Solid forms of deuterated colony stimulating factor-1 receptor (CSF-1R) inhibitor

Abstract

Described herein are solid forms of 3-(((2S, 3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2, 3-dihydrobenzo [b] [1, 4] dioxin-6-yl) methyl)-3H-imidazo [4, 5-b] pyridin-2-d, methods of making these forms, pharmaceutical compositions, and methods of use thereof.

Description

[0001] Described herein are solid forms of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d, methods of preparing these forms, pharmaceutical compositions, and methods of use thereof. Background Art

[0002] Enzymes (such as aldehyde oxidase) in living organisms can cause unwanted metabolic degradation. Aldehyde oxidase (AO) is a cytoplasmic molybdenum-containing enzyme involved in the biotransformation of a variety of drugs. The challenges represented by AO-mediated metabolism are driven by several overlapping factors, including the complex biology of the enzyme and the extensive use of structural motifs for AO substrates (e.g., nitrogen heterocycles and amides). See, for example, Manevski, N. et al., Metabolism by Aldehyde Oxidase: Drug Design and Complementary Approaches to Challenges in Drug Discovery [Metabolism by aldehyde oxidase: Complementary Approaches to Drug Design and Drug Discovery Challenges], J. Med. Chem. [Journal of Medicinal Chemistry] 2019, 62, 10955-10994. In addition, differences in AO-mediated metabolism (not only between species, but also between individuals) contribute to the variability of exposure and complicate human dose selection.

[0003] It was unexpectedly discovered that deuterium-substituted colony stimulating factor-1 ("CSF-1R") inhibitor compounds as described in PCT / US2021 / 064831 have improved ADME properties, for example, such CSF-1R inhibitor compounds substituted with deuterium at specific positions have improved ADME properties, particularly significant resistance to AO degradation, thereby potentially improving drug efficacy and drug exposure in vivo. These CSF-1R inhibitors are small molecule compounds that are able to penetrate the blood-brain barrier to reach the central nervous system (CNS). Because these compounds are able to advantageously penetrate the blood-brain barrier (a highly desirable property in neurological indications), these compounds need to be able to exhibit sufficient absorption, metabolism, distribution and excretion (ADME) properties to ensure appropriate dosing. Metabolic issues can include rapid metabolism as well as metabolic degradation, both of which can lead to toxicity and / or suboptimal dosing of the active agent.

[0004] One factor in assessing the suitability of a compound as a therapeutic agent is whether the compound can be administered as a therapeutic agent in a form that is easily absorbed by the body and is also storage stable. Pharmaceutically active substances used to prepare therapeutic agents should be as pure as possible and should ensure their stability for long-term storage under various environmental conditions. These characteristics can be used to prevent the appearance of unexpected degradation products in pharmaceutical compositions, which may be potentially toxic or simply result in reduced potency and / or efficacy of the composition.

[0005] The main problem of large-scale production of pharmaceutical compounds is that the active substance should have a stable crystalline form to ensure consistent process parameters and drug quality. If an unstable crystalline form is used, the crystal form may change during production and / or storage, leading to quality control problems and uneven preparations. Such changes may affect the reproducibility of the production process and thus lead to the final preparation not meeting the high quality and strict requirements imposed on pharmaceutical composition preparations. In this regard, it should generally be remembered that any change to the solid state of a pharmaceutical composition that can improve its physical and chemical stability has significant advantages over less stable forms of the same drug.

[0006] When a compound crystallizes from a solution or slurry, it may crystallize in different spatial lattice arrangements, a property known as "polymorphism". Each crystalline form is a "polymorph". Although polymorphs of a given substance have the same chemical composition, they may differ from each other in one or more physical properties (such as solubility, dissociation, true density, dissolution, melting point, crystal shape, morphology, particle size, compaction behavior, flow characteristics and / or solid state stability). The differences in the physical properties of different polymorphic forms are caused by different orientations of adjacent molecules in the solid and intermolecular interactions. The polymorphic forms of a compound can be distinguished, in particular, by X-ray diffraction.

[0007] Although it is known that the preparation of crystalline forms can improve the physical or pharmaceutical properties of pharmaceutically active compounds, it is impossible to predict whether a compound exists in a crystalline form or which crystalline form may have advantages for a particular purpose before the actual preparation and characterization of the crystalline form. In particular, in a non-limiting manner, these advantages may include better processability, solubility, or shelf life stability, to name a few examples. Other advantages may also include biological properties, such as improved bioavailability, reduced adverse reactions at the gastrointestinal tract (e.g., gastrointestinal irritation, partial degradation of the compound, etc.), or better delivery of the drug to the intended target site. Summary of the invention

[0008] The present disclosure relates to various solid-state forms of the deuterated CSF-1R inhibitor 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d (hereinafter designated as compounds of formula (I)), methods of preparing these forms, and pharmaceutical compositions and methods of use for treating diseases. These solid-state forms of compounds of formula (I) may satisfy at least one of the important features mentioned above.

[0009] Disclosed herein is 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d (hereinafter designated as a compound having formula (I)) as an anhydrate of crystalline Form A.

[0010] Also disclosed herein is 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d (hereinafter designated as the compound having formula (I)) as an anhydrate of crystalline Form I.

[0011] Also disclosed herein is 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d (hereinafter designated as a compound having formula (I)) as a solvate of crystalline Form II.

[0012] Also disclosed herein is 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d (hereinafter designated as a compound having formula (I)) as a solvate of crystalline Form III.

[0013] Also disclosed herein is 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d (hereinafter designated as a compound having formula (I)) as a solvate of crystalline Form IV.

[0014] Also disclosed herein is a pharmaceutical composition comprising a solid form of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d disclosed herein and a pharmaceutically acceptable carrier.

[0015] Further disclosed herein is a method of treating diseases and conditions mediated by CSF-1R in a patient in need thereof, the method comprising administering to the patient an effective amount of a solid form of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d disclosed herein.

[0016] The present disclosure also relates to solid forms of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d disclosed herein for use in treating diseases and conditions mediated by CSF-1R in a patient in need thereof.

[0017] The present disclosure further relates to the use of the disclosed solid forms of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d in the manufacture of a medicament for treating a disease mediated by CSF-1R.

[0018] The compound of formula (I) depicted below is a CSF-1R inhibitor compound with improved ADME properties, particularly significant resistance to AO degradation. The compound of formula (I) is a small molecule compound that can penetrate the blood-brain barrier to reach the central nervous system (CNS). It can be used to treat, for example, neurological diseases, including amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and Huntington's disease. The compound is described in PCT / US 2021 / 064831:

[0019] Provided herein is 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d (hereinafter designated as a compound of formula (I)) as an anhydrate of crystalline Form A characterized by having an X-ray powder diffraction pattern obtained using Cu(Kα) radiation comprising three, four, five, six or more peaks in 2-θ degrees selected from: 7.6, 11.9, 16.6, 17.2, 18.6, 19.6, 22.4±0.2 degrees, which is optionally further characterized by being substantially as Figure 1 The powder X-ray diffraction pattern shown in .

[0020] Provided herein is 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d (hereinafter designated as a compound of formula (I)) as an anhydrate of crystalline Form I characterized by having an X-ray powder diffraction pattern obtained using Cu(Ka) radiation comprising three, four, five, six or more peaks in 2-theta degrees selected from: 3.6, 6.3, 9.6, 12.6, 15.9, 21.2, 25.3±0.2 degrees, which is optionally further characterized by being substantially as Fig.12 Powder X-ray diffraction pattern shown in .

[0021] As used herein, the term "substantially pure" means that the crystalline form contains at least 90 percent, such as at least 95 percent, such as at least 97 percent, and for example at least 99 percent by weight of the indicated crystalline form. Alternatively, it will be understood that "substantially pure" means that the crystalline form contains less than 10 percent, such as less than 5 percent, such as less than 3 percent, and for example less than 1 percent by weight of impurities (including other polymorphic forms, solvated forms, or amorphous forms). BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The XRPD pattern of Compound (I) Form A is shown.

[0023] Figure 2 A PLM image of Compound (I) Form A is shown.

[0024] Figure 3 Shown is a TGA (top pattern) / DSC (bottom pattern) overlay of Compound (I) Form A.

[0025] Figure 4A and 4BShown are a) the NMR spectrum of the original starting material of Compound (I), and b) the NMR spectrum of Form A of Compound (I).

[0026] Figure 5 The HPLC trace of Compound (I) Form A is shown.

[0027] Figure 6 Shown are the XRPD patterns of Compound (I): a) Form I, b) Form A, c) Form II (dioxane solvate), d) Form III (acetic acid solvate), and e) Form IV (ACN solvate).

[0028] Figure 7 DSC / TGA of Form I is shown.

[0029] Figure 8 DSC / TGA of Form A is shown.

[0030] Fig. 9 DSC / TGA of Form II (dioxane solvate) is shown.

[0031] Fig.10 DSC / TGA of Form III (acetic acid solvate) is shown.

[0032] Fig.11 DSC / TGA of Form IV (ACN solvate) is shown.

[0033] Fig.12 Shown are the XRPD patterns of Compound (I): a) scaled-up Form I, and b) Form I (reference).

[0034] Fig.13 Shown are the XRPD patterns of Compound (I): a) Form A (reference), b) acetone at 25°C, c) EtOAc at 25°C, d) acetone at 50°C, e) EtOAc at 50°C, and f) Form I (reference).

[0035] Figures 14A-14D LC-MS are shown: a) chromatogram of Form I, b) chromatogram of Form A, c) MS spectrum of Form I, and d) MS spectrum of Form A.

[0036] Fig.15 A DVS diagram of Form A is shown.

[0037] Fig.16 The XRPD patterns of Form A are shown: a) before DVS, and b) after DVS.

[0038] Fig.17 A DVS diagram of Form I is shown.

[0039] Fig.18 The XRPD patterns of Form I are shown: a) before DVS, and b) after DVS.

[0040] The details of this disclosure are set forth in the following attached description. Although methods and materials similar or equivalent to the methods and materials described herein can be used in the practice or testing of this disclosure, illustrative methods and materials are now described. Although this disclosure provides illustrative embodiments, it will be understood that they are not intended to limit the present invention to those embodiments. On the contrary, the present invention is intended to cover all alternatives, modifications and equivalents, which may be included in the disclosure as defined in the appended claims.

[0041] Any section headings used herein are for organizational purposes only and should not be interpreted in any way as limiting the desired subject matter. If any document incorporated by reference conflicts with any term defined in this specification, the present specification shall prevail. Although the present teachings are described in conjunction with various embodiments, it is not intended that the present teachings be limited to these embodiments. On the contrary, as will be appreciated by those skilled in the art, the present teachings include various alternatives, modifications, and equivalents.

[0042] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meanings. the term

[0043] The articles "a / an" are used in this disclosure to refer to one or more than one (ie, at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0044] The term "about" or "substantially as shown in..." means approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the stated numerical values. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variation of 5%.

[0045] Unless otherwise indicated, the term "and / or" is used in this disclosure to mean "and" or "or".

[0046] The terms "article of manufacture" and "kit" are used synonymously.

[0047] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" or "excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients may also be incorporated into the compositions.

[0048] The term "crystalline" or "crystalline solid form" refers to a solid form that is substantially free of any amorphous solid form, e.g., any solid material that exhibits three-dimensional order that gives a unique XRPD pattern with more or less sharp peaks compared to an amorphous solid material. In some embodiments, the crystalline solid form is a single solid form, e.g., crystalline Form A.

[0049] The terms "polymorph", "crystalline form", "crystalline form" and "form" refer interchangeably to a solid having a specific molecular packing arrangement in a crystal lattice. Crystalline forms can be identified and distinguished from one another by at least one characterization technique, including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), dynamic vapor adsorption (DVS) and / or thermogravimetric analysis (TGA). Thus, the term "crystalline form [X] of Compound (I)" refers to a unique crystalline form that can be identified and distinguished from other forms by at least one characterization technique, including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), dynamic vapor adsorption (DVS) and / or thermogravimetric analysis (TGA). In some embodiments, the novel crystalline forms of the present disclosure are characterized by an X-ray powder diffraction pattern having at least one signal, at least one assigned 2θ value (°2θ).

[0050] "Anhydrate" refers to a crystalline form of a substance that does not contain water in its structure. By extension, "anhydrate" generally refers to a crystalline form of a substance that does not contain water and / or solvent in its structure.

[0051] The characterization (XRPD, DSC and DVS) and some properties of the various anhydrate and solvate forms described herein are detailed below.

[0052] "DSC" refers to the analytical method of Differential Scanning Calorimetry.

[0053] "TGA" refers to the analytical method of thermo gravimetric (also known as thermogravimetric) analysis.

[0054] "XRPD" refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded using a diffractometer under ambient conditions in transmission or reflection geometry.

[0055] The expression "almost complete evaporation" of the solvent means that the evaporation does not take place completely, that is to say the amount of evaporated solvent is reduced but is nevertheless still present in very low amounts. In other words, the evaporation does not take place to dryness.

[0056] "Ambient temperature" or "room temperature" refers to a temperature in the range of 18°C ​​to 25°C, unless otherwise specified.

[0057] In some embodiments, "substantially free" means less than about 10% w / w, less than about 9% w / w, less than about 8% w / w, less than about 7% w / w, less than about 6% w / w, less than about 5% w / w, less than about 4% w / w, less than about 3% w / w, less than about 2.5% w / w, less than about 2% w / w, less than about 1.5% w / w, less than about 1% w / w, less than about 0.75% w / w, less than about 0.50% w / w, less than about 0.25% w / w, less than about 0.10% w / w, or less than about 0.05% w / w of other crystalline forms of the compound and amorphous compounds. In some embodiments, "substantially free" means undetectable amounts of other crystalline forms of the compound and amorphous compounds.

[0058] "Substantially pure" means that the crystalline form contains at least 90 percent, such as at least 95 percent, such as at least 97 percent, and for example at least 99 percent by weight of the indicated crystalline form compared to the total weight of all forms of the compound.

[0059] Alternatively, it will be understood that "substantially pure" means that the crystalline form contains less than 10 percent, such as less than 5 percent, such as less than 3 percent, and for example less than 1 percent by weight of impurities (including other polymorphic forms, solvated forms or amorphous forms) compared to the total weight of all forms of the compound.

[0060] Other features, purposes and advantages of the present disclosure will be apparent from the specification and claims. In the specification and the appended claims, the singular also includes the plural, unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by ordinary technicians in the field to which the present disclosure belongs. DETAILED DESCRIPTION

[0061] The present disclosure relates to colony stimulating factor-1 receptor inhibitors ("CSF-1R inhibitors"), which are small molecules that are able to penetrate the blood-brain barrier to reach the central nervous system (CNS). The present disclosure also relates to pharmaceutical formulations comprising CSF-1R inhibitors, and to the use of CSF-1R inhibitors and pharmaceutical compositions comprising CSF-1R inhibitors for treating diseases. Such diseases include immune-mediated diseases (including multiple sclerosis, lupus nephritis, rheumatoid arthritis) and neurological diseases (including amyotrophic lateral sclerosis (ALS) and Huntington's disease).

[0062] The solid form of Compound (I) disclosed herein can be at least 50% crystalline, such as at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% crystalline. Preparation of compounds of formula (I)

[0063] Compound (I) can be prepared as follows.

[0064] Example 1-1: Preparation of 2-(5-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(benzyloxy)-3-methoxyphenoxy)-1-(6-methoxypyridin-3-yl)propan-1-one

[0065] A mixture of 2-bromo-1-(6-methoxypyridin-3-yl)propan-1-one (21.2 g, 87 mmol, 1 eq, CAS 1391089-35-2), 5-((3H-imidazo [4,5-b] pyridin-3-yl)methyl)-2-(benzyloxy)-3-methoxyphenol (32.9 g, 91.3 mmol, 1.05 eq) (WO 2017015267 Example 1-193) and potassium carbonate (30 g, 218 mmol, 2.5 eq) in acetonitrile (330 mL) was stirred at room temperature for 4 h. HPLC analysis showed complete consumption of 2-bromo-1-(6-methoxypyridin-3-yl)propan-1-one. Methyl tert-butyl ether (330 mL) was added to the slurry, and the mixture was filtered, and the solid was washed with methyl tert-butyl ether. The filtrate was washed with dilute sodium hydroxide solution (350 mL) and saturated sodium chloride solution (300 mL). The solvent was exchanged with methanol. The methanol solution was stirred at room temperature while adding seed crystals (20 mg). After stirring at room temperature for 16 h, the crystalline product was separated by filtration, washed with methanol and dried to provide 2-(5-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(benzyloxy)-3-methoxyphenoxy)-1-(6-methoxypyridin-3-yl)propan-1-one (35.9 g, yield 85%) as an off-white crystalline solid, mp 72 ° C; 1 H NMR (400MHz, CDCl3) δ8.83 (dd, J=2.4, 0.7Hz, 1H), 8.39 (dd, J=4.8, 1.4Hz, 1H), 8.13 -8.03(m,2H),7.96(s,1H),7.48-7.41(m,2H),7.36-7.21(m,4H),6.69(dd,J=8.8,0 .8Hz,1H),6.55(d,J=1.9Hz,1H),6.44(d,J=2.0Hz,1H),5.32(s,2H),5.29(q,J=6.8 ,1H),4.99(s,2H),3.98(s,3H),3.74(s,3H),1.60(d,J=6.8Hz,3H)ppm; (M+1)=525.

[0066] Example 1-2: Preparation of 4-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(((1S,2S)-1-hydroxy-1-(6-methoxypyridin-3-yl)propan-2-yl)oxy)-6-methoxyphenol

[0067] 2-(5-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(benzyloxy)-3-methoxyphenoxy)-1-(6-methoxypyridin-3-yl)propan-1-one (14 g, 25.2 mmol), potassium tert-butoxide (1.35 g, 12.01 mmol, 0.48 eq.), and RuCl2[(S)-(DM-BINAP)][(S)-DAIPEN] (CAS 220114-01-2, 0.33 g, 0.27 mmol, 0.01 eq.) were dissolved in isopropanol (230 mL) and charged into a hydrogenation reactor. The reactor was purged with nitrogen and filled with hydrogen to 70 psi. After stirring at 22 °C under 70 psi hydrogen pressure for 5 h, HPLC analysis showed complete consumption of the starting material. Hydrogenolysis is carried out by charging Pd / C (4.8 g, 34 wt %, 5% Pd on activated carbon, 50% wet) into a reactor. A Parr reactor is purged with nitrogen and filled with hydrogen to 70 psi. After stirring at 70 psi hydrogen pressure for 48 h at 22 ° C, HPLC analysis shows that the reaction is essentially complete. The reaction mixture is filtered through a diatomaceous earth pad and washed with isopropanol and methanol. The filtrate is concentrated into a clear yellow oil. The oil is dissolved in ethyl acetate (250 mL) and washed with aqueous ammonium chloride (130 mL). The aqueous layer is stripped with ethyl acetate (30 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to afford 4-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(((1S,2S)-1-hydroxy-1-(6-methoxypyridin-3-yl)propan-2-yl)oxy)-6-methoxyphenol (10.1 g, 23.1 mmol, 92% yield) as a light yellow hard foam. The product was an approximate 84:16 ratio of 1S,2S to 1R,2S diastereomers (by 1 H NMR); >98%ee (by chiral HPLC) 1 H NMR (400MHz, CDCl3) δ8.43 (d, J = 4.6Hz, 1H), 8.13-8.05 (m, 2H), 8.02 (d, J = 1.7Hz, 1H), 7.68 and 7.61 (2br d,J=8.7Hz,1H),7.31-7.23(m,2H),6.77-6.67(m,2H),6.66(d,J=2.7Hz,1H),5.36(s,2H),4.82 and 4.71(br s and d, J = 8.3Hz, 1H), 4.13 (m, 1H), 3.94 (br s, 3H), 3.83 (br s, 3H), 1.18-1.07 (d, J = 6.4Hz, 3H) ppm; (M+1) = 437.

[0068] Example 1-3: Preparation of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine

[0069] A solution of 4-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(((1S,2S)-1-hydroxy-1-(6-methoxypyridin-3-yl)propan-2-yl)oxy)-6-methoxyphenol (10.10 g; 23.14 mmol; 84:16 mixture of diastereomers; 1.00 eq.) in ethyl acetate (90 ml) with diisopropylethylamine (16.02 mL; 92.56 mmol; 4.00 eq.) and CCl4 (5.58 ml; 57.85 mmol; 2.50 eq.) was stirred at 45-50°C. Tri-n-butylphosphine (11.99 ml; 48.60 mmol; 2.10 eq.) was added dropwise over 10 min with a slight exotherm. The resulting brown solution was stirred at 45-50°C for 1.5 h. Sodium hydroxide solution (15wt%, 40mL, 6.5eq.) was added to the reaction and the mixture was stirred at 45°C for 0.5-1h. The reaction was cooled to room temperature. Separation layer. The aqueous layer was extracted with ethyl acetate (40mL). The combined organic layer was washed with saturated sodium chloride solution (50mL), dried over sodium sulfate, filtered and concentrated into wet solid. The solid was stirred for 2h in methyl tert-butyl ether (60mL), filtered and dried under vacuum. The off-white solid was dissolved in ethanol (55mL) at an elevated temperature. The solution was stirred at room temperature while adding seed crystals and cooled to 0°C-5°C. The resulting solid was filtered and dried to provide 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine (6.16 g, 63.6%) as an off-white solid powder 99A% (by HPLC), 98% ee, Pd: 1 ppm; Ru: 225 ppm. mp 164.9°C. 1H NMR (400MHz, CDCl3) δ8.45 (dd, J=4.8, 1.5Hz, 1H), 8.16 (d, J=2.4Hz, 1H), 8.13-8.03 (m, 2H ),7.56(dd,J=8.6,2.5Hz,1H),7.27(dd,J=8.0,4.8Hz,1H),6.78(d,J=8.6Hz,1H),6.53(br s,2H),5.38(s,2H),4.62(d,J=7.8Hz,1H),4.13(m,1H)3.94(s,3H),3.79(s,3H),1.17(d,J=6.4Hz,3H)ppm. (M+1)=419.

[0070] Example 1-4: Preparation of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d

[0071] 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine (20 g; 47.80 mmol) was dissolved in 2-methyltetrahydrofuran (400 mL) at 60°C. Methanol-d (20 mL, 1V, 99% D) was added followed by solid potassium tert-butoxide (5.36 g; 47.80 mmol; 1 eq). The solution was heated for 2 h. LCMS showed 87% D. The reaction solution was cooled to 22°C. The suspension was washed with aqueous 10% w / w ammonium chloride (400 mL). The organic layer was separated, diluted with ethyl acetate (200 mL), and washed with water (3×100 mL) followed by 1 / 2 saturated sodium chloride solution (100 mL). The organic layer was dried (sodium sulfate), filtered and concentrated to a solid. The solid was dried by azeotroping with toluene (2×100mL). The obtained tan solid was dissolved in 2-methyltetrahydrofuran (500mL) at 60°C, and methanol-d (40mL; 2V) was added, followed by solid potassium tert-butoxide (1.1g; 9.80mmol; 0.2eq). The solution was heated at 60°C for 3h. LCMS showed 96%-97%D after 3h. The reaction solution was cooled to room temperature and washed with aqueous 10% w / w ammonium chloride solution (200mL, 10V). The organic layer was separated and washed with water 3 times (200mL each time). The organic solution was filtered, concentrated and dried by azeotroping with toluene. The solid was dissolved in 2-methyltetrahydrofuran (560mL) at 80°C. The reaction solution was cooled to 75°C and seeded with the compound (200mg) of Example 1-3. The mixture was stirred while the temperature was cooled to 22 ° C and maintained for 1 h. The mixture was stirred at 0 ° C-5 ° C for 1 h. The resulting solid was filtered, washed with cold 2-methyltetrahydrofuran and dried in a vacuum oven to obtain 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d (100A% (by HPLC), chiral purity: 99.5%; 96.1% D (by LCMS); Pd 1ppm; Ru 20ppm, 84% yield) as an off-white powder 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, residual undeuterated, 0.02H), 8.40 (dd, J = 4.8, 1.5 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.10 (dd, J = 8.0, 1.5, 1H), 7.72 (dd, J = 8.6, 2.4 Hz, 1H), 7.36 (dd, J = 8.0, 4.8 ,1H),6.88(d,J=8.6Hz,1H),6.76(d,J=1.9,1H),6.50(d,J=1.9,1H),5.40(s,2H),4.72( d,J=7.8Hz,1H),4.26-4.29(m,1H),3.87(s,3H),3.70(s,3H),1.03(d,J=6.3Hz,3H)ppm. (M+1)=420. Pharmaceutical composition

[0072] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into pharmaceutically useful preparations. Appropriate formulation depends on the selected route of administration. An overview of the pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, 19th ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman, H. A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosure.

[0073] In some embodiments, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition. Administration of the compounds and compositions described herein can be carried out by any method capable of delivering the compound to the site of action.

[0074] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary, or paste.

[0075] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers (such as glycerol or sorbitol). Tablets can be prepared by compression or molding (optionally with one or more auxiliary ingredients). Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (such as powder or granules) in a suitable machine (optionally mixed with a binder, inert diluent, or lubricant, surfactant or dispersant). Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0076] In certain embodiments, the tablet is coated or scored, and is formulated to provide a slow or controlled release of the active ingredient therein. All formulations for oral administration should be suitable for such an administration. Push-fit capsules can contain an admixture of active ingredient and filler such as lactose, binder such as starch, and / or lubricant such as talcum or magnesium stearate and optionally stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin or liquid polyethylene glycol. In certain embodiments, stabilizer is added. A suitable coating is provided to the lozenge core. For this purpose, a concentrated sugar solution can be used, which can optionally contain gum arabic, talcum, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution (lacquer solution) and a suitable organic solvent or solvent mixture. Dye or pigment can be added to tablets or lozenge coatings for identification or characterization of different combinations of active compound dosage.

[0077] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0078] Also provided herein is a pharmaceutical composition comprising a crystalline form of a compound of formula (I) and a pharmaceutically acceptable carrier. In one aspect, in the pharmaceutical composition, the crystalline form is substantially pure and substantially free of other crystalline forms of the compound of formula (I). In another aspect, in the pharmaceutical composition, the crystalline form is at least 90 percent by weight of all forms. Dosage and treatment regimen

[0079] For any particular patient, the specific dosage level of the compound of the present application will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, route of administration and excretion rate, drug combination and the severity of the specific disease of the patient being treated. For example, the dosage can be expressed as milligrams / kg of patient body weight (mg / kg) of the compound described herein. A dosage between about 0.1 and 150 mg / kg may be appropriate. In certain embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments, a dosage between 0.5 and 60 mg / kg may be appropriate. When adjusting the dosage between patients with very different body sizes (such as when using drugs in children and adults, or when converting the effective dose in non-human patients (such as dogs) to a dosage suitable for human patients), it is particularly useful to standardize according to the patient's weight.

[0080] The daily dose can also be described as the total amount of the compound disclosed herein administered per dose or per day. The daily dose of the compound disclosed herein can be between about 1 mg and 4,000 mg, between about 2,000 and 4,000 mg / day, between about 1 and 2,000 mg / day, between about 1 and 1,000 mg / day, between about 10 and 500 mg / day, between about 20 and 500 mg / day, between about 50 and 300 mg / day, between about 75 and 200 mg / day, or between about 15 and 150 mg / day.

[0081] When administered orally, the total daily dosage for a human patient may be between 1 mg and 1,000 mg, about 1,000-2,000 mg / day, about 10-500 mg / day, about 50-300 mg / day, about 75-200 mg / day, or about 100-150 mg / day.

[0082] In certain embodiments, the method comprises administering to the patient an initial daily dose of about 1 to 800 mg of a compound disclosed herein and increasing the dose by increments until clinical efficacy is achieved. The dose may be increased by increments of about 5, 10, 25, 50, or 100 mg. The dose may be increased daily, every other day, twice a week, or once a week.

[0083] Also provided herein is a method of treating a disease and condition mediated by CSF-1R in a patient in need thereof, the method comprising administering to the patient an effective amount of a crystalline form of a compound of formula (I). In one aspect, in the method, the crystalline form is substantially pure and substantially free of other crystalline forms of the compound of formula (I). In another aspect, in the pharmaceutical composition, the crystalline form is at least 90 percent by weight of all forms. In yet another aspect, the crystalline form is Form A.

[0084] Also provided herein are crystalline forms of a compound of formula (I) for use as a medicament, as a CSF-1R receptor inhibitor, and for use in treating various diseases in which CSF-1R is involved. In one aspect, the crystalline form is substantially pure and substantially free of other crystalline forms of the compound of formula (I). In another aspect, the crystalline form is at least 90 percent by weight of all forms. In yet another aspect, the crystalline form is Form A.

[0085] Also provided herein is the use of a crystalline form of a compound of formula (I) for the manufacture of a medicament for treating a disease involving CSF-1R inhibition. In one aspect, the crystalline form is substantially pure and substantially free of other crystalline forms of the compound of formula (I). In another aspect, the crystalline form is at least 90 percent by weight of all forms. In yet another aspect, the crystalline form is Form A. Products and kits

[0086] In certain embodiments, kits and articles for use with one or more methods described herein are disclosed herein. In certain embodiments, the additional components of the kit include wrappers or containers that are separated to receive one or more containers, such as vials, tubes, etc., each container accommodating one of the individual elements to be used in the methods described herein. Suitable containers include, for example, bottles, vials, plates, syringes, and test tubes. In one embodiment, the container is formed by various materials, such as glass or plastic.

[0087] The articles of manufacture provided herein contain packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, bottles, tubes, bags, containers, and any packaging material suitable for a selected formulation and intended mode of use.

[0088] For example, the container holds one or more of the compounds described herein.Such kits may optionally include an identifying description or label or instructions related to their use in the methods described herein.

[0089] The kit typically includes a label listing the contents and / or instructions for use, and a package insert containing instructions for use. A set of instructions will also typically be included.

[0090] In one embodiment, the label is on or associated with the container. In one embodiment, the label is on the container when the letters, numbers, or other characters forming the label are affixed, molded, or etched into the container itself; the label is associated with the container when the label is present within a receptacle or carrier that also holds the container, such as a package insert. In one embodiment, the label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates instructions for use of the contents, such as in the methods described herein. abbreviation

[0091] The following abbreviations may be relevant to this application.

[0092] The following examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein. Example 2 - Characterization of Starting Materials

[0093] Compound (I) prepared according to Examples 1-4 was characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR) and high performance liquid chromatography (HPLC) before polymorph screening. The characterization results indicated that the starting material was highly crystalline, defined as free base form A, and the crystalline form was further identified as an anhydrate.

[0094] As described in more detail below, polymorph screening was performed to identify stable crystalline forms suitable for drug development. Based on the approximate solubility of the starting material in 20 different solvent systems, 102 polymorph screening experiments were set up using a wide range of methods, using anti-solvent addition, solid vapor diffusion, liquid vapor diffusion, slurrying at room temperature and 50°C, slow evaporation at room temperature and 50°C, slow cooling, and polymer induced crystallization. A total of five crystalline solid forms were observed, wherein Form A and Form I were anhydrous, while Form II was a 1,4 dioxane solvate, Form III was an acetic acid solvate, and Form IV was an ACN solvate. Competitive slurry experiments were performed to determine the relative stability of the anhydrous form, and Form A was determined to be a more thermodynamically stable form. The characterization summary of Form I and Form A is provided in Table 1-1. Table 1-1. Summary of Form I and Form A characterization Example 3 - Initial Characterization of Starting Materials

[0095] Compound (I) prepared according to Examples 1-4 was characterized by XRPD, PLM, DSC, TGA, 1H-NMR and HPLC. The results are summarized in Table 1-2, indicating that the starting material is a crystalline anhydrate. Table 1-2. Summary of characterization of compound (I) (starting material) Example 4 - Polymorph Screening Summary

[0096] Based on the approximate solubility of the starting material (see Table 2-1 below), a total of 102 polymorph screening experiments were performed using different screening techniques, including antisolvent addition (14 experiments, Table 1-6), solid vapor diffusion (14 experiments, Table 1-7), liquid vapor diffusion (9 experiments, Table 1-8), slurry at room temperature (22 experiments, Table 1-9), slurry at 50°C (16 experiments, Table 1-10), slow evaporation at room temperature and 50°C (10 experiments, Table 1-11) and slow cooling (9 experiments, Table 1-12) and polymer-induced crystallization (9 experiments, Table 1-13). Specifically, approximately 20 mg of Form A was used in each experiment. The different solid form XRPD results are summarized in Table 3 ( Figure 5 ) and DSC / TGA( Figure 6 , Figure 7 , Figure 8 , Fig. 9 and Fig.10 ). The solid forms identified as Form A and Form I are anhydrates, while Form II is a dioxane solvate, Form III is an acetic acid solvate, and Form IV is an ACN solvate. Table 1-3. Summary of polymorph screening results Example 5 - Scale-up of Form I

[0097] Given the preliminary solid state properties, Form I was scaled up to approximately 300 mg to assess production feasibility and to generate sufficient samples for further evaluation. Further evaluations included relative stability studies via competitive slurry experiments and hygroscopicity studies. The reproducible production procedures are provided in Tables 1-4. Fig.12 Form I was successfully reproduced as pure Form I on a scale of approximately 300 mg, as demonstrated by XRPD comparison in . Table 1-4. Procedure for preparing Form I Competitive slurrying experiments with anhydrous form

[0098] Slurry conversion experiments between Form I and Form A were performed using acetone and ethyl acetate as solvents to determine relative stability. At the end of the study, Form I converted to Form A ( Fig.13 ). Therefore, Form A is the more thermodynamically stable form at room temperature and 50°C. The lower melting Form I was converted to the higher melting Form A by slurrying in two different solvents at 25°C and 50°C, indicating that the two forms are monotropic, which is further confirmed by the melting points and melting enthalpies of Form I and Form A reported in Tables 1-5. Table 1-1. Comparison of melting points and melting enthalpies of Form I and Form A Free base Melting point(℃) Melting enthalpy (J / g) Form I 142.16 89.213 Form A 163.78 113.44 Example 5 - Confirmatory testing of deuterium in Form I and Form A by LC-MS

[0099] Form I and Form A tested by LC-MS eluted at retention times of 5.37 s and 5.38 s, respectively ( Figures 14A-14D ). These corresponding peaks were used to calculate the mass of each portion at the corresponding retention time. The mass spectra were found to be identical and consistent with the molecular weights of both Form I and Form A ( Figures 14A-14D ), which indicates that the deuterium atoms in Form I and Form A are still intact. Example 6 - Hygroscopicity

[0100] To understand the hygroscopicity of Form I and Form A, dynamic vapor sorption (DVS) was used to measure mass changes as a function of relative humidity at 25° C. Prior to analysis, anhydrate Form I and Form A were equilibrated at 0% RH to remove adsorbed water or residual solvent.

[0101] The results indicated that 1) at 25°C / 80% RH, Form A showed a water absorption of 0.09% ( Fig.15 ), which indicates that Form A is not hygroscopic. No form change of the samples was observed after DVS evaluation ( Fig.16 ). 2) At 25°C / 80% RH, Form I showed a water absorption of about 2.8% ( Fig.17 ), which indicates that it is hygroscopic. No form change of the sample was observed after DVS evaluation ( Fig.18 ). The DVS data suggest that at high humidity a metastable hydrate may form, which may convert back to Form I during the desorption process. Example 7 - Polymorph Screening Results in All Experiments

[0102] Anti-Solvent Addition Experimental Procedure - About 15 mg of free base was dissolved in solvent to produce a saturated solution and anti-solvent was added to 10 volume ratio and the obtained solid was characterized by XRPD. Table 1-6. Antisolvent addition experiment

[0103] Solid Vapor Diffusion Experimental Procedure - Approximately 15 mg of free base was stored in a 2 mL HPLC vial, which was placed in a 20 mL glass vial containing solvent. The solid was characterized by XRPD after 10 days. Table 1-7. Solid vapor diffusion experiment Experiment ID Solvents Observations Crystalline form SVD1 EtOH White solid Form A SVD2 2-Butanol White solid Form A SVD3 acetone White solid Form A SVD4 MEK White solid Form A SVD5 THF White solid Form A SVD6 Dimethoxyethane White solid Form A SVD7 MTBE White solid Form A SVD8 ACN White solid Form IV SVD9 Toluene White solid Form A SVD10 EtOAc White solid Form A SVD11 IPA White solid Form A SVD12 1,4-Dioxane White solid Form A SVD13 water White solid Form A SVD14 <![CDATA[CHCl3]]> White solid Form A

[0104] Liquid Vapor Diffusion Experimental Procedure - About 15 mg of free base was dissolved in solvent to produce a saturated solution in a 2 mL HPLC vial and the vial was placed in a 20 mL glass vial containing anti-solvent. The solid obtained was characterized by XRPD after 10 days. Table 1-8. Liquid vapor diffusion experiment

[0105] Slurry Experimental Procedure at Room Temperature - Approximately 15 mg of free base was slurried in different solvents in 2 mL HPLC vials at room temperature using a magnetic stirrer. The solids in the slurry were characterized by XRPD after 7 days. Table 1-9. Pulping experiments under ambient conditions * Addition of approximately 120 mg of solid to 0.5 mL of MEK solvent resulted in a thin slurry, therefore, the Form I obtained (poor crystal pattern) could be the result of recrystallization of the MEK solvate or a desolvation product.

[0106] Slurry Experimental Procedure at 50° C.—Approximately 15 mg of free base was slurried in different solvents in 2 mL HPLC vials using mechanical means at 50° C. The solids in the slurry were characterized by XRPD after 3-5 days. Table 1-10. Slurrying experiment at 50°C

[0107] Slow Evaporation Experimental Procedure at Room Temperature and 50°C - About 15 mg of free base was dissolved in solvent to produce a saturated solution in a 2 mL HPLC vial. The vial was covered with parafilm and 3-5 wells were made. The solid obtained was characterized by XRPD. Table 1-11. Slow evaporation experiment

[0108] Slow Cooling Experimental Procedure - About 15 mg of free base was dissolved in solvent to produce a saturated solution in a 4 mL glass vial. The vial was placed in a mechanical shaker and five temperature steps were run, 35° C. for 2 hours, 30° C. for 2 hours, 20° C. for 2 hours, 10° C. for 2 hours, and 5° C. for 2 hours. The obtained solid was characterized by XRPD. Table 1-12. Slow cooling experiment

[0109] Polymer-Induced Crystallization Experimental Procedure - Approximately 15 mg of the free base was dissolved in a solvent to produce a saturated solution. PVP or HPMC was added to the saturated solution to induce heteronucleation. Table 1-13. Polymer-induced crystallization experiments Experiment ID Solvents polymer Observations Crystalline form PIC1 MeOH PVP No solids obtained N / A PIC2 EtOAc PVP No solids obtained N / A PIC3 NMP PVP No solids obtained N / A PIC4 acetone PVC Turbid solution Form A PIC5 1,4-Dioxane PVA No solids obtained N / A PIC6 THF PVC Turbid solution Form A PIC7 MeOH PVA No solids obtained N / A PIC8 Acetic acid PVC Turbid solution Form III PIC9 2-BuOH HPMC Turbid solution Form A 1. Analytical methods 1.1 X-ray powder diffraction Instrument: Panalytical Empyrean powder diffractometer Parameters: X-ray tube Cu (Kα); tube voltage 45 kV; tube current 40 mA, 2-θ scanning from 2 to 40 degrees; 0.013 degrees / step; scanning rate 6 degrees / min 1.2 Thermogravimetric analysis Instrument: TA Instruments Discovery TGA Q5500 Parameters: 10°C ramp per minute, ambient temperature to 250°C / 300°C, 50mL / min N2 purge 1.3 Differential Scanning Calorimetry Instrument: TA Instruments Discovery DSC Parameters: 10°C ramp per minute, from ambient temperature to 250°C / 300°C, 50mL / min N2 purge 1.4 Polarized light microscopy Instrument: Nikon Eclipse Ci Pol Camera: Nikon Software: NIS - Element Image Software The samples were dispersed on microscope slides as slurries or, if dry, dispersed with silicone oil and examined under transmitted polarized light. 1.5 Determination of approximate solubility for polymorph screening program: 1) Weigh approximately 5 mg of material into a 4.0 ml vial 2) Initially, add solvent in the following increments at 25°C while observing the visual change from cloudy solution to clear solution o Up to 2.0 mL in increments of 50 μL (twice), 100 μL (four times), 250 μL (twice), and 500 μL (twice) 3) Approximate solubility between low concentration (still a slurry) and high concentration (clear solution) is reported Table 2-1. Approximate solubility of compound (I) at 25°C

Claims

1. A solid Form I of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d having an X-ray powder diffraction pattern obtained using Cu(Kα) radiation comprising three, four, five, six or more peaks selected from the group consisting of 3.6, 6.3, 9.6, 12.6, 15.9, 21.2, 25.3±0.2 degrees in 2-θ.

2. The solid Form I of claim 1 which is at least 50% crystalline, such as at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% crystalline.

3. The solid Form I of claim 1, having an X-ray powder diffraction pattern substantially consistent with the X-ray powder diffraction pattern shown in Figure 12.

4. The solid form I according to claim 1, characterized in that Differential Scanning Calorimetry (DSC) curve with an onset at about 134.55°C and an endothermic peak at 158.52°C.

5. The solid form I according to claim 1, characterized in that Thermogravimetric analysis (TGA) profile curves showed negligible w / w loss before 150 °C.

6. The solid form I according to claim 1, characterized in that A DSC / TGA profile curve that is substantially consistent with the DSC / TGA profile curve shown in FIG. 7 .

7. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound according to claim 1 and / or a pharmaceutically acceptable salt thereof.

8. A method for treating an immune-mediated disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound as claimed in any one of claims 1 to 6 or a composition as claimed in claim 7.

9. A method for treating multiple sclerosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound as claimed in any one of claims 1 to 6 or a composition as claimed in claim 7.

10. A method for treating lupus nephritis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 6 or the composition of claim 7.

11. A method for treating a nervous system disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound as claimed in any one of claims 1 to 6 or a composition as claimed in claim 7.

12. The method of claim 11, wherein: The neurological disease is ALS.

13. The method of claim 11, wherein: The neurological disease is PSP.

14. The method of claim 11, wherein: The neurological disease is MSA.

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