Amorphous forms of a rock2 inhibitor and formulations thereof

Abstract

The present disclosure relates to amorphous forms of (6-(4-((4-(1H-pyrazol-4- yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-1H-indol-2-yl)(3,3-difluoroazetidin-1-yl)methanone (Compound A) and processes for preparing amorphous forms of Compound A. The present disclosure also provides pharmaceutical dosage forms comprising the amorphous forms of Compound A as an active pharmaceutical ingredient and methods of preparing the pharmaceutical dosage forms.

Description

322930.48776AMORPHOUS FORMS OF A ROCK2 INHIBITOR AND FORMULATIONS THEREOFFIELD OF THE INVENTION

[0001] The present disclosure relates to amorphous forms of Compound A and processes for preparing amorphous forms of Compound A. The present disclosure also provides pharmaceutical dosage forms comprising the amorphous forms of Compound A as an active pharmaceutical ingredient and methods of preparing the pharmaceutical dosage forms.BACKGROUND

[0002] Compound A, chemically known as (6-(4-((4-(lH-pyrazol-4-yl)phenyl)amino)- pyrimidin-2-yl)-l-methyl-lH-indol-2-yl)(3,3-difluoroazetidin-l-yl)methanone, is represented by Formula I below:

[0003] Compound A is a highly selective and potent inhibitor of Rho-associated coiled- coil containing protein kinase 2 (ROCK2) that is under development by Graviton Bioscience for the treatment of a broad range of neurological conditions, autoimmune disorders and fibrotic disorders. A process for the preparation of Compound A is disclosed in U.S. Patent 11,390,609, entitled Rho-associated Protein Kinase Inhibitor, Pharmaceutical Composition Comprising Same, And Preparation Method And Use Thereof.

[0004] Many potential drugs suffer from low bioavailability when taken orally. The bioavailability of pharmaceutically active substances when taken orally, depends on the extent to which the pharmaceutically active substance is absorbed from the gastro-intestinal environment across the gastro-intestinal mucosa. Lipophilic pharmaceutical substances may be poorly absorbed from the gastro-intestinal tract, inter alia because of their poor solubility and / or dispersibility in water. There is a demand for oral drug formulations for lipophilic and / or poorly soluble drugs.176595330.1322930.48776SUMMARY OF THE INVENTION

[0005] In one aspect, the present disclosure provides amorphous forms of Compound A, or a pharmaceutically acceptable salt form thereof, in amorphous form or non - crystalline phase, wherein the amorphous form or non - crystalline phase of compound A is present in a weight percentage in respect of any crystalline form of compound A, of more than 90 % w / w, preferably at least 95 % w / w.

[0006] In an embodiment, the invention provides an amorphous solid dispersion comprising Compound A, or a pharmaceutically acceptable salt form thereof, and an orally pharmaceutically acceptable polymer.

[0007] In an embodiment, the amorphous form of Compound A is provided as an amorphous solid dispersion of Compound A, for example, with a pharmaceutically acceptable polymer, and optionally one or more surfactants.

[0008] Another aspect of the present disclosure provides a process for preparing an amorphous solid dispersion of Compound A. Solvent evaporation methods, such as spraydrying, are a preferred technique for the preparation of the amorphous Compound A. Amorphous Compound A may be prepared by the steps comprising (a) dissolving in a solvent: Compound A, one or more carrier matrix materials, and optionally one or more surfactants; and (b) removing the solvent, thereby isolating amorphous Compound A.

[0009] The amorphous solid dispersion of Compound A may be used in the preparation of solid pharmaceutical dosage forms, such as tablet, wherein the pharmaceutically acceptable carrier may comprise one or more of a disintegrant, a glidant, a lubricant, a diluent, optionally a wetting agent, optionally a binder, and optionally a coating material. The pharmaceutical composition as described herein, may be a capsule or a sachet, optionally further comprising a diluent. The pharmaceutical compositions comprising an effective amount the amorphous form of Compound A are useful for treating diseases, including neurological disorders, cancers, autoimmune diseases and inflammation, fibrosis, infectious diseases, and metabolic diseases.BRIEF DESCRIPTION OF THE FIGURES

[0010] Figure 1 shows beagle dog pharmacokinetic data demonstrating the maximum concentration (Cmax) of Compound A for different formulations.

[0011] Figure 2 shows the beagle dog pharmacokinetic data demonstrating the area under the curve (AUC) of Compound A for different formulations.2176595330.1322930.48776

[0012] Figures 3 shows the beagle dog pharmacokinetic data demonstrating the blood plasma concentration (ng / mL) of nanosuspension, Compound A for Compound A HPMCAS + 0.5% Surfactant and Compound A HPMCAS + 1% Surfactant with respect to time (hours).

[0013] Figures 4 shows the beagle dog pharmacokinetic data demonstrating the area under the curve (AUC) of Compound A for nanosuspension, Compound A HPMCAS + 0.5% Surfactant and Compound A HPMCAS + 1% Surfactant.

[0014] Figure 5 shows the beagle dog pharmacokinetic data demonstrating the maximum concentration (Cmax) of Compound A for nanosuspension, Compound A HPMCAS + 0.5% Surfactant and Compound A HPMCAS + 1% Surfactant.DETAILED DESCRIPTION OF THE INVENTION

[0015] Compound A is an orally administered API with low solubility and low permeability. Reliable dosing and absorption of the Compound A is important to ensure consistent systemic exposure. The development of a reproducible drug delivery system and the characterization of its associated dissolution profile facilitates consistent and effective dosing. The present disclosure provides an amorphous form of Compound A that enhances the solubility and improves the bio-performance of the molecule by formulating an amorphous solid dispersion.

[0016] The term Compound A as used herein refers to (6-(4-((4-(lH-pyrazol-4- yl)phenyl)amino)pyrimidin-2-yl)-l -methyl- lH-indol-2-yl)(3,3-difluoroazeti din- 1- yl)methanone, represented by Formula I below:and to pharmaceutically acceptable salts, solvates or hydrates thereof. In a preferred embodiment, the amorphous Compound A is in a free base form, which may be a solvate, hydrate or anhydrous. In embodiments, Compound A is in an anhydrous free base form.

[0017] The term “pharmaceutically-acceptable salts” in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of Compound A. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate,3176595330.1322930.48776 maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like (see, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).

[0018] The term “solid dispersion” as used herein, refers to a system in a solid state including at least two components, wherein one component is Compound A, which is dispersed (e.g., homogeneously), throughout the other component or components that form a carrier matrix.

[0019] The term “amorphous solid dispersion” as used herein, refers to solid dispersions comprising Compound A and a carrier matrix.

[0020] Amorphous Compound A, including its amorphous solid dispersions, are considered “amorphous” as used herein, when the Compound A is in a substantially amorphous solid state form. Unless otherwise specified, the term "amorphous" or "amorphous form" means that the compound is not substantially crystalline, and is a disordered solid form, i.e., a solid form substantially lacking long range crystalline order, as determined by powder X-ray diffraction. A substantially amorphous state may include at least about 80%, at least about 90%, or at least 95%, or at least 99% of the Compound A in an amorphous form. In one particular embodiment, a substantially amorphous state includes at least about 95% of the Compound A in an amorphous form. Whether the Compound A is in an amorphous form can be characterized, for example, by powder X-ray diffraction techniques as described herein, or as otherwise known to those skilled in the art.

[0021] The amorphous Compound A prepared by the methods disclosed herein provides dissolution enchantment by particle size reduction and removal of crystalline lattice. The absence of crystallinity results in no crystal lattice energy to be overcome for the Compound A to dissolve. The carrier material may additionally assist in the dissolution by improving the wetting, solubility and the stability characteristics of the Compound A in super-saturation solutions.

[0022] The amorphous form of Compound A provides good physiochemical properties such as controlled particle size, and flowability, which are useful for downstream processing, such as capsule filling, tablet compression and sachet filling. Additionally, the pharmaceutical composition comprising the amorphous form of Compound A may demonstrate a significant increase in the dissolution rate over analogous dosage forms comprising the crystalline forms of Compound A. This may result in an increase in4176595330.1322930.48776 bioavailability, and overall bio-performance, of the pharmaceutical composition comprising the amorphous Compound A. The methods and the resulting amorphous Compound A provide enhanced solubility, and prevents precipitation of the Compound A when limited dissolution occurs in the gastrointestinal tract and results in improvement of bio-performance of Compound A.

[0023] In an embodiment, the amorphous form of Compound A is formed using a solvent evaporation technique. Solvent evaporation methods, such as spray drying, are a preferred technique for the preparation of the amorphous Compound A. This technique comprises dissolving or suspending Compound A in the carrier followed by spraying the mixture stream. This allows the removal of the solvent and creation of the amorphous product.

[0024] This technique involves the creation of a dispersion of Compound A into an amorphous state in a polymeric matrix.

[0025] An amorphous form of Compound A may be prepared by the following steps: a) dissolving Compound A, one or more carrier matrix materials, and optionally one or more surfactants in a solvent; and b) removing the solvent, thereby isolating amorphous Compound A. In an embodiment, the solvent is removed by spray drying.

[0026] In the first step of the process, Compound A may be added to a solvent. Within the context of this method, the Compound A material may initially be in a variety of forms, for example, any polymorphic crystalline form or a solvate. The Compound A may be in a salt form or may be in the free-base form. If the Compound A is in the form of an acid addition salt and an amorphous Compound A in the free-base form is desired, a sufficient amount of base may be added to the solvent to form the Compound A free-base. The base may an inorganic base, such as al alkali metal hydroxide, or the base may be an amine such as diethylamine, triethyl amine, or the like. In embodiments, Compound A is added to the solvent as an anhydrous free base form.

[0027] Within the context of this method, the solvent may be selected from one or more of an alcohol, an ether, a ketone, an ester, halogenated hydrocarbon, or other appropriate solvent, which may be used in spray drying and is a solvent for the Compounds A and the carrier matrix material(s). The solvent may be selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, acetone, methyl ethyl5176595330.1322930.48776 ketone, methyl acetate, ethyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, N-methyl-2- pyrrolidone, dichloromethane and mixtures thereof.

[0028] In some embodiments, the solvent is a mixture of an alcohol (such as methanol, ethanol, etc.) and a ketone (acetone, methyl ethyl ketone, etc.), and more particularly is a mixture of methanol and acetone. The alcohol and the ketone may be in a ratio of about 4: 1 to about 1 :4, or in a ratio of about 3 : 1 to 1 :3, or in a ratio of about 2: 1 to 1 :2 (v / v).

[0029] In some embodiments, the solvent is a mixture of an alcohol and a halogenated hydrocarbon, and more particularly is a mixture of methanol and dichloromethane mixture. The alcohol and the halogenated hydrocarbon may be in a ratio of about 4: 1 to about 1:4, or in a ratio of about 3 : 1 to 1 :3, or in a ratio of about 2: 1 to 1 :2 (v / v).

[0030] In some embodiments, the solvent is a mixture of an alcohol and an ester, and more particularly is a mixture of methanol and methyl acetate. The alcohol and the ester may be in a ratio of about 4: 1 to about 1 :4, or in a ratio of about 3 : 1 to 1 :3, or in a ratio of about 2: 1 to 1 :2 (v / v).

[0031] The carrier matrix materials are components that promote or stabilize the amorphous form of Compound A when in the solid state. Preferred carrier matrix materials are polymeric materials. The polymer selection for the spray dry dispersion may play an important role on the overall product final product attributes. Polymers for use as the carrier matrix material include water-soluble polymers, an enteric polymer, or an orally pharmaceutically acceptable polymer, or mixtures thereof. The water soluble polymers include but are not limited to homopolymers and copolymers of N-vinyl lactams, especially homopolymers and copolymers of N-vinyl pyrrolidone, e.g. polyvinylpyrrolidone (PVP) (e.g. PVP K30 and PVP-VA 64), copolymers of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, such as Poloxamer, lauroyl polyoxylglycerides cellulose esters and cellulose ethers; in particular methylcellulose, hydroxyalkylcelluloses, in particular hydroxypropylcellulose, hydroxyalkylalkylcelluloses, in particular hydroxypropylmethylcellulose, high molecular polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate (also referred to as partially saponified6176595330.1322930.48776“polyvinyl alcohol”), polyvinyl alcohol, oligo- and polysaccharides such as carrageenans, galactomannans and xanthan gum, and mixtures of one or more thereof.The enteric polymers may be selected from cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methyl cellulose phthalate, ethylhydroxymethylcellulose phthalate, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethyl cellulose acetate succinate (HPMCAS) (e.g., HPMCAS-L grade HPMCAS-M grade, HPMCAS-H grade), hydroxypropylmethyl cellulose acetate maleate, hydroxypropylmethylcellulose trimellitate, carboxymethylethyl cellulose, polyvinyl butyrate phthalate, polyvinyl acetate phthalate, a methacrylic acid / ethyl acrylate copolymer and a methacrylic acid / methyl methacrylate copolymer, preferably selected from the group consisting of HPMCP, HPMC-AS, hydroxypropylmethyl cellulose acetate maleate and hydroxypropylmethylcellulose trimellitate, and mixtures thereof.

[0032] The orally pharmaceutically acceptable polymer may be selected from alkylcelluloses such as methylcellulose; hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxy ethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose; hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; carboxyalkylcelluloses such as carboxymethylcellulose; alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose; carboxyalkylalkylcelluloses such as carboxymethylethylcellulose; carboxyalkylcellulose esters; hydroxypropylmethylcellulose phthalate (HPMCP); chitin derivates such as chitosan; polysaccharides such as starches, pectines (sodium carboxymethylamylopectine), cyclodextrins or a derivative thereof, carrageenans, galactomannans, tragacanth, agar agar, gummi arabicum, guar gummi and xanthan gummi; polyacrylic acids, olyacrylates, and the salts thereof; polymethacrylic acids, polymethacrylates, the salts and esters thereof, methacrylate copolymers; polyvinylalcohol (PVA), co-polymers of PVA (e.g., Kollicoat® IR), crospovidone (PVP-CL), polvinylpyrrolidone-polyvinylacetate copolymer (PVP-PVA); polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide; polyvinylpyrrolidone (PVP) of MW ranging from 2500 to 3000000; Gelita® Collagel; or any combination thereof; and optionally a surface-active carrier.

[0033] In some embodiments, the orally pharmaceutically acceptable polymer may be HPMCAS, HPMC E5, Eudragit® E, Eudragit® L, PVP VA64, any combination thereof; and7176595330.1322930.48776 the orally pharmaceutically acceptable polymer or combination thereof may be optionally mixed with Sodium Lauryl Sulfate (SLS).

[0034] The ratio of Compound A to the carrier matrix material(s) in the spray dried product may be from 10:90 to 90: 10 by weight; or 10:90 to 70:30 by weight; or from 25:75 to 75:25 by weight; or from 33:67 to 67:33 by weight; or 50:50 by weight. In one embodiment, the ratio of Compound A to the carrier matrix material(s) in the spray dried product may be from 20:80 to 67:33 by weight.

[0035] One or more optional surfactants may be added in the carrier matrix solution prior to solvent removal. In some embodiments, the surfactant may be added in the inner phase of solid dispersion. In some embodiments, the surfactant may be added in the external phase of solid dispersion. In some embodiments, the surfactant may be added in both the inner and the external phase in the tablet, capsule, or sachet formulation. The optional surfactant may further increase the rate of dissolution of Compound A in the resulting amorphous solid form and dosage forms prepared therefrom. In some embodiments, the optional surfactant may be selected from an anionic surfactant, nonionic surfactants, and mixtures thereof. Anionic surfactants include, but are not limited to sodium lauryl sulfate, potassium laurate, sodium dodecyl sulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctyl sodium sulfosuccinate, glyceryl esters, sodium carboxymethylcellulose, cholic acid and other bile acids (e.g., cholic acid, deoxy cholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid) and salts thereof (e.g., sodium deoxycholate, etc.). Suitable cationic surfactants include but are not limited to quaternary ammonium compounds, such as benzalkonium chloride, cetyltrimethylammonium bromide, lauryldimethylbeizylammonium chloride, acyl carnitine hydrochlorides, and alkyl pyridinium halides, and mixtures thereof. Nonionic surfactants include, but are not limited to Vitamin E TPGS, a-Hydro-o- hydroxypoly(oxyethylene)poly(oxypropylene) poly-(oxyethylene) block copolymer (Pol oxamer 188), Oxirane, methyl-, polymer with oxirane (Pol oxamer 407), PEG 4000, Tween-80, polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene-derivatized lipids such as mPEG-PSPC (palmitoyl-stearoyl-phophatidylcholine), mPEG-PSPE (palmitoyl-stearoyl- phophatidylethanolamine), sorbitan esters, glycerol monostearate, polyethylene glycols, polypropylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols, polyoxyethylene-polyoxypropylene copolymers, polaxamines, methylcellulose, hydroxycellulose, hydroxy propylcellulose, hydroxy propylmethylcellulose, noncrystalline8176595330.1322930.48776 cellulose, polysaccharides, starch, starch derivatives, hydroxy ethyl starch, polyvinyl alcohol, and polyvinylpyrrolidone, and mixtures thereof.

[0036] In some embodiments, the ratio of Compound A to surfactant in the spray dried product may be 10: 1 to 1 :2 by weight. In other embodiments, the ratio of Compound A to surfactant in the spray dried product may be 4: 1 to 1 : 1 by weight. In one embodiment, the percentage by weight of the surfactant in the total composition after solvent removal is about 1% to about 15% by weight, or about 6% to about 12% by weight.

[0037] The spray-dried amorphous Compound A may be used in the preparation of solid pharmaceutical dosage forms, such as tablets, wherein the pharmaceutically acceptable carrier may comprise a one or more of disintegrant, a glidant, a lubricant, a diluent, a wetting agent, a binder, and a coating material. The pharmaceutical composition may also be a capsule or a sachet, optionally further comprising a diluent. The pharmaceutical compositions comprising an effective amount the amorphous form of Compound A are useful for treating diseases, including cancer, autoimmune diseases and inflammation, fibrosis, infectious diseases, and metabolic diseases.

[0038] The term "effective amount" in connection with an amorphous form of Compound A means an amount capable of treating or preventing a disorder, disease or condition, or symptoms thereof, as disclosed herein. As will be apparent to those skilled in the art, it is to be expected that the effective amount of an amorphous form of Compound A disclosed herein may vary depending on the severity of the indication being treated.

[0039] The present disclosure provides a method for the prevention or treatment of a disease mediated by ROCK2, wherein the method comprises administering to a subject in need thereof an effective amount of a Compound A in an amorphous form as disclosed herein.

[0040] In some embodiments, the present disclosure provides methods for the treatment of at least one disease or disorder selected from the group comprising fibrotic diseases, inflammatory diseases, and autoimmune diseases, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition as defined herein.

[0041] In other embodiments, the disclosure provides methods for the treatment of a cardiovascular disorder, a central nervous system disorder, a neoplastic disease, or a metabolic syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition as defined herein.9176595330.1322930.48776

[0042] In some embodiments, the disease mediated by ROCK2 is an autoimmune disorder including rheumatoid arthritis, systemic lupus erythematosus (SLE; lupus), psoriasis, psoriatic arthritis, multiple sclerosis, Crohn’s disease, ulcerative colitis, atopic dermatitis, eczema, or graft-versus-host disease (GVHD; acute and chronic), idiopathic pulmonary fibrosis and scleroderma.

[0043] Other autoimmune disorders that may be treated according to the methods provided in this disclosure include acute disseminated encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis, Addison’s disease, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune dysautonomia, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thyroid disease, autoimmune urticaria, axonal & neuronal neuropathies, Balo disease, Behcet’s disease, bullous pemphigoid, cardiomyopathy, Castleman disease, Celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal ostomy elitis (CRMO), Churg-Strauss syndrome, Cogan’s syndrome, coxsackie myocarditis, CREST disease, demyelinating neuropathies, dermatitis herpetiformis, dermatomyositis, Devic’s disease (neuromyelitis optica), discoid lupus, Dressier’s syndrome, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, Evans syndrome, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture’s syndrome, granulomatosis with polyangiitis (GPA), Graves’ disease, Guillain- Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, Hypogammaglobulinemia, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, immunoregulatory lipoproteins, inclusion body myositis, interstitial cystitis juvenile arthritis uvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, Linear IgA disease (LAD), Meniere’s disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, myasthenia gravis, myositis, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism, pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Turner10176595330.1322930.48776 syndrome, pars planitis (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, autoimmune polyglandular syndromes (type I, II, III), polymyalgia rheumatica, polymyositis, post myocardial infarction syndrome, post pericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriatic arthritis, pyoderma gangrenosum, pure red cell aplasia, Raynaud’s phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter’s syndrome, relapsing polychondritis, retroperitoneal fibrosis, sarcoidosis, Schmidt syndrome, scleritis, Sjogren’s syndrome, Sperm & testicular autoimmunity, stiff person syndrome, subacute bacterial endocarditis (SBE), Susac’s syndrome, sympathetic ophthalmia, Takayasu’s arteritis, temporal arteritis / Giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, Transverse myelitis, undifferentiated connective tissue disease (UCTD), type-1 autoimmune diabetes, uveitis, vasculitis, vesiculobullous dermatosis, vitiligo, and Wegener’s granulomatosis (granulomatosis with polyangiitis; GPA).

[0044] Inflammatory disorders that can be treated by methods provided in this disclosure include, but are not limited to, cardiovascular inflammation, pulmonary inflammation, renal inflammation, arteriosclerosis and sepsis.

[0045] Fibrotic disorders that can be treated by methods provided in this disclosure include idiopathic pulmonary fibrosis, renal fibrosis, kidney fibrosis, ocular fibrosis, cardiac fibrosis, NASH, scleroderma, systemic sclerosis, and cirrhosis.

[0046] In another embodiment, the disclosure provides a method for the treatment of muscular dystrophy (Duchenne muscular dystrophy). In another embodiment, the disclosure provides a method for the treatment of myotonic dystrophy.

[0047] In another embodiment, the compositions of Compound A provided herein may be used in the treatment of amyotrophic lateral sclerosis (ALS).

[0048] In other embodiments, the compositions of Compound A provided herein may be used to inhibit tumor cell growth and metastasis, and angiogenesis, and are useful for treating neoplastic diseases. Neoplastic diseases include any malignant growth or tumor caused by abnormal or uncontrolled cell division. Neoplastic diseases include lymphoma, carcinoma, leukemia, sarcoma and blastoma. Non-limiting examples include squamous cell cancer, small-cell lung cancer, pituitary cancer, esophageal cancer, astrocytoma, soft tissue sarcoma, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer,11176595330.1322930.48776 glioblastoma, cervical cancer, ovarian cancer, bladder cancer, liver cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, brain cancer, endometrial cancer, testis cancer, cholangiocarcinoma, gallbladder carcinoma, gastric cancer, melanoma, and various types of head and neck cancer.

[0049] In other embodiments, the compositions of Compound A provided herein may be used in the treatment of a cardiovascular disorder including hypertension, cardiomyopathy, cardiac remodeling, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, and erectile dysfunction.

[0050] In other embodiments, the compositions of Compound A provided herein may be used in the treatment of a pulmonary disorder including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma.

[0051] In other embodiments, the compositions of Compound A provided herein may be used in the treatment of a central nervous system disorder, including neuronal degeneration or spinal cord injury, traumatic brain injury, cerebral cavernous malformation, Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, Amyotrophic lateral sclerosis (ALS), multiple sclerosis, or Duchenne muscular dystrophy.

[0052] In other embodiments, the disclosure provides methods for the treatment of renal diseases including polycystic kidney disease, renal fibrosis, diabetic renal disease, chronic kidney disease and focal segmental glomerulosclerosis.

[0053] In other embodiments, the compositions of Compound A provided herein may be used in the treatment of a metabolic disease including insulin resistance, hyperinsulinemia, type 2 diabetes, obesity, metabolic syndrome and glucose intolerance. The compositions of Compound A may be used to effect weight loss and / or limit weight gain. In an embodiment, a composition of Compound A is used to reduce or prevent insulin resistance or restore insulin sensitivity.

[0054] In other embodiments, the compositions of Compound A provided herein may be used in the treatment of an ocular disorder including ocular hypertension, age related macular degeneration (AMD; wet and dry), choroidal neovascularization (CNV), choroidal tumor, diabetic macular edema (DME), iris neovascularization, uveitis, glaucoma, primary openangle glaucoma, acute angle-closure glaucoma, pigmentary glaucoma, congenital glaucoma, normal tension glaucoma, secondary glaucoma, neo vascular glaucoma, geographic atrophy, and retinitis of prematurity (ROP).12176595330.1322930.48776

[0055] In another embodiment, the disclosure provides methods for the treatment of sickle cell disease.

[0056] In other embodiments, the compositions of Compound A provided herein may be used to treat (i.e., cure or reduce the severity of, etc.) viral infections, particularly coronavirus infections such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV, and to treat or prevent the sequelae resulting from the viral infection, including the coronavirus infection such as SARS- CoV-1, SARS-CoV-2, and MERS-CoV. In some embodiments, the viral infection is a SARS-CoV-1 infection. In some embodiments, the viral infection is a SARS-CoV-2 infection. In some embodiments, the viral infection is a MERS-CoV infection. In embodiments, the sequelae include one or more of the group consisting of fatigue, dyspnea (difficulty breathing), cough, arthralgia (joint pain), myalgia, headache, chest pain, fever, palpitations, myocardial inflammation, ventricular dysfunction, stroke, pulmonary function abnormalities, fibrosis (such as pulmonary fibrosis), renal dysfunction rash, alopecia, olfactory and / or gustatory dysfunction, sleep dysregulation, cognitive impairment altered, memory impairment, depression, anxiety, changes in mood and combinations thereof. In embodiments, the sequelae include inflammation and / or fibrosis.

[0057] In one aspect, the present disclosure provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of an amorphous form of Compound A formulated together with one or more pharmaceutically excipients. The pharmaceutical compositions may be specially formulated for administration in solid form, including those adapted for the following: (1) oral administration, for example, tablets and capsules, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) topical application, for example, as a cream, ointment, or a controlled-release patch applied to the skin; (3) intravaginally or intrarectally, for example, as a suppository, cream or foam; (4) sublingually; (5) ocularly; or (6) nasally. Oral administrations are preferred.

[0058] The phrase "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium, calcium or zinc stearate, or steric acid). Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.13176595330.1322930.48776

[0059] In solid pharmaceutical dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the Compound A is mixed with one or more pharmaceutically-acceptable excipients including a pharmaceutically-acceptable carrier, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as polyethylene- propylene glycol copolymer or polyoxvethylene- polyoxypropylene copolymer (poloxamer) and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0060] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0061] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer14176595330.1322930.48776 matrices, liposomes and / or microspheres. They may be formulated for rapid release, e.g., freeze-dried. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0062] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0063] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.EXAMPLESExample 1 : Solvents for Spray Drying

[0064] A challenge in developing amorphous solid dispersions by spray drying is to find a suitable solvent system that dissolves, in an appreciable amount, both the drug and polymer. Compound A free base has limited solubility in many volatile organic solvents.

[0065] The solubility of Compound A free base in volatile organic solvents and their mixtures was determined visually. The solubility of Compound A free base in volatile organic solvents and their mixtures at different temperatures are summarized in Table I. Compound A free base also has limited solubility (< 5 mg / mL) in the tested singe volatile organic solvents at room temperature and hot temperature 50 °C. Improved drug solubility (> 20 mg / mL) was found in the mixture of methanol / dichloromethane and the mixture of methanol / acetone at hot temperature. The polymer solubility in the mixture of methanol / dichloromethane and the mixture of methanol / acetone was over 100 mg / mL for HPMCAS, PVP 30K and PVP-VA 64. As environment friendly solvents, the mixture of MeOH / Acetone was selected as solvent system for spray drying.15176595330.1322930.48776Table I: Solubility of free base in volatile organic solventsOrganic solvent Temperature Solubility [mg / mL]Acetone Room, 50 °C < 5Methanol Room, 50 °C < 5Ethanol Room, 50 °C < 5Isopropyl alcohol Room, 50 °C < 5Dichloromethane Room, 50 °C < 5Methyl ethyl ketone Room, 50 °C < 5Tetrahydrofuran Room, 50 °C < 5Methyl acetate Room, 50 °C < 5Methanol / Dichloromethane (1 / 1) 10-15 °C < 20Methanol / Dichloromethane (1 / 1) 30 °C 20 - 25Methanol / Dichloromethane (1 / 2) 10-15 °C < 20Methanol / Dichloromethane (1 / 2) 30 °C 20 - 40Methanol / Methyl acetate (2 / 1) 10-15 °C < 5Methanol / Methyl acetate (2 / 1) 30 °C < 5Methanol / Methyl acetate (1 / 1) 10-15 °C < 5Methanol / Methyl acetate (1 / 1) 30 °C 25 - 33.3Methanol / Methyl acetate (1 / 2) 10-15 °C < 5Methanol / Methyl acetate (1 / 2) 30 °C < 5Methanol / Acetone (2 / 1) 10-15 °C < 5Methanol / Acetone (2 / 1) 30 °C 12.5 - 25Methanol / Acetone (2 / 1) 50 °C 12.5 - 25Methanol / Acetone (1 / 1) 10-15 °C < 5Methanol / Acetone (1 / 1) 30 °C 25 - 33.3Methanol / Acetone (1 / 1) 50 °C 25 - 50Methanol / Acetone (1 / 2) 10-15 °C < 5Methanol / Acetone (1 / 2) 30 °C 25 - 33.3Methanol / Acetone (1 / 2) 50 °C 25 - 50Tetrahydrofuran / Acetone (1 / 5, 30 °C, 50 °C < 51 / 4, 1 / 3 and 1 / 2)16176595330.1322930.48776Example 2: Formulation Development of Amorphous Solid Dispersion by Spray Drying

[0066] The formulation trials / assessment were focused to test different polymers, mainly considering the amorphous physical form in solid dispersion and dissolution in biorelevant medium. HPMCAS polymers, PVP-30K, and PVPVA-64 were investigated in the preliminary formulation trials. The ratio of drug and polymer were kept at 1 :3 by weight. Five solid dispersions were produced by using a Buchi-290 spray dryer. The batch size was 12 g. The compositions, the implemented process parameters as well as the results from the spray drying trials are summarized in Table II.

[0067] The spray drying was performed at 76-83°C inlet gas temperature with a spray rate of around 40% of the pump, resulting in an outlet gas temperature (temperature which is applied on the solid dispersion) of 60-67°C. The aspiration was 100% set to a maximum gas flow rate approx. 35 m3 / h. The pressure of the nozzle was set to around 0.3 bar. No nozzle clogging was observed in the trial.

[0068] A secondary tray drying process was used to remove residual solvent after the initial spray drying process. The “wet” solid dispersion was dried further in a heated vacuum oven at a temperature of 40 °C for roughly 24 hours.

[0069] The physical properties and assay of the post-dried solid dispersion powder for the preliminary formulation trials are summarized in Table II. The bulk density of the post-dried solid dispersion powders ranges from 0.12 to 0.2 g / cm3. The bulk density for PVP-30K and PVPVA-64 solid dispersion powders were higher than that for HPMCAS solid dispersion powders.

[0070] The preliminary formulations were characterized by XRPD, mDSC and TGA. The diffractograms demonstrated that the spray-dried solid dispersions all are completely amorphous, characterized by the absence of sharp crystallographic x-ray peaks. Thermal analysis by mDSC showed that all dispersions had a single Tg, indicating an intimately mixed amorphous solid dispersion with good homogeneity. The non-reversing heat signal did not show crystallization or other events. Tg for PVP-30K solid dispersion was 166.2 °C, and Tg for other solid dispersions (PVPVA-64 and HPMCAS) were 111.3 to 118.6 °C.These relatively high glass transition temperatures are an indication of good physical stability, i.e. the propensity of the API to crystallize during long-term storage is low. To ensure long-term physical stability, solid dispersion should be stored well below the Tg at a given condition so that mobility of the drug in the glass dispersion is low.17176595330.1322930.48776Table II: Solid dispersions prepared by 1st spray drying trialsExample 3: Formulation Trials

[0071] Additional formulation trials / assessments evaluated the incorporation of sodium lauryl sulfate in the HPMCAS solid dispersions. The ratio of drug and polymer were also investigated for polymer HPMCAS at 1:1, 1:2 and 1 :3. Solid dispersions were produced by18176595330.1322930.48776 using a Buchi-290 spray dryer. The batch size was 20 g. The compositions, the implemented process parameters as well as the results from the spray drying trials are summarized in Table III. Additional formulations were prepared as reported in Tables IV and V.

[0072] The spray drying was performed at 67-77°C inlet gas temperature with a spray rate of around 40% of the pump, resulting in an outlet gas temperature (temperature which is applied on the solid dispersion) of 60-67°C. The aspiration was 100% set to a maximum gas flow rate approx. 35 m3 / h. The pressure of the nozzle was set to around 0.3 bar. No nozzle clogging was observed in the trial.Table III: Solid dispersions prepared by 2nd spray drying trials19176595330.1322930.48776Table IV: Solid dispersions prepared by 3rd spray drying trials for PVP K3020176595330.1322930.48776Table V: Solid dispersions prepared by 3rd spray drying trials for HPMCAS21176595330.1322930.48776

[0073] The dissolution performance of solid dispersions was tested in a biorelevant nonsink in and FaSSIF (pH 6.5). The nanosuspension 40 mg / mL was also tested as a reference to compare the dissolution performance of solid dispersions. The dissolution data are summarized in Table VI.Table VI: Dissolution of Compound A ASD, 500 mL pH 6.5 FaSSIF at 75 paddle speed22176595330.1322930.48776*5 mL vehicle 0.5% w / v MC**5 mL vehicle 0.5% w / v MC + 0.5% SLS***5 mL vehicle 0.5% w / v MC + 1% SLS23176595330.1322930.48776+5 mL vehicle 0.5% MC + 0.5% VitE+5 mL vehicle 0.5% w / v MC / 1% VitE+++5 mL vehicle 0.5% w / v PVP30K + 1% VitEExample 4: Impurity Assay and Results

[0074] To rapidly assess the physical and chemical stability of solid dispersion formulations of the compound of A. dispersions were aged at 25° C. / 60% RH and 40°C. / 75% RH, both open and in closed vials over a period of 4 weeks. The solid dispersions were evaluated for changes in amorphous physical state by XRPD, chemical purity by HPLC. Results are summarized in Table VII. XRPD analysis of the aged solid dispersion samples showed that all solid dispersion formulations remained amorphous with no detectable crystalline material after 4 weeks. Purity analysis of the aged solid dispersions showed that no substantial impurities were detected.Table VII. Physical and chemical stability of ASDT=14 days T=14 days T=14 days T=28 days T=28 days T=8 days25°C 40°C 40°C 25°C 40°C 40°C60%RH 75%RH 75%RH 60%RH 75%RH 75%RHForm. Testclose close open close close open24176595330.1322930.48776Example 5: Pharmacokinetic Properties

[0075] In vivo experiments were conducted to evaluate the potential benefit of the solid dispersion formulations relative to nanosuspension formulation (Formulation A). The pharmacokinetics profiles of Compound A in nanosuspension versus different solid dispersion formulations (Formulations B, C, D, E and F) was studied in fasted male beagle dogs. The suspension of the amorphous solid dispersions in different vehicles was administered to dogs at 10 mg / kg by oral gavage.

[0076] In general, all the solid dispersion formulations tested showed higher concentrations than the nanosuspension formulation (Table VIII, Figure 1 and Figure 2). Specifically, solid dispersion formulations C (HPMCAS-M 1 / 3 ASD, 0.5% MC + 1% SLS), and F (HPMCAS-M / SLS 2 / 7 / 1 ASD, 0.5% MC) showed about 4- to 5- fold higher exposure than seen with the nanosuspension formulation A and significantly reduced variability in exposure. Both formulations had the same drug-SLS ratio of 2: 1. Solid dispersion formulations B (HPMCAS-M 1 / 3 ASD, 0.5% MC + 0.5% SLS) showed approximately 3- to4-fold increase in exposure. The drug-SLS ratio of the formulation B is 4: 1. Solid dispersion formulations D (HPMCAS-M 1 / 1 ASD, 0.5% MC + 0.5% SLS) and formulations E (PVP-30K 1 / 3 ASD, 0.5% MC + 0.5% SLS) just showed slightly higher exposure compared to the nanosuspension formulation A.Table VIII: Pharmacokinetics parameters of Compound A following a single oral administration of 10 mg / kg Compound A formulations to fasted male beagle dogsPQ |- n T1 / 2 Tmax Cmax AUC(O-t) AUC(0-°°)No Formulation Vehicle hr hr ng / mL hr*ng / mL hr*ng / mLA Nanosuspen. water 869.55 2702.18B HPMCAS 0.5% w / v MC 6 1 .08 3.67 4256.91 13252.79 13259.981 / 3 ASD + 0.5% w / v SLS (0.54) (0.82) (2635.48) (7134.24) (7136.51)C HPMCAS 0.5% w / v MC 6 0.91 3.67 4263.58 14982.88 14991 .551 / 3 ASD + 1 % w / v SLS (0.22) (0.82) (662.36) (3370.48) (3373.22)B HPMCAS 0.5% w / v MC 6 0.80 3.33 3125.78 1201 1.43 12019.151 / 3 ASD + 0.5% w / v SLS (0.1 1) (1 .03) (1610.63) (7412.91) (741 1 .28)D HPMCAS 0.5% w / v MC 6 0.67 2.00 1124.32 3194.77 3199.751 / 1 ASD + 0.5% w / v SLS (0.13) (1 .10) (383.56) (1334.63) (1333.87)E PVP-30K 0.5% w / v MC 6 0.64 2.17 11 18.74 3336.81 3342.701 / 3 ASD + 0.5% w / v SLS (0.10) (0.98) (904.61) (2808.60) (2809.88)F HPMCAS / SLS 0.5% w / v MC 6 1 .09 3.67 4412.55 15033.71 15050.182 / 7 / 1 ASD (0.19) (0.82) (1589.24) (5748.51) (5744.68)25176595330.1

Claims

322930.48776We Claim:

1. A composition comprising an amorphous (6-(4-((4-(lH-pyrazol-4- yl)phenyl)amino)pyrimidin-2-yl)- 1 -methyl- lH-indol-2-yl)(3 ,3 -difluoroazeti din- 1 - yl)m ethanone (Compound A).

2. The composition of claim 1, further comprising a one or more polymeric matrix materials.

3. The composition of claim 2, wherein the one or more polymeric matrix materials are selected from a water-soluble polymer, an enteric polymer, an orally pharmaceutically acceptable polymer, or mixtures thereof.

4. The composition of claim 3, wherein the water soluble polymer is a copolymer of N- vinyl lactams, especially homopolymers and copolymers of N-vinyl pyrrolidone, e.g. polyvinylpyrrolidone (PVP) (e.g. PVP K30 and PVP-VA 64), copolymers of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, such as Poloxamer, lauroyl polyoxylglycerides cellulose esters and cellulose ethers; in particular methylcellulose, hydroxyalkylcelluloses, in particular hydroxypropylcellulose, hydroxyalkylalkylcelluloses, in particular hydroxypropylmethylcellulose, high molecular polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate (also referred to as partially saponified “polyvinyl alcohol”), polyvinyl alcohol, oligo- and polysaccharides such as carrageenans, galactomannans and xanthan gum, and mixtures of one or more thereof.

5. The composition of claim 3, wherein the enteric polymers are selected from the group consisting of cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methyl cellulose phthalate, ethylhydroxymethylcellulose phthalate, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethyl cellulose26176595330.1322930.48776 acetate succinate (HPMCAS), hydroxypropylmethyl cellulose acetate maleate, hydroxypropylmethylcellulose trimellitate, carboxymethylethyl cellulose, polyvinyl butyrate phthalate, polyvinyl acetate phthalate, a methacrylic acid / ethyl acrylate copolymer and a methacrylic acid / methyl methacrylate copolymer, preferably selected from the group consisting of HPMCP, HPMC-AS, hydroxypropylmethyl cellulose acetate maleate and hydroxypropylmethylcellulose trimellitate, and mixtures of one or more thereof.

6. The composition of claim 3, wherein the orally pharmaceutically acceptable polymer may be selected from the group comprising:: alkylcelluloses such as methylcellulose; hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose; hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; carboxyalkylcelluloses such as carboxymethylcellulose; alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose; carboxyalkylalkylcelluloses such as carboxymethylethylcellulose; carboxyalkylcellulose esters; hydroxypropylmethylcellulose phthalate (HPMCP); chitin derivates such as chitosan; polysaccharides such as starches, pectines (sodium carboxymethylamylopectine), cyclodextrins or a derivative thereof, carrageenans, galactomannans, tragacanth, agar agar, gummi arabicum, guar gummi and xanthan gummi; polyacrylic acids, olyacrylates, and the salts thereof; polymethacrylic acids, polymethacrylates, the salts and esters thereof, methacrylate copolymers; polyvinylalcohol (PVA), co-polymers of PVA (e.g., Kollicoat® IR), crospovidone (PVP-CL), polvinylpyrrolidone-polyvinylacetate copolymer (PVP-PVA); polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide; polyvinylpyrrolidone (PVP) of MW ranging from 2500 to 3000000; Gelita® Collagel; or any combination thereof; and optionally a surface-active carrier.

7. The composition according to any one of claims 2 to 6, wherein the ratio of Compound A to the carrier matrix material(s) is from 20:80 to 67:33 by weight.

8. The composition according to any one of claims 2 to 6, further comprising a surfactant.27176595330.1322930.487769. The composition of claim 8, wherein the surfactant is an anion surfactant, a nonionic surfactant, or mixtures thereof.

10. The composition of claim 9, wherein the anionic surfactant is sulfate, potassium laurate, sodium dodecylsulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctyl sodium sulfosuccinate, glyceryl esters, sodium carboxymethylcellulose, cholic acid and other bile acids (e.g., cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid) and salts thereof (e.g., sodium deoxycholate, etc.). Suitable cationic surfactants include but are not limited to quaternary ammonium compounds, such as benzalkonium chloride, cetyltrimethylammonium bromide, lauryldimethylbeizylammonium chloride, acyl carnitine hydrochlorides, and alkyl pyridinium halides.

11. The composition of claim 9, wherein the nonionic surfactant is Vitamin E TPGS, a- Hydro-o-hydroxypoly(oxyethylene)poly(oxypropylene) poly-(oxyethylene) block copolymer (Pol oxamer 188), Oxirane, methyl-, polymer with oxirane (Pol oxamer 407), PEG 4000, Tween-80, polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene- derivatized lipids such as mPEG-PSPC (palmitoyl-stearoyl-phophatidylcholine), mPEG-PSPE (palmitoyl-stearoyl-phophatidylethanolamine), sorbitan esters, glycerol monostearate, polyethylene glycols, polypropylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols, polyoxyethylenepolyoxypropylene copolymers, polaxamines, methylcellulose, hydroxycellulose, hydroxy propylcellulose, hydroxy propylmethylcellulose, noncrystalline cellulose, polysaccharides, starch, starch derivatives, hydroxy ethyl starch, polyvinyl alcohol, and polyvinylpyrrolidone.

12. The composition of any one of claims 7 to 11, wherein the ratio of Compound A to the carrier matrix material to surfactant in the spray dried product is about 10: 1 to 1 :2 by weight.

13. A solid pharmaceutical formulation comprising a therapeutically effective amount of a composition comprising amorphous Compound A according to any one of claims 1 to 12.28176595330.1322930.4877614. The solid pharmaceutical formulation of claim 13, wherein the pharmaceutical formulation is a tablet, a capsule, or a sachet.

15. The solid pharmaceutical formulation of claim 13 or 14, wherein the dose of Compound A is about 50 mg to about 100 mg.

16. A method for treating a disease, including cancer, autoimmune diseases and inflammation, fibrosis, infectious diseases, and metabolic diseases; wherein the method comprises administering the pharmaceutical dosage form of any one of claims 14-16 to a patient in need thereof.

17. A method for the preparation of amorphous Compound A comprising:(a) dissolving Compound A, one or more carrier matrix materials, and optionally one or more surfactants in a solvent; and(b) removing the solvent, thereby isolating amorphous Compound A.

18. The method of claim 17, wherein the solvent removal of step (b) comprises spray drying.

19. The method of claim 17 or claim 18, wherein the solvent is be selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, acetone, methyl ethyl ketone; tetrahydrofuran, 2-methyl tetrahydrofuran, N-methyl-2- pyrrolidone, and mixtures thereof.

20. The method according to any one of claim 17 to 19, wherein the carrier matrix materials are polymeric materials.

21. The method of claim 20, wherein the polymeric carrier matrix material comprises one or more of a water-soluble polymer, an enteric polymer, an orally pharmaceutically acceptable polymer.

22. The method of claim 21, wherein the water soluble polymer is a copolymer of N-vinyl lactams, especially homopolymers and copolymers of N-vinyl pyrrolidone, e.g. polyvinylpyrrolidone (PVP) (e.g. PVP K30 and PVP-VA 64), copolymers of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft29176595330.1322930.48776 copolymer (Soluplus®), block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, such as Poloxamer, lauroyl polyoxylglycerides cellulose esters and cellulose ethers; in particular methylcellulose, hydroxyalkylcelluloses, in particular hydroxypropylcellulose, hydroxyalkylalkylcelluloses, in particular hydroxypropylmethylcellulose, high molecular polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate (also referred to as partially saponified “polyvinyl alcohol”), polyvinyl alcohol, oligo- and polysaccharides such as carrageenans, galactomannans and xanthan gum, and mixtures of one or more thereof.

23. The method of claim 21, wherein the enteric polymers are selected from the group consisting of cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methyl cellulose phthalate, ethylhydroxymethylcellulose phthalate, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethyl cellulose acetate succinate (HPMCAS), hydroxypropylmethyl cellulose acetate maleate, hydroxypropylmethylcellulose trimellitate, carboxymethylethyl cellulose, polyvinyl butyrate phthalate, polyvinyl acetate phthalate, a methacrylic acid / ethyl acrylate copolymer and a methacrylic acid / methyl methacrylate copolymer, preferably selected from the group consisting of HPMCP, HPMC-AS, hydroxypropylmethyl cellulose acetate maleate and hydroxypropylmethylcellulose trimellitate, and mixtures of one or more thereof.

24. The method of claim 21, wherein the orally pharmaceutically acceptable polymer may be selected from the group comprising:: alkylcelluloses such as methylcellulose; hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose; hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; carboxyalkylcelluloses such as carboxymethylcellulose; alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose; carboxyalkylalkylcelluloses such as carboxymethylethylcellulose; carboxyalkylcellulose esters; hydroxypropylmethylcellulose phthalate (HPMCP);30176595330.1322930.48776 chitin derivates such as chitosan; polysaccharides such as starches, pectines (sodium carboxymethylamylopectine), cyclodextrins or a derivative thereof, carrageenans, galactomannans, tragacanth, agar agar, gummi arabicum, guar gummi and xanthan gummi; polyacrylic acids, olyacrylates, and the salts thereof; polymethacrylic acids, polymethacrylates, the salts and esters thereof, methacrylate copolymers; polyvinylalcohol (PVA), co-polymers of PVA (e.g., Kollicoat® IR), crospovidone (PVP-CL), polvinylpyrrolidone-polyvinylacetate copolymer (PVP-PVA); polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide; polyvinylpyrrolidone (PVP) of MW ranging from 2500 to 3000000; Gelita® Collagel; or any combination thereof; and optionally a surface-active carrier.

25. The method according to any one of claims 21 to 24, wherein the ratio of Compound A to the carrier matrix material(s) in the solvent is from 10:90 to 70:30 by weight.31176595330.1

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