Pharmaceutical formulations of ATX inhibitors

Abstract

An anhydrous crystalline form of autotaxin (ATX) inhibitor and methods to prepare the same. Pharmaceutical formulations comprising autotaxin (ATX) inhibitor or a pharmaceutically acceptable salt thereof

Description

[0001] Pharmaceutical formulations of ATX inhibitors

[0002] This application claims priority from NL 2037983 filed 19 June 2024, the contents and elements of which are herein incorporated by reference for all purposes.

[0003] Field of the Invention

[0004] The present invention relates to a novel crystalline form of an ATX inhibitor compound and a method of synthesis to prepare the compound and its novel crystalline form. The present invention also relates to a pharmaceutical composition comprising the ATX inhibitor compound.

[0005] Background

[0006] ATX is a secreted glycoprotein that was originally identified as a tumour cell autocrine motility factor and was later shown to be responsible for the lysophospholipase D (lysoPLD) activity in human serum that hydrolyses lysophosphatidylcholine (LPC) to LPA (Perrakis and Moolenaar 2014). There are four ATX isoforms (ATXa, -p, -y, and -6) that are derived from differential splicing of the ENPP2 gene transcript, with ATXp and ATX6 being the major stable circulating isoforms (Giganti 2008; Hashimoto 2012). The developmental importance of ATX is shown by the embryonic lethality of homozygote knockout mice (Tanaka 2006), while ATX heterozygotes are phenotypically normal with approximately 50% circulating LPA compared with wildtype mice, implying that ATX is the major source of plasma LPA (van Meeteren 2006). LPA is a bioactive phospholipid that is present in most biological fluids such as plasma, urine, bronchoalveolar fluid (BALF), saliva, cerebrospinal fluid, and tissue extracts. LPA consist of several lipid species that differ in length and can be subdivided by their degree of saturation into saturated, monounsaturated, and poly-unsaturated forms (Moolenaar 2000). LPA is rapidly degraded by lipid phosphate phosphatases (LPPs) and therefore has a limited half-life of ~1 min in plasma (Balazs 2001). LPA signalling is therefore regulated by the balance of LPA formation by ATX versus LPA degradation by LPPs (Hemmings and Brindley 2020).

[0007] LPA signalling acts through several G protein-coupled receptors (LPAR1-6), which couple to multiple signalling pathways, including those initiated by Ras and Rho GTPases. LPA signalling has been implicated in a wide range of biological processes and can be found at elevated levels in many diseases. Besides its catalysis-dependent functions related to LPA production, ATX can also mediate diverse cell signalling events through binding to integrins directly. Targeting the ATX-LPA signalling pathway is therefore a promising treatment opportunity for many diseases.

[0008] It is well established that, through the generation of LPA and subsequent signalling via LPARs, ATX is implicated in a number of cancers as a direct driver of tumour growth and tumour spread. LPA is known to exert tumour promoting effects on both stromal and immune cells in the tumour microenvironment. The development of an LPA driven fibrotic “shield” is also believed to create a barrier that limits infiltration of immune effector cells as well as limiting the penetration of therapeutics into the tumour. Furthermore, LPA inhibits T-cell activation in vitro and in vivo and ATX inhibitors may therefore function to boost tumourinfiltrating lymphocyte activity, while suppressing tumour cell motility (Lee 2020). In addition, LPA is chemorepulsive to the migration of T cells (Matas-Rico 2021), highlighting the potential value of ATX inhibitors in cancer immunotherapy particularly in combination with checkpoint therapies.

[0009] The role of the ATX-LPA signalling pathway in chronic inflammatory conditions and fibrotic diseases has been studied in many indications, including idiopathic pulmonary fibrosis (IPF), systemic scleroderma (SSc), non-alcoholic or metabolic associated steatohepatitis (NASH or MASH) and renal fibrosis. In IPF, increased levels of ATX are found in fibrotic lungs and high levels of LPA are observed in bronchoalveolar lavage fluid exhaled breath condensate (Oikonomou 2012, Montesi 2014 and Ninou 2018). The involvement of LPA in IPF has been mostly linked to its effects on fibroblasts, promoting migration, proliferation, and survival (Tager 2008, Funke 2012 and Chu 2015). However, more recently macrophages have been identified to be stimulated by high LPA levels (Ray 2017) and it could therefore be speculated that activated alveolar macrophages contribute to orchestrating the inflammatory response that leads to lung fibrosis. Interestingly, macrophages are not only stimulated by LPA, but also produce ATX themselves. Deletion of ATX from macrophages in a mouse bleomycin-induced pulmonary fibrosis model diminishes disease severity (Oikonomou 2012 and Mouratis 2015).

[0010] In view of the medical relevance of the of ATX-LPA signalling pathway, there has been considerable interest in ATX inhibitors for the treatment of patients in the clinic. In particular one compound, GLPG1690, has been studied as a potential treatment for idiopathic pulmonary fibrosis (IPF). However, the development of this compound was stopped due to an unfavourable risk-benefit profile when used in combination with the standard of care treatments nintedanib and pirfenidone.

[0011] In published patent application WO2016 / 124939, a series of novel ATX inhibitors and their use in treating medical conditions like cancer, inflammation, pain, diabetes mellitus, hypertension, atherosclerosis, thrombosis, urethral obstructive disease, fibrosis, hepatitis B and C and / or pruritus has been described. One particular compound disclosed in WO2016 / 124939 is compound 40 (also a compound of Formula I). This compound inhibits ATX with high selectivity and has shown remarkable effects in relevant disease models. For example, in a mouse model for lung fibrosis, the compound showed a greater reduction in fibrosis score compared with GLPG1690 and comparable activity with gemcitabine in a mouse model for pancreatic cancer (see Deken 2021 and Milleri 2021). Thus, a compound of Formula I has great potential for use in human patients.

[0012] However, in clinical practice the use of a compound of Formula I is hampered by its unfavourable biophysical characteristics, such as its low solubility, which translates into a low drug adsorption. For the manufacture of a pharmaceutically acceptable drug composition, good solubility is important to support drug adsorption. Moreover, the availability of a stable crystalline form is desirable, since it ensures not only chemical and solid state stability, but also facilitates provision of the substance in optimal purity. However, so far, no pharmaceutical drug composition of a compound of Formula I with favourable solubility has been found nor could a pharmaceutically acceptable crystalline form be identified.

[0013] In view of the above, there is a need in the art for modulators of ATX-LPA signalling pathway, in particular ATX inhibitors, with favourable biophysical characteristics (in particular with regard to their solubility, crystallinity and thermal stability) and / or a superior shelf-life. Moreover, there is a need in the art for compositions of a compound of Formula I with improved solubility, thermal stability and / or an advantageous shelf-life. Moreover, there is a need in the art for improved ways for treating (and preventing) diseases with ATX-LPA signalling pathway involvement by compounds with high selectivity and favourable biophysical characteristics (in particular with regard to their solubility, crystallinity and thermal stability) and / or a superior shelf-life. Moreover, there is a need in the art for pharmaceutical compositions of a compound of Formula I with improved solubility under intestinal / gastric conditions and / or improved bioavailability.

[0014] These needs define the objectives of the present invention. The present invention has been devised in light of the above considerations.

[0015] Summary of the Invention

[0016] The present invention is directed to crystalline forms of a compound of Formula I, a pharmaceutical composition comprising a compound of formula I and a synthesis method to prepare a compound of formula I.

[0017] In a first aspect, the invention provides an anhydrous crystalline form of a compound of Formula I:

[0018] The compound of Formula I may be referred to herein as “Compound 1” or N-[(S)-1-(4-chloro-phenyl)- ethy l]-3-[3-( 4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide, its IUPAC name. The anhydrous crystalline form may be of Form 1 or Form 2, as described below, or a mixture of Form 1 and Form 2.

[0019] In some embodiments of a mixture of Form 1 and Form 2, the mixture comprises more than 95% of Form 2. In further embodiments of a mixture of Form 1 and Form 2, the mixture of polymorphic forms is more than 99% of Form 2. In some embodiments of a mixture of Form 1 and Form 2, the mixture of polymorphic forms is more than 95% of Form 1 . In further embodiments of a mixture of Form 1 and Form 2, the mixture of polymorphic forms is more than 99% of Form 1 . In a second aspect, the present invention provides a method of synthesis in preparing a compound of formula I comprising one of more of the steps 1) to 5) in the following scheme:

[0020] In a third aspect, the present invention provides a pharmaceutical composition comprising Compound 1 according to the present disclosure and one or more excipients which are selected from pharmaceutically acceptable oils and lipids. In some embodiments the composition comprises a mixture of 2 or 3 excipients. In some embodiments the present disclosure relates to a pharmaceutical composition comprising Compound 1 and one or more excipients, wherein the excipients are selected from sesame oil, safflower oil, soybean oil, coconut oil, castor oil, corn oil, peanut oil, Maisine CC, almond oil, Captex 300 (caprylic / capric triglyceride), sunflower oil, capmul MCM (glycerol monocaprylate), cottonseed oil, and Kolliphor EL (macrogolglycerol ricinoleate 35).

[0021] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising Compound 1 and a mixture of lipid excipients which are Captex 300, Capmul MCM C8, and Kolliphor EL.

[0022] The inventors have found two anhydrous crystalline forms of Compound 1. These polymorphic forms have improved stability and shelf life. The anhydrous crystalline forms of Compound 1 have highly advantageous characteristics, including high purity, good solubility in lipid excipients, low hygroscopicity, good storage behaviour and long shelf-life. Thus, an ATX inhibitor with favourable characteristics can be provided.

[0023] In addition, the inventors have found a synthetic method which results in an improved yield and purity over the prior art method.

[0024] The inventors have also found a pharmaceutical formulation comprising Compound 1 with highly advantageous characteristics, including high thermal stability, reduced hygroscopicity, increased storage behaviour and shelf-life, high solubility, fast dissolution kinetics and high bioavailability. The pharmaceutical formulation also allows higher solubility of Compound 1. The pharmaceutical composition allows a higher solubility of Compound 1 , and its polymorphic forms 1 and form 2. Thus, a pharmaceutical composition of an ATX inhibitor with favourable characteristics can be provided which has the advantage that the product can be stored for longer periods of time.

[0025] The invention includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.

[0026] Summary of the Figures

[0027] Embodiments and experiments illustrating the principles of the invention will now be discussed with reference to the accompanying figures in which:

[0028] Figure 1 shows the XRPD (X-ray powder diffraction) patterns of the mixture of Form 1 and Form 2 of

[0029] Compound 1

[0030] Figure 2 shows the XRPD (X-ray powder diffraction) patterns of the mixture of Form 1 and Form 2 of Compound 1 in various solvents.

[0031] Figure 3 shows the XRPD (X-ray powder diffraction) pattern of Form 2 of Compound 1 .

[0032] Figure 4 shows the DSC (differential scanning calorimetry) analysis of Form 2 of Compound 1 .

[0033] Figure 5 shows the DSC (differential scanning calorimetry) analysis of the mixture of Form 1 and Form 2 of Compound 1 .

[0034] Figure 6 shows the DVS isotherm plot of the mixture of Form 1 and Form 2 of Compound 1 .

[0035] Figure 7 shows the FTIR (Fourier-transform infrared spectroscopy) spectrum of Compound 1.

[0036] Figure 8 shows the dissolution profile of Formulation 1 on manufacture and after storage.

[0037] Detailed Description of the Invention

[0038] Aspects and embodiments of the present invention will now be discussed with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0039] Compound 1

[0040] The synthesis and characterisation of Compound 1 are described in WO2016 / 124939 (example 40) at pages 77 and 82, respectively, which information is specifically incorporated herein by reference. This method can be termed method 1 :

[0041] In a round bottom flask fitted with a magnetic stirrer, 3-[3-(4-trifluoromethoxy- benzyl)-3H-imidazo[4,5- b]pyridin-2-yl]-propionic acid (73 mg, 0.2 mmol), EtaN (70 pl, 0.5 mmol) and (S)-1 -(4- chlorophenyl)ethylamine (31 mg, 0.20 mmol) were dissolved in DMF (2 ml). Finally, HBTU (83 mg, 0.22 mmol) was added in. Reaction mixture was allowed to stir at r.t. for 1 hour, then diluted with EtOAc, washed with water and brine, dried and evaporated under reduced pressure. The crude product was purified by reverse phase mass-directed preparative HPLC using either LCMS Method 5 or 6. Required product fractions were concentrated in the Genevac™ to afford the Compound 1 (79 mg, 79%).

[0042] LCMS Method 5 employed Waters 2545 pumps, a Waters SFO mixer with valves directing to the different columns and a Waters 2998 UV detector. The detection was done at 254 nm and an array between 210 - 600 nm. The mass spectrometer used was a Waters 3100 which detected masses between 100 and 700g / mol. A SunFire, 5 micron pore size, C18 column of dimensions 50 x 19 mm was used. The injection volume was chosen by the user and could be up to 500 pl of solution (maximum 50mg / ml). The mobile phase consisted of a mixture of water and acetonitrile containing 0.1 % formic acid. The flow rate was 25 mL / min with elution starting at 95% water:5% acetonitrile and held at this for 0.3 min, changed linearly to 5% water:95% acetonitrile over 5 min. This is then held until 5.8 min. There are 2 purification columns so the second one was equilibrated at 5% water:95% acetonitrile during the previous run so the next injection could be performed straight away.

[0043] LCMS Method 6 employed Waters 2545 pumps, a Waters SFO mixer with valves directing to the different columns and a Waters 2998 UV detector. The detection was done at 254 nm and an array between 210 - 600 nm. The mass spectrometer used was a Waters 3100 which detected masses between 100 and 700g / mol. A SunFire, 5 micron pore size, C18 column of dimensions 50 x 19 mm was used. The injection volume was chosen by the user and can be up to 500 pl of solution (maximum 50mg / ml). The mobile phase consisted of a mixture of water and acetonitrile containing 0.1% formic acid. The eluent flow rate was 25 ml / min with elution starting at 95% water:5% acetonitrile and held at this for 1 .5 min, changed linearly to 5% water:95% acetonitrile over 10 min and then held until 12 min. There are 2 purification columns so the second one was equilibrated at 5% water:95% acetonitrile during the previous run so the next injection could be performed straight away.

[0044] Based on the process disclosed in WO2016 / 124939, the authors of Shah 2016. describe a four-step preparation procedure for Compound 1 , which can be termed method 2 (see the Supplemental Information). This procedure starts with reaction of 2-chloro-3-nitropyridine with 4-trifluoro-methoxy-benzylamine in dioxane in the presence of cesium carbonate. The formed intermediate is hydrogenated under 1 atmosphere of hydrogen in ethanol using 10% Pd / C to afford the pyridine-2,3-diamine derivative. This diamine derivative is reacted with succinic anhydride in dioxane at reflux to form the cyclised imidazopyridinyl propanoic acid intermediate which is then reacted with (S)-1-(4-chloro-phenyl)ethylamine in the presence of EtaN and then HBTU for 24 hours to yield Compound 1 .

[0045] Synthesis of compound 1, method 3

[0046] A further process for synthesising compound 1 involves cooling a mixture of 3-(3-(4- (trifluoromethoxy)benzyl)-3H-imidazo[4,5-b]7yridine-2-yl)propanoic acid (103 g, 0.282 mol), (S)-1-(4- chlorophenyl)ethanamine (46.1 g, 0.296 mol) and Hunig’s base (93 mL, 0.564 mol) in ethyl acetate (1.0 L) to 0 °C. A solution of T3P (propylphosphonic anhydride; 50 wt% in ethyl acetate, 254 mL, 0.423 mol) was then added over 1 h, maintaining the temperature below 20 °C. After stirring at ambient temperature for 18 h, sodium hydroxide solution (aqueous, 2 M, 0.5 L) was added and the mixture stirred for 10 min. The phases were separated and the aqueous layer extracted with ethyl acetate (0.5 L). The combined organic layers were washed with brine (1 L), dried over magnesium sulfate and concentrated. The resultant solid was purified by dry-flash chromatography on SiO2 (80-100% ethyl acetate in heptanes). Product containing fractions were combined and concentrated. The resultant solid was triturated in 1 :1 ethyl acetate / heptanes, collected by filtration and dried at 40 °C under vacuum to give or N-[(S)-1-(4-chloro- phenyl)-ethyl]-3-[3-( 4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (102 g, 72% yield). A further aspect of the present invention provides a method of synthesis of compound 1 as described in Method 3.

[0047] A further process for synthesising Compound 1 is provided by the second aspect of the present invention, which process has an improved yield and purity.

[0048] This method is set out in the following scheme: Accordingly, the present disclosure relates to a synthesis method to prepare compound 1 comprising any one or more of the following steps 1) to 5):

[0049] 1) reacting 2-chloro-3-nitro-pyridine and 4-trifluoro-methoxy-benzylamine in the presence of a base to prepare 3-nitro-N-[[4-(trifluoromethoxy)phenyl]methyl]8yridine-2-amine.

[0050] In some embodiments the base is potassium carbonate. In some embodiments the reaction is carried out in a biphasic mixture of an organic solvent and water. In some embodiments the solvent is isopropyl alcohol and water is added to provide a biphasic mixture.

[0051] 2) 3-nitro-N-[[4-(trifluoromethoxy)phenyl]methyl]8yridine-2-amine is then converted to N2-[[4- (trifluoromethoxy)phenyl]methyl]pyridine-2,3-diamine:

[0052] In some embodiments the hydrogenation reaction is carried out in the presence of palladium on carbon and hydrogen. In some embodiments the hydrogenation reaction is carried out in an organic solvent. In further embodiments the hydrogenation reaction is carried out in ethanol in the presence of palladium on carbon and hydrogen under elevated pressure. In further embodiments the hydrogenation reaction is carried out in ethanol in the presence of palladium on carbon and hydrogen under atmospheric pressure.

[0053] 3) N2-[[4-(trifluoromethoxy)phenyl]methyl]pyridine-2,3-diamine is converted to 4-oxo-4-[[2-[[4- (trifluoromethoxy)phenyl]methylamino]-3-pyridyl]amino]butanoic acid in the presence of succinic anhydride:

[0054] In some embodiments the reaction is carried out in an organic solvent. In some embodiments the reaction is carried out in a solution of methyl-tert-butyl ether. The reaction may be carried out at 60°C. 4) 4-oxo-4-[[2-[[4-(trifluoromethoxy)phenyl]methylamino]-3-pyridyl]amino]butanoic acid is then reacted with acetic acid to form 3-[3-[[4-(trifluoromethoxy)phenyl]methyl]imidazo[4,5-b]9yridine-2- yl]propanoic acid:

[0055] In some embodiments the reaction is carried out in the presence of acetic acid and optionally water.

[0056] 5) 3-[3-[[4-(trifluoromethoxy)phenyl]methyl]imidazo[4,5-b]9yridine-2-yl]propanoic acid is activated with CDI and then reacted with (1 S)-1-(4-chlorophenyl)ethanamine to prepare compound 1 :

[0057] In some embodiments the reaction is carried out in an organic solvent. In further embodiments the organic solvent is ethyl acetate. The reaction may be carried out at 60°C.

[0058] In one embodiment, the present disclosure relates to a method of synthesis in preparing a Compound 1 comprising the steps of 1) to 5). In some embodiments the method comprises 1 or more of steps 1) to 5).

[0059] In some embodiments the method comprises 2 or more of steps 1) to 5). In some embodiments the method comprises 3 or more of steps 1) to 5). In some embodiments the method comprises 4 or more of steps 1) to 5).

[0060] In some embodiments, steps 2) and 3) may be performed in a one pot procedure:

[0061] By performing steps 2) and 3) in a one pot procedure, the use of highly combustible hydrogen gas may be avoided. Additionally, the colour of the material may be improved. Trace amounts of not fully reduced intermediates react with atmospheric oxygen to generate intense purple / black impurities that give a dark colour to the formulation. This is highly unfavourable for a pharmaceutical formulation that is typically without any colour. When steps 2) and 3) are carried out in a one pot procedure this reduces the trace amounts of oxidated impurities and therefore improves the colour of the material. In some embodiments, the hydrogenation reaction is carried out in the presence of palladium on carbon. In some embodiments, the hydrogen source is ammonium formate and / or formic acid. In some embodiments, the solvent is 2- methyltetrahydrofuran. In some embodiments, the conversion of N2-[[4- (trifluoromethoxy)phenyl]methyl]pyridine-2,3-diamine to 4-oxo-4-[[2-[[4- (trifluoromethoxy)phenyl]methylamino]-3-pyridyl]amino]butanoic acid may be carried out at 50°C optionally in the presence of succinic anhydride.

[0062] Polymorphic forms of Compound 1

[0063] Crystalline Form 2

[0064] Crystalline Form 2 is anhydrous.

[0065] In some embodiments, Compound 1 Form 2 has an X-ray powder diffraction pattern comprising at least one peak expressed at 20 ± 0.2° selected from 4.8, 14.3, 15.0, 19.1 and 21.1.

[0066] In some embodiments Compound 1 Form 2 has an X-ray powder diffraction pattern comprising at least two peaks expressed at 20 ± 0.2° selected from 4.8, 14.3, 15.0, 19.1 and 21.1.

[0067] In some embodiments Compound 1 Form 2 has an X-ray powder diffraction pattern comprising at least three peaks expressed at 20 ± 0.2° selected from 4.8, 14.3, 15.0, 19.1 and 21 .1 .

[0068] In some embodiments Compound 1 Form 2 has an X-ray powder diffraction pattern comprising at least four peaks expressed at 20 ± 0.2° selected from 4.8, 14.3, 15.0, 19.1 and 21 .1 .

[0069] In some embodiments Compound 1 Form 2 has an X-ray powder diffraction pattern comprising at least four peaks expressed at 20 ± 0.2° selected from 4.8, 14.3, 15.0, 19.1 and 21 .1 .

[0070] In some embodiments Compound 1 Form 2 has an X-ray powder diffraction pattern comprising five peaks expressed at 20 ± 0.2° which are 4.8, 14.3, 15.0, 19.1 and 21 .1 . In some embodiments Compound 1 Form 2 has an X-ray powder diffraction pattern comprising at least one peak expressed at 20 ± 0.2° selected from 4.8, 8.9, 9.6, 11.0, 14.3, 15.0, 19.1 , 21.1 , 28.6 and 33.6.

[0071] In some embodiments Compound 1 Form 2 has an X-ray powder diffraction pattern comprising at least two peaks expressed at 20 ± 0.2° selected from 4.8, 8.9, 9.6, 11 .0, 14.3, 15.0, 19.1 , 21 .1 , 28.6 and 33.6.

[0072] In some embodiments Compound 1 form 2 has an X-ray powder diffraction pattern comprising at least three peaks expressed at 20 ± 0.2° selected from 4.8, 8.9, 9.6, 11 .0, 14.3, 15.0, 19.1 , 21 .1 , 28.6 and 33.6.

[0073] In some embodiments Compound 1 Form 2 has an X-ray powder diffraction pattern comprising at least four peaks expressed at 20 ± 0.2° selected from 4.8, 8.9, 9.6, 11 .0, 14.3, 15.0, 19.1 , 21 .1 , 28.6 and 33.6.

[0074] In some embodiments Compound 1 Form 2 has an X-ray powder diffraction pattern comprising at least five peaks expressed at 20 ± 0.2° selected from 4.8, 8.9, 9.6, 11 .0, 14.3, 15.0, 19.1 , 21 .1 , 28.6 and 33.6.

[0075] In some embodiments Compound 1 Form 2 has an X-ray powder diffraction pattern comprising at least six peaks expressed at 20 ± 0.2° selected from 4.8, 8.9, 9.6, 11.0, 14.3, 15.0, 19.1 , 21.1 , 28.6 and 33.6.

[0076] In some embodiments Compound 1 Form 2 has an X-ray powder diffraction pattern comprising at least seven peaks expressed at 20 ± 0.2° selected from 4.8, 8.9, 9.6, 11 .0, 14.3, 15.0, 19.1 , 21 .1 , 28.6 and 33.6.

[0077] In some embodiments Compound 1 Form 2 has an X-ray powder diffraction pattern comprising at least eight peaks expressed at 20 ± 0.2° selected from 4.8, 8.9, 9.6, 11 .0, 14.3, 15.0, 19.1 , 21 .1 , 28.6 and 33.6.

[0078] In some embodiments Compound 1 Form 2 has an X-ray powder diffraction pattern comprising at least nine peaks expressed at 20 ± 0.2° selected from 4.8, 8.9, 9.6, 11 .0, 14.3, 15.0, 19.1 , 21 .1 , 28.6 and 33.6.

[0079] In some embodiments Compound 1 Form 2 has an X-ray powder diffraction pattern comprising ten peaks expressed at 20 ± 0.2° which are 4.8, 8.9, 9.6, 11 .0, 14.3, 15.0, 19.1 , 21 .1 , 28.6 and 33.6.

[0080] In some embodiments, Compound 1 Form 2 has an X-ray powder diffraction pattern substantially as shown in Figure 3.

[0081] In some embodiments, Compound 1 Form 2 has a DSC trace comprising a broad endothermic transition with a peak at 135.5 °C.

[0082] Crystalline Form 1

[0083] Crystalline form 1 is anhydrous.

[0084] In some embodiments, Compound 1 Form 1 has an X-ray powder diffraction pattern comprising at least one peak expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6 and 22.8.

[0085] In some embodiments Compound 1 Form 1 has an X-ray powder diffraction pattern comprising at least two peaks expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6 and 22.8.

[0086] In some embodiments Compound 1 Form 1 has an X-ray powder diffraction pattern comprising at least three peaks expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6 and 22.8.

[0087] In some embodiments Compound 1 Form 1 has an X-ray powder diffraction pattern comprising at least four peaks expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6 and 22.8.

[0088] In some embodiments Compound 1 Form 1 has an X-ray powder diffraction pattern comprising at least five peaks expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6 and 22.8. In some embodiments Compound 1 Form 1 has an X-ray powder diffraction pattern comprising at least six peaks expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6 and 22.8.

[0089] In some embodiments Compound 1 Form 1 has an X-ray powder diffraction pattern comprising at least seven peaks expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6 and 22.8.

[0090] In some embodiments Compound 1 Form 1 has an X-ray powder diffraction pattern comprising eight peaks expressed at 20 ± 0.2° which are 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6 and 22.8.

[0091] In some embodiments, Compound 1 Form 1 has an X-ray powder diffraction pattern comprising at least one peak expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6, 22,8, 23.5, 27.4 and 28.2.

[0092] In some embodiments Compound 1 Form 1 has an X-ray powder diffraction pattern comprising at least two peaks expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6, 22,8, 23.5, 27.4 and 28.2.

[0093] In some embodiments Compound 1 Form 1 has an X-ray powder diffraction pattern comprising at least three peaks expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6, 22,8, 23.5, 27.4 and 28.2.

[0094] In some embodiments Compound 1 Form 1 has an X-ray powder diffraction pattern comprising at least four peaks expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6, 22,8, 23.5, 27.4 and 28.2.

[0095] In some embodiments Compound 1 Form 1 has an X-ray powder diffraction pattern comprising at least five peaks expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6, 22,8, 23.5, 27.4 and 28.2.

[0096] In some embodiments Compound 1 Form 1 has an X-ray powder diffraction pattern comprising at least six peaks expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6, 22,8, 23.5, 27.4 and 28.2.

[0097] In some embodiments Compound 1 Form 1 has an X-ray powder diffraction pattern comprising at least seven peaks expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6, 22,8, 23.5, 27.4 and 28.2.

[0098] In some embodiments Compound 1 Form 1 has an X-ray powder diffraction pattern comprising at least eight peaks expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6, 22,8, 23.5, 27.4 and 28.2.

[0099] In some embodiments Compound 1 Form 1 has an X-ray powder diffraction pattern comprising at least nine peaks expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6, 22,8, 23.5, 27.4 and 28.2.

[0100] In some embodiments Compound 1 Form 1 has an X-ray powder diffraction pattern comprising at least ten peaks expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6, 22,8, 23.5, 27.4 and 28.2.

[0101] In some embodiments Compound 1 Form 1 has an X-ray powder diffraction pattern comprising eleven peaks expressed at 20 ± 0.2° which are 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6, 22,8, 23.5, 27.4 and 28.2.

[0102] Compound 1 Forms 1 and 2

[0103] In some embodiments, Compound 1 is a mixture of Form 1 and Form 2, which are both anhydrous. In these embodiments, the mixture may have an X-ray powder diffraction pattern comprising peaks expressed at 20 ± 0.2° selected from:

[0104] In some embodiments, a mixture of Compound 1 Forms 1 and 2 has an X-ray powder diffraction pattern substantially as shown in Figure 1 .

[0105] In some embodiments the mixture is approximately 50% of both Form 1 and Form 2.

[0106] In some embodiments the mixture is more than 60% Form 2. In some embodiments the mixture is more than 70% Form 2. In some embodiments the mixture is more than 80% Form 2. In some embodiments the mixture is more than 90% Form 2. In some embodiments the mixture is more than 95% Form 2. In some embodiments the mixture is more than 99% Form 2.

[0107] In some embodiments the mixture is more than 60% Form 1 . In some embodiments the mixture is more than 70% Form 1 . In some embodiments the mixture is more than 80% Form 1 . In some embodiments the mixture is more than 90% Form 1 . In some embodiments the mixture is more than 95% Form 1 . In some embodiments the mixture is more than 99% Form 1 .

[0108] In some embodiments crystalline Compound 1 has less than about 20% of any other form of Compound 1 . In some embodiments crystalline Compound 1 has less than about 10% of any other form of

[0109] Compound 1 . In some embodiments crystalline Compound 1 has less than about 5% of any other form of

[0110] Compound 1 . In some embodiments crystalline Compound 1 has less than about 2% of any other form of

[0111] Compound 1. In some embodiments crystalline Compound 1 is present in a substantially pure form.

[0112] The XRPD patterns described herein, and the peaks derived from them, are all measured using Ka radiation from copper (A = 1 .54 A).

[0113] Obtaining crystalline forms of Compound 1

[0114] Compound 1 can be obtained in a mixture of anhydrous crystalline Form 1 and Form 2 by trituration in ethyl acetate / heptane.

[0115] Alternatively, Compound 1 can first be purified by dry-flash chromatography on silica (80-100% ethyl acetate in heptanes). After concentration of the Compound 1 containing fractions under vacuum, the resultant solid is triturated in 1 :1 ethyl acetate / heptanes, and the mixture of anhydrous crystalline Form 1 and 2 are isolated by filtration. Compound 1 can be obtained in the anhydrous crystalline Form 2 by dissolving the compound in a mixture of toluene and n-heptane at elevated temperature followed by slowly cooling down to room temperature. Alternatively, Compound 1 is first purified by stirring in a cooled mixture of toluene and ethyl acetate followed by treatment with activated carbon. After filtration and concentration under vacuum with heating, n-heptane is added and the anhydrous crystalline Form 2 is isolated by crystallization. The final product is washed with a mixture of n-heptane and MTBE and then dried in an oven.

[0116] In some embodiments Compound 1 is recrystallised in a solvent system of toluene and n-heptane to yield Form 2. In other embodiments Compound 1 is recrystallised in a solvent system of toluene, ethyl acetate and n-heptane to yield Form 2.

[0117] In further embodiments, Compound 1 is crystallised by the following method to yield Form 2: dissolving Compound 1 in toluene at elevated temperature, such as from 60 to 90°C, adding n-heptane, stirring the resulting mixture for 20 minutes at elevated temperature, such as from 70 to 90°C, cooling the resulting mixture to room temperature, filtering the resulting solid and washing the solid with a mixture of n-heptane / MTBE, drying the washed solid under vacuum.

[0118] Therefore, not only have the inventors identified two polymorphic forms of compound 1 but also a process which provides a single polymorphic form, namely Form 2, rather than a mixture of Forms 1 and 2.

[0119] This is surprising given that following the prior art method to prepare compound 1 and polymorph screening via solubility testing results in the same mixture of polymorphic forms.

[0120] Compared to the mixture of Form 1 and Form 2 the melting point of Form 2 is 3.0°C higher (135.5°C for Form 2 vs 132.5°C for the mixture of Form 1 and Form 2, see Figures 4 and 5). Nevertheless, Form 2 has a relatively low melting point and therefore is expected to have low thermal stability. Form 2 is predicted to have poor solid state stability. Form 2 displayed low aqueous solubility which could mean that it has unfavourable adsorption.

[0121] Despite the expected low thermal stability, surprisingly it was found in a forced degradation study that Form 2 of Compound 1 showed not only good stability under heat and heat / humidity conditions but also under light and oxidative conditions. Form 2 of Compound 1 only showed limited stability in solution under strongly acidic conditions, however this is in line with the presence of an acid labile amide bond in the core structure. Form 2 therefore exhibits good stability under heat / humidity, light and oxidative conditions and therefore should have a long shelf life. This ensures that the product can be stored for a long period of time under normal storage conditions and will not degrade.

[0122] As described in more detail below, the present inventors have surprisingly found that anhydrous crystalline Form 2 of Compound 1 has high crystallinity and high thermal stability compared to its relatively low melting temperature. Moreover, anhydrous crystalline Form 2 of Compound 1 has further highly advantageous characteristics, including high optical and chemical purity, low hygroscopicity, good storage behaviour and long shelf-life. Thus, an ATX inhibitor with favourable characteristics can be provided.

[0123] Further advantageous properties of the anhydrous crystalline Form 2 of Compound 1 according to the present disclosure may include: higher polymorphic purity, flowability, dissolution rate, improved morphology or crystal habit, increased chemical, physical and / or mechanical stability, lower content of residual solvents, reduced adhesive tendencies and advantageous processing and handling characteristics such as favourable compressibility, and bulk density.

[0124] Formulation

[0125] Given that Compound 1 has poor aqueous solubility, formulations of Compound 1 were investigated to prepare a stable pharmaceutical formulation with a long shelf life and with high solubility of Compound 1 . In some embodiments the composition comprises Compound 1 and excipients and does not contain water.

[0126] In some embodiments, Compound 1 is formulated in a composition comprising one or more excipients which are selected from pharmaceutically acceptable oils and lipids. In some embodiments the composition comprises a single excipient. In some embodiments the composition comprises a mixture of 2, 3, 4 or 5 different excipients. In some embodiments the composition comprises a mixture of 3 excipients. In some embodiments the composition comprises a mixture of 2 excipients. Examples of suitable excipients include sesame oil, safflower oil, soybean oil, coconut oil, castor oil, corn oil, peanut oil, Maisine CC, almond oil, Captex 300 (caprylic / capric triglyceride), sunflower oil, Capmul MCM (glycerol monocaprylate), cottonseed oil, and Kolliphor EL (macrogolglycerol ricinoleate 35).

[0127] In some embodiments the formulation comprises a mixture of these excipients.

[0128] In further embodiments the lipid excipients are prepared from fractioned vegetable oil sources and fatty acids from coconuts and palm kernel oils. In some embodiments the mixture of oils / lipid excipients comprises medium-change triglycerides. In some embodiments the lipid excipients can be a mixture of triglycerides obtained by esterification of glycerol with caprylic (octanoic) and capric (decanoic) acids. In some embodiments the lipid excipients can be Captex ®300. In some embodiments the lipid excipient can be CAS number 65381 -09-1 (caprylic capric triglyceride). In some embodiments the pharmaceutical composition does not comprise water.

[0129] In some embodiments the lipid excipients can be a mono- and diglycerides of medium chain fatty acids. In some embodiments the lipid excipients can be a mixture of monoacylglycerols obtained by esterification of glycerol with caprylic (octanoic) and capric (decanoic) acids. In some embodiments the lipid excipients are selected from glyceryl monocaprylate, glyceryl dibehenate, glyceryl monolaurate, glyceryl monooleate, glyceryl monocaprylate, glyceryl caprylate / caprate, propylene glycol dilaurate, or propylene glycol monolaurate. In some embodiments the lipid excipients can be Capmul MCM. In some embodiments the lipid excipient can be CAS number 26402-26-6 (Glyceryl monocaprylate, also known as Glyceryl octanoate). In some embodiments the lipid excipients can be a polyethoxylated castor oil. The polyethoxylated castor oil can be prepared by reacting castor oil with ethylene oxide in a molar ratio of 1 :35. The resulting product can be a mixture for example CAS number 61791-12-6. In some embodiments the lipid excipient can be Kolliphor EL whose IUPAC name is 11 -hydroxy-17-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2- hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]et hoxy]ethoxy]heptadecanoic acid.

[0130] In some embodiments Compound 1 is formulated into a composition comprising one lipid excipient wherein the lipid excipient is selected from Maisine CC, Captex ®300 or capmul MCM. In further embodiments the pharmaceutical formulation comprises a mixture of lipid excipients selected from corn oil, Maisine CC, castor oil, Captex ®300, Capmul MCM and Kolliphor EL. In further embodiments the pharmaceutical formulation comprises a mixture of lipid excipients selected from castor oil, Maisine CC, Captex 300, Capmul MCM and Kolliphor EL. In some embodiments the pharmaceutical formulation comprises a mixture of Castor oil and Maisine CC or a mixture of Captex 300, Capmul MCM, and Kolliphor EL. In some embodiments the composition is formulated as an oral dosage form.

[0131] In some embodiments Compound 1 is formulated into an composition comprising one or more lipid excipients selected from the group consisting of Maisine CC, Capmul MCM, Castor oil, Captex 300 and Kolliphor EL. In some embodiments the composition is formulated as an oral dosage form.

[0132] In some embodiments the pharmaceutical formulation comprises a mixture of Castor oil and Maisine CC. In some embodiments the pharmaceutical formulation comprises a mixture of Castor oil and Maisine CC in a range of 30-60% castor oil and 30-60% Maisine CC. In some embodiments the pharmaceutical formulation comprises a mixture of Castor oil and Maisine CC in a ratio of about 35: 65, 40:60, 45:55, 50:50, 55:45, 60:40 or 65:35. In further embodiments the pharmaceutical formulation comprises a mixture of Castor oil and Maisine CC in a ratio of about 50:50.

[0133] In some embodiments the pharmaceutical formulation comprises a mixture of Captex 300, Capmul MCM C8, and Kolliphor EL. In some embodiments the formulation comprises a mixture of Captex 300, Capmul MCM C8, and Kolliphor EL each in the range of 10-45% by weight of the composition. In further embodiments the formulation comprises a mixture of Captex 300, Capmul MCM C8, and Kolliphor EL each in the range of 20-45% or 25-40%, 30-40% or 33-48% by weight of the composition. In some embodiments the ratio of Captex 300, Capmul MCM C8, and Kolliphor EL is 37.5:37.5:25 by weight respectively. In some embodiments the formulation is a mixture of Captex300, Capmul MCM, Kolliphor EL in a ratio of 32.5:32.5:35 (w:w:w) by weight respectively.

[0134] Suitability, Compound 1 is provided in a pharmaceutical composition formulated for oral administration. Based on the poor aqueous solubility of Compound 1 , the compound is formulated in the lipid excipients Captex 300, Capmul MCM C8, and Kolliphor EL (Formulation 1). Formulation 1 is prepared by melting Capmul MCM C8 at elevated temperature followed by the addition of Captex 300, Kolliphor EL and Compound 1 with stirring. In some embodiments a crystalline form of compound 1 is dissolved in the lipid excipients.

[0135] In further embodiments the pharmaceutical formulation of Compound 1 is formulated as an oral formulation. In further embodiments, the pharmaceutical formulation of Compound 1 is a liquid filled capsule formulation. In some embodiments the formulation is an oral solid dosage form. In some embodiments the liquid filled capsule comprises 30 mg of Compound 1 . In some embodiments the liquid filled capsule comprises 100 mg of Compound 1 . In further embodiments the liquid filled capsule comprises 200 mg of Compound 1 .

[0136] The present inventors surprisingly found that Formulation 1 has highly advantageous characteristics, including high thermal stability, reduced hygroscopicity, increased storage behaviour and shelf-life, high solubility, fast dissolution kinetics and high bioavailability. Thus, a pharmaceutical composition of an ATX inhibitor with favourable characteristics can be provided.

[0137] ***

[0138] The features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for obtaining the disclosed results, as appropriate, may, separately, or in any combination of such features, be utilised for realising the invention in diverse forms thereof.

[0139] While the invention has been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art when given this disclosure. Accordingly, the exemplary embodiments of the invention set forth above are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the spirit and scope of the invention.

[0140] For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purposes of improving the understanding of a reader. The inventors do not wish to be bound by any of these theoretical explanations.

[0141] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0142] Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise” and “include”, and variations such as “comprises”, “comprising”, and “including” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0143] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment. The term “about” in relation to a numerical value is optional and means for example + / - 10%.

[0144] Examples

[0145] EXAMPLE 1

[0146] Synthesis of (S)-N-(1-(4-chlorophenyl)ethyl)-3-(3-(4-(trifluoromethoxy)benzyl)-3H-imidazo[4,5- b]pyridin-2-yl)propionamide (Compound 1)

[0147] Compound 1

[0148] Each intermediate compound prepared in the different steps described below was characterized by standard analytical methods of chemical synthesis, including NMR (nuclear magnetic resonance), UPLC / MS (ultra performance liquid chromatography / mass spectrometry) and HPLC (high-performance liquid chromatography). Except for Step 2, all steps in the synthesis of Compound 1 are performed under nitrogen atmosphere.

[0149] Step 1 : 3-nitro-N-[[4-(trifluoromethoxy)phenyl]methyl]pyridin-2-amine (ME20190194-3) 2-Chloro-3-nitropyridine (1.00 kg) in 2-propanol (10 L), potassium carbonate (1.13 kg) and 4-trifluoro- methoxy-benzylamine (1 .45 kg) are charged to a reactor at room temperature and the resulting yellow- orange suspension is stirred at reflux. The yellow suspension is cooled to ca. 60°C before warm water (5 L) is added. The resulting biphasic mixture is cooled to room temperature under vigorous stirring and the resulting suspension is filtered. The resulting mass is washed twice with 2-propanol / water (2 / 1 , 1 .8 L) and twice with water (2 L) and dried under vacuum with heating. Yield: 1 .77 kg yellow solid. Purity by HPLC: 99.8%.

[0150] Step 2: N2-[[4-(trifluoromethoxy)phenyl]methyl]pyridine-2,3-diamine A Parr reactor is charged with a suspension of 3-nitro-N-[[4-(trifluoromethoxy)phenyl]methyl]pyridin-2- amine (ME20190194-3) (400 g) in ethanol (3.5 L), palladium on carbon (6.79 g) is added, and the reaction mixture is repeatedly purged with nitrogen (5 bar), degassed, and repeatedly purged with hydrogen (5 bar). The reaction mixture is stirred at room temperature and the pressure is maintained at 5 bar of hydrogen. The reactor is vented and repeatedly purged with nitrogen. The reaction mixture is filtered over a bed of Celite® and concentrated under vacuum with heating to yield N2-[[4- (trifluoromethoxy)phenyl]methyl]pyridine-2,3-diamine (ME20190194-4). The solids are dried at room temperature under nitrogen flow. Yield: 370 g purple solid (102%). Purity by HPLC: 99%.

[0151] Step 3: 4-oxo-4-[[2-[[4-(trifluoromethoxy)phenyl]methylamino]-3-pyridyl]amino]butanoic acid

[0152] A solution of N2-[[4-(trifluoromethoxy)phenyl]methyl]pyridine-2,3-diamine (ME20190194-4) (1.40 kg) in methyl-tert-butyl-ether (MTBE, 17.5 L) is charged with succinic anhydride (509 g). The reaction mixture is heated to ca. 50°C and stirred. The reaction mixture is seeded with product and n-heptane (2.8 L) is added slowly while maintaining the temperature at ca. 50°C. The reaction mixture is cooled down to room temperature by linear ramp. The suspension is filtered and the solids are washed twice with a mixture of MTBE and n-heptane (1 .6 / 1 , 6.1 L), dried by suction and then dried in an oven at to yield 4-oxo-4-[[2-[[4- (trifluoromethoxy)phenyl]methylamino]-3-pyridyl]amino]butanoic acid (ME20190194-6). Yield: 1.36 kg (72%). Purity by HPLC: 99.9%.

[0153] Step 4: 3-[3-[[4-(trifluoromethoxy)phenyl]methyl]imidazo[4,5-b]pyridin-2-yl]propanoic acid 4-Oxo-4-[[2-[[4-(trifluoromethoxy)phenyl]methylamino]-3-pyridyl]amino]butanoic acid (ME20190194-6) (2.68 kg) and acetic acid (2.8 L) are charged to a reactor, heated to ca. 115°C and stirred until the reaction is complete. The reaction is cooled to room temperature, diluted with acetic acid (5.8). Purified water (28 L) is added slowly and the resulting suspension is filtered and the solids are washed three times with purified water (8.4 L) and then dried in an oven to yield 3-[3-[[4- (trifluoromethoxy)phenyl]methyl]imidazo[4,5-b]pyridin-2-yl]propanoic acid (ME20190194-8). Yield: 2.27 kg (89%). Purity by HPLC: 99.1%.

[0154] Step 5: Compound 1

[0155] A mixture of 1 ,1'-carbonyldiimidazole (CDI, 1.04 kg) and 3-[3-[[4- (trifluoromethoxy)phenyl]methyl]imidazo[4,5-b]pyridin-2-yl]propanoic acid (ME20190194-8) (2.24 kg) in ethyl acetate (18.5 L) is stirred until the reaction is complete. The reaction mixture is heated to ca. 35°C and (S)-1-(4-chloro-phenyl)ethylamine (1 .37 kg), prepared by treating the respective hydrochloride with aqueous potassium hydroxide in toluene, in ethyl acetate (4.5 L) is added. The reaction mixture is heated to ca. 60°C and stirred for another two hours. The reaction mixture is cooled to room temperature and washed twice with dilute hydrochloric acid (7.0 L) and once hydrogen ammonium carbonate solution (6 L). Magnesium sulphate (0.58 kg) and activated carbon (145 g) in ethyl acetate (1 .4 L) are added and the mixture is stirred for 1 hour, filtered, concentrated under vacuum with heating before toluene (12.5 L) and n-heptane (14 L) are added. The solution is seeded with product and slowly cooled down to room temperature. The resulting suspension is filtered and the solids are washed three times with a mixture of n-heptane and MTBE (4.8 / 1 , 2 L) and then dried in an oven. Yield: 2.68 kg (87%). Purity by HPLC: 99.8%. EXAMPLE 2

[0156] Characterisation of (S)-N-(1 -(4-chlorophenyl)ethyl)-3-(3-(4-(trifluoromethoxy)benzyl)-3H- imidazo[4,5-b]pyridin-2-yl)propionamide (Compound 1) Compound 1 was characterized with regard to its solid state properties by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA).

[0157] X-Ray Powder Diffraction

[0158] The synthesis method of WO2016 / 124939 was followed to prepare Compound 1. An initial crystalline form was prepared using a solvent system of ethyl acetate and n-heptane.

[0159] The X-ray power diffraction (XRPD) pattern obtained using Cu radiation is shown in Figure 1 .

[0160] Crystallisation of Compound 1 was then attempted using the 24 different solvent systems listed in Table 1 :

[0161] Table 1: Solvent solubility screen results

[0162]

[0163] Four solvent systems did not yield sufficient solids for XRPD analysis and two solvent systems resulted in amorphous material. The corresponding XRPD patterns from the 16 solvent systems that yielded sufficient solids for XRPD are shown in Figure 2 and the reference peak list is given in Table 2.

[0164] Table 2: Reference XRPD peaks for Compound 1 Crystalline Form

[0165] It was originally thought that there is only one stable crystalline form of Compound 1 . However, the crystalline form produced by the method of Example 1 had a different XRPD pattern, which is shown in Figure 3 and the reference peak list is given in Table 3:

[0166] Table 3: Reference XRPD peaks for Compound 1 , form 2

[0167] Further method to make Form 2

[0168] Form 2 can also be crystallized via the following procedure: dissolving Compound 1 in toluene at elevated temperature, adding n-heptane, stirring the resulting mixture for 20 minutes at elevated temperature, cooling the resulting mixture to room temperature, filtering the resulting solid and washing the solid with a mixture of n-heptane / MTBE, drying the washed solid under vacuum.

[0169] After identifying Form 2, the initial crystalline form with 22 peaks (outlined in Table 1) is in fact a mixture of two polymorphs - Form 1 and Form 2.

[0170] In order to determine the unique XRPD peaks of form 1 the XPRD values for form 2 (Table 2) are subtracted from Table 1 and these are provided in Table 4.

[0171] Table 4: Presumed form 1 XRPD peaks for Compound 1 - peaks of Table 1 minus corresponding peaks of form 2

[0172] Differential Scanning Calorimetry

[0173] Form 2 of Compound 1 was analysed by differential scanning calorimetry. It was found to display a broad endothermic transition with a peak at 135.5 °C (Figure 4). This transition is associated with the melting point of the compound. The mixture of Form 1 and Form 2 of Compound 1 was also analysed by differential scanning calorimetry and was found to melt at 132.5 °C (Figure 5). Compared to the mean melting point of approved anti-cancer drugs of 179 °C (Mao 2016), the melting points of Form 1 and Form 2 of Compound 1 are relatively low indicating potential poor thermal stability.

[0174] Thermogravimetric Analysis

[0175] In thermogravimetric analysis (Figure 6), the mixture of Form 1 and Form 2 of Compound 1 displays a weight loss of 0.2% w / w from room temperature (i.e. 25 °C) to 150 °C, which is associated with the loss of residual solvent. It is clear from the curve that the loss of residual solvent shows a peak in intensity at around 136 °C. This behaviour likely indicates that at least part of the residual solvent is released exclusively when the melting point is approached. The steep weight loss observed from 150 °C onwards is associated with evaporation or degradation of the compound, also indicating potential poor thermal stability.

[0176] FTIR spectroscopy

[0177] Form 2 of Compound 1 was analysed by FTIR spectroscopy. The corresponding IR spectrum is displayed in Figure 7 and the reference peak list is given in Table 5: Table 5: List of significant IR bands and the proposed assignment

[0178] Solubility

[0179] Form 2 of Compound 1 was also characterized with regard to its solubility in aqueous media and the results are provided in Table 6. Compound 1 Form 2 shows rather poor solubility of less than 0.1 mg / mL over the whole pH range of 1 .0 to 9.0. According to the pharmaceutics classification scheme (Biopharmaceutics Classification System, BCS), a drug is highly soluble if the dose / solubility ratio is lower than 250. At the anticipated clinical dose of 200 mg Compound 1 Form 2 is not classified as highly soluble and therefore dissolution is likely to limit drug adsorption (Sandra Klein, The AAPS Journal (2010), vol. 12, No. 3, p. 397).

[0180] Table 6: Solubility of Compound 1 Form 2 in aqueous media

[0181] In sum, two polymorphic forms of Compound 1 were identified with relatively low melting points and poor pharmaceutical properties. The identified polymorphs displayed weight loss upon heating from room temperature to 150 °C, which is associated with the loss of residual solvent, and steep weight loss from 150 °C onwards, resulting in predicted insufficient solid-state stability. Form 2 displayed low aqueous solubility. Low thermal stability is a characteristic indicator for unfavourable storage behaviour and low shelf-life, whereas poor solubility is a characteristic indicator for unfavourable adsorption.

[0182] EXAMPLE 3

[0183] Stability of Compound 1 Form 2 under stress conditions

[0184] Despite the expected low thermal stability, the present inventors nevertheless investigated the stability of Compound 1 Form 2 in a forced degradation study and the results are provided in Table 7. Surprisingly it was found that Compound 1 Form 2 showed not only good stability under heat and heat / humidity conditions but also under light and oxidative conditions. Compound 1 Form 2 only showed limited stability in solution under strongly acidic conditions which is in line with the presence of an acid labile amide bond in the core structure. Table 7: Forced degradation data for Compound 1 Form 2

[0185] Abbreviations: NT = Not Tested.

[0186] EXAMPLE 4

[0187] Solubility of Compound 1 in different media The solubility of Compound 1 Form 2 was tested in various solvents and solvent mixtures and the results are provided in Table 8. Quite surprisingly it was found that Compound 1 showed higher solubility in the lipid Type 111 A MC formulation: Captex300: Capmul MCM: Kolliphor EL 32.5:32.5:35 (w:w:w) (Formulation 1) than in any of its single components. In all other solvent mixtures, the solubility was lower than that of the mixture component with the highest solubility. Even more surprisingly, it was found that stability of Compound 1 in Formulation 1 was good with no signs of compound degradation after 6 months at 40°C and 75% room humidity and 24 months at 25°C and 60% room humidity. Typically, compound stability in solution is much worse compared to compound stability in crystalline form. Table 8: Solubility data for Compound 1

[0188] EXAMPLE 5

[0189] Pharmacokinetic experiments with the Compound 1 in rats Two formulations that showed good solubilisation of Compound 1 Form 2 against a suspension of Compound 1 Form 2 in water were tested in a pharmacokinetic experiment in rats. Male Spraque Dawley Rats received Compound 1 Form 2 by oral administration as (i) a solid suspension (ii) a solution in Castor oil: Maisine CC 50:50 (w:w), or (iii) a solution in Captex300: Capmul MCM: Kolliphor EL 32.5:32.5:35 (w:w:w), in 1 % methylcellulose in water (w / w) by gavage at 30 mg / kg.

[0190] The concentration of Compound 1 in plasma was determined using an UPLC (ultra performance liquid chromatography) method with tandem mass spectrometric detection.

[0191] Results are summarized in Table 9 below. Surprisingly it was found that of the two solubilizing formulations only the formulation with Captex300, Capmul MCM and Kolliphor EL significantly increased both the Cmax and the AUC in rat.

[0192] Table 9: Summarised pharmacokinetic parameters of Compound 1 in male rat plasma

[0193] EXAMPLE 6

[0194] Development of liquid filled capsules of Compound 1

[0195] A liquid filled capsule formulation was developed as this allows for dose flexibility.

[0196] The percentage of Kolliphor EL in the Captex300: Capmul MCM: Kolliphor EL formulation was reduced from 35% to 25% to stay within the recommended daily exposure limit at the anticipated clinical dose of 200 mg Compound 1. The composition of placebo, 30 mg and 100 mg capsules is described in Table 10.

[0197] Table 10: The batch formula for Compound 1 liquid filled capsules

[0198] (*): May be corrected for purity (according to Certificate of Analysis). The capsules are manufactured according to a 5-step process consisting of heating, mixing, sieving, capsule filling, and capsule sealing. In the first step, Capmul MCM C8 is melted at elevated temperature before in step 2 Captex 300, Kolliphor EL and Compound 1 Form 2 are added with stirring and the final mixture is sieved in step 3. In step 4, the sieved mixture is transferred to the capsule filling and sealing machine and filled into hard gelatine capsules. In the last step, the capsules are closed and sealed, checked for leakage, and weight checked.

[0199] Under refrigerated conditions and upon long term storage at room temperature, the liquid formulation turns semi-solid for the 100 mg dose strength. This observed solidification of the formulation leads to a slightly slower dissolution rate of the 100 mg capsule compared to the 30 mg dose strength, however, dissolution remains within the target specification. The dissolution profile of 100 mg capsules with Formulation 1 in 900 mL pH 1.2 HCI buffer solution using a Dissolution Apparatus Type 2 and measured by HPLC is shown in Figure 8, which demonstrates how the profile changes from as manufactured on storage for 6, 12, 24 and 36 months.

[0200] EXAMPLE 7

[0201] Synthesis of 4-oxo-4-((2-((4-(trifluoromethoxy)benzyl) amino)pyridin-3-yl)amino)butanoic acid

[0202] As an alternative to the synthesis described in Example, 1 , Steps 2 and 3 can also be performed in a one pot procedure as follows:

[0203] A 100mL jacketed glass reactor is charged with 3-nitro-N-[[4-(trifluoromethoxy)phenyl]methyl]pyridin-2- amine (ME20190194-3) (6.0 g), 2-methyltetrahydrofuran (42 mL) and ammonium formate (4.83 g). Repeated purging with nitrogen was carried out and palladium on carbon (0.408 g) is added suspended in 2-methyltetrahydrofuran (6 mL) followed by another purging with nitrogen. The mixture is heated to 60-65 °C until reaction is complete and then cooled to room temperature. The reaction mixture is filtered over a bed of Celite® and concentrated under vacuum with heating. Main part of the residue (4.83 g, 87% of the batch) is dissolved in 2-methyltetrahydrofuran (27 mL) at room temperature. Succinic anhydride (1 .62 g) is added and the reaction mixture is heated at 50 °C for 1 .5 hours. Then n-Heptane (13.5 mL) is slowly charged, the mixture is cooled to 40 °C and seeded. The suspension formed is cooled to room temperature, filtered and dried to afford 4-oxo-4-((2-((4-(trifluoromethoxy)benzyl) amino)pyridin-3- yl)amino)butanoic acid (ME20190194-6). Yield: 4.54 g of light grey solid (74% over 2 steps). Purity by HPLC: 99.5%.

[0204] This method has the benefit of preventing the use of highly combustible hydrogen gas. The colour of the material was also improved. Numbered Statements:

[0205] 1 . An anhydrous crystalline form of Compound 1 :

[0206] 2. The crystalline form of Compound 1 according to statement 1 , which is in Form 2.

[0207] 3. The crystalline form of Compound 1 according to statement 2, wherein the XRPD pattern comprises at least one peak expressed at 20 ± 0.2° selected from 4.8, 14.3, 15.0, 19.1 and 21 .1.

[0208] 4. The crystalline form of Compound 1 according to statement 3, wherein the XRPD pattern comprises five peaks expressed at 20 ± 0.2° which are 4.8, 14.3, 15.0, 19.1 and 21.1.

[0209] 5. The crystalline form of Compound 1 according to statement 2, wherein the XRPD pattern comprises at least one peak expressed at 20 ± 0.2° selected from 4.8, 8.9, 9.6, 11 .0, 14.3, 15.0, 19.1 , 21.1 , 28.6 and 33.6.

[0210] 6. The crystalline form of Compound 1 according to statement 5, wherein the XRPD pattern comprises ten peaks expressed at 20 ± 0.2° which are 4.8, 8.9, 9.6, 11 .0, 14.3, 15.0, 19.1 , 21 .1 , 28.6 and 33.6.

[0211] 7. The crystalline form of Compound 1 according to statement 2, which has an X-ray powder diffraction pattern substantially as shown in Figure 3.

[0212] 8. The crystalline form of Compound 1 according to statement 1 , which is in Form 1 .

[0213] 9. The crystalline form of Compound 1 according to statement 8, wherein the XRPD pattern comprises at least one peak expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6 and 22.8.

[0214] 10. The crystalline form of Compound 1 according to statement 9, wherein the XRPD pattern comprises eight peaks expressed at 20 ± 0.2° which are 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6 and 22.8.

[0215] 11. The crystalline form of Compound 1 according to statement 8, wherein the XRPD pattern comprises at least one peak expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6, 22,8, 23.5, 27.4 and 28.2. 12. The crystalline form of Compound 1 according to statement 11 , wherein the XRPD pattern comprises eleven peaks expressed at 20 ± 0.2° which are 13.7, 13.9, 19.6, 20.3, 21 .5, 21 .9, 22.6, 22,8, 23.5, 27.4 and 28.2.

[0216] 13. The crystalline form of Compound 1 according to statement 1 , which is a mixture of two forms, wherein one form is as defined in claims 2 to 7 and the other is as defined in statements 8 to 12.

[0217] 14. The crystalline form of Compound 1 according to statement 13, which has an X-ray powder diffraction pattern substantially as shown in Figure 1 .

[0218] 15. The crystalline form of Compound 1 according to any of the preceding statements wherein said crystalline Compound 1 has less than about 20% of any other form of Compound 1 .

[0219] 16. The crystalline form of Compound 1 according to statement 15, wherein said crystalline Compound 1 is present in less than about 10% of any other form of Compound 1 .

[0220] 17. The crystalline form of Compound 1 according to statement 16, wherein said crystalline Compound 1 is present in less than about 5% of any other form of compound 1 .

[0221] 18. The crystalline form of Compound 1 according to statement 17, wherein said crystalline Compound 1 is present in less than about 2% of any other form of compound 1 .

[0222] 19. The crystalline form of Compound 1 according to any of the preceding statements, wherein said crystalline Compound 1 is present in a substantially pure form.

[0223] 20. The crystalline form of Compound 1 according to any of the preceding statements, wherein said crystalline Compound 1 is at least 99% in the form defined in any one of statements 2 to 7.

[0224] 21. A method to obtain the crystalline form of Compound 1 according to either statement 13 or statement 14, by trituration in ethyl acetate / heptane.

[0225] 22. The method of statement 21 , wherein the tituration is carried out in 1 :1 ethyl acetate / heptanes, and the crystalline form of Compound 1 is isolated by filtration.

[0226] 23. A method to obtain the crystalline form of Compound 1 as defined in any one of statements 2 to 7, wherein Compound 1 is recrystallised in a solvent system of toluene and n-heptane.

[0227] 24. A method to obtain the crystalline form of Compound 1 as defined in any one of statements 2 to 7, wherein Compound 1 is recrystallised in a solvent system of toluene, ethyl acetate and n-heptane.

[0228] 25. A method of preparing Compound 1 comprising one or more of the following steps 1) to 5): 1) reacting 2-chloro-3-nitro-pyridine and 4-trifluoro-methoxy-benzylamine in the presence of a base to prepare 3-nitro-N-[[4-(trifluoromethoxy)phenyl]methyl]pyridin-2-amine:

[0229] 2) converting 3-nitro-N-[[4-(trifluoromethoxy)phenyl]methyl]pyridin-2-amine to N2-[[4- (trifluoromethoxy)phenyl]methyl]pyridine-2,3-diamine:

[0230] 3) converting N2-[[4-(trifluoromethoxy)phenyl]methyl]pyridine-2,3-diamine to 4-oxo-4-[[2-[[4- (trifluoromethoxy)phenyl]methylamino]-3-pyridyl]amino]butanoic acid in the presence of succinic anhydride:

[0231] 4) reacting 4-oxo-4-[[2-[[4-(trifluoromethoxy)phenyl]methylamino]-3-pyridyl]amino]butanoic acid with acetic acid to form 3-[3-[[4-(trifluoromethoxy)phenyl]methyl]imidazo[4,5-b]pyridin-2-yl]propanoic acid:

[0232]

[0233] 5) reacting 3-[3-[[4-(trifluoromethoxy)phenyl]methyl]imidazo[4,5-b]pyridin-2-yl]propanoic acid with (1 S)-1 - (4-chlorophenyl)ethanamine to prepare compound 1 :

[0234] 26. A method of preparing Compound 1 according to statement 25 comprising steps 1) to 5).

[0235] 27. The method according to either statement 25 or 26, wherein step 1) is carried out in a biphasic mixture of an organic solvent and water, preferably wherein the organic solvent is isopropyl alcohol.

[0236] 28. The method according to any one of statements 25 to 27, wherein the base used in step 1) is potassium carbonate.

[0237] 29. The method according to any one of statements 25 to 28, wherein step 2) is carried out in the presence of palladium on carbon.

[0238] 30. The method according to any one of statements 25 to 29, wherein step 2) is carried out in an organic solvent, preferably wherein the organic solvent is ethanol.

[0239] 31. The method according to any one of statements 25 to 30, wherein step 3) is carried out in an organic solvent, preferably wherein the organic solvent is methyl-tert-butyl-ether.

[0240] 32. The method according to any one of statements 25 to 28, wherein steps 2) and 3) are carried out in a one pot procedure.

[0241] 33. The method according to statement 32, wherein the one pot procedure carried out in an organic solvent, preferably wherein the organic solvent is 2-methyltetrahydrofuran. 34. The method according to any one of statements 25 to 33, wherein step 4) is carried out in the presence of acetic acid and optionally water.

[0242] 35. The method according to any one of statements 25 to 34, wherein step 5) is carried out in an organic solvent, preferably wherein the organic solvent is ethyl acetate.

[0243] 36. A pharmaceutical composition comprising Compound 1 : and one or more excipients which are selected from pharmaceutically acceptable oils and lipids.

[0244] 37. The pharmaceutical composition of statement 36, wherein the composition does not contain water.

[0245] 38. The pharmaceutical composition of either statement 36 or statement 37, wherein the composition comprises a mixture of 2 or more excipients.

[0246] 39. The pharmaceutical composition of any one of statements 36 to 38, wherein the composition comprises a mixture of 3 excipients.

[0247] 40. The pharmaceutical composition of any one of statements 36 to 39, wherein the excipients are selected from sesame oil, safflower oil, soybean oil, coconut oil, castor oil, corn oil, peanut oil, Maisine CC, almond oil, Captex 300 (caprylic / capric triglyceride), sunflower oil, Capmul MCM (glycerol monocaprylate), cottonseed oil, and Kolliphor EL (macrogolglycerol ricinoleate 35).

[0248] 41. The pharmaceutical composition of statement 36, wherein the excipients are Captex 300, Capmul MCM C8, and Kolliphor EL.

[0249] 42. The pharmaceutical composition of statement 41 , wherein the composition comprises a mixture of Captex 300, Capmul MCM C8, and Kolliphor EL each in the range of 20-45% or 25-40%, 30-40% or 33-48% by weight of the composition.

[0250] 43. The pharmaceutical composition of statement 42 wherein the ratio of Captex 300, Capmul MCM, and Kolliphor EL is either 37.5:37.5:25 by weight respectively or 32.5:32.5:35 by weight respectively. 44. An oral dosage form comprising the pharmaceutical composition of any one of statements 36 to 43.

[0251] 45. The oral dosage form of statement 44 which is a liquid filled capsule.

[0252] References

[0253] A number of publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below.

[0254] The entirety of each of these references is incorporated herein.

[0255] For standard molecular biology techniques, see Sambrook, J., Russel, D.W. Molecular Cloning, A

[0256] Laboratory Manual. 3 ed. 2001 , Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press

Claims

Claims1 . An anhydrous crystalline form of Compound 1 :

2. The crystalline form of Compound 1 according to claim 1 , which is in Form 2.

3. The crystalline form of Compound 1 according to claim 2, wherein the XRPD pattern comprises at least one peak expressed at 20 ± 0.2° selected from 4.8, 14.3, 15.0, 19.1 and 21 .1 optionally wherein the XRPD pattern comprises five peaks expressed at 20 ± 0.2° which are 4.8, 14.3, 15.0, 19.1 and 21 .1 .

4. The crystalline form of Compound 1 according to claim 2, wherein the XRPD pattern comprises at least one peak expressed at 20 ± 0.2° selected from 4.8, 8.9, 9.6, 11 .0, 14.3, 15.0, 19.1 , 21 .1 , 28.6 and33.6, optionally wherein the XRPD pattern comprises ten peaks expressed at 20 ± 0.2° which are 4.8, 8.9, 9.6, 11.0, 14.3, 15.0, 19.1 , 21 .1 , 28.6 and 33.6.

5. The crystalline form of Compound 1 according to claim 2, which has an X-ray powder diffraction pattern substantially as shown in Figure 3.

6. The crystalline form of Compound 1 according to claim 1 , which is in Form 1 .

7. The crystalline form of Compound 1 according to claim 6, wherein the XRPD pattern comprises at least one peak expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21.9, 22.6 and 22.8, optionally wherein the XRPD pattern comprises eight peaks expressed at 20 ± 0.2° which are 13.7, 13.9,19.6, 20.3, 21.5, 21.9, 22.6 and 22.8.

8. The crystalline form of Compound 1 according to claim 6, wherein the XRPD pattern comprises at least one peak expressed at 20 ± 0.2° selected from 13.7, 13.9, 19.6, 20.3, 21 .5, 21.9, 22.6, 22,8, 23.5, 27.4 and 28.2, optionally wherein the XRPD pattern comprises eleven peaks expressed at 20 ± 0.2° which are 13.7, 13.9, 19.6, 20.3, 21.5, 21.9, 22.6, 22,8, 23.5, 27.4 and 28.2.

9. The crystalline form of Compound 1 according to claim 1 , which is a mixture of two forms, wherein one form is as defined in claims 2 to 5 and the other is as defined in claims 6 to 8.

10. The crystalline form of Compound 1 according to claim 9, which has an X-ray powder diffraction pattern substantially as shown in Figure 1 .

11. The crystalline form of Compound 1 according to any of the preceding claims wherein said crystalline Compound 1 has less than about 20% of any other form of Compound 1 , optionally less than about 10% of any other form of Compound 1 , optionally less than about 5% of any other form of compound 1 , optionally less than about 2% of any other form of compound 1 .

12. The crystalline form of Compound 1 according to any of the preceding claims, wherein said crystalline Compound 1 is present in a substantially pure form, optionally wherein said crystalline Compound 1 is at least 99% in the form defined in any one of claims 2 to 5.

13. A method to obtain the crystalline form of Compound 1 according to either claim 9 or claim 10, by trituration in ethyl acetate / heptane, preferably wherein the tituration is carried out in 1 :1 ethyl acetate / heptanes, and the crystalline form of Compound 1 is isolated by filtration.

14. A method to obtain the crystalline form of Compound 1 as defined in any one of claims 2 to 5, wherein Compound 1 is recrystallised in a solvent system of toluene and n-heptane, or wherein Compound 1 is recrystallised in a solvent system of toluene, ethyl acetate and n- heptane.

15. A method of preparing Compound 1 comprising one or more of the following steps 1) to 5):1) reacting 2-chloro-3-nitro-pyridine and 4-trifluoro-methoxy-benzylamine in the presence of a base to prepare 3-nitro-N-[[4-(trifluoromethoxy)phenyl]methyl]pyridin-2-amine:2) converting 3-nitro-N-[[4-(trifluoromethoxy)phenyl]methyl]pyridin-2-amine to N2-[[4- (trifluoromethoxy)phenyl]methyl]pyridine-2,3-diamine:3) converting N2-[[4-(trifluoromethoxy)phenyl]methyl]pyridine-2,3-diamine to 4-oxo-4-[[2-[[4- (trifluoromethoxy)phenyl]methylamino]-3-pyridyl]amino]butanoic acid in the presence of succinic anhydride:4) reacting 4-oxo-4-[[2-[[4-(trifluoromethoxy)phenyl]methylamino]-3-pyridyl]amino]butanoic acid with acetic acid to form 3-[3-[[4-(trifluoromethoxy)phenyl]methyl]imidazo[4,5-b]pyridin-2-yl]propanoic acid:5) reacting 3-[3-[[4-(trifluoromethoxy)phenyl]methyl]imidazo[4,5-b]pyridin-2-yl]propanoic acid with (1 S)-1 - (4-chlorophenyl)ethanamine to prepare compound 1 :

16. A method of preparing Compound 1 according to claim 15 comprising steps 1) to 5).

17. The method according to either claim 15 or 16, wherein step 1) is carried out in a biphasic mixture of an organic solvent and water, preferably wherein the organic solvent is isopropyl alcohol, and wherein the base used in step 1) is potassium carbonate.

18. The method according to any one of claims 15 to 17, wherein step 2) is carried out in the presence of palladium on carbon, and wherein step 2) is carried out in an organic solvent, preferably wherein the organic solvent is ethanol.

19. The method according to any one of claims 15 to 18, wherein step 3) is carried out in an organic solvent, preferably wherein the organic solvent is methyl-tert-butyl-ether.

20. The method according to any one of claims 15 to 17, wherein steps 2) and 3) are carried out in a one pot procedure.

21. The method according to claim 20, wherein the one pot procedure carried out in an organic solvent, preferably wherein the organic solvent is 2-methyltetrahydrofuran.

22. The method according to any one of claims 15 to 21 , wherein step 4) is carried out in the presence of acetic acid and optionally water.

23. The method according to any one of claims 15 to 22, wherein step 5) is carried out in an organic solvent, preferably wherein the organic solvent is ethyl acetate.

24. A pharmaceutical composition comprising Compound 1 :and one or more excipients which are selected from pharmaceutically acceptable oils and lipids, preferably wherein the composition does not contain water.

25. The pharmaceutical composition of claim 24, wherein the composition comprises a mixture of 2 or more excipients, such as a mixture of 3 excipients.

26. The pharmaceutical composition of claim 24 or 25, wherein the excipients are selected from sesame oil, safflower oil, soybean oil, coconut oil, castor oil, corn oil, peanut oil, Maisine CC, almond oil, Captex 300 (caprylic / capric triglyceride), sunflower oil, Capmul MCM (glycerol monocaprylate), cottonseed oil, and Kolliphor EL, preferably wherein the excipients are Captex 300, Capmul MCM C8, and Kolliphor EL (macrogolglycerol ricinoleate 35).

27. An oral dosage form comprising the pharmaceutical composition of any one of claims 24 to 26, optionally wherein the oral dosage form is a liquid filled capsule.

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