., tosylate) and excipients. For example, a granule can have about 30 wt% to about 40 wt% of Compound 1 tosylate, about 40 wt% to about 45 wt% of a binder, about 10 wt% to about 20 wt% of a filler, and about 0.5 wt% to about 5 wt% of a disintegrant. The granule can further contain about 0.5% to about 5% of a lubricant. For example, the granules may comprise a salt of Compound 1, microcrystalline cellulose, lactose, sodium carboxymethylcellulose, and magnesium stearate. The granules may further comprise one or both of extragranular sodium starch glycolate and hydroxypropyl methylcellulose. The granules may further comprise extragranular magnesium stearate. The pharmaceutical composition (e.g., granules, tablets, capsules) may comprise any salt of Compound I. In one class of embodiments, the salt is amorphous monoHBr, a crystalline monoHBr, a crystalline diHBr, amorphous monoHCl, a crystalline monoHCl, a crystalline diHCl, amorphous mononitrate, a crystalline mononitrate, amorphous monosulfate, a crystalline monosulfate, a benzenesulfonate, a hemi-edisylate, a hemi-naphthalenedisulfonate, a monotoluenesulfonate, or a ditoluenesulfonate. In another class of embodiments, the salt is amorphous monoHBr, a crystalline monoHBr, a crystalline diHBr, a crystalline diHCl, amorphous mononitrate, a crystalline mononitrate, amorphous monosulfate, a crystalline monosulfate, a crystalline monosulfate, a benzenesulfonate, a hemi-edisylate, a hemi-naphthalenedisulfonate, a monotoluenesulfonate, or a ditoluenesulfonate. In another class of embodiments, the salt is amorphous monoHBr, crystalline monoHBr, crystalline diHBr, amorphous mononitrate, crystalline mononitrate, amorphous monosulfate, crystalline monosulfate, benzenesulfonate, hemi-edisylate, hemi-naphthalenedisulfonate, monotoluenesulfonate, or ditoluenesulfonate. In another class of embodiments, the salt is a sulfate, dihydrobromide, nitrate, benzenesulfonate, hemi-edisylate, hemi-naphthalenedisulfonate, monotoluenesulfonate, or ditoluenesulfonate. In another class of embodiments, the salt is a monotoluenesulfonate or ditoluenesulfonate. In another class of embodiments, the salt is a non-HCl salt. The pharmaceutical composition may also be a suspension, such as a nanosuspension, comprising Compound I free base. The particle size of the Compound I free base can be of any desired scale, for example, nanoscale, for example, in the range of 1 nm to 1000 nm. In some embodiments, the particle size (D90) of the Compound I free base is between 1 nm and 1000 nm, 1 nm and 900 nm, 1 nm and 800 nm, 1 nm and 700 nm, 1 nm and 600 nm, 1 nm and 500 nm, 1 nm and 400 nm, 1 nm and 300 nm, 1 nm and 200 nm, 1 nm and 100 nm, 1 nm and 50 nm, or 1 nm and 10 nm, as measured by dynamic light scattering or optical diffraction analysis. The following description is provided for a nanosuspension, but other particle sizes may also be used in the formulation. The nanosuspension may include a carrier. Water is a suitable carrier. The water may be sterilized and optionally deionized. The nanosuspension may contain a polymeric additive to stabilize the suspension. For example, suitable polymers include polyvidone (PVP), methylcellulose, hydroxypropylcellulose, and HPMC. A polymer may also be used to inhibit crystal growth. Other suspension stabilizers include gums, sorbitol, glycerol, polyvinyl alcohol, ethylene oxide, and other cellulose derivatives, including other cellulose alkyl ethers, such as ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, and combinations thereof. The nanosuspension may include a surfactant. A surfactant can be used to improve the stability of the suspension by modifying the surface tension, thereby reducing the interfacial tension between successive dispersions of the nanosuspension. Surfactants can be selected from anionic, nonionic, cationic, and amphoteric surfactants. In one embodiment, the surfactant comprises a nonionic surfactant. For example, a nonionic surfactant can be selected from one or more ethoxylates (e.g., fatty alcohol ethoxylates, alkylphenol ethoxylates, fatty acid ethoxylates) and fatty acid esters of polyols (e.g., fatty acid esters of glycerol, fatty acid esters of sorbitol), including sorbitan esters, ethoxylated sorbitan and fatty acids, polyoxyethylene alkylphenols, polyoxyethylene alcohols, polyoxyethylene esters of fatty acids, polyoxyethylene thiols, polyoxyethylene alkylamines, and nonyl-phenoxy-polyethoxyethanol. In another embodiment, the surfactant is ionic. For example, the ionic surfactant can include one or more of sodium lauryl sulfate (SDS, also known as sodium lauryl sulfate), cetyl phosphate, Aerosol-OT, and hydroxyepimethylcellulose acetate succinate. Chemical instability has been found in nanosuspensions containing polysorbate 80. Without wishing to be bound by any particular theory, it is believed that the instability is caused by an oxidative mechanism. Therefore, preferably, the surfactant has a low or no peroxide content (e.g., ultrapure polysorbate 80), or an alternative surfactant that does not contain peroxides, such as SDS. In one embodiment, the nanosuspension comprises a polymer stabilizer and a surfactant. For example, the nanosuspension may comprise a non-ionic polymer (e.g., HPMC) and an ionic surfactant (e.g., SDS). When a surfactant is added to the composition, it is present in an amount from about 0.1 wt.% to about 4.0 wt.% or from about 0.5 wt.% to about 2.0 wt.%. The nanosuspension may further comprise other optional excipients including pH adjusters or regulators (eg, buffers), preservatives to prevent the growth of microorganisms, taste masking agents, sweeteners, and flavoring agents. The reagent used to adjust the pH of the nanosuspension may include, for example, potassium acetate, sodium acetate, acetic acid, adipic acid, boric acid, citric acid, hydrochloric acid, fumaric acid, malic acid, nitric acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, potassium bicarbonate, sodium bicarbonate, ammonium carbonate, sodium carbonate, potassium citrate, sodium citrate, diethanolamine, ammonium phosphate, potassium phosphate, sodium phosphate, ammonium glycolate, ammonium hydroxide, sodium hydroxide, sodium lactate or sodium propionate, or a mixture thereof. Preservatives suitable for pharmaceutical compositions, such as those for oral use, are well known in the art and can be selected from, for example, benzoic acid, sodium benzoate, potassium benzoate, parabens (e.g., methylparaben), ethylparaben, propylparaben and butylparaben, sorbic acid and potassium sorbate, or mixtures thereof. In one embodiment, the preservative is selected from sodium benzoate, methylparaben, ethylparaben, propylparaben or a combination thereof. It is contemplated that a dosage form, optionally an oral dosage form, may be prepared by including the nanosuspension in a dosage form, for example, a solid oral dosage form, such as a granule and / or a tablet. The oral dosage form may be prepared by a process comprising drying the nanosuspension. In one embodiment, the process comprises: (a) granulating the nanosuspension to form a granulated nanosuspension; (b) adding mannitol to the granulated nanosuspension prepared in step (a) to form a nanosuspension mixture; (c) spraying the nanosuspension mixture prepared in step (b) onto a fluidized bed filled with microcrystalline cellulose to form a nanosuspension wet blend; (d) drying the nanosuspension wet blend by increasing the temperature of the fluidized bed to above 40° C. to form a nanosuspension dry blend; and (e) milling the nanosuspension dry blend to form nanosuspension particles. The nanosuspension particles are optionally compressed into a dosage form (e.g., a tablet or troche). For example, the particles can have a particle size D50 in the range of about 100 μm to about 170 μm, or about 130 μm to about 140 μm, or about 135 μm. The pharmaceutical formulations described herein can be prepared by any suitable process, including those known in the art. The process may include a size modification step, for example, milling to obtain a desired particle size of the compound or salt or solvate thereof, for example, a particle size described herein. The process may also include a size selection step, for example, screening to obtain a desired particle size range or threshold. One or more excipients may also be screened to a desired particle size range or threshold. The dry ingredients may be blended together and mixed with a lubricant. The composition of the active substance and excipient may be compressed. Alternatively, the compressed mixture may be milled to obtain particles having a desired particle size. Extragranular excipients may be added and mixed with the milled mixture. Optionally, an extragranular lubricant may also be used. The resulting mixture of particles and extragranular excipients may be compressed into tablets. For example, a process comprises (a) sieving a Compound I salt, a binder, a filler, and a disintegrant; (b) blending the sieved ingredients to form a first mixture; (c) further blending the first mixture with a lubricant to form a second mixture; (d) compressing the second mixture; (e) milling the compressed second mixture; (f) blending the milled second mixture with an extragranular disintegrant and an extragranular binder to form a third mixture; (f) blending the third mixture with an extragranular lubricant to form a fourth mixture; and (g) compressing the fourth mixture to form tablets. In any such process, the active substance is a tosylate salt of Compound I, e.g., the monotosylate salt. Also contemplated are methods for treating a fibrotic disorder comprising administering a pharmaceutically effective amount of a salt of Compound 1 (e.g., a tosylate salt) or a pharmaceutical composition thereof as described herein. In some such embodiments, the method further comprises identifying a subject as having or at risk for the fibrotic disorder. In some such embodiments, the fibrotic disorder is selected from the group consisting of pulmonary fibrosis, skin fibrosis, pancreatic fibrosis, liver fibrosis, and renal fibrosis. In some embodiments, the fibrotic disorder is idiopathic pulmonary fibrosis. In some embodiments, the subject receiving the treatment method is a human. As used herein, "treating" refers to administering a compound or pharmaceutical composition to a subject for preventive and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of a disease or condition but is susceptible to or at risk for a particular disease or condition, thereby reducing the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to treating a subject who already has a disease or condition. "Fibrotic condition," "fibroproliferative condition," "fibrotic disease," "fibroproliferative disorder," "fibrotic disease," and "fibrotic disorder" are used interchangeably to refer to a condition, disease, or disorder characterized by dysregulated proliferation or activity of fibroblasts and / or abnormal accumulation of fibronectin and / or pathological or excessive accumulation of collagenous tissue. Generally, any such disease, condition, or disorder is amenable to treatment by administration of a compound having anti-fibrotic activity. Fibrotic disorders include, but are not limited to, pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis of known etiology, skin fibrosis, pancreatic fibrosis, liver fibrosis (e.g., liver fibrosis associated with chronic active hepatitis), and renal fibrosis. In other embodiments, the disease or condition to be treated may include pulmonary fibrosis, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, autoimmune lung disease, benign prostatic hypertrophy, coronary artery or myocardial infarction, atrial fibrillation, cerebral infarction, myocardial fibrosis, musculoskeletal fibrosis, postoperative adhesions, cirrhosis, renal fibrosis, fibrotic vascular disease, scleroderma, Hermansky-Pudlak syndrome, neurofibromatosis, Alzheimer's disease, diabetic retinopathy, and / or skin lesions, HIV-associated lymph node fibrosis, chronic obstructive pulmonary disease (COPD), and / or pulmonary fibrosis. COPD), inflammatory pulmonary fibrosis, rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; Gram-negative sepsis; toxic shock syndrome; myofascial pain syndrome (MPS); bacillary dysentery; asthma; adult respiratory distress syndrome; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; glomerulonephritis; scleroderma; chronic thyroiditis; Grave's disease; Ormond's disease; autoimmune gastritis; myasthenia gravis; autoimmune hemolytic anemia; autoimmune neutrophiliasis Cytopenia; thrombocytopenia; pancreatic fibrosis; chronic active hepatitis, including hepatic fibrosis; acute and chronic kidney disease; renal fibrosis, irritable bowel syndrome; febrile illness; restenosis; cerebral malaria; stroke and ischemic injury; neurotrauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergies, including allergic rhinitis and allergic conjunctivitis; myocardial hypertrophy, chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Rett's syndrome; acute synovitis; muscle degeneration, bursitis; myosinitis; tenosynovitis; herniation , ruptured or prolapsed intervertebral disc syndrome; osteopetrosis; thrombosis; silicosis; pulmonary edema; bone resorption diseases, such as osteoporosis or multiple myeloma-related bone disease; cancer, including but not limited to metastatic breast cancer, colorectal cancer, malignant melanoma, gastric cancer and non-small cell lung cancer; graft-versus-host disease; and autoimmune diseases, such as multiple sclerosis, lupus and fibromyalgia; HIV and other viral diseases, such as herpes zoster, herpes simplex I or II, influenza virus, severe acute respiratory syndrome (SARS) and cytomegalovirus; and diabetes.In addition, the methods of these embodiments can be used to treat proliferative diseases (including benign and malignant proliferations), including acute myeloid leukemia, chronic myeloid leukemia, Kaposi's sarcoma, metastatic melanoma, multiple myeloma, breast cancer (including metastatic breast cancer); colorectal cancer; malignant melanoma; gastric cancer; non-small cell lung cancer (NSCLC); bone metastasis, etc.; pain disorders, including neuromuscular pain, headache, cancer pain, toothache and arthritis pain; angiogenesis disorders, including solid tumor angiogenesis, ocular neovascularization and infantile hemangioma; disorders related to cyclooxygenase and lipoxygenase signaling pathways, including disorders related to prostaglandin endoperoxide synthase-2 (including edema, fever, analgesia and pain); organ hypoxia; thrombin-induced platelet aggregation; and protozoal diseases. In some embodiments, the subject is a human. As used herein, the term "therapeutically effective amount" refers to an amount of a compound sufficient to cure, ameliorate, slow the progression of, prevent, or reduce the likelihood of occurrence of a known disease or condition, or to exhibit a detectable therapeutic, preventive, or inhibitory effect. For example, such effects can be detected by the following illustrative experiments. The precise effective amount for a subject depends on the subject's body weight, weight, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically and prophylactically effective amount for a given situation can be determined through routine experimentation within the skill and judgment of the clinician. Also contemplated is the use of a therapeutically effective amount of a salt of Compound 1 as described herein (e.g., a tosylate salt) or a pharmaceutical composition thereof in the preparation of a medicament for treating a fibrotic disorder. In some such embodiments, the use further comprises identifying a subject as having or at risk for the fibrotic disorder. In some such embodiments, the fibrotic disorder is selected from the group consisting of pulmonary fibrosis, skin fibrosis, pancreatic fibrosis, liver fibrosis, and renal fibrosis. In some embodiments, the fibrotic disorder is idiopathic pulmonary fibrosis. In some embodiments, the subject receiving the treatment is a human. In another aspect, a package or kit according to the methods or uses described herein is provided, comprising a salt of a compound described herein (e.g., a tosylate salt) or a pharmaceutical composition thereof, optionally in a container, and a package insert, package label, instructions, or other labeling. It should be understood that the present invention provides a Compound 1 salt (e.g., a tosylate salt) or a pharmaceutical composition thereof as described herein for use in administering a Compound 1 salt (e.g., a tosylate salt) or a pharmaceutical composition thereof as described herein, according to the methods described above with respect to the present invention, to treat a patient suffering from a disease or condition described herein, or a patient who would benefit from administration of the compound according to any treatment regimen. The Compound 1 salt (e.g., a tosylate salt) or a pharmaceutical composition thereof as described herein is packaged and presented for use in treating a patient suffering from a disease or condition described herein (e.g., idiopathic pulmonary fibrosis), or a patient who would benefit from administration of the compound according to such treatment regimen. The Compound 1 salt (e.g., a tosylate salt) or a pharmaceutical composition thereof as described herein is administered to the patient according to the above treatment regimen. It will be understood that the present invention provides for the use of a Compound 1 salt (e.g., a tosylate salt) or a pharmaceutical composition thereof as described herein in the manufacture of a medicament for treating a patient suffering from a disease or condition described herein (e.g., idiopathic pulmonary fibrosis) or a patient who would benefit from administration of the compound according to any of the treatment regimens described in connection with any of the methods. The medicament manufactured according to this aspect of the invention is used to treat a patient suffering from a disease or condition described herein (e.g., idiopathic pulmonary fibrosis) or a patient who would benefit from administration of a compound according to such treatment regimens. The medicament so manufactured is administered to the patient according to the treatment regimens described above. With respect to the present invention, the present invention relates to a salt of Compound I (e.g., a tosylate salt) or a pharmaceutical composition thereof (for treating a patient) and a salt of Compound I (e.g., a tosylate salt) or a pharmaceutical composition thereof for use in treating a patient as described herein, and the preferred embodiments of each aspect of the present invention relate to methods of administering these compounds to treat a patient, and the same applies. Examples The following examples are provided to illustrate but not to limit the scope of the present invention. Examples 1- Salt screening The calculated pKa value of Compound I free base (ACD Labs pKa DB, v10.0) was 2.12 ± 0.33. Therefore, Compound I free base is considered a very weak base that can be protonated by strong acids. The experimentally determined pKa value was 2.5. Analysis of a sample of Compound I free base by powder X-ray diffraction revealed that it was crystalline, without any readily detectable amorphous content. Mass loss due to decomposition was observed at temperatures above 220°C, but thermogravimetric analysis revealed no other characteristic features, except for a small mass loss of approximately 0.1% below 220°C. This indicates that the crystalline form of Compound I free base is neither a solvate nor a hydrate. Hygroscopic properties of the crystalline form of Compound I free base revealed a maximum water uptake of less than 0.1% at 95% relative humidity. This suggests that the crystalline form of Compound I free base is non-hygroscopic and that the amount of water adsorbed is very small. DSC analysis revealed a single melting peak at 293.4°C (onset temperature). A screening process was performed on salts of Compound 1, which salts included salts and cocrystal formers adipic acid, benzenesulfonic acid, citric acid, ethanedisulfonic acid, fumaric acid, glutaric acid, ethanolamide, hydrobromic acid, hydrochloric acid, L-lactamide, L-malic acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic acid, nicotinic acid, nitric acid, oxalic acid, phosphoric acid, saccharin, sorbic acid, succinic acid, sulfuric acid, L-tartaric acid, urea and p-toluenesulfonic acid. As an initial experiment, 18 forms (including two HCl charge ratios) and four solvent systems were used in 76 conditions in the first stage screening. These results are summarized in Table 1. Since gels were produced in most of the screening experiments, a second stage screening was performed at 5 °C using five strong acids (including two HCl charge ratios) and two different solvent systems, for a total of 12 conditions. These results are summarized in Table 2. From all screening experiments, crystalline hits were isolated and characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Salt stoichiometry was determined using proton nuclear magnetic resonance (1H NMR) or HPLC combined with ion chromatography (IC). A hemi-THF solvate of the free base was also identified. Table 1 Table 2 Disperse approximately 15 mg of the free base in the chosen solvent in a glass vial, and add the corresponding acid at a 1:1 molar charge ratio (for HCl, two ratios, 1:1 and 2:1, were used to account for the presence of two basic groups in the free radical). Stir the free base and acid mixture at room temperature for 4 days. Transfer the clear solution to a slurry at 5°C for 3 days, and allow the cooled final clear solution to evaporate slowly at room temperature. Isolate the solids from each step and analyze them by XRPD. A large number of experiments from the first screening stage resulted in gel formation. Therefore, a second screening stage experiment was performed using five strong acids and two different solvents at 5° C. A total of five crystallization hits were observed. A stock solution of Compound I free base in 9:1 methanol-dichloromethane was prepared. An aliquot of the stock solution was transferred to each well of a microtiter plate, and then an aliquot of the acid stock solution was added to each well. The mixture was subjected to each of eight different experimental conditions: evaporation of the solvent from the initial solvent mixture under nitrogen, equilibration of the suspension in acetonitrile, equilibration of the suspension in ethanol, equilibration of the suspension in ethyl acetate, equilibration of the suspension in ethyl acetate-dichloromethane, equilibration of the suspension in 1:1 heptane-THF, equilibration of the suspension in isopropanol, equilibration of the suspension in 4:1 methanol-water, and equilibration of the suspension in 9:1 Twelve different acids were screened under eight different conditions; i.e., 96 experiments were performed. From these initial solvent mixtures, the solvent was evaporated at room temperature under a slight stream of nitrogen. For the suspension equilibration condition, the suspension was equilibrated at 25°C for two days, and then the added solvent was evaporated again under a slight stream of nitrogen. A solid residue was obtained within approximately 18 hours and examined by Raman microscopy. Compound I's benzenesulfonate (benzenesulfonic acid), edisylate (edisyl acid), 1,5-naphthalenedisulfonate (naphthalenedisulfonic acid), and p-toluenesulfonic acid (toluenesulfonic acid) salts were also prepared. These salts were prepared by evaporation from a solvent (e.g., methanol-dichloromethane 1:1, ethyl acetate-dichloromethane 1:2, isopropanol, etc.) of the free base and acid using a similar protocol as described above. If necessary, the amorphous salts produced in this manner were crystallized by stirring the amorphous material in an appropriate solvent (e.g., ethyl acetate, acetonitrile, etc.). The solid residues were characterized by 1H-NMR spectroscopy, X-ray diffraction, TG-FTIR, DVS, DSC, and water solubility at 25°C. 1H-NMR analysis indicated a 2:1 free base:acid stoichiometry for the naphthalenedicarboxylate and edisylate salts; for the edisylate and edisylate salts, these salts are therefore more appropriately referred to as heminaphthalate and hemiglycolate salts, respectively. In several experiments, a crystalline form identical to the free base of the compound was observed (Form A, Figure 1). This form is quite stable and exhibits a stronger tendency to crystallize than any of the salts or cocrystal systems studied. Although crystalline forms were obtained using systems containing strong acids, namely hydrobromic, hydrochloric, nitric, and sulfuric acids, many of the resulting samples were primarily amorphous. Table 3 shows the solubility data for the salt of Compound I after one hour in pure water at 25°C and after a 24 hour equilibration period (not all samples). PXRD measurements of the solid residue after the solubility test showed that conversion to the free base typically occurred within 1 hour. Table 3 In Table 4 below, some of the chemical properties of the free base and amorphous salt forms are given. Table 4 In Table 5 below, some of the chemical properties of the crystalline salt forms are given. Table 5 The sulfate salt exhibited good thermal stability and was further characterized by a distinct melting point in the region of 170°C to 180°C. Due to the low residual solvent content of the obtained sample, it was produced in a crystalline form that was easily dried. The particle size distribution and crystal habit were found to be acceptable. All produced salts showed enhanced water solubility; however, none of the solid salt forms investigated in this example were stable in the aqueous phase. PXRD measurements of the solid residues after solubility testing showed that conversion to the free base typically occurred within 1 hour. All resulting salts, whether amorphous or crystalline, at least partially deliquesce at relative humidity above about 75%. These salts should be stored at low relative humidity (preferably below 50%) in airtight containers to prevent water absorption. In addition, wet granulation with aqueous solvents should be avoided. Examples 2- Compound I hydrochloride Aqueous HCl (1.1 equivalents) was added to a solution of the free base of Compound I in dioxane. After stirring for 0.5 h, the solvent was removed under reduced pressure and the residue was dried under vacuum to afford the hydrochloride salt of Compound I. The identity of the hydrochloride salt was confirmed by H-NMR spectroscopy, Raman spectroscopy, and elemental composition analysis. H-NMR and TG-FTIR analysis indicated that the sample contained a significant amount of ethyl acetate, and the theoretically expected content was adjusted to account for this observation. An ethyl acetate solvate was suspected. Water sorption measurements of the hydrochloride salts showed that both studied salts strongly adsorbed water at high relative humidity. The amorphous salt had a maximum water uptake of approximately 40%, while the crystalline dihydrochloride had a higher maximum water uptake of approximately 54%. Examples 3- Compound I hydrobromide The amorphous monohydrobromide salt of Compound I was prepared by dissolving the free base in a 2:1 mixture of methanol and dichloromethane and adding 1 equivalent of HBr in the form of an aqueous HBr solution. The solvent was removed by rotary evaporation at 40°C to yield a solid white residue. The residue was further dried under vacuum at 40°C. The crystalline hydrobromide salt is obtained by suspension equilibrium in ethyl acetate. Using two equivalents of HBr facilitates crystallization. To approximately 200 mg of the free base in 2.0 ml of ethyl acetate is added two equivalents of HBr, followed by a 33% w / w HBr solution in acetic acid. After stirring at room temperature, the salt begins to crystallize, yielding a white powder that is easily handled. The properties of the hydrobromide salt were confirmed by H-NMR spectroscopy, Raman spectroscopy, and elemental composition analysis. The powder X-ray diffraction pattern of the hydrobromide salt sample was found to show considerable changes. Water sorption measurements of the hydrobromide salts showed that both studied salts strongly adsorbed water at high relative humidity. The amorphous salt had a maximum water uptake of approximately 29%, while the crystalline dihydrobromide salt had a maximum water uptake of approximately 47%. Visual inspection of both samples after DVS testing revealed a slightly brownish discoloration that had deliquesced during the measurement. Examples 4- Compound I sulfate The sulfate salt is produced as a monosalt; therefore, the term bisulfate is more accurate; however, for simplicity, this salt will generally be referred to herein as the sulfate salt. The amorphous sulfate salt is prepared by dissolving Compound I free base in a 2:1 mixture of methanol and dichloromethane and adding 1 equivalent of sulfuric acid (95%-97% concentrated). The solvent is removed from the clear solution by rotary evaporation at 40°C, yielding a solid white residue. This residue is further dried under vacuum at 40°C for approximately 18 hours. The crystalline sulfate salt is produced by equilibrating the amorphous salt form in ethyl acetate. The characteristics of sulfate were confirmed by H-NMR spectroscopy, Raman spectroscopy, and elemental composition analysis. Water sorption measurements of the sulfate salts showed that both studied salts strongly adsorbed water at high relative humidity. The amorphous salt had a maximum water uptake of approximately 33%, while the crystalline salt had a maximum water uptake of approximately 35%. Examples 5- Compound I Nitrates The amorphous nitrate salt of Compound I free base was prepared by dissolving it in a mixture of methanol and dichloromethane (approximately 2:1) and adding one equivalent of 70% aqueous nitric acid. The solvent was removed from the clear solution by rotary evaporation at 40°C, yielding a solid white residue. This residue was further dried under vacuum at 40°C for approximately 18 hours. When the amorphous nitrate salt was suspended in ethyl acetate, it spontaneously crystallized. The dried solid was essentially free of residual ethyl acetate. The characteristics of the crystalline nitrate were confirmed by H-NMR spectroscopy, Raman spectroscopy, and elemental composition analysis. Water sorption measurements of the nitrates showed that both studied salts strongly adsorbed water at high relative humidity. The amorphous salt had a maximum water uptake of approximately 25%, while the crystalline nitrate had a maximum water uptake of approximately 27%. In contrast to the hydrochloride, hydrobromide, and sulfate salts, the crystalline nitrate showed no initial water uptake at the start of the measurement program, which was set at 50% relative humidity. Examples 6- Compound I benzenesulfonate The amorphous benzenesulfonate salt is prepared by dissolving Compound I free base in a mixture of methanol and dichloromethane (approximately 2:1) and adding approximately 2 equivalents of benzenesulfonic acid. This yields a clear solution, which is then removed by rotary evaporation at 42°C to yield a solid white residue. Ethyl acetate is added to the residue, and the resulting white suspension is stirred at room temperature for approximately 20 hours. Alternatively, acetonitrile is added to the amorphous benzenesulfonic acid and residue, and the resulting white suspension is stirred at room temperature for approximately 20 hours. The identity of the crystalline 1:1 benzenesulfonate salt was confirmed by H-NMR spectroscopy. Further characterization included powder X-ray diffraction, TG-FTIR, DVS, DSC, and water solubility at 25°C. Dynamic vapor sorption analysis (DVS) was used to examine the hygroscopic properties of benzenesulfonic acid. At 95% relative humidity, the water adsorption capacity was 24%; however, the sample was not completely deliquesced. Below 80% relative humidity, the amount of water adsorbed was minimal. Because water adsorption is irreversible within the observed time, approximately 6% of water was still adsorbed at the end of the cycle. Examples 7- Compound I Hemi-ethylenedisulfonate The crystalline hemi-edisylate salt was prepared by mixing the two stock solutions as follows: an isopropanol stock solution of edisylic acid was added to the solid free base, the mixture was stirred at room temperature for three days, and the solid was isolated by filtration. The resulting solid was dried under vacuum at 40°C for approximately three hours. H-NMR spectroscopy confirmed the 2:1 salt of Compound I with ethanedisulfonic acid. Further characterization included powder X-ray diffraction, TG-FTIR, DVS, DSC, and water solubility at 25°C. The hygroscopic properties of hemi-edisylate were examined by dynamic vapor sorption analysis (DVS). The water adsorption capacity was approximately 32% at 95% relative humidity. Water adsorption was irreversible over time. Examples 8- Compound I Heminaphenadisulfonate All attempts to obtain crystalline naphthalenedisulfonate in a 1:1 stoichiometric manner failed, so further crystallization experiments involved preparing crystalline heminaphthalenedisulfonate. Crystalline heminaphthalenedisulfonate was successfully prepared by crystallization from a mixture of DCM and ethyl acetate. Typically, the free base is dissolved in DCM, the naphthalenedisulfonic acid is dissolved in ethyl acetate, the solutions are mixed, and the DCM is evaporated at room temperature or slightly elevated temperature (e.g., 60°C). A crystalline heminaphenadisulfonic acid salt was prepared by mixing stock solutions as follows: naphthalenedisulfonic acid in ethyl acetate with the solid free base (2 equivalents) dissolved in DCM. The mixture was heated to 60°C, and the DCM was distilled off while stirring at 60°C for approximately 2 hours before the heater was turned off. The system was then allowed to cool to room temperature. Stirring was continued at room temperature overnight while the vial remained open, and the suspension was filtered the following day. The resulting solid was dried under vacuum at 40°C for approximately three hours. H-NMR spectroscopy confirmed the 2:1 salt of Compound I with naphthalene-1,5-disulfonic acid; however, H-NMR indicated the presence of DCM and ethyl acetate as residual solvents. Further characterization included powder X-ray diffraction, TG-FTIR, DVS, DSC, and water solubility at 25°C. Dynamic vapor sorption analysis (DVS) was used to examine the hygroscopic properties of the heminadisulfonate. The water adsorption capacity was approximately 17.8% at 95% relative humidity. Water adsorption was irreversible over time. Examples 9- Compound I Tosylate Both the mono- and di-toluenesulfonate salts crystallize well and are prepared by several suitable procedures. For example, the amorphous toluenesulfonate salt is prepared by evaporating a 1:1 solution of the free base and toluenesulfonic acid in methanol-dichloromethane. Ethyl acetate is then added and the resulting suspension is stirred until crystallization is complete. These solid products are generally easy to separate and dry. In one experiment, the monotosylate salt was prepared and subjected to basic characterization. H-NMR spectroscopy confirmed a 1:1 ratio of the free base to toluenesulfonic acid. Additionally, the monotosylate salt was characterized by powder X-ray diffraction, TG-FTIR, DVS, DSC, and water solubility at 25°C. The X-ray diffraction pattern of the monotosylate salt, shown in Figure 8, exhibits peak diffraction angles (2θ) of 10.9214°, 13.2780°, 15.3605°, 16.9425°, 17.7356°, 18.2003°, 20.5139°, 23.2091°, 23.8569°, 24.7278°, 25.6871°, 26.6843°, 27.6274°, 29.1166°, and 30.5294°. Crystalline ditosylate salts were also prepared by suspension experiments using the amorphous ditosylate in either ethyl acetate or acetonitrile. PXRD patterns for both prepared samples are shown in Figure 9. H-NMR spectroscopy confirmed a 1:2 ratio of free base to toluenesulfonic acid. However, H-NMR analysis showed that solvates formed in both experiments. The sample obtained from the suspension experiment in ethyl acetate appeared to be an ethyl acetate hemisolvate, while the acetonitrile hemisolvate was obtained from the suspension experiment in acetonitrile. The hygroscopic properties of the monotosylate salt were examined using dynamic vapor sorption analysis (DVS). The amount of water adsorbed was approximately 2.8% at 95% relative humidity. Water adsorption was essentially reversible over the observed timeframe, and the adsorbed water was removed at the end of the cycle. Examples 10- Compounds with narrow particle size distribution I Preparation of tosylate salt Compound tosylate anhydrate (Form A) was successfully prepared by antisolvent crystallization at room temperature from methanol (MeOH) and methyl tert-butyl ether (MTBE, antisolvent) with the desired quality attributes. Two batches were initially synthesized in MeOH / MTBE using magnetic stirring, with addition times of 2 and 6 hours, respectively. Both yielded monotosylate Form A with the desired quality attributes, including a particle size distribution, with a volumetric efficiency of ~16 L / kg and a yield of >85%. A demonstration batch was also prepared using overhead stirring and added over a 6-hour period. This batch was characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), polarizing microscopy (PLM), particle size analyzer, proton nuclear magnetic resonance (1H NMR), gas chromatography (GC), and HPLC. Prior to filtration, the particles were cubic and approximately 50 μm in size. However, agglomeration was observed after washing and drying, resulting in a measured D90 of 150.0 μm. To investigate the effects of seed size and addition time on the final product particle size, two additional batches were prepared using overhead stirring with different batches of seed added over a two-hour period. PLM confirmed agglomeration in both batches after washing and drying. Seeding with larger ions resulted in a bimodal particle size distribution, likely due to the co-occurrence of crystal growth and nucleation during this process. Therefore, small or ground seeds are preferred for this process. The approximate solubility of monotosylate Form A was measured in MeOH / MTBE at room temperature. The results showed that the solubility of monotosylate Form A ranged from 264.0 to 348.0 mg / mL in MeOH / MTBE (v / v, 1:2), from 9.3 to 18.6 mg / mL in MeOH / MTBE (v / v, 1:3), and was <5.4 mg / mL in MeOH / MTBE (v / v, 1:3). To achieve appropriate solvent efficiency and yield, the starting concentration in MeOH was 250 mg / mL, and the final ratio of the antisolvent crystallization process in MeOH / MTBE (v / v) was 1:3. Two batches of Form A monotosylate salt were prepared via antisolvent crystallization in MeOH / MTBE (1:1 molar charge ratio) at different antisolvent addition rates. The products were characterized by XRPD, DSC, GC, PLM, and PSD. PSD data revealed a unimodal distribution with the desired D90 (~30 μm to <100 μm), likely due to the grinding effect of magnetic stirring. Regardless of the antisolvent addition time (2 or 6 hours), similar residual solvent levels and crystallinity were observed. Particle morphology and size distribution were also similar for the overhead stirring preparations, regardless of the antisolvent addition time (2 or 6 hours). See Table 6 and Figures 17 and 18 for details. The process parameters and characterization data are shown in Table 6. The D90 of the two batches of products was ~30 μm, which was attributed to the grinding effect of magnetic stirring. It was also found that the addition time of 2 or 6 hours had no significant effect on the dispersion. Table 6 In summary, the antisolvent crystallization process in MeOH / MTBE at room temperature produced the monotosylate Form A with the desired quality attributes (purity ≥99.8%, area %, yield ~90%, and residual MeOH / MTBE below the ICH limits of 3000 ppm MeOH and 5000 ppm MTBE). The crystallization process with the parameters for preparing the tosylate Form IA is summarized below: 1) Prepare an initial solution of Compound I and p-toluenesulfonic acid in MeOH at room temperature with a concentration of 250 mg / mL and a molar ratio of 1:1. 2) Supersaturate the solution by adding MTBE to prepare a MeOH / MTBE volume ratio of 3:1. 3) Add 5% Form A monotosylate seeds to the solution and age the mixture for 10-30 minutes. 4) Add MTBE to the solution over 2-6 hours to a final volume ratio of 1:3 (MeOH / MTBE), then age the solution for 1-5 hours before filtering. 5) The filtered product was washed with MTBE and dried in a vacuum oven at 50 °C overnight. Examples 11-15 Gram-scale compounds I Preparation of monotoluenesulfonate Compound I monotosylate anhydrate (Form A) was prepared as described in Example 10 and scaled up to 15 g with a yield of 91.0%. The scaled-up product was characterized by XRPD, TGA, DSC, GC, PLM, and PSD. Bulk crystals with a D90 of 150.0 μm were obtained. Compared to the previous 1.5 g batch, the particle size increased. Agglomeration was observed after washing and drying, as determined by PLM imaging. The solvent system (MeOH / MTBE) was also found to be suitable for particle growth. Examples 12- Effect of seed size on compound I Effect of Monotoluenesulfonate Particle Size Two batches of Form A monotosylate salt with different seed sizes (mean diameter Mv of 18.65 μm and 105.1 μm) were prepared within a 2-hour antisolvent addition time. The final dried products were characterized by XRPD, DSC, GC, PLM, and PSD. Smaller seeds produced crystals with an average size of ~50 μm, but agglomeration during solvent washing with MTBE and drying resulted in an increase in D90. When larger particles were used as seeds, a bimodal size distribution was observed, likely related to the co-occurrence of crystal growth and nucleation during the process. Examples 13- Compound I Synthesis of tosylate Methods for forming the mono- and di-toluenesulfonate salts of Compound I were developed and batch preparations were performed to successfully produce the monotoluenesulfonate salt. step 1 : 2- chlorine -N- methyl -3- Nitropyridine -4- Synthesis of amines A reactor was charged with 2,4-dichloro-3-nitropyridine and 3.0 volumes of DMF. The solution was stirred at 20-25°C until a clear solution was obtained. The solution was then cooled to 0-5°C, and 2.1 equivalents of a 40% aqueous solution of methylamine was slowly added at 0-5°C for at least 2 hours. The reaction mixture was stirred at 0-5°C for at least 2 hours until the conversion to product reached 95% (measured by HPLC). The reaction mixture was diluted by slowly adding 10 volumes of water at 0-5°C for at least 30 minutes. The resulting suspension was stirred at 0-5°C for at least 60 minutes. The precipitate was collected by filtration, and the filter cake was rinsed with 10 volumes of water from the reactor at 0-5°C. The wet cake was then dried under a stream of dry nitrogen to yield 2-chloro-N-methyl-3-nitropyridin-4-amine in a 78% yield. step 2 : 2- chlorine -N 4 - Picoline -3,4- Synthesis of diamines The reactor was charged with the catalyst [2% Pt on charcoal, 59% wt., water] (0.0004 equivalents of Pt), the damp 2-chloro-N-methyl-3-nitropyridin-4-amine from Step 1, and 9.4 volumes of THF. The solution was stirred, and the suspension was then transferred from the glass reactor to an autoclave. The line was flushed into the autoclave with 1.2 volumes of THF, and the autoclave was purged with nitrogen at 50 rpm for 15 minutes, followed by hydrogen at 150 rpm for 15 minutes. The autoclave was closed, and the hydrogen pressure was adjusted to 2 bar at 20-30°C. The reaction mixture was stirred at 2 bar and 20-30°C for 4-8 hours. Next, the autoclave was released to atmospheric pressure and purged with nitrogen for at least 15 minutes. Conversion to product was verified by HPLC, and the catalyst was then removed by filtration. The filtered catalyst was rinsed with 1.3 volumes of THF, and the filtrates were combined. The combined filtrates were passed through a particle filter and added to a second reactor, flushing the lines with 0.5 volumes of THF. The solution was concentrated to a final volume of 2.5 volumes by distillation under reduced pressure at 40-45°C. The solution was then diluted with 10 volumes of THF in portions while the solution was concentrated to a final volume of 2.5 volumes by distillation under reduced pressure at 45-50°C. The reactor was purged with nitrogen to atmospheric pressure, and 5.0 volumes of heptane were added to the residue at 40-50°C. The reaction mixture was cooled to 20-25°C over 2 hours and continued to stir and cool for 1 hour. The reaction mixture was then further cooled to 0-5°C over 1 hour and continued to stir for 1 hour. The precipitated product was collected by filtration, rinsed with 5.0 volumes of heptane through the reactor, and the wet cake was dried in a vacuum drying oven at a maximum of 40°C until the loss on drying was ≤2% by weight to give 2-chloro-N 4 -methylpyridine-3,4-diamine, with a yield of 85%. step 3 : 1- methyl -1,5- dihydrogen -4H- imidazolyl [4,5-c] Pyridine -4- Synthesis of ketones The reactor was charged with 2-chloro-N 4methylpyridine-3,4-diamine and 4 volumes of formic acid. The reaction mixture was heated to a steady reflux over 1 hour and maintained at reflux for 6 hours. The reaction mixture was then cooled to approximately 60°C, and conversion to the product was verified by HPLC. The reaction mixture was then concentrated to a final volume of 2 vol by distillation under reduced pressure at 60-80° C. The temperature of the solution was adjusted to 60° C. and maintained above 50° C. to avoid precipitation. Next, 10 volumes of acetone were added to the second reactor and heated to a gentle reflux. The product solution from the second reactor was slowly transferred to the acetone in the second reactor over 20 minutes, and the line was flushed with about 0.05 volumes of formic acid. The reflux of the resulting suspension was maintained for 15 minutes. The slurry was cooled to 0°C over 1 hour and stirring was continued at this temperature for 1 hour. The precipitate was collected by filtration, and the filter cake was rinsed with 3.7 volumes of cold acetone at 0-10°C through the reactor. The filter cake was dried in a stream of dry nitrogen or in a vacuum drying oven at 50°C until the drying loss was ≤2% by weight to give 1-methyl-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one in 95% yield. step 4 : 1- methyl -5-(4-( trifluoromethoxy ) Phenyl )-1,5- dihydrogen -4H- imidazolyl [4,5-c] Pyridine -4- Synthesis of ketones The first reactor (reactor A) was charged with 1-methyl-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one (1.0 mol equivalent), Cu(OAc)2·H 2O (0.1 mol equivalent) and K2CO3 (1.1 mol equivalent). The reactor was closed and the atmosphere was replaced with nitrogen. Next, 1-bromo-4-(trifluoromethoxy)benzene (1.5 mol equivalents) and N-methylpyridine (5.4 volume equivalents) were added simultaneously to form a suspension. The suspension was stirred until the temperature dropped again to approximately 20-25°C and the gas evolution slowed. The reaction mixture was heated to approximately 130-150°C, at which point a blue / green color was observed, which changed to a dark brown color after a period of time. The reaction was stirred at 130-150°C for at least 40 hours. Increasing the stirring time from 40 hours to 72 hours was necessary to achieve an acceptable level of conversion. Generally, higher reaction temperatures support faster conversions. Next, the reaction mixture was cooled to approximately 20-30°C, and 25% aqueous NH3 (0.7 vol. equiv.) was added, followed by water (3.5 vol. equiv.). The resulting suspension was transferred to a second reactor (reactor B). Water (18.1 vol. equiv.) was added to the reaction mixture via reactor A, followed by n-heptane (3.2 vol. equiv.). The resulting suspension was cooled to approximately 0-5°C and stirred for approximately 2 hours. The suspension was filtered and the filter cake was washed with water (9.7 vol eq). The filter cake was then dissolved in dichloromethane (14.1 vol eq) and transferred back to reactor B. Water (5.7 vol eq) was added to the solution through the filter, followed by 25% aqueous NH3 (1.6 vol eq). The mixture was stirred at approximately 15-25°C for approximately 1 hour. Next, the layers were separated, and dichloromethane (3.6 vol. equiv.) was added to the aqueous layer. The biphasic mixture was stirred at approximately 15-25°C for approximately 20-30 minutes. The layers were separated for at least 1 hour, and an aqueous solution of NH4Cl (2.5 mol equiv.) (7.0 vol. equiv.) was added to the combined organic layers. The biphasic mixture was stirred at approximately 15-25°C for approximately 20-30 minutes, and the layers were then separated for over 1 hour. The lower organic layer was filtered through a particle filter and diluted with toluene (7.1 vol eq) through the filter. The organic layer was concentrated at approximately 80°C under atmospheric pressure until no further evaporation of liquid was observed and a precipitate began to form. Toluene (16.6 vol eq) was added, followed by vacuum concentration, followed by more toluene (7.1 vol eq) and again vacuum concentration. The suspension was cooled to approximately 0-5°C and stirred for approximately 2 hours before filtering. The filter cake was washed with toluene (2.9 vol eq) and dried under vacuum at 50°C until the weight loss on drying was 0.5% by weight to yield 1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one with a yield of 83.1%. step 5 : 7- Bromine -1- methyl -5-(4-( trifluoromethoxy ) Phenyl )-1,5- dihydrogen -4H- imidazolyl [4,5-c] Pyridine -4- Synthesis of ketones The first reactor (reactor A) was charged with water (1.8 volume equivalents) and cooled to about 0-5°C, and then 96% sulfuric acid (14 mol equivalents) was slowly added at 0-20°C. The temperature of the solution was adjusted to about 0-5°C, and 1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c] Pyridin-4-one (1.0 mol equivalent). The temperature of the mixture was adjusted to about 0-5°C, and N-bromosuccinimide (1.0 mol equivalent) was slowly added in 3-4 portions while maintaining the temperature at about 0-5°C. The reaction mixture was stirred at about 0-5° C. for about 1 hour and then stirred at about 0-22° C. for an additional 4-16 hours. Conversion to the product was verified by HPLC, and the reaction mixture was then cooled to about 0-5° C. The second reactor (reactor B) was charged with water (42.7 volume equivalents) and cooled to approximately 0-5°C. The reaction mixture from reactor A was transferred to pre-cooled water in reactor B at a temperature below 30°C over 2 hours. The reaction mixture was flushed with water (1.6 volume equivalents), and 50% aqueous sodium hydroxide (25 mol equivalents) was carefully added at approximately 0-30°C over 2 hours until a pH of 2-5 was reached. Next, MTBE (6.5 vol eq) was added at approximately 0-20°C, and the mixture was stirred for approximately 5 minutes. A 50% aqueous sodium hydroxide solution (2 mol eq) was then added at approximately 0-30°C until the pH of the solution reached a range of 10-14. The reaction was stirred at approximately 15-25°C for at least 1.5 hours, and the layers were then allowed to separate for at least 1 hour. The suspension was filtered, and the product, which accumulated at the interface of the aqueous and organic layers, was carefully extracted. The filter cake was washed with MTBE (1.7 vol eq), water (3.0 vol eq), and then washed again with MTBE (3.0 vol eq). The product was dried under vacuum at below 50°C until the weight loss on drying was ≤1% by weight, yielding 7-bromo-1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one with a yield of 97.6%. step 6 : 1- methyl -7-(1- methyl -1H- Pyrazole -4- base )-5-(4-( trifluoromethoxy ) Phenyl )-1,5- dihydrogen -4H- imidazolyl [4,5-c] Pyridine -4- Ketone (compound I ) The reactor was charged with 7-bromo-1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one (1.0 mol equivalent), 1.6 mol equivalents of (1-methyl-1H-pyrazol-4-yl)boronic acid pinacol ester (1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, Pd[Ph3]4 (0.025 mol equivalent) and K2CO3 (2.0 mol equivalent) were added, followed by acetonitrile (10.0 volume equivalents) and water (3.0 volume equivalents). The reaction mixture was stirred at about 20-25°C for about 10-20 hours to form a suspension. The mixture was heated to gentle reflux, resulting in the formation of a yellow biphasic solution. The mixture was stirred at gentle reflux for at least 10 hours. The reaction mixture was cooled to between 30-50°C and then passed through a particle filter. The filtrate was washed with acetonitrile (2.6 volume equivalents), the combined filtrates, and the solution was concentrated under reduced pressure at below 60°C to a final volume of approximately 120 mL (4.8 volume equivalents). To the resulting suspension were added water (1.9 vol eq), methanol (26 mL, 1.0 vol eq), and dichloromethane (14.8 vol eq). The mixture was warmed to approximately 30-35°C and stirred until two clear liquid layers were observed. The layers were allowed to separate at approximately 30-35°C without stirring, and dichloromethane (3.7 vol eq) was added to the aqueous layer. The mixture was warmed to approximately 30-35°C and stirred for approximately 5 minutes, then the layers were allowed to separate at approximately 30-35°C. To the combined organic layers was added water (1.9 vol eq), and the mixture was warmed to approximately 30-35°C and stirred for approximately 5 minutes. The layers were separated at approximately 30-35°C. Charcoal was added to the combined organic layers and stirred at approximately 30-35°C for 30-60 minutes. The charcoal was removed by filtration, and the filtrate was washed with dichloromethane (39 mL, 1.6 vol eq). The solution was concentrated to 4.0 vol eq at atmospheric pressure and below 50°C, then diluted with methanol (5.0 vol eq). The solution was again concentrated to approximately 4.0 vol eq at atmospheric pressure and below 60°C, diluted with methanol (5.0 vol eq), and concentrated under reduced pressure at below 60°C to a final volume of approximately 3.0 vol eq. Methanol (2.9 volume equivalents) was added to the resulting suspension, and the suspension was then heated to about 45-55°C and stirred for about 1 hour. The suspension was cooled to about 0-5°C over about 1 hour, stirred at about 0-5°C for about 1 hour, and then filtered. The filter cake was washed with cold methanol (pre-cooled to about 0-10°C, 2.9 volume equivalents), and the product was dried under a nitrogen stream and vacuum at below 60°C until the weight loss on drying reached ≤ 1% by weight, yielding Compound I (1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one), the yield was 88.5%. step 7 : 1- methyl -7-(1- methyl -1H- Pyrazole -4- base )-5-(4-( trifluoromethoxy ) Phenyl )-1,5- dihydrogen -4H- imidazolyl [4,5-c] Pyridine -4- Ketone (compound I ) of recrystallization The reactor was charged with crude 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one, followed by the addition of glacial acetic acid (1.5 volume equivalents). The suspension was warmed to approximately 50-60°C and stirred to obtain a clear solution for approximately 10-20 minutes. The warm solution was passed through a particle filter into a second reactor. To this solution was added ethanol (10.0 volume equivalents) over 2 hours at about 45-55°C. The suspension was stirred at about 45-55°C for about 30 minutes and then cooled to about 0-5°C over about 4 hours. The suspension was then stirred at about 0-5°C for about 4-16 hours. Next, the suspension was filtered and the filter cake was washed with cold isopropanol (4.2 volume equivalents) at about 0-20° C. The product was dried under a nitrogen stream and vacuum at below 60° C. until the weight loss on drying reached ≤ 1% by weight, yielding Compound I (1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one), the yield was 93.0%. step 8 : Monotosylate (Compound I Monotosylate) 1- methyl -7-(1- methyl -1H- Pyrazole -4- base )-5-(4-( trifluoromethoxy ) Phenyl )-1,5- dihydrogen -4H- imidazolyl [4,5-c] Pyridine -4- Synthesis of ketones The reactor was charged with compound I (1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c]pyridin-4-one, 1 mol equivalent), p-toluenesulfonic acid monohydrate (1.05 mol equivalent), acetone (6.75 volume equivalents), and water (0.75 volume equivalents). The mixture was stirred at 15-25°C until a clear solution formed, which was then filtered through a particle filter and transferred to a second reactor. The filtrate was washed with acetone (2.5 vol eq) and to the combined filtrates was added MTBE (7.5 vol eq) seeded with crystals of Compound I monotosylate (0.001 mol eq) at 15-25°C. The resulting suspension was stirred at 15-25°C for about 30-60 minutes, and MTBE (22.5 volume equivalents) was added at 15-25°C over a period of about 30 minutes. Stirring was continued at 15-25°C for about 30-60 minutes, and the suspension was then filtered. The filtrate was washed with MTBE (2.5 volume equivalents), and the material was dried under vacuum at below 55°C to yield Compound I monotosylate (monotosylate salt of 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5- c] pyridin-4-one), the yield was 93%. Examples 14- Compound I Free base nano suspension tablets The Compound I nanosuspension was incorporated into a solid dosage form via fluidized bed granulation. To support pharmacokinetic studies, two dose strengths of 25 and 200 mg of Compound I and corresponding placebo were prepared. Purified water was heated to 30-40°C, and HPMC and polysorbate 80 were added with moderate mixing to form a suspension vehicle composed of water (98.6% w / w), polysorbate 80 (0.56% w / w), and HPMC (0.84% ​​w / w). A predetermined amount of Compound I was added to the suspension vehicle, and the mixture was transferred to a wet mill equipped with conditioned ZrO2 grinding media. The mixture was milled under nitrogen for 405 ± 5 minutes to prepare a nanosuspension containing Compound I (10.0% w / w), the suspension vehicle (71.5% w / w), and additional deionized water (18.5% w / w). Next, the nanosuspension is granulated. Mannitol is added to the nanosuspension prepared in the previous step, and the suspension is mixed for 15 minutes to ensure dissolution. A fluidized bed is charged with microcrystalline cellulose and the nanosuspension mixture is sprayed onto it. Once the nanosuspension is completely dispersed in the cellulose, spraying is stopped and the bed temperature is raised to above 40°C to promote drying. The mixture is milled to produce particles with a D550 diameter of 135 μm, which are then compressed into tablets. Examples 15- Jet milled compounds I Free base tablets Jet-milled Compound I, microcrystalline cellulose, lactose, and croscarmellose were sieved through a 20 mesh screen. Magnesium stearate was sieved through a 30 mesh screen. The sieved components were combined and mixed for 5 minutes. Intragranular magnesium stearate was added and mixed for 3 minutes. A mass was prepared using a press, ground with a mortar and pestle, and the ground powder was sieved through a 20 mesh screen. Extragranular croscarmellose sodium was added and mixed for 5 minutes. Extragranular magnesium stearate was added and mixed for 3 minutes to obtain the final mixture. The final compositions of the two batches prepared are shown in Tables 7 and 8 below. Table 7 Table 8 Tablets were pressed using an oval tool. The pressure was 2.0 tons and the dwell time was 30 seconds. Tablet weight, thickness, and hardness were 796-809 mg, 5.48-5.56 mm, and 162-201 N, respectively. Examples 16- Compound I Monotosylate tablets Compound I monotosylate, microcrystalline cellulose, and lactose were sieved through a 20 mesh screen. Magnesium stearate was sieved through a 30 mesh screen. Microcrystalline cellulose, lactose, and intragranular croscarmellose sodium were mixed for 5 minutes, intragranular magnesium stearate was added, and the mixture was mixed for 3 minutes. A block was prepared, then milled, and the resulting powder was sieved through a 20 mesh screen. Extragranular croscarmellose sodium and HPMC were added, and the mixture was mixed for 5 minutes to prepare the final mixture. The final composition is shown in Table 9 below. Table 9 The tablets were produced by passing the final mixture through an oval tool. Tablet weight and thickness were controlled between 797-807 mg (5.56-5.70 mm), respectively. Tablet hardness ranged from 101-197 N. Examples 17- Compound I Xylenesulfonate tablets Compound I ditoluenesulfonate was sieved through a 35 mesh screen, and all excipients were sieved through a 20 or 30 mesh screen. Compound I ditoluenesulfonate was mixed with microcrystalline cellulose, lactose, and intragranular croscarmellose sodium and mixed for 10 minutes. Magnesium stearate was added, and the mixture was mixed again for 2 minutes. Blocks were prepared by pressing with a pressure of 1.6 tons, each containing 4 g of powder. The blocks were ground with a mortar and pestle, and then sieved through a 20 mesh screen. Extragranular croscarmellose sodium and HPMC (to inhibit salt precipitation) were added to the milled powder and mixed for 4 minutes. Extragranular magnesium stearate was added and mixed for 1 minute to obtain the final mixture. The final composition is shown in Table 10 below. Table 10 Tablets were produced from the final mixture using a 12 mm round flat tool. The tablet size was targeted at 800 mg while being compressed at a pressure of 1.0 ton. The tablet hardness was determined to be approximately 180 N. Tablet weights ranged from 796 to 803 mg, and thicknesses ranged from 4.85 to 4.98 mm. Examples 18- Compound I Free base amorphous solid dispersion tablets A Compound I amorphous solid dispersion (ASD) at 50% drug loading was prepared by dissolving Compound I free base and HPMC acetate succinate (HPMCAS-MF) in methanol / dichloromethane (v / v = 1:1). The solution was then spray-dried using a mini-spray dryer at an inlet temperature of 75°C and further dried in a vacuum oven at 25°C overnight. ASD was sieved through a 20 mesh screen and all excipients were sieved through a 20 or 30 mesh screen. The sieved ASD was mixed with microcrystalline cellulose, lactose and intragranular croscarmellose sodium and then mixed for 5 minutes. Intragranular magnesium stearate was then added and the mixture was mixed for 3 minutes. The premix was crushed and the mass was then ground in a mortar and pestle and the resulting powder was sieved through a 20 mesh screen. Extragranular croscarmellose sodium was added and mixed with the milled powder for 5 minutes. Extragranular magnesium stearate was then added and the mixture was mixed for 3 minutes to obtain the final mixture. The final compositions of the two batches prepared are shown in Tables 11 and 12 below. Table 11 Table 12 The tablets were compressed using an 800 mg oval tool at a pressure of 2 tons. The tablets had a hardness range of 140-190 N. The tablets weighed 798 to 802 mg and had a thickness of 5.83 to 5.91 mm, respectively. Examples 19-21- Canine pharmacokinetic analysis The pharmacokinetic parameters of the formulations of Compound I and its salts in dogs were determined by oral administration of 200 mg of active substance (Compound I or salt) of the test formulation tablets to each dog. Blood samples were collected at various times post-administration, plasma was prepared, and parent drug analysis was performed using a qualified LC-MS-MS assay. Non-compartmental analysis was used to determine pharmacokinetic parameters from the atomic plasma analysis data. Examples 19- Cross-talk pharmacokinetic study of four oral formulations of a compound in dogs The pharmacokinetics of Compound I were determined in male beagles pretreated with pentagastrin following a single oral (PO) dose of 200 mg / tablet / dog in a 4-period crossover study with a washout period of at least 7 days for each phase. Five male non-natural, purebred beagles were used in each study phase. All dogs were pretreated with pentagastrin (6 μg / kg intramuscularly) approximately 30 minutes prior to test article administration. Four tablet formulations of the experimental product were evaluated, each containing 200 mg of the experimental product (free base equivalent). Approximately 4 hours prior to PO administration, animals were fasted overnight. Tablets were administered orally, followed by the addition of approximately 10 mL of RO (reverse osmosis) water. In Phase 1, animals were administered tablets containing Compound I in a nanosuspension formulation as described above; in Phase 2, animals were given tablets containing Compound I in jet-milled form as described above; and in Phase 4, animals received tablets containing the monotosylate salt of Compound I as described above. In Phase 3, tablets containing the amorphous solid dispersion as described above were crushed and suspended in water before administration to the animals. Each animal received one milled tablet, administered orally via gavage as an aqueous suspension formulation. Blood samples were collected prior to administration and at 0.25, 0.5, 1, 2, 4, 8, 24, 36, and 48 hours after oral dosing. Plasma was harvested, and the concentration of Compound I in each sample was determined using an unvalidated LC / MS / MS assay. The limit of quantification for Compound I was 1.02 to 5.1 ng / mL. The mean compound concentrations measured in plasma were used to construct semi-logarithmic plasma concentration-time curves (Figure 13). Pharmacokinetic analysis was performed using a non-compartmental approach. PK parameters are shown in Table 13. The mean plasma concentration-time profile of Compound I after PO dosing is shown in Figure 13. The individual and mean plasma concentrations from each phase are shown in Tables 14-17. In Phase 1 (nanosuspension), AUC0-last, Cmax, and tmax were 56,300 ng·hr / mL, 7,020 ng / mL, and 2.00 hr, respectively; in Phase 2 (jet milling), they were 46,200 ng·hr / mL, 4,290 ng / mL, and 6.40 hr, respectively; in Phase 3 (amorphous solid dispersion), they were 82,900 ng·hr / mL, 8,460 ng / mL, and 2.40 hr, respectively; and in Phase 4 (monotosylate), they were 78,500 ng·hr / mL, 8,100 ng / mL, and 1.80 hr, respectively. Based on the mean PK data, Compound I exposure (AUG and Cmax) in dogs receiving the amorphous tablet (crushed in water, Phase 3) and the monotosylate tablet (Phase 4) was comparable, with exposure from both tablet formulations being higher (within two-fold) compared to the tablets in Phases 1 and 2 (nanosuspension and jet-milled dosage forms). Table 13 Table 14 Table 15 Table 16 Table 17 Examples 20- Cross-pharmacokinetics of two oral formulations of a compound in fed dogs The pharmacokinetics of Compound I were determined in male beagles pretreated with pentagastrin following a single oral (PO) dose of 200 mg / tablet / dog in a 2-period crossover study with a washout period of at least 7 days for each phase. Six male non-natural, purebred beagles were used in each phase of the 2-period crossover study. All dogs were pretreated with pentagastrin (6 μg / kg intramuscularly) approximately 30 minutes prior to test article administration. Two tablet formulations of the test article were evaluated (a nanosuspension as described above and a monotosylate salt). Phase 1: Animals were administered a tablet containing the Compound I nanosuspension. Phase 2: Animals were administered a tablet containing the Compound I monotosylate salt. Approximately 4 hours after administration, animals in both phases were fasted overnight and, approximately 30 minutes prior to test article administration, received a 100 mL volume of homogenized Food and Drug Administration (FDA) high-fat diet orally, followed by a 7-10 mL water rinse. Blood samples were collected prior to administration and at 0.25, 0.5, 1, 2, 4, 24, 36, and 48 hours after oral dosing. Plasma was collected, and the Compound I concentration in each sample was determined by LC / MS / MS. The limit of quantification for Compound I was 20 ng / mL. The mean compound concentrations measured in plasma were used to construct semi-logarithmic plasma concentration-time curves (Figure 14). Pharmacokinetic analysis was performed using a non-compartmental approach. The PK parameters of Compound I are shown in Table 18. The mean plasma concentration-time profiles following PO doses of Compound I in the nanosuspension and monotosylate formulations are shown in Figure 14. The individual and mean plasma concentrations from each phase are shown in Tables 19 and 20. The AUC0-last, Cmax, and tmax in Phase 1 (nanosuspension) were 63,100 ng·hr / mL, 7,210 ng / mL, and 3.33 hr, respectively, and in Phase 2 (monotosylate), they were 48,800 ng·hr / mL, 5,430 ng / mL, and 3.00 hr, respectively. Based on the mean PK data, Compound I exposure in dogs administered the nanosuspension tablet formulation was slightly higher in the fed state than in dogs administered the monotosylate formulation (i.e., the monotosylate AUC and Cmax were approximately 75%-85% of those in the nanosuspension formulation when fed). This is in contrast to the fasting state, where the monotosylate salt had higher AUC and Cmax compared to the nanosuspension (i.e., 115-140% of the nanosuspension). Table 19 Table 20 Examples twenty one- canine compound I Cross-pharmacokinetics study of oral monotosylate and ditosylate salts The pharmacokinetics of Compound I were determined in male beagles pretreated with pentagastrin following a single oral (PO) dose of 200 mg / tablet / dog in a 2-period crossover design, with a washout period of at least 7 days for each phase. Five male non-natural, purebred beagles were used in each phase of the 2-period crossover study. All dogs were pretreated with pentagastrin (6 μg / kg intramuscularly) approximately 30 minutes prior to test article administration. Two tablet formulations of the test article (the monotosylate and ditosylate salts as described above) were evaluated. Approximately 4 hours prior to PO administration, animals were fasted overnight. The tablets were administered orally, followed by the addition of approximately 10 mL of reverse osmosis water. In Phase 1, animals were administered a tablet containing the monotosylate salt of Compound I, and in Phase 2, animals were administered a tablet containing the ditosylate salt of Compound I. Blood samples were collected prior to administration and at 0.25, 0.5, 1, 2, 4, 8, 24, 36, and 48 hours after the oral dose. Plasma was collected, and the concentration of Compound I in each sample was determined by LC / MS / MS. The limit of quantification for Compound I was 20 ng / mL. The mean Compound I concentration measured in plasma was used to construct a semi-logarithmic plasma concentration-time curve (Figure 1). Pharmacokinetic analysis was performed using a non-compartmental approach. The PK parameters of Compound I are shown in Table 21. The mean plasma concentration-time profiles of the compound after PO dosing for both formulations are shown in Figure 15. The individual and mean plasma concentrations from each phase are shown in Tables 22 and 23. In Phase 1 (monotosylate), AUC0-last, Cmax, and tmax were 70,200 ng·hr / mL, 6,480 ng / mL, and 2.00 hr, respectively, and in Phase 2 (ditosylate), they were 88,000 ng·hr / mL, 10,400 ng / mL, and 2.00 hr, respectively. Based on the mean PK data, Compound I exposures in dogs administered the ditosylate formulation were slightly higher per dose than those in the monotosylate formulation. Table 21 Table 22 Table 23 Examples twenty three- Effect of Polymerization Precipitation Inhibitors HPMC was included in the tablets of Example 16 to maintain supersaturation of the Compound I API after dissolution of the monotosylate salt. This effect is demonstrated in Figure 16, which shows the dissolution and precipitation of the Compound I monotosylate salt at various concentrations in a pH 6.5 phosphate buffer containing HPMC at 37°C. In the formulation without HPMC, the API concentration decreased to 80 µg / mL within 10 minutes when the monotosylate salt was dissolved in a pH 6.5 phosphate buffer at 37°C, a concentration that approximates the solubility of Compound I Form A free base. At low HPMC concentrations (1 or 2 µg / mL) in the buffer, the polymer was essentially unable to maintain supersaturation of Compound I. However, when the HPMC concentration was increased to 5 µg / mL, the polymer was able to maintain a Compound I concentration of 160 µg / mL, a concentration twice the solubility of Form A free base. The HPMC concentration in this 5 µg / mL test corresponds to 0.50% by weight of the tablet composition. The foregoing description has been given for clarity of understanding only, and no unnecessary limitations should be understood therefrom, as modifications within the scope of the invention will be apparent to those skilled in the art. Throughout this specification and subsequent patent applications, unless the context dictates otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be understood to imply the inclusion of a stated integer or step (e.g., reagent, element, step or other feature) or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. In the specification, where compositions are described as comprising components or materials, it is contemplated that, unless otherwise indicated, such compositions may also consist essentially of or consist of any combination of the components or materials. Similarly, where a method is described as comprising specific steps, it is contemplated that, unless otherwise indicated, such method may also consist essentially of or consist of any combination of the steps. The inventions exemplarily invented herein may suitably be practiced in the absence of any element or step not specifically disclosed herein. The practice of the methods disclosed herein and their individual steps can be performed manually and / or with the aid of electronic devices or provided by electronic devices. Although the processes have been described with reference to specific embodiments, those skilled in the art will appreciate that various methods of performing the operations associated with the methods may be employed. For example, unless otherwise indicated, the order of the individual steps may be varied without departing from the scope or spirit of the methods. Additionally, individual steps may be combined, omitted, or further separated into additional steps. All patents, publications, and references cited herein are hereby incorporated by reference. In the event of a conflict between the present invention and the incorporated patents, publications, and references, the present invention shall control. In order to obtain a better understanding of the present invention, fifteen drawings are attached. Figure 1 shows the XRPD trace of Compound 1 Form A (free base). Figure 2 shows XRPD traces of Compound 1 HCl salt: amorphous mono-HCl (bottom trace), crystalline di-HCl (middle trace), and crystalline mono-HCl (top trace). Figure 3 shows XRPD traces of Compound 1 HBr salt: amorphous mono-HBr (bottom trace), crystalline mono-HBr (middle trace), and crystalline di-HBr (top trace). Figure 4 shows the XRPD trace of Compound 1 sulfate salt. Figure 5 shows XRPD traces of Compound 1 amorphous nitrate salt (bottom trace) and crystalline nitrate salt (top trace). Figure 6 shows the XRPD trace of Compound 1 besylate salt. Figure 7 shows the XRPD trace of Compound 1 hemi-edisylate salt. Figure 8 shows the XRPD trace of Compound 1 monotosylate salt. Figure 9 shows XRPD traces of Compound 1 free base (bottom trace) and Compound 1 ditosylate salt (middle and top traces). Figure 10 shows XRPD traces of Compound 1 free base (bottom trace) and Compound 1 heminaphanenedisulfonate salt (middle and top traces). Figure 11 shows XRPD traces of Compound IA Form 1A phosphate salt and Compound IA Form 1A free base (bottom trace) and Compound IA Form 1A free base (top trace). 12 shows XRPD traces of Compound 1 methanesulfonic acid (Form A, bottom trace) and Compound 1 free base (Form A, top trace). Figure 13 shows the mean plasma concentrations of Compound I in male Beagle dogs following a single 200 mg oral dose of Compound I in four formulations comprising a nanosuspension of the free base, jet-milled free base, amorphous free base, or the monotosylate salt. Figure 14 shows the mean plasma concentrations of Compound I following a single 200 mg oral dose of Compound I as a nanosuspension formulation or as the monotosylate salt in male Beagle dogs. Figure 15 shows the mean plasma concentrations of Compound I following a single 200 mg oral dose of Compound I as a mono- or di-tosylate salt in male Beagle dogs. Figure 16 shows the effect of HPMC in maintaining supersaturation of Compound I after dissolution of the monotosylate salt. FIG17 shows the particle size distribution of Compound 1 monotosylate salt prepared by adding antisolvent over 6 hours. FIG18 shows the particle size distribution of Compound 1 monotosylate salt prepared by adding antisolvent over 2 hours. FIG19 shows the TGA and DSC curves of Compound 1 monotosylate salt.

Claims

1. A nano suspension comprising a free base of compound I, compound I, hydroxypropyl methylcellulose, and sodium dodecyl sulfate.

2. Use of the nano suspension as claimed in claim 1 for the preparation of a medicament for the treatment or prevention of fibrotic diseases in an individual.

3. As requested in claim 2, wherein the fibrotic disease is idiopathic pulmonary fibrosis.

4. An oral dosage form comprising a nano suspension as claimed in claim 1.

5. Use of an oral dosage form as claimed in claim 4, for the preparation of a medicament for the treatment or prevention of fibrotic diseases in an individual.

6. As requested in claim 5, wherein the fibrotic disease is idiopathic pulmonary fibrosis.

7. A process for preparing a solid oral dosage form, comprising the following steps: (a) granulating the nano suspension of claim 1 to prepare a granulated nano suspension; (b) adding mannitol to the granulated nano suspension prepared in step (a) to prepare a nano suspension mixture; (c) spraying the nano suspension mixture prepared in step (b) onto a fluidized bed filled with microcrystalline cellulose to prepare a nano suspension wet blend; (d) raising the temperature of the fluidized bed to above 40 °C to dry the nano suspension wet blend to prepare a nano suspension dry blend; and (e) milling the nano suspension dry blend to prepare nano suspension particles.

8. The process of claim 7 further includes flattening the nano-suspension particles into a tablet.

9. The process of claim 7 or 8, wherein the particles have a particle size D50 of about 100 µm to about 170 µm.

10. The process of claim 7 or 8, wherein the particles have a particle size D50 of about 135 µm.

11. A solid oral dosage form, which is manufactured by any one of the processes described in claims 7 to 10.

12. Use of a solid oral dosage form as claimed in claim 11 for the preparation of a medicament for the treatment or prevention of fibrotic diseases in an individual.

13. As claimed in claim 12, wherein the fibrotic disease is idiopathic pulmonary fibrosis.

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