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

Abstract

Disclosed 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, processes for preparing such forms, pharmaceutical compositions, and methods of using the same.

Description

Technical Field

[0001] Disclosed 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, processes for preparing such forms, pharmaceutical compositions, and methods of using the same.

Background Art

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

[0003] Surprisingly, the deuterium-substituted colony-stimulating factor-1 (「CSF-1R」) inhibitor compounds described in PCT / US Patent Application No. 2021 / 064831 have improved ADME properties. For example, the CSF-1R inhibitor compounds substituted with deuterium at specific positions have improved significant resistance to AO degradation, and thus, it has been found that they may improve drug efficacy and in vivo exposure. These CSF-1R inhibitors are small molecule compounds that can reach the central nervous system (CNS) by crossing the blood-brain barrier. Since these compounds can advantageously cross the blood-brain barrier (a highly desirable property in neurological indications), the compounds need to exhibit sufficient absorption, metabolism, distribution, and excretion (ADME) properties to ensure proper dosing. Metabolic problems can include rapid metabolism and metabolic degradation, both of which can lead to toxicity of the active agent and / or suboptimal dosing.

[0004] One factor to be evaluated is that the compound as a therapeutic agent can be easily absorbed by the body and administered in a form with storage stability. The pharmaceutically active substances used to prepare the therapeutic agent should be as pure as possible, and its stability in long-term storage should be guaranteed under various environmental conditions. These properties are useful for preventing the appearance of unintended degradation products in pharmaceutical compositions, which can potentially be toxic and simply reduce the potency and / or effectiveness of the composition.

[0005] The first concern regarding the large-scale manufacture of pharmaceutical compounds is that the active substance should have a stable crystalline morphology to ensure consistent processing parameters and pharmaceutical quality. If an unstable crystal form is used, the crystal morphology can change during manufacture and / or storage, leading to quality control issues and formulation variability. Such changes can affect the reproducibility of the manufacturing process and thereby result in a final formulation that does not meet the high quality and strict requirements imposed on the formulation of pharmaceutical compositions. In this regard, it should generally be noted that any change to the solid state of a pharmaceutical composition that can improve its physical and chemical stability provides a significant advantage over a more unstable form of the same drug.

[0006] When a compound crystallizes from a solution or slurry, it can crystallize in various space lattice arrangements, which is a property called "polymorphism". Each of the crystal forms is a "polymorph". The polymorphs of a given substance have the same chemical composition, but they can differ from each other with respect to one or more physical properties such as solubility, dissociation, true density, dissolution, melting point, crystal form, morphology, particle size, compaction behavior, flowability, and / or solid stability. The differences in the physical properties of different polymorphic forms are due to different orientations and intermolecular interactions of adjacent molecules in the solid. The polymorphic forms of a compound can be distinguished, in particular, by X-ray diffraction.

[0007] The preparation of crystalline forms is known to be able to improve the physical or pharmaceutical properties of pharmaceutically active compounds, but 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, such advantages can include, in a non-limiting manner, better processability, solubility, or storage life stability, among other examples. Other advantages can also include improvements in bioavailability, reduction of adverse reactions in the GI tract (e.g., irritation of the GI tract, partial decomposition of the compound, etc.), or, among other advantages, improvements in the delivery potential of the drug to the intended target site and other biological properties.

Summary of the Invention

Means for Solving the Problems

[0008] The present disclosure relates to various solid 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 referred to as the compound of formula (I)), a process for preparing such forms, and pharmaceutical compositions and methods of use for treating diseases. These solid forms of the compound of formula (I) can satisfy at least one of the important characteristics described 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, represented as the compound of formula (I) hereinafter, as the anhydrate in 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, represented as the compound of formula (I) hereinafter, as the anhydrate in 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, represented as the compound of formula (I) hereinafter, as the solvate in 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, as a solvate in 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, as a solvate in crystalline form IV.

[0014] Also disclosed herein is a pharmaceutical composition comprising 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] Still further disclosed herein is a method of treating a CSF-1R-mediated disease or condition in a patient in need thereof, 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 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 for use in the treatment of a CSF-1R-mediated disease or condition in a patient in need thereof.

[0017] The present disclosure further relates to the use in the manufacture of a medicament for treating a disease involving CSF-1R mediated by the disclosed 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.

[0018] The compound of formula (I) shown below is a CSF-1R inhibitor compound with improved ADME properties, particularly with significant resistance to AO degradation. The compound of formula (I) is a small molecule compound that can penetrate the blood-brain barrier and reach the central nervous system (CNS). This can be used, for example, in the treatment of neurological diseases including amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and Huntington's disease. This compound is described in PCT / US2021 / 064831. [Chemical formula]

[0019] As an anhydrate in crystalline form A, 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 referred to as the compound of formula (I), is provided, which is characterized by having an X-ray powder diffraction pattern derived using Cu(Kα) radiation and containing three, four, five, six or more peaks with respect to 2θ° selected from 7.6, 11.9, 16.6, 17.2, 18.6, 19.6, 22.4 ± 0.2 degrees, and optionally further characterized by a powder X-ray diffraction pattern substantially as shown in Figure 1.

[0020] As used herein, the anhydrate in crystalline form I is represented by the compound of formula (I) below, 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, which is characterized by having an X-ray powder diffraction pattern derived using Cu(Kα) radiation and containing three, four, five, six or more peaks with respect to 2θ° selected from 3.6, 6.3, 9.6, 12.6, 15.9, 21.2, 25.3 ± 0.2 degrees, and optionally further characterized by a powder X-ray diffraction pattern substantially as shown in Figure 12.

[0021] As used herein, the term "substantially pure" means that the crystalline form contains at least 90 weight percent, for example at least 95 weight percent, for example at least 97 weight percent, and by way of example at least 99 weight percent of the indicated crystalline form. Alternatively, it will be understood that "substantially pure" means that the crystalline form contains impurities of other polymorphs, solvate forms or amorphous forms of less than 10 weight percent, for example less than 5 weight percent, for example less than 3 weight percent, and by way of example less than 1 weight percent.

Brief Description of the Drawings

[0022]

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[0023] Details of the present disclosure are set forth in the following appended description. To practice or test the present disclosure, methods and materials similar or equivalent to those described herein can be used, although exemplary methods and materials are described herein. The present disclosure provides exemplary embodiments, but it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to embrace all alternatives, modifications, and equivalents that may be included within the scope of the present disclosure as defined by the appended claims.

[0024] Any section headings used herein are for organizational purposes only and should in no way be construed as limiting the desired subject matter. Any document incorporated by reference is superseded by this specification if it conflicts with any term defined herein. The present teachings are described in conjunction with various embodiments, but the present teachings are not intended to be limited to such embodiments. On the contrary, the present teachings embrace various alternatives, modifications, and equivalents as would be understood by those skilled in the art.

[0025] Unless otherwise specified, the following terms used in this specification and the claims are defined for the purposes of the present disclosure and have the following meanings.

[0026] The term The articles "a" and "an" are used to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. By way of example, "an element" means one element or more than one element.

[0027] The term "about" or "substantially as shown" means approximately, in the region of, generally, or in the vicinity of. When the term "about" is used in conjunction with a numerical range, the range is modified by extending the boundaries above and below the recited numerical values. Generally, the term "about" is used herein for the purpose of modifying a numerical value by a width of 5% above and below the value shown.

[0028] The term "and / or" is used in this disclosure to mean either "and" or "or" unless specifically stated otherwise.

[0029] The terms "manufactured article" and "kit" are used synonymously.

[0030] The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", or "excipient" include any solvent, dispersion medium, coating, 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. Their use in therapeutic compositions is contemplated, except where any conventional media or agent is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the compositions.

[0031] The term "crystalline" or "crystalline solid form" refers to any solid form that is substantially free of any amorphous solid form, e.g., any solid substance that exhibits three-dimensional order, which, in contrast to an amorphous solid substance, gives a distinct XRPD pattern with more or less sharp peaks. In some embodiments, the crystalline solid form is a single solid form, e.g., crystalline form A.

[0032] The terms "polymorph", "crystalline form", "crystalline morphology", and "form" are used interchangeably to refer to solids having a specific molecular packing mechanism in the crystal lattice. Crystalline forms can be identified and distinguished from each other 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 sorption (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 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 sorption (DVS), and / or thermogravimetric analysis (TGA) and distinguished from other forms. 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 at least one specified 2θ value (°2θ).

[0033] "Anhydrate" refers to a crystalline form of a substance that does not contain water in its structure. In an extended sense, "anhydrate" usually refers to a crystalline form of a substance that does not contain water and / or solvent in its structure.

[0034] The characterization (XRPD, DSC, and DVS) and some properties of the different anhydrate and solvate forms described herein are detailed below.

[0035] "DSC" refers to the analytical method of differential scanning calorimetry.

[0036] "TGA" refers to the analytical method of thermogravimetric analysis (also called thermogravimetry).

[0037] "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.

[0038] The expression "substantially complete evaporation" of the solvent means that evaporation is not complete, i.e., the amount of solvent evaporated decreases, but it still exists in a very low content. In other words, evaporation should not be carried out to dryness.

[0039] "Ambient temperature" or "room temperature" refers to a temperature in the range of 18°C to 25°C, unless otherwise specified.

[0040] In some embodiments, "substantially free of" 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 and amorphous compounds of the compound. In some embodiments, "substantially free of" means an undetectable amount of other crystalline forms and amorphous compounds of the compound.

[0041] "Substantially pure" means that the crystalline form contains at least 90 weight percent, such as at least 95 weight percent, such as at least 97 weight percent, for example at least 99 weight percent of the indicated crystalline form, compared to the total weight of all forms of the compound.

[0042] Alternatively, it will be understood that "substantially pure" means that the crystalline form contains less than 10 weight percent, such as less than 5 weight percent, such as less than 3 weight percent, for example less than 1 weight percent of impurities including other polymorphs, solvates or amorphous forms, compared to the total weight of all forms of the compound.

[0043] Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In this specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

Mode for Carrying Out the Invention

[0044] The present disclosure relates to a colony stimulating factor-1 receptor inhibitor (a "CSF-1R inhibitor"), which is a small molecule capable of reaching the central nervous system (CNS) by penetrating the blood-brain barrier. The present disclosure also relates to a pharmaceutical preparation containing a CSF-1R inhibitor, and the use of a CSF-1R inhibitor and a pharmaceutical composition containing a CSF-1R inhibitor 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.

[0045] The solid form of the compound (I) disclosed herein is at least 50% in crystalline form, for example, 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.

[0046] Preparation of the Compound of Formula (I) The compound (I) can be prepared as follows.

Example

[0047] 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

Chemical Formula

[0048] 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 [Chemical formula] 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 equivalent), and RuCl2[(S)-(DM-BINAP)][(S)-DAIPEN] (CAS 220114-01-2, 0.33 g, 0.27 mmol, 0.01 equivalent) were dissolved in isopropyl alcohol (230 mL) and charged into a hydrogenation reactor. The reactor was purged with nitrogen, filled with hydrogen, and brought to 70 psi. After stirring at 22 °C for 5 hours at a hydrogen pressure of 70 psi, HPLC analysis showed complete consumption of the starting material. Hydrogenolysis was carried out by charging Pd / C (4.8 g, 34 wt%, 5% Pd on activated carbon, 50% wet) into the reactor. The Parr reactor was purged with nitrogen, filled with hydrogen, and brought to 70 psi. After stirring at 22 °C for 48 hours at a hydrogen pressure of 70 psi, HPLC analysis showed that the reaction was essentially complete. The reaction mixture was filtered through a Celite pad and washed with isopropanol and methanol. The filtrate was concentrated to a clear yellow oil. The oil was dissolved in ethyl acetate (250 mL) and washed with an aqueous ammonium chloride solution (130 mL). The aqueous layer was back-extracted with ethyl acetate (30 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to give 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 as a pale yellow hard foam (10.1 g, 23.1 mmol, 92% yield). The product is in a ratio of about 84:16 of the 1S,2S to 1R,2S diastereomers ( 1>98% ee (by chiral HPLC); >98% ee (by chiral HPLC) 1 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 4.6 Hz, 1H), 8.13 - 8.05 (m, 2H), 8.02 (d, J = 1.7 Hz, 1H), 7.68 and 7.61 (2 br d, J = 8.7 Hz, 1H), 7.31 - 7.23 (m, 2H), 6.77 - 6.67 (m, 2H), 6.66 (d, J = 2.7 Hz, 1H), 5.36 (s, 2H), 4.82 and 4.71 (br s and d, J = 8.3 Hz, 1H), 4.13 (m, 1H), 3.94 (br s, 3H), 3.83 (br s, 3H), 1.18 - 1.07 (d, J = 6.4 Hz, 3H) ppm; (M + 1) = 437.

[0049] Examples 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

Chemical Structure

[0050] Examples 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 [Chemical formula] 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 the addition of solid potassium t-butoxide (5.36 g; 47.80 mmol; 1 equivalent). The solution was heated for 2 hours. LCMS showed 87% D. The reaction solution was cooled to 22 °C. The suspension was washed with a 10% w / w aqueous ammonium chloride solution (400 mL). The organic layer was separated, diluted with ethyl acetate (200 mL), washed with water (3 × 100 mL), and then washed with a 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 × 100 mL). The resulting tan solid was dissolved in 2-methyltetrahydrofuran (500 mL) at 60 °C, methanol-d (40 mL; 2V) was added, followed by the addition of solid potassium t-butoxide (1.1 g; 9.80 mmol; 0.2 equivalent). The solution was heated at 60 °C for 3 hours. LCMS showed 96 - 97% D after 3 hours. The reaction solution was cooled to room temperature and washed with a 10% w / w aqueous ammonium chloride solution (200 mL; 10V). The organic layer was separated and washed three times with water (200 mL each). The organic solution was filtered, concentrated, and dried by azeotroping with toluene. The solid was dissolved in 2-methyltetrahydrofuran (560 mL) at 80 °C. The reaction solution was cooled to 75 °C and seeded with the compound of Example 1-3 (200 mg). The mixture was stirred for 1 hour while cooling the temperature to 22 °C. The mixture was stirred at 0 - 5 °C for 1 hour. The resulting solid was filtered, washed with cold 2-methyltetrahydrofuran, dried in a vacuum oven, and 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 was obtained as an off-white powder.(100A% (by HPLC), chiral purity: 99.5%; 96.1% D (by LCMS); Pd 1 ppm; Ru 20 ppm, yield 84%). 1 H 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 = 8.6 Hz, 1H), 6.76 (d, J = 1.9, 1H), 6.50 (d, J = 1.9, 1H), 5.40 (s, 2H), 4.72 (d, J = 7.8 Hz, 1H), 4.26 - 4.29 (m, 1H), 3.87 (s, 3H), 3.70 (s, 3H), 1.03 (d, J = 6.3 Hz, 3H) ppm. (M+1) = 420.

[0051] Pharmaceutical composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated by conventional methods using one or more pharmaceutically acceptable inert ingredients that facilitate the processing of the active compound into a pharmaceutically useful preparation. Appropriate formulation depends on the route of administration selected. An overview of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosure.

[0052] In some embodiments, the compounds described herein are administered in a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent. Administration of the compounds and compositions described herein can be affected by any method that enables delivery to the site of action of the compound.

[0053] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as individual units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water liquid emulsions or water-in-oil liquid emulsions. In some embodiments, the active ingredient is presented as a bolus, a lozenge or a paste.

[0054] Examples of pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, and soft-sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient with a machine suitable for free-flowing forms such as powders or granules, and optionally mixing with a binder, an inert diluent, or a lubricating surface-active or dispersing agent. Molded tablets can be made by molding a mixture of a powdered compound moistened with an inert liquid diluent with a suitable machine.

[0055] In some embodiments, the tablets are coated or divided and formulated to provide delayed or controlled release of the active ingredient therein. All formulations for oral administration need to be in a dosage form suitable for such administration. Push-fit capsules may contain the active ingredient mixed with a binder such as lactose, starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added. The sugar-coated tablet core is provided with a suitable coating. For this purpose, optionally, a concentrated sugar solution containing gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture may be used. For identification or to characterize different combinations of doses of the active compound, a dye or pigment may be added to the tablets or the sugar-coated tablet coating.

[0056] In addition to the ingredients specifically described above, the compounds and compositions described herein may also include other agents commonly used in the art, taking into account the type of formulation in question. For example, those suitable for oral administration may include flavoring agents.

[0057] Also provided herein are pharmaceutical compositions 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 occupies at least 90 weight percent of all forms.

[0058] Methods of Administration and Treatment Regimen The specific dosage level of the compounds of the present application for any particular patient will depend on a variety of factors including the activity of the specific compound being used, age, weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combinations, and the severity of the particular disease in the patient being treated. For example, the dosage can be expressed as milligrams of the compound described herein per kilogram of patient body weight (mg / kg). Dosages of about 0.1 to 150 mg / kg may be appropriate. In certain embodiments, about 0.1 to 100 mg / kg may be suitable. In other embodiments, dosages of 0.5 to 60 mg / kg may be appropriate. Normalization according to patient weight is particularly useful when adjusting dosages between patients of widely different sizes, such as when using the drug in both children and adult humans, or when converting effective dosages in non-human patients such as dogs to dosages suitable for human patients.

[0059] The daily dosage can also be described as the total amount of the compounds disclosed herein administered per dosage or per day. The daily dosage of the compounds disclosed herein can be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day.

[0060] When administered orally, the total daily dosage for a human patient can be 1 mg to 1,000 mg, about 1,000 to 2,000 mg / day, about 10 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 100 to 150 mg / day.

[0061] In certain embodiments, the method includes administering to the patient an initial daily dose of about 1 to 800 mg of the compound described herein and increasing the dosage in increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dosage. The dosage can be increased daily, every other day, twice a week, or once a week.

[0062] Also provided herein is a method of treating a CSF-1R-mediated disease or condition 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 comprises at least 90 weight percent of all forms. In yet another aspect, the crystalline form is Form A.

[0063] Also provided herein is a crystalline form of a compound of formula (I) for use as a medicament, for use as an inhibitor of the CSF-1R receptor, and for use in the treatment of 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 comprises at least 90 weight percent of all forms. In yet another aspect, the crystalline form is Form A.

[0064] Also provided herein is the use of a crystalline form of a compound of formula (I) for the manufacture of a medicament for the treatment of a disease involving inhibition of CSF-1R. 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 comprises at least 90 weight percent of all forms. In yet another aspect, the crystalline form is Form A.

[0065] Manufactured Articles and Kits In certain embodiments, kits and articles of manufacture for use in one or more of the methods described herein are disclosed. In some embodiments, the additional components of the kit include a package or container that is compartmentalized to receive one or more containers, such as vials, tubes, etc., each of the containers containing one of the distinct elements used in the methods described herein. Suitable containers include, for example, bottles, vials, plates, syringes, test tubes. In one embodiment, the containers are formed from a variety of materials such as glass or plastic.

[0066] The articles of manufacture provided herein contain a packaging material. Examples of pharmaceutical packaging materials include, but are not limited to, bottles, tubes, bags, containers, and any packaging material suitable for the selected formulation and intended mode of use.

[0067] For example, the containers contain one or more of the compounds described herein. Such kits optionally include a description, label or instructions for use for its use in the methods described herein.

[0068] Kits typically include a label and / or instructions describing the contents, and an accompanying document containing instructions for use. A series of instructions are also typically included.

[0069] In one embodiment, the label is on or associated with the container. In one embodiment, the label is present on the container when letters, numbers or other characters forming the label are attached, molded, or etched onto the container itself, and is associated with the container, for example as an accompanying document, when present in a receiver or carrier that also holds the container. In one embodiment, the label is used to indicate that the contents must be used for a specific therapeutic use. The label also indicates instructions regarding the use of the contents, such as the methods described herein.

[0070] Abbreviations The following abbreviations may be relevant to this application.

[0071] [Table 1]

[0072] [Table 2]

[0073] The following examples are provided for illustrative purposes only and do not limit the claims provided herein.

[0074] Example 2 - Characterization of Starting Materials The compound (I) prepared according to Examples 1 to 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 undergoing polymorph screening. The results of the characterization showed that the starting material was highly crystalline, defined as free base form A, and the crystal form was further identified as the anhydrate.

[0075] As described in more detail below, polymorph screening was performed to identify stable crystal forms suitable for pharmaceutical development. Based on the approximate solubility of the starting material in 20 different solvent systems, a wide range of approaches were used to set up 102 polymorph screening experiments using anti-solvent addition, solid-vapor diffusion, liquid-vapor diffusion, slurries at RT and 50 °C, slow evaporation at RT and 50 °C, slow cooling, and polymer-induced crystallization. A total of five crystalline solid forms were observed, of which Forms A and I were anhydrates, 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 anhydrates, and it was determined that Form A was the more thermodynamically stable form. A summary of the characterization of Forms I and A is provided in Table 1-1.

[0076] [Table 3]

[0077] Example 3 - Initial Characterization of Starting Materials The compound (I) prepared according to Examples 1 to 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.

[0078] [Table 4]

[0079] Example 4 - Summary of Polymorph Screening Based on the approximate solubility of this starting material (see Table 2-1 below), different screening techniques including poor solvent addition (14 experiments, Table 1-6), solid-vapor diffusion (14 experiments, Table 1-7), liquid-vapor diffusion (9 experiments, Table 1-8), slurry at RT (22 experiments, Table 1-9), slurry at 50 °C (16 experiments, Table 1-10), slow evaporation at RT and 50 °C (10 experiments, Table 1-11) and slow cooling (9 experiments, Table 1-12) as well as polymer-induced crystallization (9 experiments, Table 1-13) were used to perform a total of 102 polymorph screening experiments. Specifically, about 20 mg of Form A was used for each experiment. The different solid forms are summarized in Table 3 together with the XRPD results (Figure 5) and DSC / TGA (Figures 6, 7, 8, 9 and 10). The identified solid forms that were Form A and Form I were anhydrates, while Form II was a dioxane solvate, Form III was an acetic acid solvate, and Form IV was an ACN solvate.

[0080] [Table 5]

[0081] Example 5 - Scale-up of Form I Considering the preliminary solid properties, Form I was scaled up at approximately 300 mg to evaluate production feasibility and generate sufficient samples for further evaluation. Further evaluations included relative stability tests by competitive slurry experiments and hygroscopicity tests. The reproduction procedure is provided in Table 1-4. Form I was successfully reproduced as pure Form I at a scale of approximately 300 mg, as demonstrated by the XRPD comparison in Figure 12.

[0082]

Table 6

[0083] Competitive Slurry Experiment of the Anhydrous Form Using acetone and ethyl acetate as solvents, slurry conversion experiments between Form I and Form A were conducted to determine relative stability. At the end of the study, Form I was converted to Form A at RT and 50 °C in both acetone and ethyl acetate (Figure 13). Therefore, Form A is the thermodynamically more stable form at RT and 50 °C. The lower melting Form I was converted to the higher melting Form A by slurry at 25 °C and 50 °C in two different solvents, suggesting the monotropism of these two forms, which is further confirmed by the melting points and melting enthalpies of Form I and Form A reported in Table 1-5.

[0084]

Table 7

[0085] Example 5 - Confirmation Test for Deuterium of Form I and Form A by LC-MS Forms I and A, tested by LC-MS, eluted with retention times of 5.37 seconds and 5.38 seconds, respectively (Figures 14A - 14D). Using each of these respective peaks, the mass of each portion at each retention time was calculated. The mass spectra were identical for both Form I and Form A and were found to match the molecular weight (Figures 14A - 14D), suggesting that the deuterium atoms in Form I and Form A remained intact.

[0086] Example 6 - Hygroscopicity To understand the hygroscopicity of Forms I and A, dynamic vapor sorption (DVS) measurements were used to measure the mass change as a function of relative humidity at 25°C. The anhydrous Forms I and A were equilibrated at 0% RH to remove adsorbed moisture or residual solvent prior to analysis.

[0087] The results showed that 1) Form A showed 0.09% water uptake at 25°C / 80% RH (Figure 15), suggesting that Form A is non - hygroscopic. No morphological changes were observed for the samples after DVS evaluation (Figure 16). 2) Form I showed approximately 2.8% water uptake at 25°C / 80% RH (Figure 17), suggesting that it is hygroscopic. No morphological changes were observed for the samples after DVS evaluation (Figure 18). The DVS data suggested the possibility of formation of a metastable hydrate at high humidity that could convert to Form I during desorption.

[0088] Example 7 - Results of Polymorph Screening in All Experiments Poor solvent addition experimental procedure - Approximately 15 mg of the free base was dissolved in a solvent to make a saturated solution, and the poor solvent was added up to a 10 - volume ratio. The resulting solid was characterized by XRPD.

[0089] [Table 8]

[0090] Solid Vapor Diffusion Experimental Procedure - Approximately 15 mg of the free base was stored in a 2 mL HPLC vial, and the vial was placed in a 20 mL glass vial containing the solvent. After 10 days, the solid was characterized by XRPD.

[0091]

Table 9

[0092] Liquid Vapor Diffusion Experimental Procedure - Approximately 15 mg of the free base was dissolved in the solvent to prepare a saturated solution in a 2 mL HPLC vial, and the vial was placed in a 20 mL glass vial containing the poor solvent. After 10 days, the obtained solid was characterized by XRPD.

[0093]

Table 10

[0094] Slurry Experiment Procedure at RT - Approximately 15 mg of the free base was slurried in different solvents in a 2 mL HPLC vial using a magnetic stirrer at RT. After 7 days, the solid in the slurry was characterized by XRPD.

[0095]

Table 11

[0096] Slurry Experiment Procedure at 50 °C - Approximately 15 mg of the free base was slurried in different solvents in a 2 mL HPLC vial using mechanical stirring at 50 °C. After 3 - 5 days, the solid in the slurry was characterized by XRPD.

[0097]

Table 12

[0098] RT and Slow Evaporation Experiment Procedure at 50 °C - Approximately 15 mg of the free base was dissolved in a solvent, and a saturated solution was prepared in a 2 mL HPLC vial. The vial was covered with a paraffin film, and 3 to 5 holes were created. The resulting solid was characterized by XRPD.

[0099]

Table 13

[0100] Slow Cooling Experiment Procedure - Approximately 15 mg of the free base was dissolved in a solvent, and a saturated solution was prepared in a 4 mL glass vial. The vial was placed on a mechanical shaker and run through five temperature steps: 2 hours at 35 °C, 2 hours at 30 °C, 2 hours at 20 °C, 2 hours at 10 °C, and 2 hours at 5 °C. The resulting solid was characterized by XRPD.

[0101]

Table 14

[0102] Polymer-Induced Crystallization Experiment Procedure - Approximately 15 mg of the free base was dissolved in a solvent, and a saturated solution was prepared. PVP or HPMC was added to the saturated solution to induce heteronucleation.

[0103]

Table 15

[0104] 1. Analytical Methods 1.1 X-ray Powder Diffraction Equipment: Panalytical Empyrean Powder Diffractometer Parameters: X-ray tube Cu(Kα); tube voltage 45 kV; tube current 40 mA Scan from 2 to 40° 2θ; 0.013° / step; scan speed 6° / min 1.2 Thermogravimetric Analysis Equipment: TA Instruments Discovery TGA Q5500 Parameters: Lamp at 10 °C / min, ambient temperature to 250 / 300 °C, N2 purge at 50 mL / min 1.3 Differential Scanning Calorimetry Equipment: TA Instruments Discovery DSC Parameters: Lamp at 10 °C / min, from ambient temperature to 250 / 300 °C, N2 purge at 50 mL / min 1.4 Polarizing Microscopy Equipment: Nikon Eclipse Ci Pol Camera: Nikon Software: NIS-Elements image software The sample was dispersed on a microscope slide as a slurry or, if dry, the sample was dispersed in silicone oil and examined under transmitted polarized light. 1.5 Determination of Approximate Solubility for Polymorph Screening Procedure: 1) Weigh approximately 5 mg of the material into a 4.0 ml vial. 2) First, add the solvent in the following increments at 25 °C while observing the visual change from a turbid solution to a clear solution. o Increments of 50 μL (twice), 100 μL (four times), 250 μL (twice) and 500 μL (twice) up to a maximum of 2.0 mL 3) Report the approximate solubility between the low concentration (still a slurry) and the high concentration (clear solution).

[0105]

Table 16

Claims

1. Solid form I of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridine-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 derived using Cu(Kα) rays with respect to 2θ° selected from 3.6, 6.3, 9.6, 12.6, 15.9, 21.2, 25.3 ± 0.2 degrees, containing 3, 4, 5, 6, or more peaks.

2. Solid form I according to claim 1, which is at least 50% crystalline, for example, 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. Solid form I according to claim 1, having an X-ray powder diffraction pattern substantially in accordance with that shown in Figure 12.

4. Solid form I according to claim 1, characterized by a differential scanning calorimetry (DSC) curve having an endothermic peak at approximately 134.55°C and 158.52°C.

5. Solid form I according to claim 1, characterized by a thermogravimetric analysis (TGA) profile having a very small weight loss observed before 150°C.

6. Solid form I according to claim 1, characterized by a DSC / TGA profile substantially conforming to that shown in Figure 7.

7. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a solid form I and / or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.

8. The pharmaceutical composition according to claim 7 for treating an immune-mediated disease in a subject who needs treatment for an immune-mediated disease.

9. A pharmaceutical composition according to claim 7 for treating multiple sclerosis in a person who needs treatment for multiple sclerosis.

10. The pharmaceutical composition according to claim 7 for treating lupus nephritis in a person requiring treatment for lupus nephritis.

11. The pharmaceutical composition according to claim 7 for treating a neurological disorder in a person who needs to be treated for a neurological disorder.

12. The pharmaceutical composition according to claim 11, wherein the neurological disease is ALS.

13. The pharmaceutical composition according to claim 11, wherein the neurological disorder is PSP.

14. The pharmaceutical composition according to claim 11, wherein the neurological disorder is MSA.

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