JP2026507424A - Pharmaceutical compositions and solid forms of compound 1 with the fumarate salt for the treatment of inflammatory disorders - Google Patents

Abstract

Provided herein are novel compositions and solid forms of Compound (I) useful for the prevention and/or treatment of, inter alia, allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and/or IL-23.
[Chemical formula 1]
[Selection diagram] None

Description

The present invention relates to novel pharmaceutical compositions and novel solid forms of the compounds useful in the treatment of inflammatory diseases and/or diseases associated with hypersecretion of IFNα, interferon ("interferonopathies," particularly type I or type III interferonopathies), IL-12, and/or IL-23. The present invention also relates to the preparation of pharmaceutical compositions, the preparation of solid forms, the preparation of Compound 1, the use of pharmaceutical compositions and solid forms, and pharmaceutical unit dosage compositions comprising the compositions and solid forms in the treatment of inflammatory diseases and/or diseases associated with hypersecretion of IFNα, interferon ("interferonopathies," particularly type I or type III interferonopathies), IL-12, and/or IL-23.

Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transduce cytokine signaling from membrane receptors to STAT transcription factors. Four JAK family members have been described: JAK1, JAK2, JAK3, and TYK2. Upon cytokine binding to its receptor, JAK family members autophosphorylate and/or transphosphorylate each other, subsequently phosphorylating STATs, which then translocate to the nucleus and regulate transcription. JAK-STAT intracellular signaling contributes to the expression of various cytokines and endocrine factors, including interferons, most interleukins, and EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL (Vainchenker, Dusa, and Constantineescu 2008).

The combined study of genetic models and small-molecule JAK inhibitors has revealed the therapeutic potential of JAK inhibitors (JAKinibs) (Babon et al. 2014). Over the past decade, JAKinibs with varying degrees of selectivity profiles for JAK family members have been developed. Notably, while targeting multiple JAKs may not be harmful (Brökman, Giovannatti, and Peters 2011), the development of selective JAKinibs would be highly desirable to tailor treatment courses to patient needs, despite the challenges it represents (Fabian et al. 2005). For example, while JAK2 inhibition has proven useful in the treatment of polycythemia and myelofibrosis, undesirable effects associated with JAK2 inhibition have been observed (O'Shea and Plenge 2012). Therefore, compounds with JAK2 inhibitory components are not suitable for the treatment of non-JAK2-mediated diseases.

Using TYK2 knockout mice, it has been shown that signaling of IL-6, IL-10, IL-11, IL-12, IL-13, IL-19, IL-20, IL-22, IL-23, IL-27, IL-28, IL-29, IL-31, IL-35, and/or type 1 interferons is dependent on TYK2 (Schwartz et al. 2016). However, recent studies have shown that JAK1 is the primary driver of IFNα, IL-6, IL-10, and IL-22 signaling, whereas TYK2 is involved in type 1 interferon (including IFNα and IFNβ), IL-23, and IL-12 signaling (Gillooly et al. 2016; Sohn et al. 2013). Because IL-12 and IL-23 activity is particularly elevated in patients with autoimmune diseases such as psoriasis and/or inflammatory bowel disorders (O'Shea and Plenge, 2012), selective TYK2 inhibition, while avoiding JAK2-dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling, may be particularly beneficial in treating these diseases (Neubauer et al. 1998, Parganas et al. 1998).

Furthermore, TYK2 has been reported as a target for multiple autoimmune diseases, providing protection against inflammatory diseases and type 2 diabetes with limited effects on the immune system (Dendrou et al. 2016).

Thus, there continues to be an unmet medical need for the development of new and improved therapies in the treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies," particularly type I or type III interferonopathies), IL-12, and/or IL-23, particularly diseases such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.

In this regard, new drugs, in particular compound 1 (4-methyl-5-[3-methyl-7-[(6-morpholin-4-ylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-5-yl]oxypyridine-2-carbonitrile), are being developed.

Compound 1 is a small molecule inhibitor of the JAK family of tyrosine kinases, more specifically TYK2, and is currently being investigated as a drug for the treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies," particularly type I or type III interferonopathies), IL-12, and/or IL-23. The identification and synthesis of Compound 1 (also known as Cpd1) was previously described in WO 2019/076716.

An important characteristic of various biologically active substances (such as pharmaceuticals, medicines, and biocides, commonly referred to as drugs) is their "bioavailability," i.e., the concentration of the active substance in a form that can be absorbed and utilized by the target organ or organism. Bioavailability is often related to the drug's solubility in water, which can depend on many parameters, such as acid-base properties, crystalline form, and/or polymorphism.

Although drugs in their free base form may have low solubility in water, the presence of acidic sites (e.g., carboxylic acids, phenols, sulfonic acids) or basic sites (e.g., amino groups, basic nitrogen centers) can be advantageously used to generate salts of the drug. The resulting ionic compounds, due to their ionic properties and lower dissolution energy, are much more soluble in water and may therefore have improved bioavailability. A guideline of 50 μg/mL for water solubility is provided by Lipinski et al. (Lipinski et al. 2001).

Many salt-forming agents are available, and salt selection must be carefully designed. The goal of salt selection is to identify the best salt form suitable for development and is primarily based on four key criteria: water solubility at various pH levels, high crystallinity, low hygroscopicity, and optimal chemical stability (Stahl et al. 2011).

Cocrystals (or cocrystals) are aggregations of two or more chemical entities in a crystal lattice via non-covalent interactions. Over the past decade, cocrystals have been identified as potential alternative solid forms for pharmaceuticals. Cocrystal forms include solvates, solid solutions, eutectics, salts, ionic liquids, solid dispersions, and supramolecular gelators (Row, Kaur, and Cherukuvada 2016).

Polymorphism is a solid-state property of some molecules (and molecular complexes) in which a single molecule can occur in a variety of different crystalline structures with different physical properties, which can be characterized by determining the melting point, thermal behavior using thermogravimetric analysis (TGA) or differential scanning calorimetry (DSC), X-ray pattern diffraction (XRPD), infrared absorption fingerprint, and/or solid-state ( ¹³ C) NMR spectrum.

Once a suitable solid form, such as a crystalline or polymorphic form of a drug or its salt, can be identified, further investigations can be conducted to qualitatively and quantitatively identify alternative solid forms. The availability of such solid forms can be highly unpredictable and may require a combination of intuition, careful empirical design, perseverance, and serendipity. In addition to the challenges associated with finding one or more defined solid forms, the properties of any forms thus discovered must be carefully evaluated to confirm whether one or more of them are indeed suitable for pharmaceutical development. In a first aspect, the crystallinity of a drug can affect its solubility, dissolution rate, flowability, hardness, compressibility, and/or melting point, among other physical and mechanical properties. In a second aspect, crystalline forms may have advantages over amorphous forms; for example, purification to the high purity required by most regulatory authorities may be more efficient and therefore less costly for crystalline forms than amorphous solids. Additionally, handling of crystalline forms may be improved over amorphous forms, which may be, for example, oily or sticky; indeed, drying of crystalline materials with well-defined drying or desolvation temperatures may be more easily controlled than amorphous solids, which may in some cases have a greater affinity for organic solvents and variable drying temperatures. Finally, downstream processing of crystalline drugs may in some cases allow for enhanced process control. In a third aspect, physical and chemical stability and/or shelf life may be improved for certain crystalline forms over amorphous forms.

Additional pharmacokinetic and pharmacodynamic properties of drugs can be associated with a particular solid or crystalline structural form, and producing and maintaining that same form from production to administration to patients can be paramount. Therefore, obtaining salt, crystalline, and/or co-crystalline forms for amorphous materials is challenging but highly desirable (Hilfiker et al. 2006).

Accordingly, provided herein are, inter alia, novel pharmaceutical compositions and novel solid forms of the present invention (e.g., co-crystal and/or salt forms of Compound 1 and specific crystalline forms thereof), methods for preparing pharmaceutical compositions and/or solid forms and/or Compound 1, and pharmaceutical unit dosage compositions comprising the compositions and/or solid forms. The novel compositions and solid forms possess desirable pharmacological properties with a favorable pharmaceutical profile, particularly improved in vivo exposure over existing forms.

1 shows the ¹ H-NMR spectrum of the HCl salt form of Compound 1.

Shown are ^{the 1} H-NMR spectrum of Compound 1 (green) and the ¹ H-NMR spectrum of the HCl salt form of Compound 1 (red).

1 shows the XRPD of the HCl salt form of Compound 1.

1 shows the DSC curve of the HCl salt form of Compound 1.

1 shows the TGA curve of the HCl salt form of Compound 1.

1 shows the DVS curve of the HCl salt form of Compound 1.

1 shows the ¹ H-NMR spectrum of the mesylate form of Compound 1.

Shown are ^{the 1} H-NMR spectrum of Compound 1 (green) and the ¹ H-NMR spectrum of the mesylate salt form of Compound 1 (red).

1 shows the XRPD of the mesylate salt form of Compound 1.

1 shows the DSC curve of the mesylate salt form of Compound 1.

1 shows the TGA curve of the mesylate salt form of Compound 1.

1 shows the DVS curve of the mesylate salt form of Compound 1.

1 shows the ¹ H-NMR spectrum of the maleate co-crystal form of Compound 1.

Shown are ^{the 1} H-NMR spectrum of Compound 1 (green) and the ¹ H-NMR spectrum of the maleate co-crystal form of Compound 1 (red).

1 shows the DSC curve of the maleate co-crystal form of Compound 1.

1 shows the ¹ H-NMR spectrum of phosphate co-crystal Form A of Compound 1.

1 shows the DSC curve of Compound 1 phosphate salt Form A.

1 shows the TGA curve of phosphate co-crystal Form A of Compound 1.

1 shows the DVS curve of phosphate co-crystal Form A of Compound 1.

1 shows an XRPD of phosphate co-crystal Form A of Compound 1.

1 shows the ¹ H-NMR spectrum of phosphate co-crystal Form B of Compound 1.

1 shows the DSC curve of phosphate salt Form B of Compound 1.

1 shows the TGA curve of phosphate co-crystal Form B of Compound 1.

Figure 1 shows the ^1H -NMR spectrum of the fumarate co-crystal form of compound 1. ^1H NMR (400MHz, DMSO- _d6 ) δ ppm: 13.13 (s, 1H), 9.84 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.64 (d, J = 9.7 Hz, 1H), 7.43 (d, J = 9.7 Hz, 1H), 3.63 (s, 2H), 3.77 - 3.65 (m, 4H), 3.61 (s, 3H), 3.49 - 3.40 (m, 4H), 2.31 (s, 3H).

Shown are the ¹ H-NMR spectrum of Compound 1 (top) and the ¹ H-NMR spectrum of the fumarate co-crystal form of Compound 1 (bottom). Top: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.86 (s, 1H), 8.53 (s, 1H), 8.20 (s, 1H), 8.19 (s, 1H), 8.15 - 8.08 (m, 1H), 7.64 (d, J = 9.7 Hz, 1H), 7.43 (d, J = 9.7 Hz, 1H), 3.75 (t, J = 4.8 Hz, 4H), 3.61 (s, 3H), 3.50 - 3.42 (m, 4H), 2.31 (d, J = 0.7 Hz, 3H). Bottom ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 13.13 (s, 1H), 9.84 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.64 (d, J = 9.7 Hz, 1H), 7.43 (d, J = 9.7 Hz, 1H), 3.63 (s, 2H), 3.77 - 3.65 (m, 4H), 3.61 (s, 3H), 3.49 - 3.40 (m, 4H), 2.31 (s, 3H).

1 shows the XRPD of the fumarate co-crystal form of Compound 1.

1 shows the DSC curve for the fumarate co-crystal form of Compound 1. Sample 1.7 mg. Integral -336.00 mJ, normalized -197.65 Jg ^-1 ; Onset 253.90°C, Peak 259.72°C, End 262.42°C.

1 shows the TGA curve of the fumarate co-crystal form of Compound 1. Sample 1.94 mg, step -0.2946%, -5.74147e ^-03 mg.

1 shows the DVS curves for the fumarate co-crystal form of Compound 1. The white circle line represents adsorption #1, the black square line represents desorption #1, and the white triangle line represents adsorption #2.

1 shows the DSC-TGA curve of the L-tartrate co-crystal form of Compound 1.

1 shows the DVS curve of the L-tartrate co-crystal form of Compound 1.

1 shows the XRPD of the L-tartrate salt co-crystal form of Compound 1.

1 shows the ¹ H-NMR spectrum of the L-tartrate co-crystal form of Compound 1.

1 shows the DSC-TGA curve of the L-malate co-crystal form of Compound 1.

1 shows the DVS curve of the L-malate co-crystal form of Compound 1.

1 shows an XRPD of the L-malate co-crystalline form of Compound 1.

1 shows the ¹ H-NMR spectrum of the L-malate co-crystal form of Compound 1.

1 shows the DSC-TGA curve of the saccharinate co-crystal form of Compound 1.

1 shows the DVS curve of the saccharinate co-crystal form of Compound 1.

1 shows an XRPD of the saccharinate co-crystal form of Compound 1.

1 shows the ¹ H-NMR spectrum of the saccharinate co-crystal form of Compound 1.

1 shows the XRPD of Compound 1 hydrate (Form A).

1 shows the XRPD of anhydrous Compound 1 (Form C).

1 shows an XRPD of an amorphous composition comprising Compound 1 and fumaric acid.

Provided herein are solid forms of the invention that are useful for the prevention and/or treatment of, inter alia, allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and/or IL-23. In particular, compounds comprised in the solid forms of the invention inhibit the JAK family of tyrosine kinases, more specifically TYK2. Also provided herein, inter alia, are pharmaceutical compositions comprising the solid forms of the invention, as well as methods for the prevention and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and/or IL-23.

Thus, in first and second aspects of the present invention, there are provided the following pharmaceutical compositions and solid forms of Compound 1, respectively:

In further aspects, the solid forms of the present invention are crystalline forms. In particular aspects, the solid forms of the present invention are co-crystalline forms. In more particular aspects, the solid forms of the present invention are co-crystalline forms comprising two components. In further particular aspects, the solid forms of the present invention are co-crystalline forms comprising two components in a 1:1 ratio. In another aspect, the solid forms of the present invention are co-crystalline forms comprising Compound 1 and fumaric acid in a 1:1 ratio. In another aspect, the solid forms of the present invention are amorphous. In another aspect, the solid forms of the present invention are anhydrous. In another aspect, the solid forms are solvated. In another aspect, the solid forms are unsolvated.

In certain aspects, the solid forms of the present invention are provided for use in the prevention and/or treatment of, among other things, allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and/or IL-23. In certain aspects, the solid forms of the present invention are provided for use in the prevention and/or treatment of, among other things, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.

Furthermore, it has been unexpectedly demonstrated that the solid forms of the present invention exhibit improved bioavailability compared to other solid forms of Compound 1.

In a further aspect, a pharmaceutical composition is provided, comprising, inter alia, a solid form of the present invention and a pharmaceutical carrier, excipient, or diluent. In certain aspects, the pharmaceutical composition may further comprise an additional therapeutically active ingredient suitable for use in combination with the solid form of the present invention. In more specific aspects, the additional therapeutically active ingredient is an agent for the prevention and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNα, interferon ("interferonopathies," particularly type I or type III interferonopathies), IL-12, and/or IL-23.

Furthermore, the solid forms of the invention useful in the pharmaceutical compositions and treatment methods provided herein, as prepared and used, are pharmaceutically acceptable.

In a further aspect, there is provided a method for treating a mammal (particularly a human) suffering from a condition selected from those enumerated herein, in particular an allergic disease, an inflammatory disease, a metabolic disease, an autoinflammatory disease, an autoimmune disease, a proliferative disease, a transplant rejection, a disease involving a disorder of cartilage metabolism, a congenital cartilage malformation, and/or a disease associated with hypersecretion of IFNα, interferon ("interferonopathy", in particular type I or type III interferonopathy), IL-12, and/or IL-23, the method comprising administering an effective amount of a pharmaceutical composition or solid form of the invention described herein.

Also provided herein are, inter alia, pharmaceutical compositions comprising the solid forms of the present invention, and suitable pharmaceutical carriers, excipients, or diluents for use in medicaments. In certain aspects, the pharmaceutical compositions are for use in the prevention and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies," particularly type I or type III interferonopathies), IL-12, and/or IL-23.

In an additional aspect, provided herein are methods for synthesizing the solid forms of the present invention, using, inter alia, the exemplary synthetic protocols and routes disclosed hereinafter.

Other objects and advantages will become apparent to those skilled in the art upon consideration of the following detailed description.

DEFINITIONS The following terms are intended to have the meanings presented below and are useful in understanding the description and intended scope of the present invention.

Unless otherwise specified, the term "substituted" is defined as set forth below. Furthermore, it should be understood that the terms "group" and "radical" can be considered interchangeable when used herein.

The articles "a" and "an" may be used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an analog" means one analog or multiple analogs.

The term "cocrystal" or "co-crystal" refers to a crystalline material consisting of Compound 1 and a co-crystal former ("coformer") in the same crystal lattice. The terms "cocrystal" and "co-crystal" are used interchangeably herein.

References to a particular "dose" or "administration amount" refer to the equivalent amount of free base Compound 1 administered, i.e., do not include the weight of any salt, solvate, or co-crystal counterparts or components.

"Palladium precursor" means a material containing palladium that requires further activation or reaction to produce an active catalyst. Examples of palladium precursors are Pd(π-cinnamyl)Cl dimer, Pd(OAc) ₂ , Pd(Cl) ₂ , _Pd2 (dba) ₃ , Pd(dba _{) 2} , Pd( _PPh3 ) ₄ , Pd( _PPh3 ) _2Cl2 , Pd(acac) ₂ , and _Pd (PhCN) _2Cl2 .

"Pharmaceutically acceptable" means approved or approved by a regulatory authority of the federal or state government or corresponding agency of a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, and more specifically, in humans.

"Pharmaceutically acceptable salt" refers to a salt of a solid form of the present invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specific examples of such salts include: (1) acid addition salts (formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphor acid, and the like). or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or coordinates with an organic base (ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.). Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the compound contains a basic functional group, include salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

"Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier with which a solid form of the present invention is administered.

As used herein, the term "pharmaceutical composition" refers to a mixture containing a pharmaceutically acceptable active ingredient in combination with a suitable pharmaceutically acceptable excipient. In particular, the pharmaceutically acceptable ingredient is a solid form of the present invention.

Pharmaceutical excipients are substances other than pharmaceutically acceptable active ingredients that have been appropriately evaluated for safety and intentionally included in oral solid dosage forms. For example, excipients can aid in the processing of a drug delivery system during its manufacture; protect, support, or enhance stability, bioavailability, or patient acceptability; aid in product specification; or enhance any other attribute of the overall safety, efficacy, or delivery of the drug during storage or use. Examples of excipients include, but are not limited to, inert solid diluents (fillers, e.g., lactose), binders (e.g., starch), glidants (e.g., colloidal silica), lubricants (e.g., non-ionic lubricants such as vegetable oils), disintegrants (e.g., starch, polyvinylpyrrolidone), better polymers (e.g., hydroxypropyl methylcellulose), colorants (e.g., iron oxide), and/or surfactants (e.g., non-ionic surfactants). (Rowe et al. 2009)

As used herein, the term "pharmaceutical formulation" refers to the process by which different chemicals, including an active drug, are combined to produce a final pharmaceutical product. Examples of formulations include oral formulations (tablets, capsules), parenteral formulations (liquids, lyophilized powders), or topical formulations (skin, inhalation).

"Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier with which a solid form of the present invention is administered.

"Solvate" refers to a form of a compound that is associated with a solvent, usually by a solvolysis reaction. This physical association involves hydrogen bonding. Traditional solvents include water, ethanol, acetic acid, and the like. Solid forms of the invention may be prepared, for example, in crystalline form, and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric and non-stoichiometric solvates. In certain instances, a solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

The terms "inert solid diluent" or "solid diluent" or "diluent" refer to materials used to produce suitable dosage form size, performance, and processing characteristics of tablets and/or capsules. Inert solid diluents may also be referred to as fillers or fill materials. Specific examples of diluents include cellulose powder, silicified microcrystalline cellulose acetate, compressible sugar, powdered sugar, corn starch, and pregelatinized starch, dextrates, dextrin, dextrose, erythritol, ethyl cellulose, fructose, fumaric acid, glycerol palmitic acid stearate, inhaled lactose, isomalt, kaolin, lactitol, lactose, anhydrous, monohydrate, and corn starch, spray-dried monohydrate microcrystalline cellulose, maltodextrin, maltose, mannitol, medium-chain triglycerides, microcrystalline cellulose, polydextrose, polymethacrylate, simethicone, sorbitol, pregelatinized starch, sterilizable maize, sucrose, sugar spheres, sulfobutyl ether beta-cyclodextrin, talc, tragacanth, trehalose, or xylitol. More specific examples of diluents include cellulose powder, silicified microcrystalline cellulose acetate, compressible sugar, corn starch, and pregelatinized starch, dextrose, fructose, glycerol palmitate stearate, anhydrous, monohydrate, and corn starch, spray-dried monohydrate and microcrystalline cellulose, maltodextrin, maltose, mannitol, medium-chain triglycerides, microcrystalline cellulose, polydextrose, sorbitol, starch, pregelatinized, sucrose, sugar spheres, trehalose, or xylitol.

"Lubricant" refers to a material that prevents ingredients from clumping together or from sticking to tablet punches or capsule-filling machines. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die walls. Specific examples of lubricants include canola oil, hydrogenated castor oil, cottonseed oil, glyceryl behenate, glyceryl monostearate, glyceryl palmitate stearate, magnesium stearate, medium-chain triglycerides, mineral oil, light mineral oil, octyldodecanol, poloxamer, polyethylene glycol, polyoxyethylene stearate, polyvinyl alcohol, starch, or hydrogenated vegetable oil. More specific examples of lubricants include magnesium stearate, glyceryl behenate, glyceryl monostearate, or hydrogenated vegetable oil.

"Disintegrants" refer to substances that swell when wet, causing the tablet to break down in the digestive tract and release the active ingredient for absorption. They ensure that when the tablet comes into contact with water, it quickly breaks down into smaller pieces, facilitating dissolution. Specific examples of disintegrants include alginic acid, powdered cellulose, chitosan, colloidal silicon dioxide, corn starch and pregelatinized starch, crospovidone, glycine, guar gum, low-substituted hydroxypropyl cellulose, methylcellulose, microcrystalline cellulose, croscarmellose sodium, or povidone.

The term "colorant" refers to an agent that imparts color to a formulation. Specific examples of colorants include iron oxides or synthetic organic dyes (U.S. Food and Drug Administration, Code of Federal Regulations, Title 21 CFR Part 73, Subpart B).

The term "plasticizing agent" or "plasticizer" refers to a substance added to promote the flexibility of a film or coating. Specific examples of plasticizers include polyethylene glycol or propylene glycol.

The term "pigment" refers to an insoluble colorant.

The terms "film coating" or "coating" or "coating material" refer to a substance used to create a cosmetic or functional layer on the exterior surface of a dosage form. Specific examples of film coatings include glucose syrup, maltodextrin, alginate, or carrageenan.

"Glidant" refers to a material used to promote powder flow by reducing interparticle friction and cohesion. These are used in combination with lubricants due to their inability to reduce die wall friction. Specific examples of glidants include powdered cellulose, colloidal silicon dioxide, hydrophobic colloidal silica, silicon dioxide, or talc. More specific examples of glidants include colloidal silicon dioxide, hydrophobic colloidal silica, silicon dioxide, or talc.

"Flavoring agent" refers to a material that can be used to mask unpleasant-tasting active ingredients and improve patient acceptance of completing a course of medication. Flavoring agents can be natural (e.g., fruit extracts) or artificial. Non-limiting examples of flavoring agents include mint, cherry, anise, peach, apricot, licorice, raspberry, or vanilla.

"Prodrug" refers to a compound, including derivatives of the solid forms of the present invention, that has a cleavable group and becomes pharmaceutically active in vivo by solvolysis or under physiological conditions. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, etc.

"Subject" includes a human. The terms "human," "patient," and "subject" are used interchangeably herein.

"Effective amount" means the amount of a solid form of the present invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated.

"Preventing" or "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder (i.e., preventing at least one clinical symptom of the disease from developing in a subject who may be exposed to a disease-causing agent or who may be predisposed to the disease prior to the onset of the disease).

The term "prophylaxis" is related to "prevention" and refers to measures or procedures aimed at preventing, rather than treating or curing, a disease. Non-limiting examples of preventive measures may include the administration of vaccines, the administration of low molecular weight heparin to hospital patients at risk of thrombosis due to immobility, and the administration of antimalarial drugs such as chloroquine before visiting geographic areas where malaria is endemic or where there is a high risk of contracting malaria.

"Treating" or "treatment" of any disease or disorder, in one embodiment, refers to ameliorating the disease or disorder (i.e., halting the disease or reducing the sign, extent, or severity of at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treating" refers to modulating the disease or disorder, either physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing physical parameters), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease.

As used herein, the term "allergic disease" refers to a group of conditions characterized by impaired immune system hypersensitivity, including allergic airway diseases (e.g., asthma, rhinitis), sinusitis, eczema, and urticaria, as well as food allergies or allergies to insect venom.

As used herein, the term "asthma" refers to a pulmonary disorder characterized by altered pulmonary gas flow associated with airway narrowing of any cause (intrinsic, extrinsic, or both, allergic or non-allergic). The term asthma may be used with one or more adjectives to indicate the cause.

As used herein, the term "inflammatory disease" refers to a group of conditions including rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway diseases (e.g., asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory liver diseases (e.g., primary biliary cholangitis (PBC) and/or primary sclerosing cholangitis (PSC)), inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis), endotoxin-driven disease states (e.g., post-bypass surgery complications or chronic endotoxin states, e.g., contributing to chronic heart failure), and related diseases involving cartilage, such as joints. In particular, the term refers to rheumatoid arthritis, osteoarthritis, allergic airway diseases (e.g., asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease. More specifically, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel disease. Most specifically, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease.

As used herein, the term "metabolic disease" refers to a group of conditions involving the body's ability to process certain nutrients and vitamins. Metabolic disorders include phenylketonuria (PKU), type 2 diabetes, hyperlipidemia, gout, and rickets. Specific examples of metabolic disorders are type 2 diabetes and/or obesity.

As used herein, the term "autoinflammatory disease" refers to a group of diseases including cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndromes (TRAPS), Behçet's disease, systemic juvenile idiopathic arthritis (SJIA), or Still's disease.

As used herein, the term "autoimmune disease" refers to a group of diseases including COPD, asthma (e.g., intrinsic asthma, extrinsic asthma, dust-related asthma, infantile asthma), particularly chronic or refractory asthma (e.g., late-onset asthma and airway hyperresponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type 1 diabetes and its associated complications, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto's thyroiditis and autoimmune thyroiditis), contact dermatitis and further eczematous dermatitis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), interferon-associated diseases, atherosclerosis, and obstructive airway diseases, including amyotrophic lateral sclerosis. In particular, the term refers to COPD, asthma, systemic lupus erythematosus, type 1 diabetes, interferonism, and inflammatory bowel disease.

As used herein, the term "proliferative disorder" refers to conditions such as cancer (e.g., uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g., polycythemia vera, essential thrombocythemia, and myelofibrosis), leukemia (e.g., acute myeloid leukemia, acute and chronic lymphoblastic leukemia), multiple myeloma, psoriasis, restenosis, scleroderma, or fibrosis. In particular, the term refers to cancer, leukemia, multiple myeloma, and psoriasis.

As used herein, the term "cancer" refers to a malignant or benign growth of cells in the skin or body organs, such as, but not limited to, the breast, prostate, lung, kidney, pancreas, stomach, or intestine. Cancers tend to invade adjacent tissues and spread (metastasize) to distant organs, such as the bone, liver, lung, or brain. As used herein, the term "cancer" includes both metastatic tumor cell types (including, but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mast cell tumor) and tissue cancer types (including, but not limited to, colorectal cancer, prostate cancer, small cell and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, kidney cancer, stomach cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer, and uterine leiomyosarcoma). In particular, the term "cancer" includes acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, endometrial carcinoma, ependymoblastoma, ependymoma, esophageal cancer, Ewing's sarcoma family of tumors, eye cancer, retinoblastoma, esophageal cancer ... tumor, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor (endocrine pancreas), Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt's lymphoma, cutaneous T-cell Lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoma, Waldenstrom's hypergammaglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, non-pharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papilloma, parathyroid cancer, penile cancer, pharyngeal cancer, moderately differentiated pineal parenchymal tumor, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell neoplasm/multiple This refers to myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing's sarcoma family of tumors, Kaposi's sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's hypergammaglobulinemia, and Wilms' tumor.

As used herein, the term "leukemia" refers to neoplastic diseases of the blood and blood-forming organs. Such diseases can cause bone marrow and immune system dysfunction, making the host highly susceptible to infection and bleeding. In particular, the term "leukemia" refers to acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic lymphoblastic leukemia (CLL).

As used herein, the term "transplant rejection" refers to acute or chronic rejection of cells, tissues, or solid organs, for example, pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, nervous tissue, heart, lung, combined cardiopulmonary system, kidney, liver, intestine, pancreas, trachea, or esophagus, or graft-versus-host disease.

As used herein, the term "diseases involving disorders of cartilage metabolism" includes osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, painful osteodystrophy, Tietze's syndrome or costochondritis, fibromyalgia, osteochondritis, neuropathic or neuropathic arthritis, joint disorders, endemic forms of arthritis (such as endemic osteoarthritis, Muserenyi's disease, and Handigodu's disease), degeneration due to fibromyalgia, fibromyalgia, systemic lupus erythematosus, scleroderma, and ankylosing spondylitis. In certain embodiments, the term refers to ankylosing spondylitis.

As used herein, the term "congenital cartilage malformation" includes conditions such as hereditary chondrolysis, chondrodysplasia, and pseudochondrodysplasia, particularly, but not limited to, microtia, anotia, metaphyseal chondrodysplasia, and related disorders.

As used herein, diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and/or IL-23 include conditions such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, multiple sclerosis, trisomy 21, psoriatic arthritis, ulcerative colitis, and/or Crohn's disease.

As used herein, the term "solid forms of the invention" and equivalent expressions are meant to encompass the amorphous or crystalline solid forms described herein, and this expression includes, where the context allows, pharmaceutically acceptable salts, crystals, and co-crystals, and their respective solvates, e.g., hydrates, and solvates of pharmaceutically acceptable salts/co-crystals/crystals. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to encompass, where the context allows, their salts and solvates.

Solid forms, such as crystalline or amorphous forms, may be referred to herein as being characterized by the graphical data "shown" or "substantially shown" in the figures. Such data include, for example, powder X-ray diffractograms and solid-state NMR spectra. It is well known in the art that graphical data potentially provides a "fingerprint" containing additional technical information that further defines each solid form that cannot be described solely by reference to numerical values or peak positions. Those skilled in the art will understand that such graphical representations of data may be subject to minor variations in peak relative intensities and/or peak positions due to certain factors, including, for example, variations in instrumentation, sample concentration, and/or purity.

Other derivatives of the solid forms of the present invention are active in both their acid and acid-derivative forms, although the acid-sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (Bundgard, H., 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the solid forms of the present invention are particularly useful prodrugs. In some cases, it may be desirable to prepare double ester-type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters _. Particularly such prodrugs are _{C1-8 alkyl} , _{C2-8 alkenyl} , _C6-10 optionally substituted aryl, and ( _C6-10 aryl)-( _C1-4 alkyl) esters of _the solid forms of the present invention.

All isotopic forms of the solid forms of the present invention also include either (i) forms in which all atoms of a given atomic number have a mass number (or mixture of mass numbers) that is predominant in nature (referred to herein as "natural isotopic forms"), or (ii) forms in which one or more atoms have the same atomic number but a mass number that differs from the mass number of atoms that are predominant in nature (referred to herein as "unnatural variant isotopic forms"). It is understood that atoms may naturally exist as mixtures of mass numbers. The term "unnatural variant isotopic forms" also includes embodiments in which the proportion of atoms of a given atomic number that have mass numbers that are less common in nature (referred to herein as "uncommon isotopes") is increased compared to that occurring in nature, e.g., to a level of >20%, >50%, >75%, >90%, >95%, or >99% by atomic number of atoms of that atomic number (the latter embodiments being referred to as "isotopically enriched variant forms"). The term "non-natural variant isotopic form" also includes embodiments in which the proportion of an uncommon isotope is reduced compared to that found in nature. Isotopic forms can include radioactive forms (i.e., incorporating a radioactive isotope) and non-radioactive forms. Radioactive forms are typically isotopically enriched variant forms.

Thus, non-natural variant isotopic forms of a compound may include one or more artificial or uncommon isotopes such as deuterium ( ² H or D), carbon-11 ( ¹¹ C), carbon-13 ( ¹³ C), carbon- ¹⁴ ( ¹⁴ C), nitrogen-13 ( ¹³ N), nitrogen-15 ( ¹⁵ N), oxygen-15 ( ¹⁵ O), oxygen-17 ( ¹⁷ O), oxygen-18 ( ¹⁸ O), phosphorus-32 ( ³² P), sulfur-35 ( ³⁵ S), chlorine-36 ( ³⁶ Cl), chlorine-37 ( ³⁷ Cl), fluorine-18 ( ¹⁸ F), iodine-123 ( ^{123 I), iodine-125 ( 125} I) at one or more atoms, or may include an increased proportion of such isotopes at one or more atoms compared to the proportion predominant in nature.

Non-natural variant isotopic forms containing radioactive isotopes may be used, for example, in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Non-natural variant isotopic forms incorporating deuterium (i.e., ² H or D) may offer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some situations. Furthermore, non-natural variant isotopic forms incorporating positron-emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N can be prepared and may be useful in positron emission topography (PET) studies to examine substrate receptor occupancy.

It should also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are referred to as "isomers." Isomers that differ in the arrangement of their atoms in space are referred to as "stereoisomers."

Stereoisomers that are not mirror images of one another are called "diastereomers," while stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

"Tautomers" refer to compounds that are interchangeable forms of a particular compound structure and differ in the replacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the shifting of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are also formed by treatment with acid or base.

Tautomeric forms may be relevant to achieving optimal chemical reactivity and biological activity of a desired compound.

The compounds contained in the solid forms of the present invention may have one or more asymmetric centers. Accordingly, such compounds may be produced as individual (R) or (S) stereoisomers, or as mixtures thereof.

Unless otherwise indicated, the description or naming of a compound in the specification and claims is intended to include both individual enantiomers and mixtures thereof, racemic or otherwise. Methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

It is understood that the solid forms of the present invention can be metabolized to produce biologically active metabolites.

Provided herein are solid forms of the invention useful for the prevention and/or treatment of, inter alia, allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and/or IL-23. In particular, pharmaceutical compositions or solid forms of the invention comprising Compound 1 inhibit JAK, a family of tyrosine kinases, more specifically TYK2. Also provided herein, inter alia, are pharmaceutical compositions comprising the solid forms of the present invention, and methods for the prevention and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNα, interferon ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and/or IL-23 by administering a pharmaceutical composition comprising a solid form of the present invention or a solid form of the present invention comprising Compound 1.

Thus, provided herein are, inter alia, pharmaceutical compositions and solid forms of the invention comprising Compound 1:

In one embodiment, the solid form of the present invention is a cocrystal. In another embodiment, the pharmaceutical composition of the present invention comprises Compound 1 and fumaric acid. In a particular embodiment, the solid form of the present invention is a fumarate cocrystal. In a more particular embodiment, the solid form of the present invention is a fumarate cocrystal in which Compound 1 and fumaric acid are present in a 1:1 ratio.

In one embodiment, compound 1 is present in its natural isotopic form.

In one embodiment, Compound 1 is a non-natural variant isotopic form. In certain embodiments, the non-natural variant isotopic form is a form in which deuterium (i.e., ^2H or D) is incorporated and hydrogen is specified in the chemical structure at one or more atoms of Compound 1. In one embodiment, the atoms of Compound 1 are in an isotopic form that is not radioactive. In one embodiment, one or more atoms of Compound 1 are in an isotopic form that is radioactive. Preferably, the radioisotope is a stable isotope. Preferably, the non-natural variant isotopic form is a pharmaceutically acceptable form.

In one embodiment, Compound 1 is provided, wherein a single atom of the compound exists in a non-natural variant isotopic form. In another embodiment, Compound 1 is provided, wherein two or more atoms exist in a non-natural variant isotopic form.

Non-natural isotopically variant forms can generally be prepared by conventional techniques known to those of skill in the art or by processes described herein (e.g., by processes similar to those described in the accompanying Examples for preparing natural isotopically variant forms). Thus, non-natural isotopically variant forms can be prepared by substituting appropriate isotopically variant (or labeled) reagents for the conventional reagents used in the Examples.

In one embodiment, Compound 1 is not an isotopic variant.

HCl Salt Form of Compound 1 One solid form is the HCl salt form of Compound 1, which exhibits peaks in an XRPD spectrum. A particular form of this solid form is the HCl salt form of Compound 1, and may be characterized by an X-ray powder diffraction pattern having one or more peaks at the following positions: 4.8, 6.0, 7.6, 8.7, 9.2, 9.7, 11.7, 11.9, 12.3, 14.2, 14.5, 15.0, 16.4, 18.0, 19.2, 21.4, 22.5, 23.6, 24.1, or 25.8 degrees 2θ±0.2 degrees 2θ. A particular form of this solid form may be characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 1C. Particular forms of this solid form may be characterized by an X-ray powder diffraction pattern having one or more peaks at the following positions: 4.8, 6.0, 7.6, 8.7, 9.2, 9.7, 11.7, 11.9, 12.3, 14.2, 14.5, 15.0, 16.4, 18.0, 19.2, 21.4, 22.5, 23.6, 24.1, or 25.8 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 1C.

A particular form of this solid form is the HCl salt form of Compound 1, and may be characterized by an X-ray powder diffraction pattern having at least 1, 5, 10, 15, or more peaks at the following positions: 4.8, 6.0, 7.6, 8.7, 9.2, 9.7, 11.7, 11.9, 12.3, 14.2, 14.5, 15.0, 16.4, 18.0, 19.2, 21.4, 22.5, 23.6, 24.1, or 25.8 degrees 2θ ± 0.2 degrees 2θ. Particular forms of this solid form may be characterized by an X-ray powder diffraction pattern having at least 1, 5, 10, 15, or more peaks at the following positions: 4.8, 6.0, 7.6, 8.7, 9.2, 9.7, 11.7, 11.9, 12.3, 14.2, 14.5, 15.0, 16.4, 18.0, 19.2, 21.4, 22.5, 23.6, 24.1, or 25.8 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 1C.

One solid form is the HCl salt form of Compound 1, which may be characterized by an X-ray powder diffraction pattern containing peaks at at least 4.8, 6.0, 7.6, 9.7, and 11.7 degrees 2θ±0.2 degrees 2θ.

One solid form is the HCl salt form of Compound 1, which may be characterized by an X-ray powder diffraction pattern containing peaks at 4.8, 6.0, 7.6, 9.7, and 11.7 degrees 2θ±0.2 degrees 2θ.

One solid form is the HCl salt form of Compound 1, which may be characterized by an X-ray powder diffraction pattern having peaks at all of the following positions: 4.8, 6.0, 7.6, 8.7, 9.2, 9.7, 11.7, 11.9, 12.3, 14.2, 14.5, 15.0, 16.4, 18.0, 19.2, 21.4, 22.5, 23.6, 24.1, and 25.8 degrees 2θ ± 0.2 degrees 2θ. Particular forms of this solid form may be characterized by an X-ray powder diffraction pattern having peaks at all of the following positions: 4.8, 6.0, 7.6, 8.7, 9.2, 9.7, 11.7, 11.9, 12.3, 14.2, 14.5, 15.0, 16.4, 18.0, 19.2, 21.4, 22.5, 23.6, 24.1, and 25.8 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 1C.

One solid form is the HCl salt form of Compound 1, which can be characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1C.

One solid form is the HCl salt form of Compound 1, which can be characterized by a ¹ H NMR spectrum substantially as shown in FIG. 1A.

One solid form is the HCl salt form of Compound 1, which can be characterized by a DSC curve substantially according to Figure 1D.

One solid form is the HCl salt form of Compound 1, which can be characterized by a TGA curve substantially according to Figure 1E.

One solid form is the HCl salt form of Compound 1, which can be characterized by a DVS curve substantially according to Figure 1F.

Mesylate Salt of Compound 1 One solid form is the mesylate salt form of Compound 1, which exhibits peaks in an XRPD spectrum. A particular form of this solid form is the mesylate salt form of Compound 1 and may be characterized by an X-ray powder diffraction pattern having one or more peaks at the following positions: 8.5, 9.3, 9.8, 11.3, 12.1, 15.1, 15.2, 16.7, 17.0, 17.2, 17.5, 17.7, 18.7, 20.4, 22.1, 22.5, 22.6, 25.3, 25.6, or 26.2 degrees 2θ±0.2 degrees 2θ. A particular form of this solid form may be characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 2C. Particular forms of this solid form may be characterized by an X-ray powder diffraction pattern having one or more peaks at the following positions: 8.5, 9.3, 9.8, 11.3, 12.1, 15.1, 15.2, 16.7, 17.0, 17.2, 17.5, 17.7, 18.7, 20.4, 22.1, 22.5, 22.6, 25.3, 25.6, or 26.2 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 2C.

A particular form of this solid form is the mesylate salt form of Compound 1 and may be characterized by an X-ray powder diffraction pattern having at least 1, 5, 10, 15, 20, 25, or more peaks at the following positions: 8.5, 9.3, 9.8, 11.3, 12.1, 15.1, 15.2, 16.7, 17.0, 17.2, 17.5, 17.7, 18.7, 20.4, 22.1, 22.5, 22.6, 25.3, 25.6, or 26.2 degrees 2θ ± 0.2 degrees 2θ. Particular forms of this solid form may be characterized by an X-ray powder diffraction pattern having at least 1, 5, 10, 15, 20, 25, or more peaks at the following positions: 8.5, 9.3, 9.8, 11.3, 12.1, 15.1, 15.2, 16.7, 17.0, 17.2, 17.5, 17.7, 18.7, 20.4, 22.1, 22.5, 22.6, 25.3, 25.6, or 26.2 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 2C.

One solid form is the mesylate salt form of Compound 1, which may be characterized by an X-ray powder diffraction pattern comprising peaks at at least 8.5, 12.1, 15.1, 15.2, 16.7, and 25.3 degrees 2θ±0.2 degrees 2θ.

One solid form is the mesylate salt form of Compound 1, which may be characterized by an X-ray powder diffraction pattern containing peaks at 8.5, 12.1, 15.1, 15.2, 16.7, and 25.3 degrees 2θ±0.2 degrees 2θ.

A particular form of this solid form is the mesylate form of Compound 1, which may be characterized by an X-ray powder diffraction pattern having peaks at all of the following positions: 8.5, 9.3, 9.8, 11.3, 12.1, 15.1, 15.2, 16.7, 17.0, 17.2, 17.5, 17.7, 18.7, 20.4, 22.1, 22.5, 22.6, 25.3, 25.6, and 26.2 degrees 2θ ± 0.2 degrees 2θ. Particular forms of this solid form may be characterized by an X-ray powder diffraction pattern having peaks at all of the following positions: 8.5, 9.3, 9.8, 11.3, 12.1, 15.1, 15.2, 16.7, 17.0, 17.2, 17.5, 17.7, 18.7, 20.4, 22.1, 22.5, 22.6, 25.3, 25.6, and 26.2 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 2C.

One solid form is the mesylate salt form of Compound 1, which can be characterized by an X-ray powder diffraction pattern substantially as shown in Figure 2C.

One solid form is the mesylate salt form of Compound 1, which may be characterized by a ¹ H NMR spectrum substantially as shown in FIG. 2A.

One solid form is the mesylate salt form of Compound 1, which can be characterized by a DSC curve substantially according to Figure 2D.

One solid form is the mesylate salt form of Compound 1, which can be characterized by a TGA curve substantially according to Figure 2E.

One solid form is the mesylate salt form of Compound 1, which can be characterized by a DVS curve substantially according to Figure 2F.

Maleate Co-Crystal Form or Co-Crystal Form I of Compound 1
One solid form is a maleate co-crystalline form of Compound 1.

A particular form of this solid form may be characterized by a ¹ H-NMR spectrum substantially according to FIG. 3A.

A particular form of this solid form may be characterized by a DSC curve substantially according to Figure 3C.

Phosphate co-crystal Form A or Co-crystal Form IIA of Compound 1
One solid form is phosphate co-crystal Form A of Compound 1. A particular form of this solid form is phosphate co-crystal Form A of Compound 1 and may be characterized by an X-ray powder diffraction pattern having one or more peaks at the following positions: 4.2, 4.6, 6.4, 7.7, 8.4, 10.2, 12.5, 12.8, 13.9, 15.6, 16.8, 17.5, 18.6, 19.3, 20.4, 22.1, 22.9, 24.1, 24.8, or 25.1 degrees 2θ±0.2 degrees 2θ. A particular form of this solid form may be characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 4E. Particular forms of this solid form may be characterized by an X-ray powder diffraction pattern having one or more peaks at the following positions: 4.2, 4.6, 6.4, 7.7, 8.4, 10.2, 12.5, 12.8, 13.9, 15.6, 16.8, 17.5, 18.6, 19.3, 20.4, 22.1, 22.9, 24.1, 24.8, or 25.1 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 4E.

A particular form of this solid form is phosphate co-crystal Form A of Compound 1, which may be characterized by an X-ray powder diffraction pattern having at least 1, 5, 10, 15, 20, 25, or more peaks at the following positions: 4.2, 4.6, 6.4, 7.7, 8.4, 10.2, 12.5, 12.8, 13.9, 15.6, 16.8, 17.5, 18.6, 19.3, 20.4, 22.1, 22.9, 24.1, 24.8, or 25.1 degrees 2θ ± 0.2 degrees 2θ. Particular forms of this solid form may be characterized by an X-ray powder diffraction pattern having at least 1, 5, 10, 15, or more peaks at the following positions: 4.2, 4.6, 6.4, 7.7, 8.4, 10.2, 12.5, 12.8, 13.9, 15.6, 16.8, 17.5, 18.6, 19.3, 20.4, 22.1, 22.9, 24.1, 24.8, or 25.1 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 4E.

One solid form is phosphate co-crystal Form A of Compound 1, which can be characterized by an X-ray powder diffraction pattern containing peaks at at least 4.2, 7.7, 8.4, 12.8, 17.5, and 18.6 degrees 2θ±0.2 degrees 2θ.

One solid form is phosphate co-crystal Form A of Compound 1, which can be characterized by an X-ray powder diffraction pattern containing peaks at 4.2, 7.7, 8.4, 12.8, 17.5, and 18.6 degrees 2θ±0.2 degrees 2θ.

A particular form of this solid form is phosphate co-crystal Form A of Compound 1, which can be characterized by an X-ray powder diffraction pattern having peaks at all of the following positions: 4.2, 4.6, 6.4, 7.7, 8.4, 10.2, 12.5, 12.8, 13.9, 15.6, 16.8, 17.5, 18.6, 19.3, 20.4, 22.1, 22.9, 24.1, 24.8, and 25.1 degrees 2θ ± 0.2 degrees 2θ. Particular forms of this solid form may be characterized by an X-ray powder diffraction pattern having peaks at all of the following positions: 4.2, 4.6, 6.4, 7.7, 8.4, 10.2, 12.5, 12.8, 13.9, 15.6, 16.8, 17.5, 18.6, 19.3, 20.4, 22.1, 22.9, 24.1, 24.8, and 25.1 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 4E.

One solid form is phosphate co-crystal Form A of Compound 1, which can be characterized by an X-ray powder diffraction pattern substantially as shown in Figure 4E.

One solid form is phosphate co-crystal Form A of Compound 1, which can be characterized by ^{a 1} H-NMR spectrum substantially according to FIG. 4A.

One solid form is phosphate co-crystal Form A of Compound 1, which can be characterized by a DSC curve substantially according to Figure 4B.

One solid form is phosphate co-crystal Form A of Compound 1, which can be characterized by a TGA curve substantially according to Figure 4C.

One solid form is phosphate co-crystal Form A of Compound 1, which can be characterized by a DVS curve substantially according to Figure 4D.

Phosphate Co-Crystal Form B or Co-Crystal Form IIB of Compound 1
One solid form is phosphate co-crystal Form B of Compound 1.

One solid form is phosphate co-crystal Form B of Compound 1, which can be characterized by a ¹ H-NMR spectrum substantially according to FIG. 5A.

One solid form is phosphate co-crystal Form B of Compound 1, which can be characterized by a DSC curve substantially according to Figure 5B.

One solid form is phosphate co-crystal Form B of Compound 1, which can be characterized by a TGA curve substantially according to Figure 5C.

Fumarate Co-Crystal Form or Co-Crystal Form III of Compound 1
In one embodiment, the solid form of the invention is a fumarate co-crystal of Compound 1. In particular embodiments, the solid form of the invention is a fumarate co-crystal of Compound 1 and may be characterized by an X-ray powder diffraction pattern with one or more peaks at the following positions: 3.4, 6.8, 7.1, 8.6, 11.0, 12.4, 13.8, 14.3, 14.8, 15.5, 17.1, 18.3, 20.5, 20.8, 21.2, 22.4, 22.9, 23.9, 24.9, 25.6, or 26.5 degrees 2θ±0.2 degrees 2θ. In more particular embodiments, the solid form of the invention may be characterized by an X-ray powder diffraction pattern substantially as shown in Figure 6C. In a most particular embodiment, the solid form of the present invention may be characterized by an X-ray powder diffraction pattern having one or more peaks at the following positions: 3.4, 6.8, 7.1, 8.6, 11.0, 12.4, 13.8, 14.3, 14.8, 15.5, 17.1, 18.3, 20.5, 20.8, 21.2, 22.4, 22.9, 23.9, 24.9, 25.6, or 26.5 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 6C.

In certain embodiments, the solid form of the present invention is a fumarate co-crystal of Compound 1 and may be characterized by an X-ray powder diffraction pattern having at least 1, 5, 10, 15, 20, 25, or more peaks at the following positions: 3.4, 6.8, 7.1, 8.6, 11.0, 12.4, 13.8, 14.3, 14.8, 15.5, 17.1, 18.3, 20.5, 20.8, 21.2, 22.4, 22.9, 23.9, 24.9, 25.6, or 26.5 degrees 2θ ± 0.2 degrees 2θ. In a most particular embodiment, the solid form of the present invention may be characterized by an X-ray powder diffraction pattern having at least 1, 5, 10, 15, 20, 25, or more peaks at the following positions: 3.4, 6.8, 7.1, 8.6, 11.0, 12.4, 13.8, 14.3, 14.8, 15.5, 17.1, 18.3, 20.5, 20.8, 21.2, 22.4, 22.9, 23.9, 24.9, 25.6, or 26.5 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 6C.

In one embodiment, the solid form of the present invention is a fumarate co-crystal of Compound 1 and may be characterized by an X-ray powder diffraction pattern comprising peaks at at least 3.4, 7.1, 8.6, 12.4, 13.8, 14.3, and 14.8 degrees 2θ ± 0.2 degrees 2θ.

In another embodiment, the solid form of the present invention is a fumarate co-crystal of Compound 1 and may be characterized by an X-ray powder diffraction pattern containing peaks at 3.4, 7.1, 8.6, 12.4, 13.8, 14.3, and 14.8 degrees 2θ ± 0.2 degrees 2θ. In a particular embodiment, the solid form of the present invention is a fumarate co-crystal of Compound 1 and may be characterized by an X-ray powder diffraction pattern containing peaks at all of the following positions: 3.4, 6.8, 7.1, 8.6, 11.0, 12.4, 13.8, 14.3, 14.8, 15.5, 17.1, 18.3, 20.5, 20.8, 21.2, 22.4, 22.9, 23.9, 24.9, 25.6, and 26.5 degrees 2θ ± 0.2 degrees 2θ. In a most particular embodiment, the solid form of the present invention may be characterized by an X-ray powder diffraction pattern having peaks at all of the following positions: 3.4, 6.8, 7.1, 8.6, 11.0, 12.4, 13.8, 14.3, 14.8, 15.5, 17.1, 18.3, 20.5, 20.8, 21.2, 22.4, 22.9, 23.9, 24.9, 25.6, and 26.5 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 6C.

In one embodiment, the solid form of the present invention is a fumarate co-crystal of Compound 1 and can be characterized by an X-ray powder diffraction pattern substantially as shown in Figure 6C.

In one embodiment, the solid form of the present invention is a fumarate co-crystalline form of Compound 1, which may be characterized by a ¹ H-NMR spectrum substantially according to Figure 6A.

In one embodiment, the solid form of the present invention is a fumarate co-crystal of Compound 1 and can be characterized by a DSC curve substantially according to Figure 6D.

In one embodiment, the solid form of the present invention is a fumarate co-crystal of Compound 1 and can be characterized by a TGA curve substantially according to Figure 6E.

In one embodiment, the solid form of the present invention is a fumarate co-crystal of Compound 1 and may be characterized by a DVS curve substantially according to Figure 6F.

L-Tartrate Co-Crystal Form or Co-Crystal Form IV of Compound 1
One solid form is the L-tartrate co-crystalline form of Compound 1. A particular form of this solid form is the L-tartrate co-crystalline form of Compound 1 and may be characterized by an X-ray powder diffraction pattern having one or more peaks at the following positions: 3.7, 7.5, 7.8, 8.2, 10.2, 10.6, 13.2, 14.2, 15.0, 15.3, 15.6, 16.6, 17.4, 17.7, 19.0, 19.1, 20.4, 20.8, 22.7, 23.4, 23.7, 24.4, 26.2, 27.2, 29.3, or 32.6 degrees 2θ±0.2 degrees 2θ. A particular form of this solid form may be characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 7C. Particular forms of this solid form may be characterized by an X-ray powder diffraction pattern having one or more peaks at the following positions: 3.7, 7.5, 7.8, 8.2, 10.2, 10.6, 13.2, 14.2, 15.0, 15.3, 15.6, 16.6, 17.4, 17.7, 19.0, 19.1, 20.4, 20.8, 22.7, 23.4, 23.7, 24.4, 26.2, 27.2, 29.3, or 32.6 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 7C.

A particular form of this solid form is an L-tartrate co-crystalline form of Compound 1, which may be characterized by an X-ray powder diffraction pattern having at least 1, 5, 10, 15, 20, 25, or more peaks at the following positions: 3.7, 7.5, 7.8, 8.2, 10.2, 10.6, 13.2, 14.2, 15.0, 15.3, 15.6, 16.6, 17.4, 17.7, 19.0, 19.1, 20.4, 20.8, 22.7, 23.4, 23.7, 24.4, 26.2, 27.2, 29.3, or 32.6 degrees 2θ ± 0.2 degrees 2θ. Particular forms of this solid form may be characterized by an X-ray powder diffraction pattern having at least 1, 5, 10, 15, or more peaks at the following positions: 3.7, 7.5, 7.8, 8.2, 10.2, 10.6, 13.2, 14.2, 15.0, 15.3, 15.6, 16.6, 17.4, 17.7, 19.0, 19.1, 20.4, 20.8, 22.7, 23.4, 23.7, 24.4, 26.2, 27.2, 29.3, or 32.6 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 7C.

One solid form is an L-tartrate co-crystalline form of Compound 1, which may be characterized by an X-ray powder diffraction pattern containing peaks at at least 3.7, 7.5, 7.8, 13.2, 15.5, and 16.6 degrees 2θ±0.2 degrees 2θ.

One solid form is an L-tartrate co-crystalline form of Compound 1, which can be characterized by an X-ray powder diffraction pattern containing peaks at 3.7, 7.5, 7.8, 13.2, 15.5, and 16.6 degrees 2θ ± 0.2 degrees 2θ.

A particular form of this solid form is the L-tartrate co-crystalline form of Compound 1, which may be characterized by an X-ray powder diffraction pattern having peaks at all of the following positions: 3.7, 7.5, 7.8, 8.2, 10.2, 10.6, 13.2, 14.2, 15.0, 15.3, 15.6, 16.6, 17.4, 17.7, 19.0, 19.1, 20.4, 20.8, 22.7, 23.4, 23.7, 24.4, 26.2, 27.2, 29.3, and 32.6 degrees 2θ ± 0.2 degrees 2θ. Particular forms of this solid form may be characterized by an X-ray powder diffraction pattern having peaks at all of the following positions: 3.7, 7.5, 7.8, 8.2, 10.2, 10.6, 13.2, 14.2, 15.0, 15.3, 15.6, 16.6, 17.4, 17.7, 19.0, 19.1, 20.4, 20.8, 22.7, 23.4, 23.7, 24.4, 26.2, 27.2, 29.3, and 32.6 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 7C.

One solid form is an L-tartrate salt co-crystal of Compound 1, which can be characterized by an X-ray powder diffraction pattern substantially as shown in Figure 7C.

One solid form is the L-tartrate salt co-crystalline form of Compound 1, which can be characterized by a ¹ H-NMR spectrum substantially according to FIG. 7D.

One solid form is the L-tartrate co-crystalline form of Compound 1, which can be characterized by a DSC-TGA curve substantially according to Figure 7A.

One solid form is the L-tartrate co-crystalline form of Compound 1, which can be characterized by a DVS curve substantially according to Figure 7B.

L-Malate Co-Crystal Form or Co-Crystal Form V of Compound 1
One solid form is the L-malate co-crystalline form of Compound 1. A particular form of this solid form is the L-malate co-crystalline form of Compound 1, which has the following positions: 6.3, 9.0, 10.6, 11.1, 12.6, 12.9, 13.9, 14.0, 15.0, 15.9, 16.2, 16.6, 16.8, 17.0, 17.9, 18.3, 18.7, 19.4, 20.4, 20.7, 21.1, 21.2, 21.6, 22.2, 22.3, 23.0, 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 39.0, 40.0, 41.0, 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 49.0, 50.0, 51.0, 52.0, 53.0, 54.0, 55.0, 56.0, 57.0, 58.0, 59.0, 60.0, 61.0, 62.0, 63.0, 64.0, 65.0, 66.0, 67.0, 68.0, 69.0, 70.0, 71.0, 72.0, 73.0, 74.0, 75.0 8C. A particular form of this solid form may be characterized by an X-ray powder diffraction pattern having one or more peaks at 2.6, 23.3, 24.0, 24.8, 25.4, 25.9, 26.4, 26.6, 27.3, 28.0, 28.3, 29.7, 30.2, 30.8, 31.2, 31.6, 32.1, 33.8, 34.5, 35.1, 37.1, 38.4, 39.9, 41.5, or 43.2 degrees 2θ±0.2 degrees 2θ. A particular form of this solid form may be characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 8C. Specific forms of this solid form are at the following positions: 6.3, 9.0, 10.6, 11.1, 12.6, 12.9, 13.9, 14.0, 15.0, 15.9, 16.2, 16.6, 16.8, 17.0, 17.9, 18.3, 18.7, 19.4, 20.4, 20.7, 21.1, 21.2, 21.6, 22.2, 22.3, 22.6, 23.3, 24.0, 24.8, 25.4 , 25.9, 26.4, 26.6, 27.3, 28.0, 28.3, 29.7, 30.2, 30.8, 31.2, 31.6, 32.1, 33.8, 34.5, 35.1, 37.1, 38.4, 39.9, 41.5, or 43.2 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 8C .

A particular form of this solid form is the L-malate co-crystalline form of Compound 1, which has the following positions: 6.3, 9.0, 10.6, 11.1, 12.6, 12.9, 13.9, 14.0, 15.0, 15.9, 16.2, 16.6, 16.8, 17.0, 17.9, 18.3, 18.7, 19.4, 20.4, 20.7, 21.1, 21.2, 21.6, 22.2, 22.3, 22.6, 23.3, 24. The compound may be characterized by an X-ray powder diffraction pattern having at least 1, 5, 10, 15, 20, 25, or more peaks at 0, 24.8, 25.4, 25.9, 26.4, 26.6, 27.3, 28.0, 28.3, 29.7, 30.2, 30.8, 31.2, 31.6, 32.1, 33.8, 34.5, 35.1, 37.1, 38.4, 39.9, 41.5, or 43.2 degrees 2θ±0.2 degrees 2θ. Specific forms of this solid form are at the following positions: 6.3, 9.0, 10.6, 11.1, 12.6, 12.9, 13.9, 14.0, 15.0, 15.9, 16.2, 16.6, 16.8, 17.0, 17.9, 18.3, 18.7, 19.4, 20.4, 20.7, 21.1, 21.2, 21.6, 22.2, 22.3, 22.6, 23.3, 24.0, 24.8, 25.4, 25.9, 26. 4, 26.6, 27.3, 28.0, 28.3, 29.7, 30.2, 30.8, 31.2, 31.6, 32.1, 33.8, 34.5, 35.1, 37.1, 38.4, 39.9, 41.5, or 43.2 degrees 2θ ± 0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 8C.

One solid form is an L-malate co-crystalline form of Compound 1, which may be characterized by an X-ray powder diffraction pattern containing peaks at at least 6.3, 10.6, 15.0, 16.2, and 17.0 degrees 2θ±0.2 degrees 2θ.

A particular form of this solid form is the L-malate co-crystalline form of Compound 1, which can be characterized by an X-ray powder diffraction pattern containing peaks at 6.3, 10.6, 15.0, 16.2, and 17.0 degrees 2θ ± 0.2 degrees 2θ.

A particular form of this solid form is the L-malate co-crystalline form of Compound 1, which has the following positions: 6.3, 9.0, 10.6, 11.1, 12.6, 12.9, 13.9, 14.0, 15.0, 15.9, 16.2, 16.6, 16.8, 17.0, 17.9, 18.3, 18.7, 19.4, 20.4, 20.7, 21.1, 21.2, 21.6, 22.2, 22.3, The compound may be characterized by an X-ray powder diffraction pattern having peaks at all of the following angles: 22.6, 23.3, 24.0, 24.8, 25.4, 25.9, 26.4, 26.6, 27.3, 28.0, 28.3, 29.7, 30.2, 30.8, 31.2, 31.6, 32.1, 33.8, 34.5, 35.1, 37.1, 38.4, 39.9, 41.5, and 43.2 degrees 2θ±0.2 degrees 2θ. Specific forms of this solid form are at the following positions: 6.3, 9.0, 10.6, 11.1, 12.6, 12.9, 13.9, 14.0, 15.0, 15.9, 16.2, 16.6, 16.8, 17.0, 17.9, 18.3, 18.7, 19.4, 20.4, 20.7, 21.1, 21.2, 21.6, 22.2, 22.3, 22.6, 23.3, 24.0, 24.8, 25.4 , 25.9, 26.4, 26.6, 27.3, 28.0, 28.3, 29.7, 30.2, 30.8, 31.2, 31.6, 32.1, 33.8, 34.5, 35.1, 37.1, 38.4, 39.9, 41.5, and 43.2 degrees 2θ ± 0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 8C.

One solid form is the L-malate co-crystalline form of Compound 1, which can be characterized by an X-ray powder diffraction pattern substantially as shown in Figure 8C.

One solid form is the L-malate co-crystalline form of Compound 1, which can be characterized by a ¹ H NMR spectrum substantially as shown in FIG. 8D.

One solid form is the L-malate co-crystalline form of Compound 1, which can be characterized by a DSC-TGA curve substantially according to Figure 8A.

One solid form is the L-malate co-crystalline form of Compound 1, which can be characterized by a DVS curve substantially according to Figure 8B.

Saccharinate Co-Crystal Form or Co-Crystal Form VI of Compound 1
One solid form is the saccharinate co-crystal form of Compound 1. A particular form of this solid form is the saccharinate co-crystal form of Compound 1, which has the following positions: 5.6, 6.5, 9.0, 9.8, 11.1, 11.3, 12.4, 13.0, 13.9, 14.7, 15.0, 15.6, 15.8, 16.4, 16.7, 17.0, 17.9, 18.5, 19.2, 19.4, 19.7, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 25.0, 25.6, 25.8, 25.8, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 27 9.5, 20.8, 21.3, 21.6, 22.4, 23.9, 24.8, 25.5, 26.1, 27.0, 27.4, 27.9, 29.5, 30.3, 31.3, 32.0, 32.7, 33.6, 36.3, 36.9, 38.2, or 42.2 degrees 2θ ± 0.2 degrees 2θ. A particular form of this solid form may be characterized by an X-ray powder diffraction pattern substantially as shown in Figure 9C. Specific forms of this solid form are those at the following positions: 5.6, 6.5, 9.0, 9.8, 11.1, 11.3, 12.4, 13.0, 13.9, 14.7, 15.0, 15.6, 15.8, 16.4, 16.7, 17.0, 17.9, 18.5, 19.2, 19.4, 19.7, 20.0, 20.5, 20.8, 21.3, 21.6, 22.4, 9C , and having one or more peaks at 23.9, 24.8, 25.5, 26.1, 27.0, 27.4, 27.9, 29.5, 30.3, 31.3, 32.0, 32.7, 33.6, 36.3, 36.9, 38.2, or 42.2 degrees 2θ±0.2 degrees 2θ.

A particular form of this solid form is the saccharinate co-crystal form of Compound 1, which has the following positions: 5.6, 6.5, 9.0, 9.8, 11.1, 11.3, 12.4, 13.0, 13.9, 14.7, 15.0, 15.6, 15.8, 16.4, 16.7, 17.0, 17.9, 18.5, 19.2, 19.4, 19.7, 20.0, 20.5, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.6, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.6, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 25.0, 25.6, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 28.0, 28.1, 28.2, 28 The compound may be characterized by an X-ray powder diffraction pattern having at least 1, 5, 10, 15, or more peaks at 1.3, 21.6, 22.4, 23.9, 24.8, 25.5, 26.1, 27.0, 27.4, 27.9, 29.5, 30.3, 31.3, 32.0, 32.7, 33.6, 36.3, 36.9, 38.2, or 42.2 degrees 2θ±0.2 degrees 2θ. Specific forms of this solid form are at the following positions: 5.6, 6.5, 9.0, 9.8, 11.1, 11.3, 12.4, 13.0, 13.9, 14.7, 15.0, 15.6, 15.8, 16.4, 16.7, 17.0, 17.9, 18.5, 19.2, 19.4, 19.7, 20.0, 20.5, 20.8, 21.3, 21.6, 22.4, 23.9, 24.8 , 25.5, 26.1, 27.0, 27.4, 27.9, 29.5, 30.3, 31.3, 32.0, 32.7, 33.6, 36.3, 36.9, 38.2, or 42.2 degrees 2θ ± 0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 9C.

One solid form is a saccharinate co-crystalline form of Compound 1, which may be characterized by an X-ray powder diffraction pattern containing peaks at at least 5.6, 6.5, 11.3, 13.0, and 15.0 degrees 2θ±0.2 degrees 2θ.

A particular form of this solid form is a saccharinate co-crystalline form of Compound 1, which may be characterized by an X-ray powder diffraction pattern containing peaks at 5.6, 6.5, 11.3, 13.0, and 15.0 degrees 2θ ± 0.2 degrees 2θ.

A particular form of this solid form is the saccharinate co-crystal form of Compound 1, which has the following positions: 5.6, 6.5, 9.0, 9.8, 11.1, 11.3, 12.4, 13.0, 13.9, 14.7, 15.0, 15.6, 15.8, 16.4, 16.7, 17.0, 17.9, 18.5, 19.2, 19.4, 19.7, 20.0, 21.0, 22.0, 23.0, 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 39.0, 40.0, 41.0, 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 49.0, 50.0, 51.0, 52.0, 53.0, 54.0, 55.0, 56.0, 57.0, 58.0, 59.0, 60.0, 61.0, 62.0, 63.0, 64.0, 65.0, 66.0, 67.0, 68.0, 69.0, 70.0, 71.0, 72.0, 73.0, 74.0, 75.0, 76.0, 77.0, 78.0, 79 It may be characterized by an X-ray powder diffraction pattern having peaks at all of the following angles: 0.5, 20.8, 21.3, 21.6, 22.4, 23.9, 24.8, 25.5, 26.1, 27.0, 27.4, 27.9, 29.5, 30.3, 31.3, 32.0, 32.7, 33.6, 36.3, 36.9, 38.2, and 42.2 degrees 2θ±0.2 degrees 2θ. Specific forms of this solid form are those at the following positions: 5.6, 6.5, 9.0, 9.8, 11.1, 11.3, 12.4, 13.0, 13.9, 14.7, 15.0, 15.6, 15.8, 16.4, 16.7, 17.0, 17.9, 18.5, 19.2, 19.4, 19.7, 20.0, 20.5, 20.8, 21.3, 21.6, 22.4, The compound may be characterized by an X-ray powder diffraction pattern having peaks at 23.9, 24.8, 25.5, 26.1, 27.0, 27.4, 27.9, 29.5, 30.3, 31.3, 32.0, 32.7, 33.6, 36.3, 36.9, 38.2, and 42.2 degrees 2θ ± 0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in FIG. 9C.

One solid form is the saccharinate salt form of Compound 1, which can be characterized by an X-ray powder diffraction pattern substantially as shown in Figure 9C.

One solid form is the saccharinate salt form of Compound 1, which may be characterized by a ¹ H NMR spectrum substantially as shown in Figure 9D.

One solid form is a saccharinate co-crystalline form of Compound 1, which can be characterized by a DSC-TGA curve substantially according to Figure 9A.

One solid form is a saccharinate co-crystalline form of Compound 1, which can be characterized by a DVS curve substantially according to Figure 9B.

Pharmaceutical Compositions When used as pharmaceuticals, the solid forms of the present invention comprising Compound 1 are typically administered in the form of pharmaceutical compositions. Such compositions can be prepared in a manner well known in the pharmaceutical arts and include solid forms comprising Compound 1. Generally, the solid form comprising Compound 1 is administered in a pharmaceutically effective amount. The amount of Compound 1 actually administered will typically be determined by a physician in light of relevant circumstances, including the condition being treated, the selected route of administration, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

The pharmaceutical compositions of the present invention can be administered by a variety of routes, including oral, rectal, transdermal, subcutaneous, intraarticular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, solid forms containing Compound 1 are preferably formulated as either injectable or oral compositions, or as ointments, lotions, or patches for transdermal administration.

Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each containing a predetermined quantity of active agent calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient, vehicle, or carrier. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or pills, tablets, capsules, and the like in the case of solid compositions. In such compositions, Compound 1 is typically a minor component (about 0.1 to about 70% by weight, or preferably about 1 to about 60% by weight, and even more preferably about 1 to about 40% by weight), with the remainder being various vehicles, excipients, or carriers, and processing aids useful in forming the desired dosage form.

Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients: binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint orange flavor, or compounds of a similar nature.

The above ingredients for orally administrable compositions are merely representative. Other materials, as well as processing techniques, etc., are described in Part 8 of Remington's Pharmaceutical Sciences, ^17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania (incorporated herein by reference).

The pharmaceutical compositions or solid forms of the present invention can also be administered in sustained-release form or from sustained-release drug delivery systems. A description of representative sustained-release materials can be found in Remington's Pharmaceutical Sciences.

The following formulation examples illustrate representative pharmaceutical compositions that may be prepared according to the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

Formulation 1—Tablets A solid form containing Compound 1 can be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small amount of magnesium stearate can be added as a lubricant. The mixture can be formed into 270 mg tablets (90 mg of Compound 1 per tablet) in a tablet press.

Formulation 2—Capsules A solid form containing Compound 1 can be mixed as a dry powder with a starch diluent in an approximately 1:1 weight ratio. The mixture can be filled into 250 mg capsules (125 mg of Compound 1 per capsule).

Formulation 3—Liquid A solid form containing Compound 1 (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg). The resulting mixture can be blended, passed through a No. 10 mesh US sieve, and then mixed with a pre-made solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color can be diluted with water and added with stirring. Sufficient water can then be added with stirring. Sufficient water can then be added to produce a total volume of 5 mL.

Formulation 4—Tablets A solid form containing Compound 1 can be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small amount of magnesium stearate can be added as a lubricant. The mixture can be formed into 450 mg tablets (150 mg of Compound 1) in a tablet press.

Pharmaceutical Unit Dose Compositions The present invention further provides pharmaceutical unit dose compositions.

In one embodiment, the present invention provides a pharmaceutical unit dose composition comprising 70 mg to 300 mg of Compound 1.

In a specific embodiment, the unit dose is in a form selected from a liquid, a tablet, a capsule, or a gelcap. In a most specific embodiment, the unit dose is in the form of a tablet. In another most specific embodiment, the unit dose is in the form of a capsule.

Compounds for Use in Treatment and/or Methods of Treatment In one embodiment, provided herein are solid forms of the invention or pharmaceutical compositions comprising solid forms of the invention, inter alia, for use in medicine. In particular embodiments, provided herein are solid forms of the invention or pharmaceutical compositions comprising solid forms of the invention, for use in the prevention and/or treatment of, inter alia, allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and/or IL-23.

In another embodiment, provided herein is a solid form of the invention or a pharmaceutical composition comprising a solid form of the invention for use in the manufacture of a medicament for use in the prevention and/or treatment of, inter alia, allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and/or IL-23.

In a further method of treatment aspect, provided herein is a method for the prophylaxis and/or treatment of a mammal suffering from, inter alia, an allergic disease, an inflammatory disease, a metabolic disease, an autoinflammatory disease, an autoimmune disease, a proliferative disease, a transplant rejection, a disease involving disorders of cartilage metabolism, a congenital cartilage malformation, and/or a disease associated with hypersecretion of IFNα, interferon ("interferonopathies," particularly type I or type III interferonopathies), IL-12, and/or IL-23, particularly a disease selected from systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, multiple sclerosis, trisomy 21, psoriatic arthritis, ulcerative colitis, and/or Crohn's disease, the method comprising administering an effective amount of a solid form of Compound 1 of the present invention or a pharmaceutical composition comprising a solid form of the present invention for the treatment or prevention of the condition.

In one embodiment, provided herein, inter alia, is a solid form of the invention or a pharmaceutical composition comprising a solid form of the invention, and another therapeutic agent. In certain embodiments, the other therapeutic agent is a therapeutic agent for an allergic disease, an inflammatory disease, a metabolic disease, an autoinflammatory disease, an autoimmune disease, a proliferative disease, transplant rejection, a disease involving disorders of cartilage metabolism, congenital cartilage malformations, and/or a disease associated with hypersecretion of IFNα, interferon ("interferonopathies," particularly type I or type III interferonopathies), IL-12, and/or IL-23.

In one embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in medicine. In a specific embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in the prevention and/or treatment of an allergic disease. In a specific embodiment, the allergic disease is asthma.

In another embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in the manufacture of a medicament for use in the prevention and/or treatment of an allergic disorder. In a particular embodiment, the allergic disorder is asthma.

In a further method of treatment aspect, the present invention provides a method of preventing and/or treating a mammal suffering from an allergic disease, the method comprising administering a solid form of the invention or a pharmaceutical composition comprising a solid form of the invention for the treatment or prevention of the condition. In a particular embodiment, the allergic disease is asthma.

In one embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention, and another therapeutic agent. In certain embodiments, the other therapeutic agent is a therapeutic agent for an allergic disorder. In certain embodiments, the allergic disorder is asthma.

In one embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in medicine. In a particular embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in the prevention and/or treatment of an inflammatory disease. In a particular embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel disease. In a more particular embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease.

In another embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in the manufacture of a medicament for use in the prevention and/or treatment of an inflammatory disease. In specific embodiments, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel disease. In more specific embodiments, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease.

In a further method of treatment aspect, the present invention provides a method for the prevention and/or treatment of a mammal suffering from an inflammatory disease, the method comprising administering an effective amount of a solid form of Compound 1 of the present invention or a pharmaceutical composition comprising a solid form of the present invention for the treatment or prevention of the condition. In certain embodiments, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel disease. In more specific embodiments, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease.

In one embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention, and another therapeutic agent. In a specific embodiment, the other therapeutic agent is a therapeutic agent for an inflammatory disease. In a specific embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel disease. In a more specific embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease.

In one embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in medicine. In a particular embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in the prevention and/or treatment of a metabolic disease. In a particular embodiment, the metabolic disease is type II diabetes and/or obesity.

In another embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in the manufacture of a medicament for use in the prevention and/or treatment of a metabolic disease. In a particular embodiment, the metabolic disease is type II diabetes and/or obesity.

In a further method of treatment aspect, the present invention provides a method for preventing and/or treating a mammal suffering from a metabolic disease, the method comprising administering an effective amount of a solid form of Compound 1 of the present invention or a pharmaceutical composition comprising a solid form of the present invention for treating or preventing the condition. In certain embodiments, the metabolic disease is type II diabetes and/or obesity.

In one embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention, and another therapeutic agent. In certain embodiments, the other therapeutic agent is a therapeutic agent for a metabolic disorder. In certain embodiments, the metabolic disorder is type II diabetes and/or obesity.

In one embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in medicine. In a particular embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in the prevention and/or treatment of an autoimmune disease. In a particular embodiment, the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type 1 diabetes, interferonopathy, and inflammatory bowel disease.

In another embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in the manufacture of a medicament for use in the prevention and/or treatment of an autoimmune disease. In certain embodiments, the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type 1 diabetes, interferonopathy, and inflammatory bowel disease.

In a further method of treatment aspect, the present invention provides a method for the prevention and/or treatment of a mammal suffering from an autoimmune disease, the method comprising administering an effective amount of a solid form of Compound 1 of the present invention or a pharmaceutical composition comprising a solid form of the present invention for the treatment or prevention of the condition. In certain embodiments, the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type 1 diabetes, interferonopathy, and inflammatory bowel disease.

In one embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention, and another therapeutic agent. In certain embodiments, the other therapeutic agent is a therapeutic agent for an autoimmune disease. In certain embodiments, the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type 1 diabetes, interferonopathy, and inflammatory bowel disease.

In one embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in medicine. In a particular embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in the prevention and/or treatment of an autoinflammatory disease. In a particular embodiment, the autoimmune disease is cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndromes (TRAPS), Behçet's disease, systemic juvenile idiopathic arthritis (SJIA), or Still's disease.

In another embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in the manufacture of a medicament for use in the prevention and/or treatment of an autoinflammatory disease. In certain embodiments, the autoimmune disease is cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndromes (TRAPS), Behçet's disease, systemic juvenile idiopathic arthritis (SJIA), or Still's disease.

In a further method of treatment aspect, the present invention provides a method for the prevention and/or treatment of a mammal suffering from an autoinflammatory disease, the method comprising administering an effective amount of a solid form of Compound 1 of the present invention or a pharmaceutical composition comprising a solid form of the present invention for the treatment or prevention of the condition. In certain embodiments, the autoimmune disease is cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndromes (TRAPS), Behcet's disease, systemic juvenile idiopathic arthritis (SJIA), or Still's disease.

In one embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention, and another therapeutic agent. In certain embodiments, the other therapeutic agent is a therapeutic agent for an autoinflammatory disease. In certain embodiments, the autoimmune disease is cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndromes (TRAPS), Behçet's disease, systemic juvenile idiopathic arthritis (SJIA), or Still's disease.

In one embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in medicine. In a specific embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in the prevention and/or treatment of a proliferative disease. In a specific embodiment, the proliferative disease is cancer, leukemia, multiple myeloma, and psoriasis.

In another embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in the manufacture of a medicament for use in the prevention and/or treatment of a proliferative disorder. In certain embodiments, the proliferative disorder is cancer, leukemia, multiple myeloma, and psoriasis.

In a further method of treatment aspect, the present invention provides a method for the prevention and/or treatment of a mammal suffering from a proliferative disorder, the method comprising administering an effective amount of a solid form of Compound 1 of the present invention or a pharmaceutical composition comprising a solid form of the present invention for the treatment or prevention of the condition. In certain embodiments, the proliferative disorder is cancer, leukemia, multiple myeloma, and psoriasis.

In one embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention, and another therapeutic agent. In certain embodiments, the other therapeutic agent is a therapeutic agent for a proliferative disorder. In certain embodiments, the proliferative disorder is cancer, leukemia, multiple myeloma, and psoriasis.

In one embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in medicine. In a particular embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in the prevention and/or treatment of a disease associated with a disorder of cartilage metabolism. In a particular embodiment, the disease associated with a disorder of cartilage metabolism is ankylosing spondylitis.

In another embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in the manufacture of a medicament for use in the prevention and/or treatment of a disease associated with a disorder of cartilage metabolism. In a particular embodiment, the disease associated with a disorder of cartilage metabolism is ankylosing spondylitis.

In a further method of treatment aspect, the present invention provides a method for the prevention and/or treatment of a mammal suffering from a disease associated with a disorder of cartilage metabolism, the method comprising administering an effective amount for the treatment or prevention of the condition of Compound 1 of the present invention in a solid form or a pharmaceutical composition comprising a solid form of the present invention. In a particular embodiment, the disease associated with a disorder of cartilage metabolism is ankylosing spondylitis.

In one embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in medicine. In a specific embodiment, the present invention provides a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in the prevention and/or treatment of a disease associated with hypersecretion of IFNα, IL-12, and/or IL-23. In a specific embodiment, the disease associated with hypersecretion of IFNα, IL-12, and/or IL-23 is a disease selected from systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, multiple sclerosis, trisomy 21, psoriatic arthritis, ulcerative colitis, and/or Crohn's disease.

In another embodiment, the present invention provides a solid form of a compound of the present invention or a pharmaceutical composition comprising a solid form of the present invention for use in the manufacture of a medicament for use in the prevention and/or treatment of a disease associated with hypersecretion of IFNα, IL-12, and/or IL-23. In a specific embodiment, the disease associated with hypersecretion of IFNα, IL-12, and/or IL-23 is a disease selected from systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, multiple sclerosis, trisomy 21, psoriatic arthritis, ulcerative colitis, and/or Crohn's disease.

In a further method of treatment aspect, the present invention provides a method for the prevention and/or treatment of a mammal suffering from a disease associated with hypersecretion of IFNα, interferon ("interferonosis," particularly type I or type III interferonosis), IL-12, and/or IL-23, the method comprising administering an effective amount of a solid form of Compound 1 of the present invention or a pharmaceutical composition comprising a solid form of the present invention for the treatment or prevention of the condition. In certain embodiments, the disease associated with hypersecretion of IFNα, interferon ("interferonosis," particularly type I or type III interferonosis), IL-12, and/or IL-23 is a disease selected from systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, multiple sclerosis, trisomy 21, psoriatic arthritis, ulcerative colitis, and/or Crohn's disease.

In some embodiments, injection dose levels can range from about 0.1 mg/kg/h to at least 10 mg/kg/h, all from about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady-state levels. The maximum total dose is expected to not exceed about 1 g/day for a 40-80 kg human patient.

For the prevention and/or treatment of long-term conditions, such as degenerative conditions, treatment regimens can extend over months or years in some embodiments. In such embodiments, oral administration may be preferred for patient convenience and tolerability. For oral administration, a typical regimen is one to four times daily, e.g., one to three times daily, typically one to two times daily, and most typically once daily. Alternatively, for agents with long-lasting effects, oral administration once every two weeks, once weekly, and once daily are typical regimens. In particular, the administration regimen can be every one to fourteen days, more specifically every one to ten days, even more specifically every one to seven days, and most specifically every one to three days.

Using these dosing patterns, in some embodiments, each dose can provide 70-300 mg of a solid form of the present invention, with particular doses each providing 75-300 mg, more specifically 90-300 mg, even more specifically 90-225 mg, even more specifically 90-225 mg, and most specifically 90-150 mg.

Transdermal doses are generally selected to provide blood levels similar to or lower than those achieved using injected doses.

When used to prevent the onset of a condition, the solid forms of the invention are administered at the dosage levels described above, typically under the advice and supervision of a physician, to patients at risk of developing the condition. Patients at risk of developing a particular condition generally include those with a family history of the condition or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

The solid forms of the present invention may be administered as the sole active agent or may be administered in combination with other therapeutic agents (including other solid forms of the present invention that exhibit the same or similar therapeutic activity and that have been determined to be safe and effective for such co-administration). In certain embodiments, co-administration of two (or more) agents may allow significantly lower doses of each to be used, thereby reducing observed side effects.

In one embodiment, a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention is administered as a medicament. In certain embodiments, the pharmaceutical composition further comprises an additional active ingredient.

In one embodiment, the solid form of the present invention or a pharmaceutical composition comprising the solid form of the present invention is co-administered with another therapeutic agent for the treatment and/or prevention of a disease involving inflammation. Specific agents include, but are not limited to, immunomodulators such as azathioprine, corticosteroids (e.g., prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, mycophenolate mofetil, muromonab-CD3 (OKT3, e.g., Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.

In one embodiment, a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention is co-administered with another therapeutic agent for the treatment and/or prevention of arthritis (e.g., rheumatoid arthritis). Specific agents include, but are not limited to, analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, synthetic DMARDs (e.g., but not limited to, methotrexate, leflunomide, sulfasalazine, auranofin, gold sodium thiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, tofacitinib, baricitinib, fostamatinib, and cyclosporine), and biologic DMARDs (e.g., but not limited to, infliximab, etanercept, adalimumab, rituximab, and abatacept).

In one embodiment, the solid form of the invention or a pharmaceutical composition comprising the solid form of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of a proliferative disorder. Specific agents include methotrexate, leucovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubine, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibodies (e.g., Herceptin™), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g., Iressa®, Tafamidis®), and the like. Examples of therapeutic agents include, but are not limited to, VEGF inhibitors (e.g., ceva™, Erbitux™), VEGF inhibitors (e.g., Avastin™), proteasome inhibitors (e.g., Velcade™), Glivec®, and hsp90 inhibitors (e.g., 17-AAG). Additionally, the pharmaceutical compositions or solid forms of the present invention may be administered in combination with other therapies, including, but not limited to, radiation therapy or surgery. In certain embodiments, the proliferative disorder is selected from cancer, myeloproliferative disorders, or leukemia.

In one embodiment, the solid form of the present invention or a pharmaceutical composition comprising the solid form of the present invention is co-administered with another therapeutic agent for the treatment and/or prevention of an autoimmune disease. Specific agents include, but are not limited to, glucocorticoids, cytostatics (e.g., purine analogs), alkylating agents (e.g., nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds, and others), antimetabolites (e.g., methotrexate, azathioprine, and mercaptopurine), cytotoxic antibiotics (e.g., dactinomycin anthracycline, mitomycin C, bleomycin, and mithramycin), antibodies (e.g., anti-CD20, anti-CD25, or anti-CD3 (OTK3) monoclonal antibodies, Atgam®, and Thymoglobuline®), cyclosporine, tacrolimus, rapamycin (sirolimus), interferons (e.g., IFN-β), TNF-binding proteins (e.g., infliximab, etanercept, or adalimumab), mycophenolate, fingolimod, and myriocin.

In one embodiment, a solid form of the invention or a pharmaceutical composition comprising a solid form of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of asthma and/or rhinitis and/or COPD. Specific agents include, but are not limited to, beta2-adrenergic receptor agonists (e.g., salbutamol, levalbuterol, terbutaline, and bitolterol), epinephrine (inhalant or tablet), anticholinergics (e.g., ipratropium bromide), and glucocorticoids (oral or inhaled). Long-acting beta-2 agonists (e.g., salmeterol, formoterol, bambuterol, and sustained-release oral albuterol), inhaled steroid and long-acting bronchodilator combinations (e.g., fluticasone/salmeterol, budesonide/formoterol), leukotriene antagonists and synthesis inhibitors (e.g., montelukast, zafirlukast, and zileuton), mediator release inhibitors (e.g., cromoglycate and ketotifen), biological modulators of IgE responses (e.g., omalizumab), antihistamines (e.g., cetirizine, cinnarizine, fexofenadine), and vasoconstrictors (e.g., oxymetazoline, xylometazoline, naphazoline, and tramazoline).

Additionally, the solid forms of the present invention or pharmaceutical compositions comprising the solid forms of the present invention may be administered in combination with emergency therapies for asthma and/or COPD. Such therapies include oxygen or heliox administration, nebulized salbutamol or terbutaline, optionally in combination with an anticholinergic (e.g., ipratropium), systemic steroids (oral or intravenous, e.g., prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, nonspecific beta-agonists, injected or inhaled (e.g., epinephrine, isoetharine, isoproterenol, metaproterenol), anticholinergics (IV or nebulized, e.g., glycopyrrolate, atropine, ipratropium), methylxanthines (theophylline, aminophylline, bamifylline), inhaled anesthetics with bronchodilatory effects (e.g., isoflurane, halothane, enflurane), ketamine, and intravenous magnesium sulfate.

In one embodiment, a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention is co-administered with another therapeutic agent for the treatment and/or prevention of inflammatory bowel disease (IBD). Specific agents include, but are not limited to, glucocorticoids (e.g., prednisone, budesonide), synthetic disease-modifying agents, immunomodulators (e.g., methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine, and cyclosporine), and biologic disease-modifying agents, immunomodulators (infliximab, adalimumab, rituximab, and abatacept).

In one embodiment, the solid form of the present invention or a pharmaceutical composition comprising the solid form of the present invention is co-administered with another therapeutic agent for the treatment and/or prevention of systemic lupus erythematosus (SLE). Specific medications include, but are not limited to, human monoclonal antibodies (belimumab (Benlysta)), disease-modifying antirheumatic drugs (DMARDs), such as antimalarials (e.g., Plaquenil, hydroxychloroquine), immunosuppressants (e.g., methotrexate and azathioprine), cyclophosphamide and mycophenolate, immunosuppressants and analgesics (e.g., nonsteroidal anti-inflammatory drugs), opiates (e.g., dextropropoxyphene and co-codamol), opioids (e.g., hydrocodone, oxycodone, MS Contin, or methadone) and fentanyl duragesic transdermal patches, and S1P receptor modulators (e.g., fingolimod, siponimod, ozanimod, cenerimod, and ponesimod).

In one embodiment, the solid form of the present invention or a pharmaceutical composition comprising the solid form of the present invention is co-administered with another therapeutic agent for the treatment and/or prevention of psoriasis. Specific agents include bath solutions, moisturizers, medicated creams and ointments containing coal tar, dithranol (anthralin), corticosteroids (desoximethasone (Topicort™)), fluocinonide, vitamin D3 analogs (e.g., calcipotriol), argan oil, and retinoids (etretinate, acitretin, tazarotene), systemic treatments (e.g., methotrexate, cyclosporine, retinoids, thioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus). These include, but are not limited to, topical treatments such as steroids, fumarates, or biologics (e.g., Amevive™, Enbrel™, Humira™, Remicade™, Raptiva™, and ustekinumab (an IL-12 and IL-23 blocker)). Additionally, the solid forms of the present invention or pharmaceutical compositions comprising the solid forms of the present invention may be administered in combination with other therapies, including, but not limited to, phototherapy or photochemotherapy (e.g., psoralens and ultraviolet A phototherapy (PUVA)).

In one embodiment, a solid form of the present invention or a pharmaceutical composition comprising a solid form of the present invention is co-administered with another therapeutic agent for the treatment and/or prevention of an allergic reaction. Specific agents include, but are not limited to, antihistamines (e.g., cetirizine, diphenhydramine, fexofenadine, levocetirizine), glucocorticoids (e.g., prednisone, betamethasone, beclomethasone, dexamethasone), epinephrine, theophylline, or antileukotrienes (e.g., montelukast or zafirlukast), anticholinergics, and decongestants.

As will be apparent to one of skill in the art, co-administration includes any means of delivering two or more therapeutic agents to a patient as part of the same treatment regimen. Two or more agents can be administered simultaneously in a single formulation, i.e., a single pharmaceutical composition, but this is not required. The agents can also be administered in different formulations and at different times.

Embodiments of the Invention According to the First, Second and Third Aspects The embodiments described below relate to the first, second and third aspects of the invention.
Embodiment A1 is Compound 1 (4-methyl-5-[3-methyl-7-[(6-morpholin-4-ylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-5-yl]oxypyridine-2-carbonitrile).
,
or a pharmaceutically acceptable solvate thereof, and fumaric acid.
Embodiment A2 provides a composition according to embodiment A1, in which compound 1 and fumaric acid are present in a ratio of 2:1 to 1:2, preferably in a ratio of 1.5:1 to 1:1.5, more preferably in a ratio of 1.2:1 to 1:1.2, even more preferably in a ratio of 1.1:1 to 1:1.1, even more preferably in a ratio of about 1:1, and most preferably in a ratio of 1:1.
Embodiment A3 provides a composition according to embodiment A1 or A2, wherein Compound 1 and fumaric acid together form a solid form.
Embodiment A4 provides the composition of any one of embodiments A1, A2, or A3, wherein compound 1 and fumaric acid form a salt or co-crystal.
Embodiment A5 provides the composition of any one of embodiments A1, A2, A3, or A4, wherein compound 1 and fumaric acid form a co-crystal.
Embodiment A6 provides the composition of any one of embodiments A1, A2, A3, A4, or A5, wherein Compound 1 and fumaric acid together form a solid form, and the solid form is an unsolvated form.
Embodiment A7 provides a solid form according to any one of embodiments A1, A2, A3, A4, or A5, wherein Compound 1 and fumaric acid together form a solid form, and the solid form is a solvate.
Embodiment A8 provides a solid form of any one of Embodiments A1, A2, A3, A4, A5, A6, or A7, wherein Compound 1 and fumaric acid together form a solid form, and the solid form exhibits a peak on an XRPD spectrum.
Embodiment A9 provides the solid form of any one of embodiments A1, A2, A3, A4, A5, A6, A7, or A8, wherein Compound 1 and fumaric acid together form a solid form, and the solid form is a fumarate co-crystalline form of Compound 1.
Embodiment A10 provides the solid form of any one of embodiments A1, A2, A3, A4, A5, A6, A7, A8, or A9, wherein the solid form can be characterized by an X-ray powder diffraction pattern with one or more peaks at the following positions: 3.4, 6.8, 7.1, 8.6, 11.0, 12.4, 13.8, 14.3, 14.8, 15.5, 17.1, 18.3, 20.5, 20.8, 21.2, 22.4, 22.9, 23.9, 24.9, 25.6, or 26.5 degrees 2θ ± 0.2 degrees 2θ.
Embodiment A11 provides the solid form of any one of embodiments A1, A2, A3, A4, A5, A6, A7, A8, A9, or A10, wherein the solid form can be characterized by an X-ray powder diffraction pattern substantially as shown in Figure 6C.
Embodiment A12 provides the solid form of any one of embodiments A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, or A11, wherein the solid form may be characterized by an X-ray powder diffraction pattern with one or more peaks at the following positions: 3.4, 6.8, 7.1, 8.6, 11.0, 12.4, 13.8, 14.3, 14.8, 15.5, 17.1, 18.3, 20.5, 20.8, 21.2, 22.4, 22.9, 23.9, 24.9, 25.6, or 26.5 degrees 2θ ± 0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in Figure 6C.
Embodiment A13 provides a solid form of any one of embodiments A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, or A12, wherein the solid form can be characterized by an X-ray powder diffraction pattern comprising peaks at at least 3.4, 7.1, 8.6, 12.4, 13.8, 14.3, and 14.8 degrees 2θ ± 0.2 degrees 2θ.
Embodiment A14 provides the solid form of any one of embodiments A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, or A13, wherein the solid form may be characterized by an X-ray powder diffraction pattern comprising peaks at 3.4, 7.1, 8.6, 12.4, and 13.8 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in Figure 6C.
Embodiment A15 provides a solid form of any one of embodiments A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, or A13, wherein the solid form may be characterized by an X-ray powder diffraction pattern comprising peaks at 7.1, 8.6, 12.4, 13.8, and 14.3 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in Figure 6C.
Embodiment A16 provides a solid form of any one of embodiments A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, or A13, wherein the solid form may be characterized by an X-ray powder diffraction pattern comprising peaks at 8.6, 12.4, 13.8, 14.3, and 14.8 degrees 2θ±0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in Figure 6C.
Embodiment A17 provides a solid form of any one of embodiments A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, or A13, wherein the solid form may be characterized by an X-ray powder diffraction pattern comprising peaks at 3.4 and/or 7.1 and/or 8.6 and/or 12.4 and/or 13.8 and/or 14.3 and/or 14.8 degrees 2θ ± 0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in Figure 6C.
Embodiment A18 provides a solid form of any one of embodiments A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, or A17, wherein the solid form may be characterized by an X-ray powder diffraction pattern with peaks at all of the following positions: 3.4, 6.8, 7.1, 8.6, 11.0, 12.4, 13.8, 14.3, 14.8, 15.5, 17.1, 18.3, 20.5, 20.8, 21.2, 22.4, 22.9, 23.9, 24.9, 25.6, and 26.5 degrees 2θ ± 0.2 degrees 2θ.
Embodiment A19 provides the solid form of any one of embodiments A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, or A18, wherein the solid form may be characterized by an X-ray powder diffraction pattern having peaks at all of the following positions: 3.4, 6.8, 7.1, 8.6, 11.0, 12.4, 13.8, 14.3, 14.8, 15.5, 17.1, 18.3, 20.5, 20.8, 21.2, 22.4, 22.9, 23.9, 24.9, 25.6, and 26.5 degrees 2θ ± 0.2 degrees 2θ, and an X-ray powder diffraction pattern substantially as shown in Figure 6C.
Embodiment A20 provides a solid form of any ^one of embodiments A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, or A19, wherein the solid form can be characterized by a 1 H-NMR spectrum substantially according to Figure 6A.
Embodiment A21 provides a solid form of any one of embodiments A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, or A20, wherein the solid form can be characterized by a DSC curve substantially according to Figure 6D.
Embodiment A22 provides a solid form of any one of embodiments A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, or A21, wherein the solid form can be characterized by a TGA curve substantially according to Figure 6E.
Embodiment A23 provides a solid form of any one of embodiments A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, or A22, wherein the solid form can be characterized by a DVS curve substantially according to Figure 6F.
Embodiment A24 provides a pharmaceutical composition comprising the solid form of any one of embodiments A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, or A23, and a pharmaceutical carrier, excipient, or diluent.
Embodiment A25 provides a pharmaceutical composition according to embodiment A24 that comprises a further therapeutically active ingredient.
Embodiment A26 provides a pharmaceutical composition according to embodiment A25, wherein the further therapeutically active ingredient is an agent for the prevention and/or treatment of an allergic disease, an inflammatory disease, a metabolic disease, an autoinflammatory disease, an autoimmune disease, a proliferative disease, transplant rejection, a disease involving disorders of cartilage metabolism, congenital cartilage malformations, and/or a disease associated with hypersecretion of IFNα, interferons ("interferonopathies", in particular type I or type III interferonopathies), IL-12, and/or IL-23, in particular a disease selected from systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.
Embodiment A27 is directed to inflammatory diseases and/or diseases associated with hypersecretion of IFNα and/or interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and/or IL-23, particularly systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, chromosome 21 translocation, and/or IL-22 translocation. Provided is a solid form according to any one of embodiments A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, or A23, or a pharmaceutical composition according to any one of embodiments A24, A25, or A26, for use in the treatment of a disease selected from lysomy, ulcerative colitis, and/or Crohn's disease.
Embodiment A28 is directed to inflammatory diseases and/or diseases associated with hypersecretion of IFNα and/or interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and/or IL-23, in particular systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21. A21, A22, or A23, or a pharmaceutical composition according to any one of embodiments A24, A25, or A26, in the manufacture of a medicament for the treatment of a disease selected from ulcerative colitis, ulcerative colitis, and/or Crohn's disease.
Embodiment A29 is directed to inflammatory diseases and/or diseases associated with hypersecretion of IFNα and/or interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and/or IL-23, in particular systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease, comprising administering to a patient an effective amount of a solid form of any one of embodiments A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, or A23, or a pharmaceutical composition of any one of embodiments A24, A25, or A26.

Embodiments of the Invention According to the Fourth Aspect The embodiments described below relate to the fourth aspect of the invention.
Embodiment B1 is directed to compound 1 (4-methyl-5-[3-methyl-7-[(6-morpholin-4-ylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-5-yl]oxypyridine-2-carbonitrile) for use in the treatment of inflammatory diseases and/or diseases associated with hypersecretion of IFNα and/or interferons (“interferonopathies”, particularly type I or type III interferonopathies), IL-12, and/or IL-23, particularly diseases selected from systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.
,
or a pharmaceutically acceptable solvate thereof, wherein Compound 1 is administered at a total daily dose of at least 70 mg/day to 300 mg/day.
Embodiment B2 relates to the use of Compound 1 (4-methyl-5-[3-methyl-7-[(6-morpholin-4-ylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-5-yl]oxypyridine-2-carbonitrile) in the manufacture of a medicament for the treatment of inflammatory diseases and/or diseases associated with hypersecretion of IFNα and/or interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and/or IL-23, particularly diseases selected from systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.
,
or a pharmaceutically acceptable solvate thereof, wherein Compound 1 is administered at a total daily dose of at least 70 mg/day to 300 mg/day.
Embodiment B3 is a method of treating inflammatory diseases and/or diseases associated with hypersecretion of IFNα and/or interferons (“interferonopathies”, particularly type I or type III interferonopathies), IL-12, and/or IL-23, particularly diseases selected from systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease, comprising administering to a patient Compound 1 (4-methyl-5-[3-methyl-7-[(6-morpholin-4-ylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-5-yl]oxypyridine-2-carbonitrile)
,
or a pharmaceutically acceptable solvate thereof, wherein Compound 1 is administered at a total daily dose of at least 70 mg/day to 300 mg/day.
Embodiment B4 provides a pharmaceutical composition comprising a fumarate co-crystal of Compound 1 for use, a use of a pharmaceutical composition comprising a fumarate co-crystal of Compound 1, or a method according to any one of the preceding embodiments, wherein the total daily dose of Compound 1 is administered as a once-daily dose (q.d.).
Embodiment B5 provides a pharmaceutical composition comprising a fumarate co-crystal of Compound 1 for use, a use of a pharmaceutical composition comprising a fumarate co-crystal of Compound 1, or a method according to any one of the preceding embodiments, wherein Compound 1 is administered at a total daily dose of at least 75 mg/day to 300 mg/day, preferably 75 mg/day to 250 mg/day.
Embodiment B6 provides a pharmaceutical composition comprising a fumarate co-crystal of Compound 1 for use, a use of a pharmaceutical composition comprising a fumarate co-crystal of Compound 1, or a method according to any one of the preceding embodiments, wherein Compound 1 is administered at a total daily dose of 75 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 125 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 175 mg/day, 180 mg/day, 190 mg/day, 200 mg/day, 225 mg/day, or 250 mg/day.
Embodiment B7 provides a pharmaceutical composition comprising a fumarate co-crystal of Compound 1 for use, a use of a pharmaceutical composition comprising a fumarate co-crystal of Compound 1, or a method according to any one of the preceding embodiments, wherein Compound 1 is administered at a total daily dose of 75 mg/day, or 90 mg/day, or 150 mg/day, or 200 mg/day, or 225 mg/day, or 250 mg/day.
Embodiment B8 provides a pharmaceutical composition comprising a fumarate co-crystal of Compound 1 for use, a use of a pharmaceutical composition comprising a fumarate co-crystal of Compound 1, or a method according to any one of the preceding embodiments, wherein Compound 1 is administered at a total daily dose of 150 mg/day or 225 mg/day.
Embodiment B9 provides a pharmaceutical composition comprising a fumarate co-crystal of Compound 1 for use, a use of a pharmaceutical composition comprising a fumarate co-crystal of Compound 1, or a method according to any one of the preceding embodiments, wherein Compound 1 is administered at a total daily dose of 150 mg/day.
Embodiment B10 provides a pharmaceutical composition comprising a fumarate co-crystal of Compound 1 for use, a use of a pharmaceutical composition comprising a fumarate co-crystal of Compound 1, or a method according to any one of the preceding embodiments, wherein the treatment is for psoriasis.
Embodiment B11 provides a pharmaceutical composition comprising a fumarate co-crystal of Compound 1 for use, a use of Compound 1, or a method according to any one of the preceding embodiments, wherein the treatment is for psoriatic arthritis.
Embodiment B12 provides a pharmaceutical composition comprising a fumarate co-crystal of Compound 1 for use, a use of a pharmaceutical composition comprising a fumarate co-crystal of Compound 1, or a method according to any one of the preceding embodiments, wherein the treatment is for Crohn's disease.
Embodiment B13 provides a pharmaceutical composition comprising a fumarate co-crystal of Compound 1 for use, a use of a pharmaceutical composition comprising a fumarate co-crystal of Compound 1, or a method according to any one of the preceding embodiments, wherein the treatment is for ulcerative colitis.
Embodiment B14 provides a pharmaceutical composition comprising a fumarate co-crystal of Compound 1 for use, a use of a pharmaceutical composition comprising a fumarate co-crystal of Compound 1, or a method according to any one of the preceding embodiments, wherein the treatment is for systemic lupus erythematosus.
Embodiment B15 provides a pharmaceutical composition comprising a fumarate co-crystal of Compound 1 for use, a use of a pharmaceutical composition comprising a fumarate co-crystal of Compound 1, or a method according to any one of the preceding embodiments, wherein the treatment is for cutaneous lupus erythematosus.
Embodiment B16 provides a pharmaceutical composition comprising a fumarate co-crystal of Compound 1 for use, a use of a pharmaceutical composition comprising a fumarate co-crystal of Compound 1, or a method according to any one of the preceding embodiments, wherein the treatment is for lupus nephritis.
Embodiment B17 provides a pharmaceutical composition comprising a fumarate co-crystal of Compound 1 for use, a use of a pharmaceutical composition comprising a fumarate co-crystal of Compound 1, or a method according to any one of the preceding embodiments, wherein the treatment is for dermatomyositis.
Embodiment B18 provides a pharmaceutical composition comprising a fumarate co-crystal of Compound 1 for use, a use of a pharmaceutical composition comprising a fumarate co-crystal of Compound 1, or a method according to any one of the preceding embodiments, wherein the treatment is for polymyositis.
Embodiment B19 provides a pharmaceutical composition comprising a fumarate co-crystal of Compound 1 for use, a use of a pharmaceutical composition comprising a fumarate co-crystal of Compound 1, or a method according to any one of the preceding embodiments, wherein the pharmaceutical composition comprising a fumarate co-crystal of Compound 1 is administered orally.
Embodiment B20 provides a pharmaceutical composition comprising a fumarate co-crystal of Compound 1 for use, a use of a pharmaceutical composition comprising a fumarate co-crystal of Compound 1, or a method according to any one of the preceding embodiments, wherein the pharmaceutical composition comprising a fumarate co-crystal of Compound 1 is orally administered to a patient in a fed state.
Embodiment B21 provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a fumarate co-crystal of Compound 1 for use, the use of a pharmaceutical composition comprising a fumarate co-crystal of Compound 1, or a method according to any one of embodiments B01 through B20.
Embodiment B22 relates to a compound comprising 70 mg to 300 mg of Compound 1:
or a pharmaceutically acceptable solvate thereof, wherein the unit dosage form is suitable for oral administration of up to a maximum total dose of Compound 1 of 300 mg per day.
Embodiment B23 provides a dosage form according to embodiment B22 comprising Compound 1 in a unit dosage form of 75 mg to 300 mg.
Embodiment B24 provides a dosage form according to embodiment B22 or B23, comprising 75 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 225 mg, 250 mg, or 300 mg of Compound 1 in the unit dosage form.
Embodiment B25 provides a dosage form according to embodiment B22 or B23, comprising 75 mg to 225 mg of Compound 1 in the unit dosage form.
Embodiment B26 provides a dosage form according to any one of embodiments B22, B23, B24, or B25, comprising 150 mg of Compound 1 in the unit dosage form.
Embodiment B27 provides the dosage form of any one of embodiments B22, B23, B24, B25, or B26, wherein the unit dose is in a form selected from a liquid, a tablet, a capsule, or a gelcap.
Embodiment B28 provides a dosage form according to any one of embodiments B22, B23, B24, B25, B26, or B27, wherein the unit dose is in the form of a tablet or capsule.
Embodiment B29 provides the dosage form of any one of embodiments B22, B23, B24, B25, B26, B27, or B28, wherein the unit dose is in the form of a tablet.
Embodiment B30 provides a dosage form according to any one of embodiments B22, B23, B24, B25, B26, B27, B28, or B29 for use in treating inflammatory diseases and/or diseases associated with hypersecretion of IFNα and/or interferons ("interferonopathies", particularly Type I or Type III interferonopathies), IL-12, and/or IL-23, particularly a disease selected from systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.
Embodiment B31 provides the use of a dosage form according to any one of B22, B23, B24, B25, B26, B27, B28, or B29 in the manufacture of a medicament for the treatment of inflammatory diseases and/or diseases associated with hypersecretion of IFNα and/or interferons ("interferonopathies", particularly Type I or Type III interferonopathies), IL-12, and/or IL-23, particularly a disease selected from systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.
Embodiment B32 provides a method of treating inflammatory diseases and/or diseases associated with hypersecretion of IFNα and/or interferons ("interferonopathies", particularly Type I or III interferonopathies), IL-12, and/or IL-23, particularly diseases selected from systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease, comprising administering to a patient a dosage form of any one of embodiments B22, B23, B24, B25, B26, B27, B28, or B29.

Embodiments of the Invention According to the Fifth and Sixth Aspects The embodiments described directly below relate to the fifth and sixth aspects of the invention, namely, processes for producing compound 1 according to the invention and processes for producing compositions comprising compound 1.
Embodiment C1 provides a process for making compound 1, or a pharmaceutically acceptable salt thereof, comprising reacting intermediate 3 with intermediate 4 in the presence of a base, a palladium precursor, and 1-[(S _P )-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine.
Embodiment C2 provides the process described in Embodiment C1, wherein the molar ratio between intermediate 3 and intermediate 4 is from about 1.5:1 to about 1:1.5, preferably from about 1.1:1 to 1:1.1.
Embodiment C3 provides the process of Embodiment C1 or C2, wherein the molar ratio between intermediate 3 and 1-[(S _P )-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine is from about 1:0.01 to about 1:0.1, preferably from about 1:0.02 to about 1:0.05, and more preferably about 1:0.024.
Embodiment C4 provides the process of any one of embodiments C1, C2 _, or C3, wherein the palladium precursor is selected from Pd(π-cinnamyl) _{Cl dimer, Pd(OAc) 2 ,} Pd(Cl) ₂ , Pd ₂ ( _dba ) ₃ , Pd(dba) _{2 ,} Pd(PPh ₃ ) ₄ , Pd(PPh 3 ) ₂ Cl ₂ , Pd(acac) _{2 , and Pd(PhCN) 2 Cl} 2 , more preferably Pd(π-cinnamyl)Cl dimer, Pd 2 (dba) ₃ , Pd( _dba ) ₂ , and Pd(PPh 3 ) 4 , and most preferably Pd(π-cinnamyl)Cl dimer.
Embodiment C5 provides the process of any one of Embodiments C1, C2, C3, or C4, wherein the molar ratio between intermediate 3 and the palladium precursor is from about 1:0.001 to about 1:0.05, preferably from about 1:0.05 to about 1:0.02, and more preferably about 1:0.01.
Embodiment C6 provides the process of any one of embodiments C1, _C2 , _{C3 , C4 ,} or _C5 , wherein the base is selected from K2CO3, _DABCO , _DBU , _NaOtBu , _Cs2CO3 , _Li2CO3 , Na2CO3, DMAP, NaHMDS, and _NEt3 , more preferably _K2CO3 , DBU, and _Cs2CO3 , and most preferably _{Cs2CO3 .}
Embodiment C7 provides the process of any one of embodiments C1, C2, C3, C4, C5, or C6, wherein the process is carried out in the presence of at least one solvent.
Embodiment C8 provides the process of embodiment C7, wherein the solvent is selected from acetonitrile, xylene, DMF, or tert-amyl alcohol, preferably acetonitrile, DMF, or tert-amyl alcohol.
Embodiment C9 provides the process of any one of embodiments C1, C2, C3, C4, C5, C6, C7, or C8, wherein the process further comprises isolating compound 1 from the reaction mixture by the addition of acetonitrile and/or water, optionally followed by filtering the solid.
Embodiment C10 is an embodiment of the present invention, wherein the process comprises:
- mixing intermediate 3, intermediate 4 and a base in degassed tert-amyl alcohol or DMF and stirring under an inert atmosphere, preferably under nitrogen or argon;
- adding the palladium precursor and 1-[(S _P )-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine as solids or as premixed solutions in acetonitrile to the reaction mixture under an inert atmosphere, preferably under a nitrogen or argon atmosphere;
- stirring the reaction mixture at about 100°C for at least 2 hours;
- cooling the reaction mixture to room temperature and adding acetonitrile;
- filtering the reaction mixture and washing it with water and then with acetonitrile;
- drying the solid filtrate.
Embodiment C11 provides the process of any one of embodiments C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10, wherein intermediate 3 in the process is obtained after a step of reacting compound E with a suitable reagent, preferably an acid, more preferably HCl, to produce intermediate 3 or a salt thereof.
Embodiment C12 provides the process of embodiment C11, wherein compound E in the process is prepared after the step of reacting compound D with a Lewis acid, a Bronsted acid, preferably a zinc salt, and a tri C ₁ -C ₃ alkyl orthoformate, preferably trimethyl or triethyl orthoformate, more preferably trimethyl orthoformate, to produce compound E.
Embodiment C13 provides the process of embodiment C12, wherein compound D in the process is prepared after the step of reacting compound C with a suitable base, preferably K ₂ CO ₃ or Na ₂ CO ₃ , and 5-hydroxy-4-methyl-pyridine-2-carbonitrile to produce compound D.
Embodiment C14 provides the process of embodiment C13, wherein compound C in the process is prepared after the step of reacting compound B with methylamine, preferably 40% methylamine in water or 33% methylamine in methanol, to produce compound C.
Embodiment C15 provides the process according to embodiment C14, wherein compound B in the process is prepared after reacting compound A with a suitable base, preferably K ₃ PO ₄ , and di-tert-butyl dicarbonate to produce compound B.
Embodiment C16 is an embodiment of the present invention, wherein the process comprises:
- suspending compound 1 in a suitable solvent, preferably acetic acid, acetone, ethanol, or THF, more preferably acetic acid;
- adding to said suspension at least one equivalent of fumaric acid, preferably in a C _1-4 alcohol or aqueous solution;
- aging the reaction mixture;
- filtering and drying the reaction mixture.
Embodiment C17 is a process for making a fumarate co-crystalline form of Compound 1, comprising:
- suspending compound 1 in a suitable solvent, preferably acetic acid, acetone, ethanol, or THF, more preferably acetic acid;
- adding to said suspension at least one equivalent of fumaric acid, preferably in a C _1-4 alcohol or aqueous solution;
- aging the reaction mixture;
- filtering and drying the reaction mixture.
Embodiment C18 provides the process described in embodiment C16 or C17, wherein 1 to 5 equivalents of fumaric acid are added to the suspension.
Embodiment C19 provides the process of any one of embodiments C16, C17, or C18, wherein the aging step is carried out at about 20° C. to about 80° C., preferably about 25° C. to 60° C., for at least 72 hours.
Embodiment C20 provides the process of any one of embodiments C16, C17, C18, or C19, further comprising centrifuging or filtering the reaction mixture after the aging step.
Embodiment C21 provides the process of any one of embodiments C16, C17, C18, C19, or C20, wherein the drying step is conducted under vacuum at a temperature of about 20° C. to about 60° C., preferably about 30° C., for at least 12 hours.

General Chemical Synthesis Procedures Methods for the preparation of compound 1 are described in WO2019/076716 (compound 1 is referred to as "compound 38" in WO2019/076716), and a summary is provided below.

The solid forms of the present invention can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, it is understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one of ordinary skill in the art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art (Greene, T. W.; Wuts, P. G. M.; 1991).

The following methods are presented with detailed and comparative examples for the preparation of the solid forms of the present invention as defined above. The solid forms of the present invention can be prepared from known or commercially available starting materials and reagents by those skilled in the art of organic synthesis.

All reagents were commercial grade and were used as is without further purification unless otherwise noted. Commercially available anhydrous solvents were used for reactions performed under an inert atmosphere. Reagent grade solvents were used in all other cases unless otherwise noted. Column chromatography was performed on silica gel 60 (35-70 μm). Thin layer chromatography was performed using pre-coated silica gel F-254 plates (0.25 mm thick). ¹ H NMR spectra were recorded on a Bruker Advance NMR spectrometer (300, 400, or 500 MHz), or alternatively, on a Varian INOVA 400 MHz NMR spectrometer equipped with a Varian ATB probe. Chemical shifts (δ) for ¹ H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) or the appropriate residual solvent peak, i.e., CHCl ₃ (δ 7.27), as an internal reference. Multiplicities are given as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin), multiplet (m), and broad term (br). Electrospray MS spectra were obtained on a Waters platform LC/MS spectrometer or using a Waters Acquity H-Class UPLC coupled to a Waters Mass detector 3100 spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID x 50 mm length, Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID x 30 mm length, or Waters Xterra MS 5 μm C18, 100 x 4.6 mm. The method uses either an ACN/ _H2O gradient ( _H2O containing either 0.1% TFA or 0.1% _NH3 ) or a MeOH/ _H2O gradient ( _H2O containing 0.05% TFA).

Synthesis of Compound 1 Preparation Example 1. Synthesis of Compound 1 1.1. Synthesis of Intermediate 1: 7-chloro-5-iodo-3-methyl-3H-imidazo[4,5-b]pyridine
1.1.1. Step i: Synthesis of 2,4-dichloro-6-iodo-pyridin-3-ylamine:
To a solution of 2,4-dichloro-3-aminopyridine (250 g, 1.54 mmol, 1 equiv.) in dry ACN (1.2 L) at room temperature under a _N atmosphere was added NIS (382 g, 1.70 mmol, _1.1 equiv.) and TFA (35.45 mL, 0.46 mmol, _0.3 equiv.). The mixture was stirred at 40° C. for 18 h in a 3 _L round-bottom flask. The reaction mixture was then quenched with saturated _NaSO (500 mL) and NaHCO (700 mL). The organic layer was washed _with saturated NaHCO, and the aqueous layer was washed _twice with EtOAc (2×700 mL). The combined organic layers were dried over MgSO, filtered, and concentrated to dryness to give the crude product. Purification by column chromatography using cyclohexane and EtOAc (10%) gave the desired product. LCMS: m/z=289 [M+H].

1.1.2. Step ii: Synthesis of 4-chloro-6-iodo-N2-methyl-pyridine-2,3-diamine:
2,4-Dichloro-6-iodo-pyridin-3-amine (20 g, 0.07 mmol, 1 eq.) was dissolved in n-butanol (300 mL) in an autoclave (600 mL). Methylamine (33% in EtOH, 28.72 mL, 0.28 mmol, 4 eq.) was added at room temperature under _N. The mixture was stirred at 180 °C for 18 h and then cooled to room temperature. This step was repeated twice, after which the reaction mixtures were combined and concentrated to give the desired compound, which was used directly in the next step. LCMS: m/z = 284 [M+H].

1.1.3. Step iii: Synthesis of 7-chloro-5-iodo-3-methyl-3H-imidazo[4,5-b]pyridine:
To a solution of 4-chloro-6-iodo-N-2-methyl-pyridine-2,3-diamine (60 g, 0.21 mmol, 1 eq.) in formic acid (30 mL) was added trimethyl orthoformate (69.5 mL, 0.64 mmol, 3 eq.). The mixture was stirred at 60° C. for 1 h. The reaction was concentrated to dryness, after which the residue was diluted with DCM and quenched with saturated aqueous NaHCO ₃ solution. After extraction with DCM, the organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated to dryness to give the crude material. This was purified by column chromatography using a cyclohexane/EtOAc eluent of 10-60% EtOAc to give the desired product. LCMS: m/z=294 [M+H]. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 8.46 (s, 1H), 7.83 (s, 1H), 3.81 (s, 3H).

1.2. Synthesis of Intermediate 2: 5-(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-4-methyl-pyridine-2-carbonitrile
1.2.1. Step i: Synthesis of 5-hydroxy-4-methylpyridine-2-carbonitrile:
A mixture of 5-bromo-2-cyano-4-methylpyridine (CAS No. 886364-86-9, 26.8 g, 136 mmol, 1 equiv.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (CAS No. 73183-34-3, 48.4 g, 190 mmol, 1.4 equiv.), Pd(dppf)Cl ₂ , DCM (5.55 g, 6.80 mmol, 0.05 equiv.), and potassium acetate (40 g, 408 mmol, 3 equiv.) in 1,4-dioxane (500 mL) was stirred at 110 °C under N ₂ for 2 h. The reaction mixture was then cooled to 0° C. and H ₂ O ₂ (30% aqueous solution, 83 mL, 816 mmol, 6.0 equiv.) was added dropwise. After 2 h, the reaction mixture was diluted with DCM and washed with water. The aqueous phase was acidified to pH 4-5 and extracted three times with DCM. The combined organic extracts were dried and evaporated in vacuo. The crude material obtained was purified by column chromatography (petroleum ether/EtOAc gradient elution 30%-50% EtOAc). The resulting material was triturated with pentane and diethyl ether to give the desired product.

1.2.2. Step ii: Synthesis of 5-(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-4-methyl-pyridine-2-carbonitrile:
Intermediate 1 (68.51 g, 233.83 mmol, 1.0 equiv.), 7-chloro-5-iodo-3-methyl- _{3H-imidazo[4,5-b]pyridine (47.0 g, 350.75 mmol, 1.5 equiv.), CuI (8.89 g, 46.77 mmol, 0.2 equiv.), TMHD (97.45 mL, 467.66 mmol, 2 equiv.), and Cs 2} CO ₃ (152 g, 467.66 mmol, 2 equiv.) were mixed together under air, DMF (234 mL) was added, and the mixture was stirred at 85° C. for two nights. If complete conversion was not achieved, additional CuI (0.1 equiv.) and TMHD (1 equiv.) were added, after which the mixture was further stirred at 85° C. for another night. The mixture was then cooled to 0° C. The resulting thick paste was then filtered, and the cake was washed with ice-cold DMF (2 x 20 mL), followed by ice-cold MTBE (3 x 150 mL). After the cake was dried, it was suspended in 500 mL of 10% aqueous TMEDA. It was stirred for 2 hours, filtered, and the cake was washed with _H2O to give the desired product. LCMS: m/z = 300 [M+H] ⁺ .

1.3. Synthesis of intermediate 3: 5-(7-amino-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-4-methyl-pyridine-2-carbonitrile
To a mixture of intermediate 2 (5.0 g, 16.72 mmol, 1.0 equiv.), benzophenone imine (CAS No. 1013-88-3, 2.81 mL, 16.72 mmol, 1.0 equiv.), Pd ₂ Cl ₂ (allyl) ₂ (CAS No. 12012-95-2, 122 mg, 0.33 mmol, 0.02 equiv.), XantPhos (CAS No. 161265-03-8, 387 mg, 0.67 mmol, 0.04 equiv.), and Cs ₂ CO ₃ (6.54 g, 20.07 mmol, 1.2 equiv.) under a N ₂ atmosphere was added 1,4-dioxane (100 mL), and the mixture was stirred at 110° C. for 24 hours. After cooling to room temperature, the mixture was diluted with EtOAc and filtered through Celite. The cake was washed with EtOAc (100 mL) and the filtrate was poured into 2N aqueous HCl (200 mL) and stirred for 10 minutes. After extraction with EtOAc, the aqueous phase was neutralized to pH=7 using NaHCO _3. This was followed by extraction with EtOAc (5×100 mL), after which the combined organic layers were dried over MgSO ₄ , filtered and concentrated to dryness to give the crude material, which was triturated with DCM to give the desired product. LCMS: m/z=281 [M+H] ⁺ .

1.4. Synthesis of Compound 1: 4-methyl-5-[3-methyl-7-(6-morpholin-4-yl-pyridazin-3-ylamino)-3H-imidazo[4,5-b]pyridin-5-yloxy]-pyridine-2-carbonitrile
Intermediate 3 (409 g, 1.459 mol, 1.0 equiv.) and Intermediate 4 (4-(6-bromopyridazin-3-yl)morpholine, CAS No. 927673-86-7, 392 g, 1.1 equiv.) were added to an isomeric xylene mixture (8 L) at room temperature. To the mixture, under stirring at room temperature, was added potassium phosphate tribasic (929.0 g, 3.0 equiv.). The reaction mixture was heated from room temperature to 135° C. for 2 hours and 30 minutes. A suspension of Pd(OAc) ₂ (2 mol %, 6.6 g) and XantPhos (CAS No. 161265-03-8, 4 mol %, 33.8 g) in xylene (50 mL) was then added to the hot mixture. The reaction was heated to reflux for 1 hour and 30 minutes. A suspension of Pd(OAc) ₂ (2 mol%, 6.6 g) and XantPhos (4 mol%, 33.8 g) in xylene (50 mL) was then added and the reaction heated to reflux for an additional 1 hour 30 minutes. A suspension of Pd(OAc) ₂ (2 mol%, 6.6 g) and XantPhos (4 mol%, 33.8 g) in xylene (50 mL) was then added one last time. The reaction was refluxed for an additional 1 hour 30 minutes. The reaction mixture was cooled to room temperature and stirred overnight. The suspension was filtered and washed with ACN (5 L). The solid was washed with water (15 L) until a neutral pH was obtained, dried under suction, and then suspended in ACN (6.5 L) and stirred at room temperature for 1 hour. The suspension was filtered, washed with ACN (2 L) and dried. Chromatography on SiO ₂ (1 g SiO ₂ for 1 g crude) using eluents CHCl ₃ /acetone (70/30) then CHCl ₃ /MeOH (96/4) gave the desired product (compound 1).
Example 2. Alternative Synthetic Preparation of Compound 1 2.1. Alternative Synthesis of Intermediate 3: 5-(7-amino-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-4-methyl-pyridine-2-carbonitrile

2.1.1. Step i: Synthesis of tert-butyl (2,6-dichloro-3-nitropyridin-4-yl)carbamate 4-Amino-2,6-dichloro-3-nitropyridine (CAS No. 2897-43-0, 520 g, 2.5 mol, 1.0 equiv.) was added to ACN (5.2 L) at room temperature. To the mixture was added Boc ₂ O (710 g, 3.25 mol, 1.3 equiv.) and K ₃ PO ₄ (1000 g, 4.71 mol, 1.9 equiv.) with stirring at room temperature. The reaction mixture was heated to reflux for 1-2 hours. A solution of Boc ₂ O (110 g, 0.5 mol, 0.2 equiv.) in ACN (100 mL) was then added, and the reaction mixture was heated to reflux for an additional hour. The reaction mixture was cooled to room temperature and filtered onto a pad _{of Na2SO4} . _{The Na2SO4} was washed with ACN (2 L). The filtrate was evaporated under reduced pressure and redissolved in DCM (5 L). The DCM layer was washed with water. The organic layer was extracted with DCM (5 _L ) and the combined organic layers were dried over _Na2SO4 , filtered and evaporated to give the desired product. LCMS: m/z = 306/308 [M+H].

2.1.2. Step ii: Synthesis of tert-butyl N-[6-chloro-2-(methylamino)-3-nitropyridin-4-yl]carbamate tert-Butyl-(2,6-dichloro-3-nitropyridin-4-yl)carbamate (770 g, 2.5 mol, 1.0 equiv.) was added to isopropanol (11 L) at room temperature. To the mixture, under stirring at room temperature, was added methylamine 33% in EtOH (800 mL, 3.0 equiv.) over 1 hour 30 minutes. The reaction mixture was stirred at room temperature for 1 hour 30 minutes. The suspension was filtered and washed with iPrOH (1 L) and then with water (4 L). After drying, the desired product was obtained. LCMS: m/z = 302.9/304.8 [M+H].

2.1.3. Step iii: tert-Butyl N-[6-[(6-cyano-4-methylpyridin-3-yl)oxy]-2-(methylamino)-3-nitropyridin-4-yl]carbamate tert-Butyl N-[6-chloro-2-(methylamino)-3-nitropyridin-4-yl]carbamate (788 g, 2.6 mol, 1.0 equiv.) was added to ACN (5.5 L) at room temperature. To the mixture was added 5-hydroxy-4-methyl-pyridine-2-carbonitrile (384 g, 2.86 mol, 1.1 equiv.) and Na ₂ CO ₃ (414 g, 3.9 mol, 1.5 equiv.) with stirring at room temperature. The reaction mixture was heated to reflux for 48 hours. The reaction mixture was cooled to room temperature, and the insoluble material was filtered and washed with ACN (2 L). The combined organic layers were evaporated. The crude was washed with water (5 L), collected and dried to give the desired product. LCMS: m/z = 401.1 [M+H]; m/z = 399.2 [M-H]. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.70 (s, 1H), 9.05 (q, 1H), 8.62 (s, 1H), 8.13 (s, 1H), 7.23 (s, 1H), 2.59 (d, 3H), 2.24 (s, 3H), 1.50 (s, 9H).

2.1.4. Step iv: tert-Butyl N-(5-((6-cyano-4-methylpyridin-3-yl)oxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)carbamate. tert-Butyl N-[6-[(6-cyano-4-methylpyridin-3-yl)oxy]-2-(methylamino)-3-nitropyridin-4-yl]carbamate (150 g, 375 mmol, 1.0 equiv.) was added to a mixture of acetic acid (750 mL, 35 equiv.) and trimethyl orthoformate (750 mL, 18 equiv.) at room temperature. To the mixture was added <10 μm Zn dust in small portions (total of 120 g, 4.9 equiv., added in 15 g increments) with vigorous stirring at 20-21° C. Each addition was made after the reaction mixture had cooled to 20-21° C. After the last addition, the reaction mixture was stirred for 1 h. The suspension was filtered over Dicalite 4158 (Carlo Erba, ref. P8880014), washed with THF (1 L) and the combined organic layers were concentrated under vacuum. The residue was slowly poured into a cold mixture of 20% ammonia solution (100 mL) and water (2 L). The resulting solid was filtered, washed with water (2 L) and dried to give the desired product. LCMS: m/z = 381.0 [M+H]; m/z = 379.2 [M-H]. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.32 (bs, 1H), 8.55 (s, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.54 (s, 1H), 3.60 (s, 3H), 2.27 (s, 3H), 1.49 (s, 9H).

2.1.5. Step v: 5-((7-amino-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)-4-methylpyridine-2-carbonitrile tert-Butyl N-(5-((6-cyano-4-methylpyridin-3-yl)oxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)carbamate (197 g, 0.518 mol, 1.0 equiv) was suspended in a mixture of 4 N aqueous HCl (1 L) and THF (1 L). The reaction mixture was heated at 60° C. for 5 h. The reaction mixture was cooled to room temperature and the solid was filtered, washed with THF (1 L) and dried to give the desired product as the hydrochloride salt. LCMS: m/z=281.4 [M+H]. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.28 (s, 1H), 8.54 (s, 1H), 8.12 (s, 1H), 7.57 (bs, 2H), 6.33 (s, 1H), 3.67 (s, 3H), 2.25 (s, 3H).

2.2. Alternative synthesis of intermediate 3: 5-(7-amino-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-4-methyl-pyridine-2-carbonitrile
A reaction vessel was charged with tert-butyl N-(5-((6-cyano-4-methylpyridin-3-yl)oxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)carbamate (17.85 kg, 46.92 mol, 1.0 equiv), water (80.5 L, 4.5 vol), glacial acetic acid (26.1 L, 1.5 vol), and 1-butanol (13.7 L, 0.8 vol) at room temperature. The reaction mixture was heated to 60° C. and an aqueous solution (17.8 L, 1 vol) of hydrochloric acid (9.06 kg, 91.94 mol, 2.0 equiv) in water was added slowly. The reaction mixture was stirred at 60° C. for at least 5 hours and, upon complete conversion, was cooled to room temperature and aged for at least 1 hour. The resulting suspension was filtered and the isolated solid was washed with MeOH (52.4 L, 3 vol) and then MeOH (26.8 L, 1.5 vol) before being dried under vacuum under a stream of N to 50° C. to give 13.36 kg of the desired intermediate.

2.3. Alternative Synthesis of Compound 1: 4-Methyl-5-[3-methyl-7-[((6-morpholin-4-yl-pyridazin-3-yl)amino)-3H-imidazo[4,5-b]pyridin-5-yl]oxy]-pyridine-2-carbonitrile Intermediate 3 (280 mg, 1 mmol, 1.0 equiv.), intermediate 4 (4-(6-bromopyridazin-3-yl)morpholine, CAS No. 927673-86-7, 268 mg, 1.1 mmol, 1.1 equiv.), and Cs ₂ CO ₃ (977 mg, 3 mmol, 3 equiv.) were mixed at room temperature under argon, and degassed tert-amyl alcohol or DMF (5.5 mL) was added. [Pd(cinnamyl)Cl] ₍ 5.18 mg, 0.010 mmol, 0.01 equiv.) and JosiPhos (CAS No. 158923-11-6, 13 mg, 0.024 mmol, 0.024 equiv.) are added under argon either as solids or as premixed solutions in 1 mL of degassed ACN. The mixture is heated to 100° C. for at least 2 hours. The reaction mixture is then cooled to room temperature and ACN is added. The suspension is filtered and the solid is triturated first with water and then with ACN and dried to give the desired product.

Example 3. Ligand Screening for Palladium-Catalyzed Coupling Reactions 3.1. Study Objective To evaluate the performance of different catalytic systems for the reaction between intermediate 3 and intermediate 4 described in Example 2.2 towards the formation of compound 1 via a palladium-catalyzed coupling reaction.

Palladium(II) or palladium(0) precursors known in the art to be compatible with cross-coupling reactions are suitable palladium precursors for this transformation. Preferably, the palladium precursor is selected from Pd(π-cinnamyl)Cl dimer, Pd(OAc) ₂ , Pd(Cl _{) 2} , Pd2(dba) ₃ , Pd(dba) ₂ , Pd( _PPh3 ) ₄ , Pd( _{PPh3 )2Cl2, Pd(acac)2 , and} Pd(PhCN) _2Cl2 . More preferably, the palladium precursor is selected from Pd(π- _cinnamyl )Cl dimer, _Pd2 (dba) ₃ , Pd(dba) ₂ , and Pd( _PPh3 ) ₄ . Even more preferably, the palladium precursor is Pd(π-cinnamyl)Cl dimer.

Bases known in the art to be compatible with cross-coupling reactions are suitable bases for _this transformation. Preferably, the base is selected from _K2CO3 , DABCO, DBU, _NaOtBu , _Cs2CO3 , _Li2CO3 , _Na2CO3 , _DMAP , NaHMDS, and _NEt3 . More preferably, the base is selected from _{K2CO3 , DABCO} , DBU, and _Cs2CO3 . Even more preferably, _the base _{is Cs2CO3} .

3.2. Standard Reaction Conditions Intermediate 3 (140 mg, 0.5 mmol, 1.0 equiv.), intermediate 4 (4-(6-bromopyridazin-3-yl)morpholine, CAS No. 927673-86-7, 134 mg, 0.55 mmol, 1.1 equiv.), and the corresponding base (3.0 equiv.) were dissolved in DMF (2.8 mL). Then, the corresponding palladium precursor (0.01 equiv.) and ligand (0.024 equiv.) were added. The reaction mixture was stirred at 100° C. for 3 h.

The reaction was cooled to room temperature, filtered through Celite, and washed with acetonitrile. Volatiles were evaporated under reduced pressure. The crude residue was purified by column chromatography on _SiO2 using eluents _CHCl3 /acetone (70/30) followed by _CHCl3 /MeOH (96/4) to give compound 1.

3.3. Screening of Palladium Precursors Using _Cs2CO3 as the base and JosiPhos as the ligand, different palladium (Pd) precursors were tested under the reaction conditions described above (section 3.2), and the results are shown in Table _II below.

3.4. Screening of Bases Using Pd(p-cinnamyl) chloride dimer as the Pd precursor and JosiPhos as the ligand, different bases were tested under the reaction conditions described above (section 2.2.), and the results are shown in Table III below.

3.5. Ligand Screening Different ligands were tested under standard reaction conditions and the results are summarized in Table V.

The ligands used in this study are all commercially available and the following abbreviations were used to identify them:

The results of the screening study are summarized below.

As shown in Table V, the ligand JosiPhos (columns 1 and 2) showed the highest yields.

Example 4. Preparation of Salts of Compound 1 4.1. Objective of the Study This study evaluated the formation of pharmaceutically acceptable salts containing Compound 1 and an acid. Salt formation was evaluated using three different solvents and 21 different acids.

The acids tested in this study were selected from hydrochloric acid, sulfuric acid, ethane-1,2-disulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, maleic acid, phosphoric acid, ethanesulfonic acid, L-glutamic acid, malonic acid, gentisic acid, fumaric acid, D-glucuronic acid, L-phosphoric acid, gluconic acid, benzoic acid, succinic acid, glutaric acid, and acetic acid.

4.2 General Information The choice of acid was based on the DpKa between Compound 1 and the corresponding acid or counterion. Preferably, the DpKa between Compound 1 and the acid is greater than 1 pKa unit.

Compound 1 has three potential ionization centers, and therefore, three different pKa values for Compound 1 were determined as 6.0, 4.3, and -1.0.

The solvents used to evaluate salt formation were acetone, ethanol, and THF.

Different stoichiometric ratios between Compound 1 and the corresponding acid were tested. Preferably, the stoichiometric ratios used in this experiment were 2:1, 1:1, 1:2, and 1:3 (Compound 1:acid ratio).

4.3 General Protocol for Salt Formation A stoichiometric amount of the corresponding acid was added to a suspension of Compound 1 (approximately 17 mg) in a selected solvent targeting a concentration of approximately 17 mg/mL to approximately 34 mg/mL. The suspension was subjected to a thermal cycling profile.

In all experiments, solids were isolated from solution by centrifugation and dried under vacuum (10 mbar). The mother liquor was also evaporated under vacuum. All resulting dried solids were analyzed by high-throughput XRPD. The solids were then exposed to accelerated aging conditions (AAC) at 40°C and 75% relative humidity for two days and reanalyzed by HT-XRPD to verify their physical stability.

4.4. Results Under the above conditions, several pharmaceutically acceptable salts were isolated with the five acids listed above. The results are summarized in Table VI below.

4.4.1. HCl Salt of Compound 1 The HCl salt was obtained from the salt formation experiment described above using 2 molar equivalents of hydrochloric acid in EtOH as the solvent.

The ¹ H-NMR spectrum of the HCl salt showed changes in chemical shifts compared to compound 1 in its free base form. The chemical shift observed in FIG. 1B at 9.8 ppm corresponding to the N—H bond suggests the formation of a salt.

The ¹ H-NMR spectrum of the HCl salt of compound 1 is shown in FIG. 1A.

The DSC curve for the HCl salt of compound 1 is shown in Figure 1D.

The TGA curve for the HCl salt of compound 1 is shown in Figure 1E.

The DVS curve for the HCl salt of Compound 1 is shown in Figure 1F.

The XRPD pattern of the HCl salt of Compound 1 is shown in Figure 1C.

4.4.2. Mesylate Salt of Compound 1 or Methanesulfonic Acid Derivative of Compound 1 The mesylate salt was obtained from the salt formation experiment described above using 1 molar equivalent of methanesulfonic acid in acetone as the solvent.

The ¹ H-NMR spectrum of the mesylate salt of Compound 1 is shown in FIG. 2A.

The ¹ H-NMR spectrum of the mesylate salt showed changes in chemical shifts compared to Compound 1 in its free base form. The chemical shifts observed in Figure 2B suggest the formation of a salt.

The HR-XRPD pattern of the mesylate salt of Compound 1 is shown in Figure 2C.

The DSC curve for the mesylate salt of Compound 1 is shown in Figure 2D.

The TGA curve for the mesylate salt of Compound 1 is shown in Figure 2E.

The DVS curve of the mesylate salt of Compound 1 is shown in Figure 2F.

Example 5. Preparation of Co-Crystal Forms of Compound 1 5.1. Objective of the Study This study evaluated the formation of co-crystal forms containing Compound 1 and co-formers. Fourteen different co-formers were used to evaluate co-crystal formation in three solvents. The co-formers tested in this study were selected from maleic acid, phosphoric acid, fumaric acid, salicylic acid, L-tartaric acid, citric acid, L-malic acid, L-ascorbic acid, succinic acid, nicotinic acid, caffeine, saccharin, meglumine, and sorbitol.

5.2. General Information The solvents used to evaluate co-crystal formation were DCM, methyl ethyl ketone, MeOH, THF, isopropyl acetate.

Different stoichiometric ratios between Compound 1 and the corresponding coformer were tested. Preferably, the stoichiometric ratios used in this experiment were 2:1, 1:1, and 1:2 (Compound 1:coformer).

5.3. Co-crystal Formation Experimental Protocols Different types of experiments were performed on co-crystal formation, including:
- Solvent equilibrium (i.e., slurry)
- Trituration or solvent drop-trituration - Evaporation - Temperature cycling 5.3.1 Solvent equilibration technique Compound 1 (0.1 mmol, 46.0±1.0 mg, corrected for TGA weight loss) as the free base was suspended in the corresponding solvent selected from DCM (1 mL), THF (1 mL), methyl ethyl ketone (3 mL), and methanol (3 mL) at 20/40° C. for 10-15 minutes. The corresponding coformer (0.1 mmol) was then added as a solid. The suspension was stirred at 20/40° C. for 2 days. The resulting solid was isolated by filtration or centrifugation and then dried under vacuum at room temperature for approximately 2 hours.
5.3.2. Addition-Grinding Technique Compound 1 as the free base and the corresponding coformer were ground in a mortar with a pestle by adding methyl ethyl ketone (100-200 μL) as a solvent.

5.3.3 Evaporation Technique Compound 1 as the free base was dissolved in 10 mL of DCM or THF and stirred for 30 minutes. The corresponding coformer was dissolved in DCM or THF (2.0-2.5 mL) or water (60-120 μL) and stirred for 10 minutes, and the resulting solution was then added to the solution containing Compound 1. The sample was then evaporated under a low nitrogen flow.

5.3.4. Temperature Cycling Technique Amorphous samples obtained from the evaporation technique (described in Section 5.3.3) were subjected to the following temperature cycles: 4 cycles from 20 to 40° C. with stirring for 2 hours at each temperature.

5.3.5. Results The following co-crystal forms were isolated according to the different techniques described above:

5.3.6. Maleate Co-Crystal Form or Co-Crystal Form I of Compound 1
Co-crystal Form I was obtained from the formation experiment described above using 2 molar equivalents of maleic acid in THF as the solvent.

The ¹ H-NMR spectrum of the maleate co-crystal form of compound 1 is shown in FIG. 3A.

The ¹ H-NMR spectrum of the maleate co-crystal form of compound 1 (red in FIG. 3B) showed no chemical shift changes compared to the free base of compound 1 (green in FIG. 3B).

The DSC curve for the maleate co-crystal form of Compound 1 is shown in Figure 3C.

5.3.7. Phosphate Co-Crystal Form or Co-Crystal Form II of Compound 1
Two different phosphate co-crystal forms of Compound 1 with different stoichiometries were identified: an equimolar amount of phosphoric acid was used to obtain the monophosphate co-crystal form (phosphate co-crystal Form A of Compound 1), and two molar equivalents of phosphoric acid were used to obtain the diphosphate co-crystal form (phosphate co-crystal Form B of Compound 1).

5.3.7.1. Phosphate Co-Crystal Form A or Co-Crystal Form IIA of Compound 1
The ¹ H-NMR spectrum of phosphate co-crystal Form A showed no changes in chemical shifts compared to Compound 1 free base.

The stoichiometry of phosphoric acid and compound 1 was analyzed by HPLC.

The ¹ H-NMR spectrum of phosphate co-crystal Form A of Compound 1 is shown in FIG. 4A.

The DSC curve for phosphate co-crystal Form A of Compound 1 is shown in Figure 4B.

The TGA curve for phosphate co-crystal Form A of Compound 1 is shown in Figure 4C.

The DVS curve for phosphate co-crystal Form A of Compound 1 is shown in Figure 4D.

The XRPD pattern of phosphate co-crystal Form A of Compound 1 is shown in Figure 4E.

XRPD of phosphate salt co-crystal Form A of Compound 1 shows the following peak pattern:

5.3.7.2. Phosphate Co-Crystal Form B or Co-Crystal Form IIB of Compound 1
Phosphate co-crystal Form B of Compound 1 was obtained as a pure crystalline phase in a single salt formation experiment carried out with two molar equivalents of phosphoric acid in acetone.

The ¹ H-NMR spectrum of the phosphate co-crystal Form B of Compound 1 showed no changes in chemical shifts compared to Compound 1 free base.

The ¹ H-NMR spectrum of phosphate co-crystal Form B of Compound 1 is shown in FIG. 5A.

The DSC curve for phosphate co-crystal Form B of Compound 1 is shown in Figure 5B.

The TGA curve for phosphate co-crystal Form B of Compound 1 is shown in Figure 5C.

5.3.8. Fumarate Co-Crystal Form or Co-Crystal Form III of Compound 1
The fumarate co-crystalline form of Compound 1 was obtained from the formation experiments described above using 1 molar equivalent of fumaric acid using acetone, ethanol, or THF as the solvent.

The ¹ H-NMR spectrum of the fumarate co-crystal form of Compound 1 is shown in FIG. 6A.

The ¹ H-NMR spectrum of the fumarate co-crystal form of Compound 1 (red in FIG. 6B) showed no chemical shift changes compared to the free base of Compound 1 (green in FIG. 6B).

The XRPD pattern of the fumarate co-crystalline form of Compound 1 is shown in Figure 6C.

The DSC curve for the fumarate co-crystal form of Compound 1 is shown in Figure 6D.

The TGA curve for the fumarate co-crystal form of Compound 1 is shown in Figure 6E.

The DVS curve of the fumarate co-crystal form of Compound 1 is shown in Figure 6F.

5.3.1. L-Tartrate Salt Co-Crystal Form or Co-Crystal Form IV of Compound 1
The L-tartrate co-crystalline form of compound 1 was obtained from the formation experiment described above using one molar equivalent of the corresponding acid.

The ¹ H-NMR spectrum of the L-tartrate co-crystal form of Compound 1 showed no changes in chemical shifts compared to the free base of Compound 1. The ¹ H-NMR spectrum of the L-tartrate co-crystal form of Compound 1 is shown in Figure 7D.

The DSC-TGA curve for the L-tartrate co-crystal form of Compound 1 is shown in Figure 7A.

The DVS curve for the L-tartrate co-crystal form of Compound 1 is shown in Figure 7B.

XRPD of the L-tartrate co-crystalline form of Compound 1 shows the following peak pattern:

5.3.2. L-Malate Co-Crystal Form or Co-Crystal Form V of Compound 1
The L-malate co-crystalline form of Compound 1 was obtained from the formation experiment described above using 0.5 molar equivalents of L-malic acid using THF as the solvent.

The ¹ H-NMR spectrum of the L-malate co-crystal form of Compound 1 showed no changes in chemical shifts compared to the free base of Compound 1. The ¹ H-NMR spectrum of the L-malate co-crystal form of Compound 1 is shown in Figure 8D.

The DSC-TGA curve for the L-malate co-crystalline form of Compound 1 is shown in Figure 8A.

The DVS curve for the L-malate co-crystal form of Compound 1 is shown in Figure 8B.

XRPD of the L-malate co-crystalline form of Compound 1 shows the following peak pattern:

5.3.3. Saccharinate Co-Crystal Form or Co-Crystal Form VI of Compound 1
The saccharinate co-crystal form was obtained from the formation experiment described above using one molar equivalent of saccharin.

The ¹ H-NMR spectrum of the saccharinate co-crystal form of Compound 1 showed no changes in chemical shifts compared to the free base of Compound 1. The ¹ H-NMR spectrum of the saccharinate co-crystal form of Compound 1 is shown in Figure 9D.

The DSC-TGA curve for the saccharinate co-crystal form of Compound 1 is shown in Figure 9A.

The DVS curve for the saccharinate co-crystal form of Compound 1 is shown in Figure 9B.

XRPD of the saccharinate co-crystalline form of Compound 1 shows the following peak pattern:

research equipment

Example 6. Preparation of a solid form of the fumarate salt co-crystal of Compound 1.
6.1. Objective of the Study The objective of this study was to investigate the existence of different solid forms of the fumarate cocrystal of Compound 1.

6.2. Solid Forms of Compound 1 Compound 1 as a free base exists in an amorphous form and two polymorphic forms: Form A is a hydrate polymorph of Compound 1, and Form C is a polymorph of anhydrous Compound 1.

The XRPD pattern of Form A (hydrate of Compound 1) is shown in Figure 10A.

Form A (hydrate of Compound 1) exhibits the following peak pattern:

The XRPD pattern of Form C (hydrate of Compound 1) is shown in Figure 10B.

Form C (anhydrous Compound 1) exhibits the following peak pattern:

6.3. Screening for Different Polymorphic Forms of the Fumarate Co-crystal of Compound 1 The solvents used to evaluate the polymorphic forms of the fumarate co-crystal of Compound 1 are shown in Table XVII below.

6.4. Experimental Protocol for Investigation of Polymorphic Forms of Fumarate Co-Crystal of Compound 1 Different types of techniques for polymorph screening were performed, including:
- Temperature cycling - Solvent drop milling - Vapor diffusion (from amorphous materials)
- Vapor diffusion (from the mother liquor and antisolvent)
- Addition of antisolvent - Slow evaporation - Impingement cooling

6.4.1. Temperature Cycling Techniques For polymorph screening of the 32 selected solvents, the following steps were performed.
Approximately 1920 mg of Compound 1 fumarate co-crystal (as Form III) was weighed and dissolved in 384 mL of 1,4-dioxane:water (80:20% v/v) with heating using a heat gun until a clear solution was obtained.
- The solution was pipetted into 20 mL vials in 15.15 mL aliquots (5 mg/mL).
- Each vial was placed in a freezer for 3 hours, then the frozen samples were placed in a freeze dryer under vacuum for 72 hours.
- The solid from one representative vial was analyzed by XRPD and 1H-NMR analysis, which confirmed that an amorphous form had been achieved.
- An appropriate volume of a suitable solvent system was added to each of the freeze-dried samples to obtain a slurry.
For solvent systems with boiling points above -70°C, the samples were then subjected to temperature cycling from 5 to 70°C at a ramp rate of 0.1°C/min with 1 hour hold at both temperatures for 96 hours (2.5 cycles).
- The solids were then isolated from the slurries by centrifugation at 60°C and the solids were analysed by XRPD.
Some samples were clear solutions with a solid shell present, which was analyzed by XRPD.
Some samples were dry solids due to solvent evaporation, in which case an additional 2 mL of solvent was added to each vial and stirred overnight at 40°C before centrifugation and analysis by XRPD.
For solvent systems with boiling points above -70°C, the samples were then subjected to temperature cycling from 5 to 50°C or 5 to 30°C at a ramp rate of 0.1°C/min with 1 hour holds at both temperatures for 96 hours (2.5 cycles).
- The solids were then isolated from the slurries by centrifugation at 50°C or 30°C and the solids were analysed by XRPD.
Some samples were clear solutions with a solid shell present, which was analyzed by XRPD.
Some samples were dry solids due to solvent evaporation, in which case an additional 2 mL of solvent was added to each vial and stirred overnight at 40°C before centrifugation and analysis by XRPD.
- All wet solids are dried under vacuum at 40°C and reanalyzed by XRPD.
- The mother liquor was divided into 4 x 2 mL vials and used for mother liquor experiments: vapor diffusion, slow evaporation, antisolvent addition, and rapid cooling.
Note: Isolation was performed at elevated temperature to maximize recovery of material in saturated solution.

6.4.2. Solvent Dropping Technique Using amorphous material, the following steps were performed to explore a broader polymorph landscape by using solvent drop-milling.
- 500 mg of Compound 1 fumarate co-crystal (as Form III) was weighed and transferred into a DURAN flask.
- 100 mL of 1,4-dioxane:H2O (80:20% v/v) was added to the DURAN and dissolution was facilitated by using a heat gun.
This solution was used for both solvent drop milling and vapor diffusion experiments.
- 2 mL aliquots were pipetted into 2 mL bead mill vials.
- The samples were then placed in the freezer for 3 hours.
- The frozen samples were then placed in a freeze dryer under vacuum for 24 hours.
One representative vial was used for XRPD and 1H NMR analysis of the lyophilized material to confirm that an amorphous form had been achieved.
The three types of beads and 2 μL of the appropriate solvent system were then added to each vial containing 10 mg of Compound 1 amorphous fumarate co-crystal.
- The sample was placed in a bead mill and ground for 1 hour.
- 10 x 90 seconds at a speed of 5000 rpm, with 10 second intervals.
- Each sample was then analyzed by XRPD.
- All wet solids were dried under vacuum at 40°C and re-analyzed by XRPD.

6.4.3. Vapor Diffusion (from Amorphous Materials) Technique For solvent vapor diffusion experiments from amorphous materials, the following procedure was performed.
- Using previously prepared amorphous material (following temperature cycling or dropwise solvent addition techniques), 3 mL of the appropriate solvent system was pipetted into a 20 mL vial.
Each sample of amorphous material held in a 2 mL vial was uncapped and placed into an assigned 20 mL vial.
- The 20 mL vials were then capped, sealed with parafilm and allowed to diffuse at 20°C for 1 week before characterization.
- Samples that still contain amorphous material by XRPD are placed in an oven at 40°C for 1 week to facilitate diffusion.
- All solids are dried under vacuum at 40°C for 24 hours and reanalyzed by XRPD.

6.4.4. Vapor Diffusion (from Mother Liquors and Antisolvents) Techniques For vapor diffusion of the above polymorph screening samples (thermocycling or solvent dropwise addition techniques) and mother liquors obtained from their antisolvents, the following steps were performed.
-0.5 mL of the filtered mother liquor was placed in a 2 mL vial.
- 3 mL of the appropriate anti-solvent was pipetted into a 20 mL vial.
- The uncapped 2 mL vial was placed inside a 20 mL vial, capped and sealed with parafilm.
- They are left at 20°C for 1 week before characterisation.
- All wet solids are dried under vacuum at 40°C for 24 hours and reanalyzed by XRPD.

6.4.5. Antisolvent Addition Techniques For antisolvent addition using the polymorph screening samples described above (thermocycling or solvent dropwise addition techniques) and the mother liquors obtained from those antisolvents, the following steps were performed.
Approximately 0.5 mL of the filtered mother liquor was placed in a 2 mL vial equipped with a stir bar and the vial was placed in a 40°C water bath.
-100 μL of the appropriate antisolvent was added until precipitation occurred or until 1.5 mL had been added.
The sample was then stirred at 5°C for 72 hours.
- The sample, which was found to be a slurry, was isolated by centrifugation and analyzed by XRPD.
- The sample, which was a clear solution, was placed in the freezer for one week.
- All wet solids are dried under vacuum at 40°C for 24 hours and analyzed by XRPD.

6.4.6. Slow Evaporation Technique To slowly evaporate the mother liquors obtained from the polymorph screening samples described above (thermal cycling or solvent dropwise addition technique), the following steps were performed.
-0.5 mL of the filtered mother liquor was transferred to a 2 mL vial.
- The vials were uncapped and left to evaporate at 20°C for 1 week before characterization.
- In experiments where it remained as a clear solution, it was evaporated at 40°C for 1 week.
- All wet solids were dried under vacuum at 40°C for 24 hours and re-analyzed by XRPD.

6.4.7. Rapid Cooling Technique To rapidly cool the mother liquor obtained from the polymorph screening samples described above (thermocycling or solvent dropwise addition technique), the following steps were performed.
-0.5 mL of the filtered mother liquor was transferred to a 2 mL vial.
- The vials were capped and placed in a freezer at -18°C for 1 week before characterization.
- All wet solids are dried under vacuum at 40°C for 24 hours and reanalyzed by XRPD.

6.4.8. Results Solid forms were isolated and identified according to the different techniques described above. Generally, the solid form identified in the co-crystal screens using most solvents was the fumarate co-crystal form of Compound 1, i.e., co-crystal Form III (see 5.3.8 above), which has the XRPD pattern shown in Figure 6C and exhibits the peaks shown in Table XI. However, in certain experiments using acetic acid, the solvate crystalline form was observed, while in other experiments, amorphous material was recovered, and in some other experiments using certain techniques, dissociation of the co-crystal occurred, yielding either polymorphic Form A or Form C of Compound 1 as the free base or fumaric acid.

Biological Examples Example 7. PK Dog Study of Fumarate Co-Crystal Form of Compound 1 7.1.1. Experimental Setup The exposure of Compound 1 as the free base was evaluated in beagle dogs in different pharmacokinetic studies (fasted and fed conditions).

Compound 1, as the free base form, was administered orally at a single dose of up to 30 mg/kg as a suspension in Solutol/MC, 0.5% (2/98 v/v), and as a suspension in citrate buffer, as an amorphous solid dispersion (ASD) powder dispersed in HPMC-acetate succinate, at a single dose of up to 100 mg/kg. Blood samples were collected over 24 hours, and plasma was analyzed.

The fumarate co-crystal form of Compound 1 was administered orally at a single dose of 100 mg/kg as a suspension in 5% HPMC in a pharmacokinetic study and at 12.5, 25, and 50 mg/kg in a chronic toxicity study. Blood samples were collected over a 24-hour period, and plasma was analyzed.

7.1.2. Results A higher absorption rate (C _max ) and extent of absorption (AUC) was observed for the fumarate co-crystal form compared to the free base form.

A summary of the pharmacokinetic parameters after single dose administration is provided below in Table XVIII.

7.2. PK Dog Study of Compound 1 Mesylate Form and Compound 1 HCl Salt Form 7.2.1. Experimental Setup The exposure of Compound 1 as the free base was evaluated in beagle dogs in a pharmacokinetic study (fasted).

Compound 1, in its free base form, was prepared as a spray-dried powder according to the protocol described in Section 7.3.2.

Compound 1 free base as a spray-dried powder was administered orally at a single dose of 30 or 100 mg/kg at a drug load of 20% by weight in cellulose acetate phthalate (CAP) and 25% by weight in hydroxypropylmethylcellulose acetate succinate (HPMC-AS). Blood samples were collected over 24 hours, and plasma was analyzed.

The mesylate form of Compound 1 was administered orally as a single dose of 30 or 100 mg/kg as a suspension in 2% HPMC and 0.5% Solutol in water. Blood samples were collected over 24 hours and plasma was analyzed.

The HCl salt form of Compound 1 was administered orally as a single dose of 30 mg/kg as a suspension in 2% HPMC and 0.5% Solutol in water. Blood samples were collected over 24 hours and plasma was analyzed.
7.2.2. Preparation of spray-dried powder of Compound 1 7.2.2.1. Spray dryer settings:
Buchi B-290 Mini Spray Dryer with inert loop B-295 at -15°C.
・Inlet temperature 110℃.
・Suction speed: 100%.
- Nozzle type: Twin fluid nozzle.
Nozzle pressure: 50 psi.
- Feeding rate: 10 mL/min.
- Spray solvent: DCM/MeOH (3:1).
- Solution concentration: 10% w/w solids.
Batch size: 52g solids.

To minimize residual solvent content, all formulations were dried overnight in a vacuum oven at 40°C.

7.2.2.2. Protocol The preparation of Compound 1 free base as a spray-dried powder was carried out according to the following steps.
Compound 1 and cellulose acetate phthalate (CAP) (20% w/w compound 1 in CAP, 10% w/w solid concentration) are mixed and dissolved in DCM/MeOH (3:1) to obtain the corresponding solution.
- The solution is connected to a spray dryer and the particles are dried using the appropriate settings.
- To remove any remaining solvent, the spray dried powder is transferred to a suitable dryer for post-drying (eg in a vacuum oven at 40°C overnight).
- Pack spray dried powder tightly to prevent exposure to moisture.
- An appropriate amount of spray dried powder is suspended in citrate buffer to allow oral administration by gavage.

7.2.3. Results A higher absorption rate (C _max ) and extent (AUC) were observed for the free base (as ASD) compared to the mesylate or HCl salt forms of Compound 1.

A summary of the pharmacokinetic parameters after single dose administration is provided below in Table XIX.

Finally, those skilled in the art will appreciate that the foregoing description is exemplary and explanatory in nature and is intended to illustrate the present invention and its preferred embodiments. Through routine experimentation, those skilled in the art will recognize that obvious modifications and variations can be made without departing from the spirit of the present invention. All such modifications that come within the scope of the appended claims are intended to be included therein. It is therefore intended that the present invention be defined not by the foregoing description, but by the following claims and their equivalents.

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in this specification to the same extent as if each individual publication was fully set forth.

It should be understood that factors such as differences in the cell penetration abilities of various compounds may contribute to discrepancies between the activity of compounds in in vitro biochemical and cellular assays.

At least some of the chemical names of the solid forms of the invention provided and described in this application may have been generated on an automated basis using commercially available chemical naming software programs and have not been independently verified. Exemplary programs that perform this function include the Lexichem naming tool sold by Open Eye Software, Inc., and the Autonom software tool sold by MDL, Inc. In the event that the depicted chemical name and the depicted structure differ, the depicted structure shall control.
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Claims (41)

Compound 1 (4-methyl-5-[3-methyl-7-[(6-morpholin-4-ylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-5-yl]oxypyridine-2-carbonitrile)
,
or a pharmaceutically acceptable solvate thereof, and fumaric acid. The pharmaceutical composition according to claim 1, wherein compound 1 and fumaric acid form a salt or a co-crystal, preferably a co-crystal. The pharmaceutical composition of claim 1 or 2, wherein Compound 1 and fumaric acid are present in a ratio of approximately 1:1. Compound 1 (4-methyl-5-[3-methyl-7-[(6-morpholin-4-ylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-5-yl]oxypyridine-2-carbonitrile)
Solid form of the fumarate cocrystal of . The solid form of claim 4, characterized by an X-ray powder diffraction pattern having one or more peaks at the following positions: 3.4, 6.8, 7.1, 8.6, 11.0, 12.4, 13.8, 14.3, 14.8, 15.5, 17.1, 18.3, 20.5, 20.8, 21.2, 22.4, 22.9, 23.9, 24.9, 25.6, or 26.5 degrees 2θ ± 0.2 degrees 2θ. The solid form of claim 4 or 5, characterized by an X-ray powder diffraction pattern including at least three of the peaks at 3.4, 7.1, 8.6, 12.4, 13.8, 14.3, and 14.8 degrees 2θ ± 0.2 degrees 2θ. The solid form of claim 4, 5, or 6, characterized by an X-ray powder diffraction pattern including at least four of the peaks at 3.4, 7.1, 8.6, 12.4, 13.8, 14.3, and 14.8 degrees 2θ ± 0.2 degrees 2θ. The solid form of claim 4, 5, 6, or 7, characterized by an X-ray powder diffraction pattern including at least five of the peaks at 3.4, 7.1, 8.6, 12.4, 13.8, 14.3, and 14.8 degrees 2θ ± 0.2 degrees 2θ. The solid form of claim 4, 5, 6, 7, or 8, characterized by an X-ray powder diffraction pattern including at least six of the peaks at 3.4, 7.1, 8.6, 12.4, 13.8, 14.3, and 14.8 degrees 2θ ± 0.2 degrees 2θ. The solid form of claim 4, 5, 6, 7, 8, or 9, characterized by an X-ray powder diffraction pattern including peaks at 3.4, 7.1, 8.6, 12.4, 13.8, 14.3, and 14.8 degrees 2θ ± 0.2 degrees 2θ. The solid form of claim 4, 5, 6, 7, 8, 9, or 10, wherein the powder X-ray diffraction pattern further comprises one or more peaks at the following positions: 15.5, 17.1, 18.3, 20.5, 20.8, 21.2, 22.4, 22.9, 23.9, 24.9, 25.6, or 26.5 degrees 2θ ± 0.2 degrees 2θ. The solid form of claim 4, 5, 6, 7, 8, 9, 10, or 11, wherein the powder X-ray diffraction pattern further comprises at least three of the following peaks at the following positions: 15.5, 17.1, 18.3, 20.5, 20.8, 21.2, 22.4, 22.9, 23.9, 24.9, 25.6, or 26.5 degrees 2θ ± 0.2 degrees 2θ. The solid form of claim 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein the powder X-ray diffraction pattern further comprises at least five of the following peaks at the following positions: 15.5, 17.1, 18.3, 20.5, 20.8, 21.2, 22.4, 22.9, 23.9, 24.9, 25.6, or 26.5 degrees 2θ ± 0.2 degrees 2θ. The solid form of claim 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the X-ray powder diffraction pattern further comprises at least seven of the peaks at the following positions: 15.5, 17.1, 18.3, 20.5, 20.8, 21.2, 22.4, 22.9, 23.9, 24.9, 25.6, or 26.5 degrees 2θ ± 0.2 degrees 2θ. The solid form of claim 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, characterized by an X-ray powder diffraction pattern including peaks at 3.4, 6.8, 7.1, 8.6, 11.0, 12.4, 13.8, 14.3, 14.8, 15.5, 17.1, 18.3, 20.5, 20.8, 21.2, 22.4, 22.9, 23.9, 24.9, 25.6, and 26.5 degrees 2θ ± 0.2 degrees 2θ. The solid form of claim 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the solid form is a crystalline form. A pharmaceutical composition comprising the solid form of any one of claims 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 and a pharmaceutically acceptable carrier. The pharmaceutical composition of any one of claims 1, 2, 3, or 17, comprising an additional therapeutic agent. A pharmaceutical composition according to any one of claims 1, 2, 3, 17, or 18, or a solid form according to any one of claims 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, for use in medicine. Allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNα, interferon ("interferonopathy", in particular type I or type III interferonopathy), IL-12, and/or IL-23, in particular systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, The pharmaceutical composition of any one of claims 1, 2, 3, 17, or 18, or the solid form of any one of claims 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, for use in the prevention and/or treatment of a disease selected from polymyositis, Sjogren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease. Allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNα, interferon ("interferonopathy", in particular type I or type III interferonopathy), IL-12, and/or IL-23, in particular systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjoegren's disease A method for preventing and/or treating a disease selected from Renn's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease, comprising administering to a patient a pharmaceutical composition according to any one of claims 1, 2, 3, 17, or 18, or a solid form according to any one of claims 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. 70 mg to 300 mg of Compound 1 as a fumarate co-crystal:
or a pharmaceutically acceptable solvate thereof, wherein the unit dosage form is suitable for oral administration of up to a maximum total dose of Compound 1 of 300 mg per day. The dosage form of claim 22, wherein each unit dosage form contains 75 mg to 300 mg of Compound 1. The dosage form of claim 22 or 23, wherein the unit dosage form contains 75 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 225 mg, 250 mg, or 300 mg of Compound 1. The dosage form described in claim 22 or 23, wherein each unit dosage form contains 75 mg to 225 mg of Compound 1. The dosage form of claim 22, 23, 24, or 25, wherein each unit dosage form contains 150 mg of Compound 1. The dosage form of claim 22, 23, 24, 25, or 26, wherein the unit dose is in a form selected from a liquid, a tablet, a capsule, or a gelcap. The dosage form of claim 22, 23, 24, 25, 26, or 27, wherein the unit dose is in the form of a tablet or capsule. The dosage form of claim 22, 23, 24, 25, 26, 27, or 28, wherein the unit dose is in the form of a tablet. The dosage form of claim 22, 23, 24, 25, 26, 27, 28, or 29 for use in the treatment of inflammatory diseases and/or diseases associated with hypersecretion of IFNα and/or interferon ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and/or IL-23, particularly diseases selected from systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease. Use of the dosage form of claim 22, 23, 24, 25, 26, 27, 28, or 29 in the manufacture of a medicament for the treatment of inflammatory diseases and/or diseases associated with hypersecretion of IFNα and/or interferon ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and/or IL-23, particularly diseases selected from systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease. A method for treating inflammatory diseases and/or diseases associated with hypersecretion of IFNα and/or interferon ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and/or IL-23, particularly diseases selected from systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease, comprising administering to a patient a dosage form according to any one of claims 22, 23, 24, 25, 26, 27, 28, or 29. A process for preparing compound 1 or a pharmaceutically acceptable salt thereof, comprising reacting intermediate 3 and intermediate 4 in the presence of a solvent, a base, a palladium precursor, and a JosiPhos ligand.
34. The process of claim ₃₃ , wherein the base is _Cs2CO3 . The process described in claim 33 or 34, wherein the palladium precursor is Pd(π-cinnamyl)Cl dimer. The process of claim 33, 34, or 35, wherein the JosiPhos ligand is (R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine. 1. A process for producing a fumarate co-crystalline form of Compound 1, comprising:
i. suspending compound 1 in a solvent, preferably at room temperature;
ii. adding at least one equivalent of fumaric acid to the suspension;
iii. Aging the reaction mixture, preferably at 25° C. for 72 hours;
iv. Centrifuging the reaction mixture;
v. drying the solid under vacuum, preferably at 30° C. for at least 12 hours. 1. A process for producing fumarate co-crystal Form III, comprising:
i) reacting intermediate 3 and intermediate 4 in the presence of a solvent, a base, a palladium precursor, and JosiPhos as a ligand;
ii) isolating compound 1 from the reaction mixture;
iii) suspending compound 1 in a solvent, preferably at room temperature;
iv) adding at least one equivalent of fumaric acid to the suspension;
v) aging the reaction mixture, preferably at 25° C. for 72 hours;
vi) centrifuging the reaction mixture;
vii) drying the solid under vacuum, preferably at 30° C. for at least 12 hours. 39. The process of claim ₃₈ , wherein the base is _Cs2CO3 . The process described in claim 38 or 39, wherein the palladium precursor is Pd(π-cinnamyl)Cl dimer. The process of claim 38, 39, or 40, wherein the JosiPhos ligand is (R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine.