Crystalline imidazo[4,5-b]pyridine compounds, pharmaceutical compositions, and their use in treating medical conditions - Patents.com

Abstract

The present invention provides crystalline imidazo[4,5-b]pyridine compounds, pharmaceutical compositions, methods for inhibiting tropomyosin-related kinase and / or c-FMS, and methods for treating medical diseases and conditions, such as pain.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to European Patent Application No. 21207942.0, filed November 12, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention provides crystalline imidazo[4,5-b]pyridine compounds, pharmaceutical compositions, methods for inhibiting tropomyosin-related kinase and / or c-FMS, and methods for treating medical diseases and conditions, such as pain. [Background technology]

[0003] Pain may function as a protective mechanism that allows healthy humans and animals to avoid tissue damage and / or prevent further damage to damaged tissue. However, there are many cases where pain persists beyond its usefulness. This kind of unnecessary suffering due to pain can impair a person's physical mobility, mental ability, ability to sleep normally, ability to work, and may even cause depression. One type of pain that affects a significant number of patients is osteoarthritis pain. Osteoarthritis pain can be debilitating. For example, patients suffering from osteoarthritis pain in the knee joint often lose the ability to perform simple daily activities such as walking or climbing stairs. Even sitting in a chair or lying in bed can be painful and can interfere with sleep. Prolonged relief of osteoarthritis pain in the knee joint would provide substantial benefits to patients suffering from osteoarthritis pain in the knee joint.

[0004] Compounds that inhibit tropomyosin-related kinase have been reported for use in treating pain, such as osteoarthritis pain. Tropomyosin-related kinase is a high-affinity receptor that is activated by soluble growth factors called neutrophins. Activation of tropomyosin-related kinase leads to activation of downstream kinases involved in cell signaling, such as cell proliferation, survival, angiogenesis, and metastasis. International Patent Application Publication Nos. WO2015 / 089139 and WO2016 / 100677 describe certain compounds that inhibit tropomyosin-related kinase. Further compounds that inhibit tropomyosin-related kinase and have superior properties are desirable.

[0005] The present invention addresses this need for additional compounds, and provides other related advantages. Summary of the Invention

[0006] The present invention provides crystalline imidazo[4,5-b]pyridine compounds, pharmaceutical compositions, methods for inhibiting tropomyosin-related kinase and / or c-FMS, and methods for treating medical diseases and conditions, such as pain. For example, one aspect of the present invention provides the compound crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3. The crystalline compound can be characterized according to an X-ray powder diffraction pattern that includes peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2. Crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 offers the advantage of being more thermodynamically stable than crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 1. Crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 can be used in the pharmaceutical compositions and methods of treatment described herein. Various aspects and embodiments are described in further detail below.

[0007] Thus, one aspect of the present invention provides a crystalline form of the compound 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate, which exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at a diffraction angle (2θ): 16.6±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at a diffraction angle (2θ): 22.6±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises peaks at diffraction angles (2θ): 22.9±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises peaks at diffraction angles (2θ): 12.8±0.2, 13.2±0.2, 17.3±0.2, 19.0±0.2, 23.9±0.2, 26.5±0.2, 28.4±0.2, and 28.8±0.2. The compound can be part of a pharmaceutical composition that includes a pharma- ceutically acceptable carrier.

[0008] Another aspect of the present invention provides a method for treating a disease or condition selected from the group consisting of inflammatory diseases, autoimmune diseases, pain, osteoarthritis, bone metabolism defects, and cancer. The method comprises administering a therapeutically effective amount of a compound described herein to a subject in need thereof to treat the disease or condition. In certain embodiments, the disease or condition is pain, such as pain caused by osteoarthritis. In certain embodiments, the disease or condition is osteoarthritis.

[0009] Another aspect of the present invention provides a method for inhibiting the activity of a tropomyosin-associated kinase. The method comprises contacting a tropomyosin-associated kinase with an effective amount of a compound described herein to inhibit the activity of the tropomyosin-associated kinase. In certain embodiments, the tropomyosin-associated kinase is tropomyosin-associated kinase A. In certain embodiments, the tropomyosin-associated kinase is tropomyosin-associated kinase B. In certain embodiments, the tropomyosin-associated kinase is tropomyosin-associated kinase C.

[0010] Another aspect of the invention provides a method of inhibiting activity of a cellular receptor for colony stimulating factor 1. The method includes contacting the cellular receptor for colony stimulating factor 1 with an effective amount of a compound described herein to inhibit activity of the cellular receptor for colony stimulating factor 1.

[0011] Another aspect of the present invention provides a method for preparing the compound 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate in crystalline form exhibiting an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2. The method comprises: a. mixing (i) a first solution containing acetone, water, and 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine and (ii) an aliquot of 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate in crystalline form exhibiting an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2 to obtain a first mixture; b. maintaining the first mixture at a temperature in the range of about 45° C. to about 55° C. for a period of at least 2 hours to produce a crystallization mixture containing enriched 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate in a crystalline form exhibiting an X-ray powder diffraction pattern including peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2; and c. isolating the compound in crystalline form from the crystallization mixture.

[0012] In certain embodiments, the ratio of acetone to water in the first solution is about 80:20 w / w. In certain embodiments, the first solution has a temperature ranging from about 45° C. to about 55° C. Further embodiments are described herein below. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 shows the X-ray powder diffraction diagram of crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3, as further described in Example 3. [Diagram 2] FIG. 2 shows the differential scanning calorimetry curve of crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3, as further described in Example 3. [Diagram 3] FIG. 1 shows a DVS isotherm plot of crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3, as further described in Example 3. [Figure 4]FIG. 1 shows a thermogravimetric analysis / mass spectrometry (TGA-MS) profile of crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3, as further described in Example 3. [Diagram 5] FIG. 1 is a graph showing the results of a dialysis dissolution experiment evaluating the dialysis dissolution of test compositions: crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 ("Form 3 Compound"), and crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 1 ("Form 1 Compound"), in solution simulating intra-articular fluid, as further described in Example 5. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The present invention provides crystalline imidazo[4,5-b]pyridine compounds, pharmaceutical compositions, methods for inhibiting tropomyosin-related kinase and / or c-FMS, and methods for treating medical diseases and conditions, such as pain. For example, one aspect of the present invention provides the compound crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3. The crystalline compound can be characterized according to an X-ray powder diffraction pattern that includes peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2. Crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 offers the advantage of being more thermodynamically stable than crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 1. Crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 can be used in the pharmaceutical compositions and methods of treatment described herein. The practice of the present invention will employ, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology.Such techniques are explained in such references as "Comprehensive Organic Synthesis" (BM Trost & I. Fleming, eds., 1991-1992), "Handbook of experimental immunology" (DM Weir & CC Blackwell, eds.), "Current protocols in molecular biology" (FM Ausubel et al., eds., 1987, and periodic updates), and "Current protocols in immunology" (JE Coligan et al., eds., 1991), each of which is incorporated herein by reference in its entirety.

[0015] Various aspects of the invention are described in the following sections, however, the aspects of the invention described in a particular section are not limited to any particular section. Further, if a variable is not accompanied by a definition, the previous definition of the variable takes precedence.

[0016] definition The terms used in this specification have their usual meanings, and the meaning of such terms is independent at each occurrence.Nevertheless, unless otherwise stated, the following definitions apply throughout the specification and claims.Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure.When a chemical compound is referred to using both a chemical structure and a chemical name, and there is ambiguity between the structure and the name, the structure takes precedence.

[0017] As used herein, the terms "a" and "an" mean "one or more" and include plurals unless the context is inappropriate.

[0018] As used herein, the terms "subject" and "patient" are used interchangeably and refer to an organism that is treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murine, simian, equine, bovine, porcine, canine, feline, etc.), and most preferably, humans.

[0019] As used herein, the term "effective amount" refers to an amount of a compound sufficient to achieve a beneficial or desired result (e.g., a therapeutic, ameliorative, inhibitory, or preventative result). An effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treating" includes any effect, e.g., alleviation, reduction, modulation, mitigation, or elimination, that results in the improvement of a condition, disease, disorder, or the like, or the alleviation of symptoms thereof.

[0020] Unless otherwise specified, the term "about" refers to a range of ±10% of the stated value. The invention includes embodiments where a value is within ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the stated value.

[0021] The chemical name "3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine" refers to the compound having the formula: [ka]

[0022] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier that makes the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic uses.

[0023] As used herein, the term "pharmaceutical acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions, etc.), and various types of wetting agents. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0024] As used herein, the term "pharmaceutical acceptable salt" refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention that can provide the compound of the present invention or its active metabolites or residues after administration to a subject. As is well known to those skilled in the art, the "salts" of the compounds of the present invention can be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be utilized in the preparation of salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0025] Examples of bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and bases of the formula NW4 + In the formula, W is C 1~4 Alkyl and the like.

[0026] Exemplary salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate (also known as toluenesulfonate), undecanoate, and the like. Other examples of salts include, for example, Na + , NH4 + , and NW4 + (Wherein, W is C 1~4Examples of salts include the anion of a compound of the present invention combined with a suitable cation, such as an alkyl group, such as an alkyl group. Further examples of salts include, but are not limited to, ascorbate, borate, nitrate, phosphate, salicylate, sulfate, and the like. Further, acids generally considered suitable for forming pharma- ceutically useful salts from basic pharmaceutical compounds are described, for example, by P.Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S.Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P.Gould, International J.of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (website of the Food & Drug Administration, Washington, DC), the disclosures of which are incorporated herein by reference.

[0027] Certain compounds contained in the compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, certain compounds described herein may be optically active. The present invention includes cis and trans isomers, R and S enantiomers, diastereoisomers, (D) isomers, (L) isomers, racemic mixtures thereof, and other mixtures thereof, and at the same time contemplates all such compounds as being within the scope of the present invention. Compounds may contain one or more asymmetric centers. For example, asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, such as racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereoisomers, are intended to be included in the present invention. Additional asymmetric centers may exist depending on the nature of the various substituents on the molecule. Each such asymmetric center independently produces two optical isomers, and all possible optical isomers, diastereoisomers in mixtures, and pure or partially purified compounds are intended to be included within the scope of the present invention.

[0028] Diastereomeric mixtures can be separated into their individual diastereoisomers based on their physical chemical differences by methods well known to those skilled in the art, such as, for example, chromatography and / or fractional recrystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., hydrolysis). Alternatively, specific enantiomers of the compounds of the present invention can be prepared by asymmetric synthesis. Furthermore, if the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid), diastereomeric salts can be formed with a suitable optically active acid or base, followed by separation of the diastereoisomers so formed by fractional recrystallization or chromatographic means known in the art, and then recovery of the pure enantiomers.

[0029] The individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers or may be mixed, for example, as a racemate or with all other or selected stereoisomers. The chiral center(s) in the compounds of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations. Furthermore, to the extent that the compounds described herein may exist as atropisomers (e.g., substituted biaryls), all such atropisomer forms are considered as part of the present invention.

[0030] The present invention includes compounds in which one or more of the atoms have the same atomic number but are artificially enriched with a particular isotope that differs in atomic mass or mass number from that found predominantly in nature. The present invention is intended to include all suitable isotopic variations of the compounds of the invention. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H). Protium is the hydrogen isotope found predominantly in nature. Enrichment with deuterium may provide certain therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements, or may result in compounds useful as standards for characterizing biological samples. Isotopically enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art, or by processes similar to those described in the schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates.

[0031] Throughout this specification, when compositions are described as having, including, or comprising certain components, or processes and methods are described as having, including, or comprising certain steps, it is further contemplated that there are compositions of the invention that consist essentially of, or consist of, the recited components, and that there are processes and methods of the invention that consist essentially of, or consist of, the recited processing steps.

[0032] Generally, compositions specifying percentages are by weight unless otherwise specified.

[0033] I. Crystalline imidazo[4,5-b]pyridine compounds The present invention provides a crystalline imidazo[4,5-b]pyridine compound, described herein as crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3. The crystalline imidazo[4,5-b]pyridine compound may be characterized by X-ray powder diffraction, differential scanning calorimetry, and other spectroscopic techniques. Methods of preparing and using the compound are described herein below. Crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 offers the advantage of being more thermodynamically stable than crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 1. Crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 1 is described in International Patent Application Publication No. WO2016 / 100677.

[0034] Thus, one aspect of the present invention provides a crystalline form of the compound 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate, which exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at a diffraction angle (2θ): 16.6±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at a diffraction angle (2θ): 22.6±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at diffraction angle (2θ): 22.9±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises peaks at one, two, three, four or more of the following diffraction angles (2θ): 12.8±0.2, 13.2±0.2, 17.3±0.2, 19.0±0.2, 23.9±0.2, 26.5±0.2, 28.4±0.2, and 28.8±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises peaks at diffraction angles (2θ): 12.8±0.2, 13.2±0.2, 17.3±0.2, 19.0±0.2, 23.9±0.2, 26.5±0.2, 28.4±0.2, and 28.8±0.2.

[0035] In certain embodiments, the relative intensity of the peak at said diffraction angle (2θ) is at least 15%. In certain embodiments, the relative intensity of the peak at said diffraction angle (2θ) is at least 20%. In certain embodiments, the relative intensity of the peak at said diffraction angle (2θ) is at least 30%.

[0036] In certain embodiments, the compounds are characterized by the following X-ray powder diffraction pattern, expressed as the diffraction angle 2θ, the interplanar distance d, and the relative intensity (expressed as a percentage relative to the most intense peak). [Table 1]

[0037] In certain embodiments, the compound has an X-ray powder diffraction pattern substantially as shown in FIG.

[0038] In certain embodiments, the compound has a differential scanning calorimetry curve substantially similar to that shown in FIG.

[0039] Crystalline compounds can be prepared, for example, by crystallization from acetone / water solutions as described in the Examples.

[0040] II. Therapeutic Applications of Crystalline Imidazo[4,5-b]pyridine Compounds and Pharmaceutical Compositions The crystalline imidazo[4,5-b]pyridine compounds described herein can be used to treat inflammatory diseases, autoimmune diseases, pain, osteoarthritis, bone metabolic defects, and cancer. Accordingly, one aspect of the present invention provides a method for treating a disease or condition selected from the group consisting of inflammatory diseases, autoimmune diseases, pain, osteoarthritis, bone metabolic defects, and cancer. The method comprises administering a therapeutically effective amount of a compound described herein to a subject in need thereof to treat the disease or condition. The compound can be formulated as a pharmaceutical composition. Preferably, the compound is 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate in crystalline form exhibiting an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at a diffraction angle (2θ): 16.6±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at a diffraction angle (2θ): 22.6±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at a diffraction angle (2θ): 22.9±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises peaks at diffraction angles (2θ): 12.8±0.2, 13.2±0.2, 17.3±0.2, 19.0±0.2, 23.9±0.2, 26.5±0.2, 28.4±0.2, and 28.8±0.2.

[0041] In certain embodiments, the disease or condition is an inflammatory disease. In certain embodiments, the disease or condition is an autoimmune disease. In certain embodiments, the disease or condition is pain. In certain embodiments, the disease or condition is pain caused by osteoarthritis. In certain embodiments, the disease or condition is joint pain caused by osteoarthritis, e.g., knee joint pain caused by osteoarthritis. In certain embodiments, the disease or condition is post-operative pain. In certain embodiments, the disease or condition is osteoarthritis. In certain embodiments, the disease or condition is cancer.

[0042] In certain embodiments, the subject is a human.

[0043] Another aspect of the present invention provides a method for inhibiting the activity of a tropomyosin-associated kinase. The method comprises contacting a tropomyosin-associated kinase with an effective amount of a compound described herein to inhibit the activity of the tropomyosin-associated kinase. In certain embodiments, the tropomyosin-associated kinase is tropomyosin-associated kinase A. In certain embodiments, the tropomyosin-associated kinase is tropomyosin-associated kinase B. In certain embodiments, the tropomyosin-associated kinase is tropomyosin-associated kinase C. Preferably, the compound is 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate in crystalline form exhibiting an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at a diffraction angle (2θ): 16.6±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at a diffraction angle (2θ): 22.6±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at a diffraction angle (2θ): 22.9±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises peaks at diffraction angles (2θ): 12.8±0.2, 13.2±0.2, 17.3±0.2, 19.0±0.2, 23.9±0.2, 26.5±0.2, 28.4±0.2, and 28.8±0.2.

[0044] Another aspect of the present invention provides a method of inhibiting activity of a cellular receptor for colony stimulating factor 1. The method comprises contacting the cellular receptor for colony stimulating factor 1 with an effective amount of a compound described herein to inhibit activity of the cellular receptor for colony stimulating factor 1. Preferably, the compound is 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate in crystalline form exhibiting an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at diffraction angle (2θ): 22.6±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises peaks at diffraction angles (2θ): 22.9±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises peaks at diffraction angles (2θ): 12.8±0.2, 13.2±0.2, 17.3±0.2, 19.0±0.2, 23.9±0.2, 26.5±0.2, 28.4±0.2, and 28.8±0.2.

[0045] Another aspect of the present invention provides the use of a compound as described herein in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disorder as described herein, such as pain.

[0046] Another aspect of the present invention provides the use of a compound described herein for treating a medical disorder, such as a medical disorder described herein (eg, pain).

[0047] III. Methods for Preparing Crystalline Imidazo[4,5-b]pyridine Compounds Another aspect of the present invention provides a method for preparing a crystalline imidazo[4,5-b]pyridine compound. The method generally involves crystallizing 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 from a solution containing acetone, water, and 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine.

[0048] Thus, one aspect of the present invention provides a method for preparing 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate in crystalline form exhibiting an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2. The method comprises: a. mixing (i) a first solution containing acetone, water, and 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine and (ii) an aliquot of 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate in crystalline form exhibiting an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2 to obtain a first mixture; b. maintaining the first mixture at a temperature in the range of about 45° C. to about 55° C. for a period of at least 2 hours to produce a crystallization mixture containing enriched 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate in a crystalline form exhibiting an X-ray powder diffraction pattern including peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2; and c. isolating from the crystallization mixture the crystalline form of said 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate exhibiting an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2.

[0049] The method may be further characterized according to particular features of the method and / or additional embodiments. For example, in certain embodiments, the ratio of acetone to water in the first solution is about 80:20 w / w. In certain embodiments, the first solution has a temperature in the range of about 45° C. to about 55° C. In certain embodiments, the first solution has a temperature of about 50° C. In certain embodiments, the first mixture has a temperature of about 50° C.

[0050] In certain embodiments, step (b) comprises maintaining the first mixture at a temperature of about 50° C. for a period of at least 2 hours. In certain embodiments, step (b) comprises maintaining the first mixture at a temperature in the range of about 45° C. to about 55° C. for a period of at least 3 hours. In certain embodiments, step (b) comprises maintaining the first mixture at a temperature of about 50° C. for a period of at least 3 hours. In certain embodiments, step (b) comprises maintaining the first mixture at a temperature in the range of about 45° C. to about 55° C. for a period of about 3 hours. In certain embodiments, step (b) comprises maintaining the first mixture at a temperature of about 50° C. for a period of about 3 hours.

[0051] In certain embodiments, the method further comprises, after step (b), allowing the crystallization mixture to cool to a temperature in the range of about -5°C to about 5°C (e.g., at a rate of about -5°C per hour) and then heating the crystallization mixture to a temperature in the range of about 45°C to about 55°C. In certain embodiments, the method further comprises, after step (b), allowing the crystallization mixture to cool to a temperature in the range of about -5°C to about 5°C (e.g., at a rate of about -5°C per hour), maintaining the crystallization mixture at a temperature in the range of about -5°C to about 5°C for at least 1 hour, and then heating the crystallization mixture to a temperature in the range of about 45°C to about 55°C. In certain embodiments, the method further comprises, after step (b), allowing the crystallization mixture to cool to a temperature of about 0°C (e.g., at a rate of about -5°C per hour) and then heating the crystallization mixture to a temperature of about 50°C. In certain embodiments, the method further comprises, after step (b), cooling the crystallization mixture to a temperature of about 0° C. (e.g., at a rate of about −5° C. per hour), maintaining the crystallization mixture at a temperature of about 0° C. for at least 1 hour, and then heating the crystallization mixture to a temperature of about 50° C.

[0052] In certain embodiments, the isolating step (c) comprises filtering the crystallization mixture to obtain crystals of 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate in a crystalline form exhibiting an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at a diffraction angle (2θ): 16.6±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at a diffraction angle (2θ): 22.6±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at diffraction angle (2θ): 22.9±0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises peaks at diffraction angles (2θ): 12.8±0.2, 13.2±0.2, 17.3±0.2, 19.0±0.2, 23.9±0.2, 26.5±0.2, 28.4±0.2, and 28.8±0.2. In certain embodiments, the method further comprises washing the crystals with a solvent (e.g., a mixture of acetone and water, more preferably, a mixture of 80:20 w / w acetone and water). In certain embodiments, the method further comprises washing the crystals with a solvent (e.g., a mixture of acetone and water, more preferably, a mixture of 80:20 w / w acetone and water) and then drying the crystals under vacuum at a temperature of less than 35° C. (e.g., for a period of at least 4 hours).

[0053] In certain embodiments, the method further includes combining acetone, water, and 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine, heating the resulting solution to a temperature of about 65° C. to about 75° C., and then cooling the resulting solution to obtain a first solution. In certain embodiments, the method further comprises mixing acetone, water, and 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine, heating the resulting solution to a temperature of about 65° C. to about 75° C., then cooling the resulting solution to a temperature of about 50° C. to about 60° C., and filtering the solution (e.g., through a cartridge of about 0.1 μm to about 0.5 μm, or more preferably, through a cartridge of about 0.2 μm), thereby obtaining a first solution. In certain embodiments, the cooling to obtain the first solution is performed at a rate of about −10° C. per hour.

[0054] In certain embodiments, the method further comprises mixing acetone, water, and 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine, heating the resulting solution to a temperature of about 70° C., and then cooling the resulting solution to obtain a first solution.

[0055] In certain embodiments, the method further comprises mixing acetone, water, and 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine, heating the resulting solution to a temperature of about 70° C., and then allowing the resulting solution to cool to a temperature of about 55° C., and filtering the solution (e.g., through a cartridge of about 0.1 μm to about 0.5 μm, or more preferably, through a cartridge of about 0.2 μm), thereby obtaining a first solution. In certain embodiments, the cooling to obtain the first solution is performed at a rate of about −10° C. per hour.

[0056] IV. Combination Therapy Another aspect of the present invention provides combination therapy. The crystalline imidazo[4,5-b]pyridine compounds can be used in combination with additional therapeutic agents to treat medical diseases or conditions, such as inflammatory diseases, autoimmune diseases, pain, osteoarthritis, bone metabolism defects, and cancer. In certain embodiments, the additional therapeutic agent is for treating pain. In certain embodiments, the additional therapeutic agent is for treating pain caused by osteoarthritis. In certain embodiments, the additional therapeutic agent is for treating osteoarthritis.

[0057] The amount of the crystalline imidazo[4,5-b]pyridine compound and the additional therapeutic agent, and the relative timing of administration may be selected to achieve a desired combined therapeutic effect. For example, when a combination therapy is administered to a patient in need of such administration, the therapeutic agents in the combination, or pharmaceutical compositions or compositions containing the therapeutic agents, may be administered in any order, for example, sequentially, in parallel, together, simultaneously, etc. Furthermore, for example, the crystalline imidazo[4,5-b]pyridine compound may be administered while the additional therapeutic agent(s) is exerting its prophylactic or therapeutic effect, or vice versa.

[0058] The dosage and administration schedule of the active ingredients used in combination therapy may be determined by the attending clinician. In certain embodiments, the crystalline imidazo[4,5-b]pyridine compound and the additional therapeutic agent(s) are administered at a dosage that is generally used when such agents are used in monotherapy to treat the disorder. In other embodiments, the crystalline imidazo[4,5-b]pyridine compound and the additional therapeutic agent(s) are administered at a dosage that is less than the dosage that such agents are generally used when such agents are used in monotherapy to treat the disorder. In certain embodiments, the crystalline imidazo[4,5-b]pyridine compound and the additional therapeutic agent(s) are present in the same composition suitable for oral administration.

[0059] In certain embodiments, the crystalline imidazo[4,5-b]pyridine compounds may act additively or synergistically. A synergistic combination may allow for a lower dosage and / or less frequent administration of one or more agents of the combination therapy. A lower dosage or less frequent administration of one or more agents may reduce the toxicity of the treatment without reducing the efficacy of the treatment.

[0060] Another aspect of the invention is a kit comprising a therapeutically effective amount of a crystalline imidazo[4,5-b]pyridine compound, a pharma- ceutically acceptable carrier, vehicle, or diluent, and, optionally, at least one additional therapeutic agent as described above.

[0061] V. Illustrative Embodiments An exemplary embodiment is given below. 1. The compound 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate in crystalline form exhibiting an X-ray powder diffraction pattern including peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2.

[0062] 2. The compound of embodiment 1, wherein the X-ray powder diffraction pattern further comprises a peak at a diffraction angle (2θ): 16.6±0.2.

[0063] 3. The compound of embodiment 1 or 2, wherein the X-ray powder diffraction pattern further comprises a peak at a diffraction angle (2θ): 22.6±0.2.

[0064] 4. The compound according to any one of embodiments 1 to 3, wherein the X-ray powder diffraction pattern further comprises a peak at a diffraction angle (2θ): 22.9±0.2.

[0065] 5. The compound of any one of embodiments 1-4, wherein the X-ray powder diffraction pattern further comprises peaks at diffraction angles (2θ): 12.8±0.2, 13.2±0.2, 17.3±0.2, 19.0±0.2, 23.9±0.2, 26.5±0.2, 28.4±0.2, and 28.8±0.2.

[0066] 6. The compound according to any one of the preceding embodiments, wherein the relative intensity of said peak at said diffraction angle (2θ) is at least 15%.

[0067] 7. The compound of embodiment 1, wherein the relative intensity of said peak at said diffraction angle (2θ) is at least 20%.

[0068] 8. The compound of embodiment 1, wherein the relative intensity of said peak at said diffraction angle (2θ) is at least 30%.

[0069] 9. The compound of embodiment 1, characterized by the following X-ray powder diffraction pattern, expressed as the diffraction angles 2θ, the interplanar distance d, and the relative intensities (expressed as a percentage relative to the most intense peak): [Table 2]

[0070] 10. The compound of embodiment 1, wherein the X-ray powder diffraction pattern is substantially as shown in FIG.

[0071] 11. The compound of any one of embodiments 1-10, wherein the compound has a differential scanning calorimetry curve substantially the same as that shown in FIG.

[0072] 12. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 11 and a pharma- ceutically acceptable carrier.

[0073] 13. A method for treating a disease or condition selected from the group consisting of inflammatory diseases, autoimmune diseases, pain, osteoarthritis, bone metabolic defects, and cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-11 to treat said disease or condition.

[0074] 14. The method of embodiment 13, wherein the disease or condition is an inflammatory disease.

[0075] 15. The method of embodiment 13, wherein the disease or condition is an autoimmune disease.

[0076] 16. The method of embodiment 13, wherein the disease or condition is pain.

[0077] 17. The method of embodiment 13, wherein the disease or condition is pain resulting from osteoarthritis.

[0078] 18. The method of embodiment 13, wherein the disease or condition is post-operative pain.

[0079] 19. The method of embodiment 13, wherein the disease or condition is osteoarthritis.

[0080] 20. The method of embodiment 13, wherein the disease or condition is cancer.

[0081] 21. The method of any one of embodiments 13 to 20, wherein the subject is a human.

[0082] 22. A method for inhibiting the activity of tropomyosin associated kinase, comprising contacting tropomyosin associated kinase with an effective amount of a compound according to any one of embodiments 1 to 11, thereby inhibiting the activity of said tropomyosin associated kinase.

[0083] 23. The method of embodiment 22, wherein the tropomyosin-related kinase is tropomyosin-related kinase A.

[0084] 24. The method of embodiment 22, wherein the tropomyosin-related kinase is tropomyosin-related kinase B.

[0085] 25. The method of embodiment 22, wherein the tropomyosin-related kinase is tropomyosin-related kinase C.

[0086] 26. A method for inhibiting activity of a cellular receptor for colony stimulating factor 1, comprising contacting said cellular receptor for colony stimulating factor 1 with an effective amount of a compound according to any one of embodiments 1 to 11, thereby inhibiting activity of said cellular receptor for colony stimulating factor 1.

[0087] 27. A method for preparing a compound of embodiment 1, comprising: a. mixing (i) a first solution containing acetone, water, and 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine and (ii) an aliquot of 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate in crystalline form exhibiting an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2 to obtain a first mixture; b. maintaining the first mixture at a temperature ranging from about 45° C. to about 55° C. for a period of at least 2 hours to produce a crystallization mixture containing enriched 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate in a crystalline form exhibiting an X-ray powder diffraction pattern including peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2; c. isolating the compound of embodiment 1 from the crystallization mixture.

[0088] 28. The method of embodiment 27, wherein the ratio of acetone to water in the first solution is about 80:20 w / w.

[0089] 29. The method of embodiment 27 or 28, wherein the first solution has a temperature in the range of about 45°C to about 55°C.

[0090] 30. The method of embodiment 27 or 28, wherein the first solution has a temperature of about 50° C.

[0091] 31. The method of any one of embodiments 27-30, wherein the first mixture has a temperature of about 50°C.

[0092] 32. The method of any one of embodiments 27-31, further comprising combining acetone, water, and 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine, heating the resulting solution to a temperature of about 65° C. to about 75° C., and then cooling the resulting solution to obtain the first solution.

[0093] 33. The method of embodiment 32, wherein the cooling to obtain the first solution is carried out at a rate of about -10°C per hour.

[0094] VI. Pharmaceutical Compositions and Dosage Considerations As mentioned above, the present invention provides pharmaceutical compositions comprising one or more of the above compounds in a therapeutically effective amount, formulated with one or more pharma- ceutically acceptable carriers (additives) and / or diluents. The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for (1) oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue, (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or as a sustained release formulation, (3) topical application, e.g., creams, ointments, or controlled release patches or sprays applied to the skin, (4) vaginal or rectal administration, e.g., as a vaginal suppository, cream, or foam, (5) sublingual, (6) ocular, (7) transdermal, or (8) nasal administration. In certain embodiments, the present invention provides a pharmaceutical composition comprising a crystalline imidazo[4,5-b]pyridine compound described herein and a pharma- ceutically acceptable carrier.

[0095] The phrase "therapeutically effective amount," as used herein, means an amount of a compound, material, or composition, including a compound of the invention, that is effective to produce some desired therapeutic effect in at least a subpopulation of cells in an animal, at a reasonable benefit / risk ratio applicable to any medical treatment.

[0096] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of safe medical judgment, and commensurate with a reasonable benefit / risk ratio.

[0097] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0098] Examples of pharma- ceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0099] The formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations can be conveniently provided in unit dosage form and prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0100] In certain embodiments, a formulation of the invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents such as bile acids, and polymeric carriers such as polyesters and polyanhydrides, and a compound of the invention, hi certain embodiments, the above formulations render the compounds of the invention orally bioavailable.

[0101] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0102] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion, or an elixir or syrup, or pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or mouthwash, each containing a predetermined amount of a compound of the present invention as the active ingredient. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0103] In the solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, lozenges, etc.), the active ingredient may be mixed with sodium citrate or dicalcium phosphate, and / or (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders, such as paraffin; and (6) absorption enhancers. The pharmaceutical compositions are mixed with one or more pharma- ceutically acceptable carriers, such as additives, e.g., quaternary ammonium compounds, and surfactants, e.g., poloxamers and sodium lauryl sulfate, (7) wetting agents, e.g., cetyl alcohol, glycerol monostearate, and nonionic surfactants, (8) absorbents, e.g., kaolin and bentonite clay, (9) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof, (10) coloring agents, and (11) controlled release agents, e.g., crospovidone or ethylcellulose. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also include buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard shell gelatin capsules, using such excipients as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0104] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0105] Tablets and other solid dosage forms of the pharmaceutical composition of the present invention, such as dragees, capsules, pills, and granules, can be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art, if desired. They can also be formulated to slow or controlled release the active ingredient therein, for example, using hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microparticles in various proportions to obtain the desired release profile. They can also be formulated for rapid release, for example, lyophilized. They can also be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also contain opacifying agents, if desired, and can be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the digestive tract, if desired, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0106] The liquid dosage form for oral administration of the compound of the present invention includes pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to active ingredient, liquid dosage form can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (specifically cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and mixtures thereof.

[0107] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0108] Suspensions may contain, in addition to the active compounds, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0109] Formulations of pharmaceutical compositions of the invention for rectal or vaginal administration may be provided as suppositories, which can be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0110] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0111] Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharma- ceutically acceptable carrier, and with any preservatives, buffers, or propellants, as may be required.

[0112] The ointments, pastes, creams, and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0113] Powders and sprays can contain, in addition to the compounds of the invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain common propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0114] Transdermal patch has the additional advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be prepared by dissolving or dispersing the compound in suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0115] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the present invention.

[0116] Pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more compounds of the present invention in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or with sterile powders which can be prepared immediately before use into a sterile injectable solution or dispersion which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the preparation isotonic with the blood of the recipient, or suspending or thickening agents.

[0117] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0118] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersing agents. Prevention of microbial action on the target compound can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc., in the composition. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0119] In some cases, it is desirable to delay the absorption of drugs by subcutaneous or intramuscular injection in order to prolong the effect of drugs.This can be achieved by using a liquid suspension of poorly water-soluble crystalline or amorphous materials.In this case, the absorption rate of the drug depends on the dissolution rate, which may depend on the crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oily solvent.

[0120] Injectable depot forms are made by forming microencapsulated matrices of the compound of interest in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0121] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they may be administered as they are or, for example, in combination with a pharma- ceutically acceptable carrier, as a pharmaceutical composition containing 0.1 to 99% (more preferably, 10 to 30%) of the active ingredient.

[0122] The preparations of the present invention can be administered orally, parenterally, topically, or rectally.They are naturally administered in a form suitable for each administration route.For example, they are administered in the form of tablets or capsules, by injection, inhalation, eye drops, ointments, suppositories, etc., by administration by injection, infusion or inhalation, by lotion or ointment topically, by suppositories rectally.Oral administration is preferred.

[0123] The phrases "parenteral administration" and "administered parenterally", as used herein, mean modes of administration other than enteral administration and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intrathecal, and intrasternal injection and infusion.

[0124] The phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally," as used herein, refer to administration of a compound, drug, or other material such that it is taken up into the patient's body and is therefore subject to metabolic and other similar processes, e.g., subcutaneous administration, rather than directly into the central nervous system.

[0125] These compounds may be administered to humans and other animals for treatment by any suitable route of administration, including oral, nasal (such as by spray), rectal, intravaginal, parenteral, intracisternal, and topical (such as by powders, ointments or drops), including buccal and sublingual.

[0126] Regardless of the selected route of administration, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated into pharma- ceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0127] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0128] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of the invention, or ester, salt, or amide thereof, employed, the route of administration, the timing of administration, the rate of excretion or metabolism of the particular compound employed, the rate and extent of absorption, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and medical history of the patient being treated, and similar factors well known in the medical arts.

[0129] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian may start the dosage of the compound of the invention used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0130] In general, a suitable daily dose of the compound of the present invention is that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose generally depends on the factors described above. Preferably, the compound is administered at about 0.01 mg / kg to about 200 mg / kg, more preferably about 0.1 mg / kg to about 100 mg / kg, and even more preferably about 0.5 mg / kg to about 50 mg / kg. When the compound described herein is co-administered with another agent (e.g., as a sensitizer), the effective amount may be less than when the agent is used alone.

[0131] If desired, the effective daily amount of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage form. Preferred administration is a single daily administration.

[0132] The present invention further provides unit dosage forms (such as tablets or capsules) comprising a therapeutically effective amount of a crystalline imidazo[4,5-b]pyridine compound described herein for the treatment of a medical disease or condition described herein. EXAMPLES

[0133] The invention having been generally described herein will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention. Starting materials described herein can be obtained from commercial sources or can be readily prepared from commercially available materials using transformations known to those of ordinary skill in the art.

[0134] Example 1 - Preparation of Crystalline 3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine Monohydrate Form 3 The title compound was prepared according to the following procedure: A suspension of sesquihydrate 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine in a mixture of acetone and water (wherein the mixture was 80 / 20 w / w acetone to water) was heated to a temperature of 50° C. without stirring. Crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 was then isolated from the resulting mixture.

[0135] The sesquihydrate 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine starting material used in this example is described in International Patent Application Publication No. WO2016 / 100677.

[0136] Example 2 - Preparation of Crystalline 3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine Monohydrate Form 3 The title compound was prepared according to the following procedure: 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine was dissolved in a mixture of 80 / 20 w / w acetone and water and heated to a temperature of 70° C. The resulting solution was cooled to a temperature of 55° C. and then filtered through a 0.2 μm cartridge. The filtered solution was cooled to a temperature of 50° C. (wherein cooling was performed at a rate of −10° C. per hour) and then the solution was charged with 2% by weight of crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3. The resulting mixture was kept at 50° C. for at least 3 hours, and then subjected to two cooling / heating cycles to increase the size of the crystals. In each heating / cooling cycle, the mixture was first cooled to 0° C. (wherein cooling was performed at a rate of −5° C. per hour), the mixture was kept at the temperature of 0° C. for 1 hour, and then the mixture was heated to a temperature of 50° C. After completion of the two cooling / heating cycles, the crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 was isolated from the mixture using a filter drier, washed twice with a mixture of 80 / 20 w / w acetone / water and then dried under vacuum for at least 4 hours while maintaining the temperature below 35° C. to obtain the final material, i.e., crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3.

[0137] Example 3 - Physical Characterization of Crystalline 3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine Monohydrate Form 3 Crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 was characterized by X-ray powder diffraction, single crystal X-ray diffraction, differential scanning calorimetry, dynamic vapor sorption, thermogravimetric analysis / mass spectrometry (TGA-MS), and particle morphology analysis. The results are shown below.

[0138] X-ray powder diffraction The X-ray powder diffractogram of crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 is shown in Figure 1. A tabular characterization of the X-ray powder diffractogram of Figure 1 is shown in the table below, which lists the diffraction angles 2θ, interplanar distances d, and relative intensities (expressed as a percentage of the most intense peak). [Table 3]

[0139] Single crystal X-ray diffraction Crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 crystals were characterized by single crystal X-ray diffraction. The crystal structure was confirmed by XRSCD at 27° C. The monoclinic lattice was confirmed to be in space group C2 / c. The lattice parameters of the crystal are shown below. [Table 4]

[0140] Differential scanning calorimetry The differential scanning calorimetry curve of crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate form 3 is shown in Figure 2. The mass loss at a temperature of 130°C corresponds to the release of one water molecule.

[0141] Dynamic Vapor Sorption The dynamic vapor sorption isotherm plot of crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 is shown in Figure 3. The dynamic vapor sorption isotherm plot results are from a procedure in which, after a drying step at 0% relative humidity, the compound sample was subjected to two cycles of increasing and decreasing the relative humidity by 5% at 25°C, with the sample weight recorded throughout the experiment.

[0142] The results indicate that crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 is not hygroscopic.

[0143] Thermogravimetric analysis / mass spectrometry (TGA-MS) The TGA-MS profile of crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate form 3 is shown in Figure 4. The mass profile showed a step at 130 °C. The mass loss of 3.7% corresponds to the loss of one water molecule per 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine and reflects the dehydration of 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate.

[0144] Particle morphology analysis It has been found that the particles of crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 contain rod-shaped particles. The rod-shaped particles have the advantage of providing better flowability in a dry granular form. The rod-shaped particles also have the advantage of providing better filtration when filtering liquid suspensions containing the particles.

[0145] Example 4 - Comparison of stability between crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate form 3 and crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate form 1 The stability of crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 was compared to crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 1. As a physical property, the temperature of dehydration was analyzed. Crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 1 is as described in International Patent Application Publication No. WO2016 / 100677.

[0146] Crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 1 was observed to dehydrate at room temperature under a stream of nitrogen gas.

[0147] In contrast, crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 did not dehydrate until heated to a temperature of 130° C.

[0148] Example 5 - Dialysis dissolution analysis of crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate form 3 and crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate form 1 in simulated intra-articular fluid The dialysis dissolution of the test compositions was analyzed in the simulated intra-articular fluid described below. crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3, and Crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 1

[0149] The procedure was as follows: the test composition was placed in a dialysis bag with medium A. The dialysis bag was then closed and placed in a sealed bottle containing medium B. Media A and B were preheated to 37° C. before use in the experiment. The sealed bottle was placed in a rotary mixer system operating at 20 RPM to avoid suspension settling inside the dialysis bag. At 3, 6, 24, 29, 48, 72, 144, 168, 192, 216, and 240 hours, aliquots of medium B were removed from the bottle and analyzed by high performance liquid chromatography with UV detection to confirm the amount of 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine in medium B due to dialysis dissolution of the test composition from medium A through the dialysis bag into medium B. One test composition was analyzed at 360 hours. Vehicle A was 40 g / L bovine serum albumin (BSA) (+0.2 g / L sodium azide), 3 g / L hyaluronate in reconstituted phosphate buffered saline at pH 7.4. Vehicle B was 40 g / L bovine serum albumin (BSA) (+0.2 g / L sodium azide) in reconstituted phosphate buffered saline at pH 7.4.

[0150] The percent dissolution of each test composition over time observed is shown in Figure 5. The data in Figure 5 shows that crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 had a significantly lower dialysis dissolution rate compared to crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 1. For example, the data in FIG. 5 shows that crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 1 had a half-dissolution time of 66 hours, while crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 had a half-dissolution time of 112 hours.

[0151] Additionally, the data in FIG. 5 shows that at day 7, crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 1 had an average release rate of 0.54% / hr, while crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate Form 3 had an average release rate of 0.35% / hr.

[0152] Example 6 - Pharmacokinetic analysis of crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate form 3 and crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate form 1 following intra-articular administration to rats Male rats were administered test substances: either crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate form 3 ("Form 3 compound") or crystalline 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate form 1 ("Form 1 compound") via intra-articular administration into the left knee joint, and then monitored for pharmacokinetic properties. The experimental procedures and results are shown below.

[0153] Part I - Experimental Procedure Male Sprague Dawley rats were divided into four groups, each containing 12 rats, ranging in weight from 250g to 300g, aged 7 to 9 weeks. According to the experimental design described in Table 1 below, the test substances were administered in the form of a suspension via intra-articular injection into the left knee joint of the rats. [Table 5]

[0154] Each test article contained the specified methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate compound suspended in a vehicle. The vehicle was 2% povidine K17, 4.5% sorbitol in aqueous phosphate buffer at pH 7.4. Each test article in the form of a suspension contained 20 mg / mL of the specified crystalline form of methoxy-4-((4-methoxy-benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate.

[0155] Blood samples were taken from the rats' jugular vein via a syringe and needle and transferred to tubes containing K3EDTA. Blood samples were taken from the first 6 animals / group at 2 min, 10 min, 1 h, 4 h, 12 h, 72 h, 336 h, and 672 h after administration of the test substance. Blood samples were taken from the second 6 animals / group at 5 min, 0.5 h, 2 h, 8 h, 24 h, 168 h, 1008 h, and 1344 h after administration of the test substance. After centrifugation of the blood samples, the plasma was cooled using dry ice, and then analytical analysis was performed using liquid chromatography-mass spectrometry to confirm the amount of the compound methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine.

[0156] After sacrifice at the time of the last blood collection, approximately 672 hours after dosing, the left knee joints of the rats (without injuring the joint capsule) were collected along with 5-10 mm of both the tibia and femur from the first 6 animals / group. The collected knee joints were weighed. After sacrifice at the time of the last blood collection, approximately 1344 hours after dosing, the left knee joints of the rats (without injuring the joint capsule) were collected along with 5-10 mm of both the tibia and femur from the second 6 animals / group. The collected knee joints were weighed. Tissue samples were kept on dry ice and then stored at -60°C to -80°C. Knee joint samples were ground and then extracted with acetonitrile / water to a solution that was analyzed using liquid chromatography-mass spectrometry to confirm the amount of the compound methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine.

[0157] Part II - Results The results of the pharmacokinetic parameters observed in plasma are shown below in Tables 2 and 3. The mean knee joint concentrations of the compound methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine are shown below in Table 4. The observed knee joint / plasma concentration ratios of the compound methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine are shown below in Table 5. [Table 6] [Table 7] [Table 8] [Table 9]

[0158] The results in the above table show that compared to the Form 1 compound, the Form 3 compound was absorbed slower and longer lasting. Compared to the Form 1 compound, the Form 3 compound had a plasma Cmax that was 1.4-3.0 times lower. Compared to the Form 1 compound, the Form 3 compound had a plasma AUC that was 1.7-2.0 times lower. Compared to the Form 1 compound, the Form 3 compound had a terminal half-life that was 2.4-2.8 times longer. Additionally, compared to the Form 1 compound, the Form 3 compound had a mean residence time that was 2.7-3.7 times longer.

[0159] It was observed that when a 0.1 mg dose of compound was administered, knee joint concentrations of the compound methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine at 672 hours were consistently higher than plasma concentrations of methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine in most animals administered the Form 3 compound, whereas knee joint concentrations of the compound methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine were below the limit of quantification in most animals administered the Form 1 compound.

[0160] When administered a dose of 1 mg of compound, knee joint concentrations of the compound methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine were observed to be 5.40-13.6 times higher in animals administered Form 3 compound compared to animals administered Form 1 compound.

[0161] When administered a dose of 1 mg of compound, the knee joint / plasma concentration ratios of the compound methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine were 1.96-2.64 times higher in animals administered the Form 3 compound compared to animals administered the Form 1 compound.

[0162] Incorporation by Reference The entire disclosure of each of the patent documents and scientific articles referenced herein is incorporated by reference for all purposes.

[0163] Equivalent The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are therefore to be considered in all respects as illustrative rather than limiting the invention described herein. The scope of the invention is therefore indicated by the appended claims rather than the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. The compound 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate in crystalline form exhibiting an X-ray powder diffraction pattern containing peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.

2.

2. The compound of claim 1, wherein the X-ray powder diffraction pattern further includes a peak at a diffraction angle (2θ): 16.6±0.

2.

3. The compound according to claim 2, wherein the X-ray powder diffraction pattern further includes a peak at a diffraction angle (2θ): 22.6±0.

2.

4. The compound according to claim 3 , wherein the X-ray powder diffraction pattern further includes a peak at a diffraction angle (2θ): 22.9±0.

2.

5. 5. The compound of claim 4, wherein the X-ray powder diffraction pattern further comprises peaks at diffraction angles (2θ): 12.8±0.2, 13.2±0.2, 17.3±0.2, 19.0±0.2, 23.9±0.2, 26.5±0.2, 28.4±0.2, and 28.8±0.

2.

6. 5. The compound of claim 4, wherein the relative intensity of said peak at said diffraction angle (2θ) is at least 15%.

7. 2. The compound of claim 1, wherein the relative intensity of said peak at said diffraction angle (2θ) is at least 20%.

8. 2. The compound of claim 1 characterized by the following X-ray powder diffraction pattern, expressed as diffraction angles 2θ, interplanar distances d, and relative intensities (expressed as percentages relative to the most intense peak): Table 1

9. 2. The compound of claim 1, wherein the X-ray powder diffraction pattern is substantially as shown in FIG.

10. 2. The compound of claim 1, wherein the compound has a differential scanning calorimetry curve substantially the same as that shown in FIG.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is in the form of a suspension.

13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition contains water.

14. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition further comprises a polymer carrier.

15. The pharmaceutical composition of claim 13, further comprising sorbitol.

16. A medicament for treating a disease or condition selected from the group consisting of inflammatory diseases, autoimmune diseases, pain, osteoarthritis, bone metabolic defects, and cancer, the medicament comprising a compound according to any one of claims 1 to 10.

17. The pharmaceutical of claim 16 , wherein the disease or condition is pain.

18. The pharmaceutical composition of claim 16, wherein the disease or condition is pain caused by osteoarthritis.

19. The pharmaceutical of claim 16, wherein the disease or condition is osteoarthritis.

20. A medicament for inhibiting the activity of tropomyosin-related kinase, said medicament comprising a compound according to any one of claims 1 to 10.

21. The pharmaceutical composition of claim 20, wherein the tropomyosin-related kinase is tropomyosin-related kinase A.

22. A medicament for inhibiting the activity of a cellular receptor for colony stimulating factor 1, said medicament comprising a compound according to any one of claims 1 to 10.

23. 10. A method for preparing a compound of claim 1, comprising: a. (i) combining a first solution containing acetone, water, and 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine with (ii) an aliquot of 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate in crystalline form, the aliquot exhibiting an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2 to obtain a first mixture; b. maintaining the first mixture at a temperature in the range of about 45°C to about 55°C for a period of at least 2 hours to produce a crystallization mixture containing crystalline form-enriched 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate that exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.2; and c. isolating the compound of claim 1 from the crystallization mixture.

24. the ratio of acetone to water in the first solution is about 80:20 w / w; the first solution has a temperature in the range of about 45°C to about 55°C; 24. The method of claim 23, wherein the first mixture has a temperature of about 50°C.

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