Crystalline forms

Abstract

There is provided inter alia a substance which is an acid addition salt of a compound of formula (I) wherein the substance is in a solid crystalline form. The substance is an inhibitor of ALK5.

Description

[0001]AGO-P3287PCT SpecificationCRYSTALLINE FORMS Field of the inventionThe invention relates to solid crystalline salt forms of a potent ALK5 inhibitor, andcompositions, medical uses and processes for manufacturing thereof.Background of the inventionTransforming growth factor-β (TGF-β) belongs to the TGF-β superfamily, which comprises TGF-β1, TGF-β2, and TGF-β3, among other proteins. TGF-β is involved in many cellular processes, including cell proliferation, cell migration, invasion, epithelial−mesenchymaltransition, extracellular matrix production and immune suppression. TGF-β and its receptorsare often chronically overexpressed in various human diseases, including cancer, inflammation, tissue fibrosis and autoimmunity. Therefore, blockade of TGF-β signalling pathway is considered an attractive approach for drug development (Heldin C. H. et al., (2016)). TGF-β signals via two related transmembrane type I and type II serine / threonine kinase receptors. Following TGF-β binding to the constitutively active type II receptor, the type I receptor (TGFβR1, also called activin receptor-like kinase 5 (ALK5), which term is used hereafter) is phosphorylated and creates a binding site for Smad2 and Smad3 proteins, which are further phosphorylated. Phosphorylated Smad2 / Smad3 proteins form a heteromeric complex with Smad4, which translocate into the nucleus, assembles with specific DNA-binding cofactors and co-modulators, and binds to the promoters of TGF-β target genes involved in cell differentiation, proliferation, apoptosis, migration, and extracellular matrix production.(Akhurst R. J. et al., (2012)).In most cell types, activin receptor-like kinase 5 (ALK5) is the predominant TGF-β receptor I that is activated by TGF-β through TGF-β receptor II. This interaction requires both extracellular and intracellular domains for signal transduction. ALK5 and TGF-β receptor II proteins can also form active heterooligomeric complexes in the absence of ligand. These complexes are able to transduce basal signals when both receptors are co-expressed because of their intrinsic affinity for interaction. (Bierie B. et al., (2006)).AGO-P3287PCT SpecificationThe functional TGFβRII–TGFβRI (ALK5) heteromeric signalling complex is commonly associated with human cancer, and it regulates the activation of downstream Smad- dependent and Smad-independent pathways. In fact, many studies have identified mutations in components that are associated with the TGF-β pathway, and which correlate with cancer occurrence and prognosis in many human tissues. The overexpression of TGF-β1 has been associated with breast, colon, oesophageal, gastric, hepatocellular, lung and pancreaticcancer inter alia. Importantly, the overexpression of TGF-β in human cancer correlates withtumour progression, metastasis, angiogenesis and poor prognostic outcome. Furthermore, TGF-β inhibits alveolar epithelial cell growth and repair, so it is a key player in fibroticprocesses, acting on both fibroblasts and alveolar epithelial cells (Saito A. et al., (2018)).Extensive evidence suggests that the canonical ALK5 / Smad3 pathway is critically involved in the pathogenesis of fibrosis in many tissues. Oral administration of a small molecular weight selective inhibitor of the kinase activity of ALK5 inhibited fibrogenesis in a rat model of progressive TGF-β1-induced pulmonary fibrosis. Furthermore, Smad3 null mice exhibit attenuated fibrosis in a wide range of experimental models and are resistant to bleomycin-induced pulmonary fibrosis. (Biernacka A. et al., (2011)). Similar to the role of TGF-β inpulmonary fibrosis, in COPD patients TGF-β promotes fibrotic airway remodelling, which can further contribute to diminished lung function. Some of the increases in TGF-β1 in the airway epithelium of COPD patients may be a direct response to cigarette smoke, the most significantrisk factor for development of this disease state (Aschner Y. et al., (2016)). The transforminggrowth factor (TGF-β) cytokines play a central role in development and progression of chronic respiratory diseases. TGF-β overexpression in chronic inflammation, remodelling, fibrotic processes, and susceptibility to viral infection is established in the most prevalent chronic respiratory diseases including pulmonary fibrosis, asthma, COPD and lung cancer. Compounds which have utility as potent inhibitors of ALK5 are described in WO 2022 / 069509A1. Example 19 of the above-mentioned patent publication discloses a non-crystalline form of2-(piperazin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1- yl)acetamido) benzoate:AGO-P3287PCT Specification (“the compound of formula (I)”), which compound is a potent inhibitor of ALK5. Polymorphism is an important consideration in the development of a medicinal product because of its influence on the physicochemical and biopharmaceutical properties of the compound. This characteristic arises whenever an entity, such as small molecule, can adopt different crystalline lattices. The resulting variation in solid state packing can lead to differences in storage stability, solubility profiles and density thereby affecting formulation and product manufacturing, as well as dissolution characteristics: an important factor in determining bioavailability in vivo. There is therefore a need to provide solid forms of the compound of formula (I) for use in the treatment of diseases ameliorated by inhibition of ALK5, particularly having appropriatephysical and chemical properties, including properties pertinent to its administration orallyand / or by inhalation, such as high melting point, good polymorphic and chemical stability uponstorage, relatively low hygroscopicity and adequate solubility.Summary of the invention In a first aspect, the present invention provides a substance which is an acid addition salt of a compound of formula (I): AGO-P3287PCT Specificationwherein the acid addition salt is selected from the group consisting of a fumaric acid additionsalt, a succinic acid addition salt and a hydrochloric acid addition salt, and the substance is ina solid crystalline form.In a second aspect, the present invention provides a substance which is a fumaric acidaddition salt of a compound of formula (I): wherein the substance is in a solid crystalline form.In a third aspect, the present invention provides a substance which is a succinic acid additionsalt of a compound of formula (I): wherein the substance is in a solid crystalline form.In a fourth aspect, the present invention provides a substance which is a hydrochloric acidaddition salt of a compound of formula (I): wherein the substance is in a solid crystalline form.AGO-P3287PCT SpecificationSuch substances may be referred to herein as a “substance of the invention” or a “substanceas defined herein”. Detailed Description of the invention Brief Description of the FiguresFigure 1A: XRPD pattern of a representative sample of crystalline Form 1 of the hydrobromicacid addition salt of the compound of formula (I).Figure 1B: 1H-NMR spectrum of a representative sample of crystalline Form 1 of thehydrobromic acid addition salt of the compound of formula (I).Figure 1C: Thermal analysis (TGA and DSC) of a representative sample of crystalline Form1 of the hydrobromic acid addition salt of the compound of formula (I).Figure 2A: XRPD pattern of a representative sample of crystalline Form 2 of the hydrobromicacid addition salt of the compound of formula (I).Figure 2B: 1H-NMR spectrum of a representative sample of crystalline Form 2 of thehydrobromic acid addition salt of the compound of formula (I). Figure 2C: Thermal analysis (TGA and DSC) of a representative sample of crystalline Form 2 of the hydrobromic acid addition salt of the compound of formula (I).Figure 3: XRPD pattern of a representative sample of crystalline Form 3 of the hydrobromicacid addition salt of the compound of formula (I).Figure 4A: XRPD pattern of a representative sample of crystalline Form 1 of the fumaric acidaddition salt of the compound of formula (I).Figure 4B: FTIR spectrum of a representative sample of crystalline Form 1 of the fumaric acidaddition salt of the compound of formula (I).Figure 4C: FTR spectrum of a representative sample of crystalline Form 1 of the fumaric acidaddition salt of the compound of formula (I).Figure 4D: 1H-NMR spectrum of a representative sample of crystalline Form 1 of the fumaricacid addition salt of the compound of formula (I). Figure 4E: Thermal analysis (TGA and DSC) of a representative sample of crystalline Form1 of the fumaric acid addition salt of the compound of formula (I).Figure 4F: Plots of water absorption and desorption from DVS study on a representativesample of crystalline Form 1 of the fumaric acid addition salt of the compound of formula (I)and on the compound of formula (I) as free base.Figure 4G: ORTEP plot of the asymmetric unit of the crystalline Form 1 of the fumaric acidaddition salt of the compound of formula (I).AGO-P3287PCT SpecificationFigure 4H: Vertical alignment of the XRPD pattern obtained for crystalline Form 1 of thefumaric acid addition salt of the compound of formula (I) and the pattern simulated from asingle crystal structure.Figure 4J: XRPD pattern of a representative sample of crystalline Form 1 of the fumaric acidaddition salt of the compound of formula (I) prepared by another method.Figure 5A: XRPD pattern of a representative sample of crystalline Form 1 of the succinic acidaddition salt of the compound of formula (I).Figure 5B: 1H-NMR spectrum of a representative sample of crystalline Form 1 of the succinicacid addition salt of the compound of formula (I).Figure 5C: Thermal analysis (TGA and DSC) of a representative sample of crystalline Form1 of the succinic acid addition salt of the compound of formula (I).Figure 5D: GVS isotherm plot of a representative sample of crystalline Form 1 of the succinicacid addition salt of the compound of formula (I).Figure 5E: XRPD overlay pattern of a representative sample of crystalline Form 1 of thesuccinic acid addition salt of the compound of formula (I) before and after GVS analysis.Figure 6A: XRPD pattern of a representative sample of crystalline Pattern 1 of thehydrochloric acid addition salt of the compound of formula (I).Figure 6B: 1H-NMR spectrum of a representative sample of crystalline Pattern 1 of thehydrochloric acid addition salt of the compound of formula (I). Figure 6C: Thermal analysis (TGA and DSC) of a representative sample of crystalline Pattern1 of the hydrochloric acid addition salt of the compound of formula (I).Figure 6D: GVS isotherm plot of a representative sample of crystalline Pattern 1 of thehydrochloric acid addition salt of the compound of formula (I).Figure 6E: XRPD overlay pattern of a representative sample of crystalline Pattern 1 of thehydrochloric acid addition salt of the compound of formula (I) before and after GVS analysis. Solid crystalline formsThe term “cocrystal” as used herein refers to a solid that is a crystalline single phase materialcomposed of two or more different molecular or ionic compounds, generally in a stoichiometricratio that possess distinct physical, crystallographic and spectroscopic properties whencompared to the chemical species individually and the interaction between at least two of the components is not ionic. The term “fumarate” as used herein refers to deprotonated forms of fumaric acid, such asmono- or di- deprotonated forms corresponding to deprotonation at one of or both of thecarboxylic acid moieties of fumaric acid.AGO-P3287PCT SpecificationThe term “succinate” as used herein refers to deprotonated forms of succinic acid, such asmono- or di- deprotonated forms corresponding to deprotonation at one of or both of thecarboxylic acid moieties of succinic acid.The term “pharmaceutically acceptable” as used herein pertains to diluents, carriers and / orexcipients which are within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each diluent, carrier, and / or excipient must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.The inventors of the present invention have developed substances which are novel solidcrystalline forms of the compound of formula (I) having good physical and chemical stabilityand other favourable properties.Thus, in a first aspect, the present invention provides a substance which is an acid addition salt of a compound of formula (I): wherein the acid addition salt is selected from the group consisting of a fumaric acid additionsalt, a succinic acid addition salt and hydrochloric acid addition salt, and the substance is in asolid crystalline form (a “substance of the invention”).In a second aspect, the present invention provides a substance which is a fumaric acidaddition salt of a compound of formula (I):AGO-P3287PCT Specification wherein the substance is in a solid crystalline form (a “substance of the invention”).In a third aspect, the present invention provides a substance which is a succinic acid additionsalt of a compound of formula (I): wherein the substance is in a solid crystalline form (a “substance of the invention”).In a fourth aspect, the present invention provides a substance which is a hydrochloric acidaddition salt of a compound of formula (I): wherein the substance is in a solid crystalline form (a “substance of the invention”).Suitably the substance of the invention is a monofumaric acid addition salt of the compoundof formula (I). As referred to herein the term “monofumaric acid addition salt” refers to a fumaricacid addition salt having a molar ratio of fumarate to the compound of formula (I) in the acidaddition salt of 1:1.AGO-P3287PCT SpecificationSuitably the substance of the invention is a monosuccinic acid addition salt of the compound of formula (I). As referred to herein the term “monosuccinic acid addition salt” refers to a succinic acid addition salt having a molar ratio of succinate to the compound of formula (I) in the acid addition salt of 1:1.Suitably the substance of the invention is a tri- or tetra-hydrochloric acid addition salt of thecompound of formula (I). As referred to herein the term “tri- or tetra-hydrochloric acid additionsalt” refers to a hydrochloric acid addition salt having a molar ratio of chlorate to the compoundof formula (I) in the acid addition salt of 3:1 to 4:1.In one embodiment, the solid crystalline form of the substance of the invention is the form ofa cocrystal. Suitably, the substance of the invention is in the form of a cocrystal wherein the cocrystal is a cocrystal of the fumaric acid addition salt of the compound of formula (I) and fumaric acid. Thus the cocrystal of the fumaric acid addition salt of the compound of formula (I) with fumaricacid comprises both fumaric acid and fumarate (associated with the compound of formula (I)as a salt). Suitably, the compound of formula (I) is protonated i.e. is in protonated form.Suitably, the molar ratio of fumarate and fumaric acid taken together to the compound offormula (I) in protonated form in the cocrystal is about 1.5:1. More suitably, the cocrystal is acocrystal of (a) the monofumaric acid addition salt of the compound of formula (I) and (b) fumaric acid where (a) and (b) are in a molar ratio of about 2:1. Suitably, the substance of the invention is in the form of a cocrystal wherein the cocrystal is acocrystal of the succinic acid addition salt of the compound of formula (I) and succinic acid.Thus the cocrystal of the succinic acid addition salt of the compound of formula (I) with succinicacid comprises both succinic acid and succinate (associated with the compound of formula (I)as a salt). Suitably, the compound of formula (I) is protonated i.e. is in protonated form.Suitably, the molar ratio of succinate and succinic acid taken together to the compound offormula (I) in protonated form in the cocrystal is about 1.5:1. More suitably, the cocrystal is acocrystal of (a) the monosuccinic acid addition salt of the compound of formula (I) and (b)succinic acid where (a) and (b) are in a molar ratio of about 2:1.AGO-P3287PCT SpecificationA person skilled in the art can determine by means of standard techniques whether or not asubstance is in a solid crystalline form and what are the physical characteristics of that form.Examples of such techniques include thermogravimetric analysis (TGA), differential scanningcalorimetry (DSC), and X-ray crystallography (e.g. single crystal X-ray crystallography and X-ray powder diffraction (XRPD)).An XRPD pattern of a substance is characterised by the diffraction angle (2θ) and interplanarspacing (d) parameters of an X-ray diffraction spectrum. These are related by Bragg'sequation, nλ=2d Sin θ, (where n=1; λ=wavelength of the cathode used; d=interplanar spacing;and θ=diffraction angle). Herein, interplanar spacings, diffraction angle and overall patternare important for identification of crystal in the X-ray powder diffraction, due to the characteristics of the data. The relative intensity of the peaks should not be strictly interpreted since it may be varied depending on the direction of crystal growth, particle sizes andmeasurement conditions. Thus, in an XRPD pattern, the skilled person may expect to seevariation in the relative intensity of peaks. In addition, the diffraction angles usually meanangles which coincide in the range of 2θ±0.2°. XRPD patterns are typically collected usingCuKα1-radiation. Suitably, the XRPD patterns as described below were collected using CuKα1-radiation. Exemplary methods are described in the Examples section hereof.Thus, in one embodiment, the solid crystalline form of the substance of the invention which isthe fumaric acid addition salt of the compound of formula (I) has an XRPD pattern containingthree, four, five, six, seven, eight, nine or ten peaks selected from (± 0.2) 9.3, 10.5, 17.7, 18.0,18.5, 18.8, 20.4, 23.2, 23.7 and 24.0 degrees 2-theta. Additional XRPD pattern peaks for thesolid crystalline form of the substance may be selected from (± 0.2) 16.5, 20.0, 20.9, 21.1, and22.7 degrees 2-theta. Thus, suitably the solid crystalline form of the substance which is the fumaric acid addition salt of the compound of formula (I) has an XRPD pattern containingthree, four, five, six, seven, eight, nine or ten peaks selected from (± 0.2) 9.3, 10.5, 17.7, 18.0,18.5, 18.8, 20.4, 23.2, 23.7 and 24.0 degrees 2-theta and one, two, three, four or five peaksselected from (± 0.2) 16.5, 20.0, 20.9, 21.1, and 22.7 degrees 2-theta.Suitably, the solid crystalline form of the substance of the invention which is the fumaric acidaddition salt of the compound of formula (I) has the X-ray powder diffraction patternsubstantially as shown in Fig.4A, such as the X-ray powder diffraction pattern comprises thesame characteristic peaks as shown in Fig.4A. Preferably, the X-ray powder diffraction patterncomprises the same characteristic peaks as shown in Fig. 4A under the same experimentalconditions. More preferably, the X-ray powder diffraction pattern is as shown in Fig. 4A.AGO-P3287PCT SpecificationIn an embodiment, the solid crystalline form of the substance of the invention which is the fumaric acid addition salt of the compound of formula (I) has unit cell dimensions of about10.46 Å, about 12.77 Å, about 16.09 Å, α angle of about 71.0°, β angle of about 71.5°, and γangle of about 66.7°, such as unit cell dimensions of 10.46 (± 0.5) Å, 12.77 (± 0.5) Å, 16.09 (±0.5) Å, α angle of 71.0 (± 0.5)°, β angle of 71.5 (± 0.5)°, and γ angle of 66.7 (± 0.5)°, such10.46 (± 0.2) Å, 12.77 (± 0.2) Å, 16.09 (± 0.2) Å, α angle of 71.0 (± 0.2)°, β angle of 71.5 (±0.2)°, and γ angle of 66.7 (± 0.2)°, in particular 10.46 (± 0.1) Å, 12.77 (± 0.1) Å, 16.09 (± 0.1)Å, α angle of 71.0 (± 0.1)°, β angle of 71.5 (± 0.1)°, and γ angle of 66.7 (± 0.1)°, moreparticularly, 10.46 Å, 12.77 Å, 16.09 Å, α angle of 71.0°, β angle of 71.5°, and γ angle of 66.7°.In a second embodiment, the solid crystalline form of the substance of the invention which isthe succinic acid addition salt of the compound of formula (I) has an XRPD pattern containingthree, four, five, six, seven, eight, nine or ten peaks selected from (± 0.2) 4.1, 8.1, 11.7, 12.3,12.8, 13.4, 14.4, 16.3, 17.7 and 23.4 degrees 2-theta. Additional XRPD pattern peaks for thesolid crystalline form of the substance may be selected from (± 0.2) 9.9, 10.8, 11.0, 17.5, 18.2,18.8, 19.1, 19.3, 19.5, 19.7, 20.1, 20.6, 21.1, 21.4, 22.5, 22.9, 23.9, 24.4, 24.8, 25.1, 25.4,25.8, 26.2, 26.6, 27.1, 27.5, 28.5, 28.8, 29.1, 29.6, 29.9 and 30.3 degrees 2-theta. Thus,suitably the solid crystalline form of the substance which is the succinic acid addition salt ofthe compound of formula (I) has an XRPD pattern containing three, four, five, six, seven, eight,nine or ten peaks selected from (± 0.2) 9.9, 10.8, 11.0, 17.5, 18.2, 18.8, 19.1, 19.3, 19.5, 19.7,20.1, 20.6, 21.1, 21.4, 22.5, 22.9, 23.9, 24.4, 24.8, 25.1, 25.4, 25.8, 26.2, 26.6, 27.1, 27.5,28.5, 28.8, 29.1, 29.6, 29.9 and 30.3 degrees 2-theta and one, two, three, four or five peaksselected from (± 0.2) 4.1, 8.1, 11.7, 12.3, 12.8, 13.4, 14.4, 16.3, 17.7 and 23.4 degrees 2-theta.Suitably, the solid crystalline form of the substance of the invention which is the succinic acidaddition salt of the compound of formula (I) has the X-ray powder diffraction pattern substantially as shown in Fig.5A, such as the X-ray powder diffraction pattern comprises the same characteristic peaks as shown in Fig.5A. Preferably, the X-ray powder diffraction pattern comprises the same characteristic peaks as shown in Fig.5A under the same experimental conditions. More preferably, the X-ray powder diffraction pattern is as shown in Fig.5A. In a third embodiment, the solid crystalline form of the substance of the invention which is the hydrochloric acid addition salt of the compound of formula (I) has an XRPD pattern containingthree, four, five, six, seven, eight, nine or ten peaks selected from (± 0.2) 4.5, 7.7, 9.2, 15.4,20.6, 22.1, 26.0, 26.3, 27.5 and 28.8 degrees 2-theta. Additional XRPD pattern peaks for thesolid crystalline form of the substance may be selected from (± 0.2) 10.9, 12.6, 12.7, 13.1,AGO-P3287PCT Specification13.4, 14.7, 17.4, 18.9, 23.4, 24.1, 27.0, 27.3, 28.0 and 28.2 degrees 2-theta. Thus, suitablythe solid crystalline form of the substance which is the hydrochloric acid addition salt of thecompound of formula (I) has an XRPD pattern containing three, four, five, six, seven, eight,nine or ten peaks selected from (± 0.2) 10.9, 12.6, 12.7, 13.1, 13.4, 14.7, 17.4, 18.9, 23.4,24.1, 27.0, 27.3, 28.0 and 28.2 degrees 2-theta and one, two, three, four or five peaks selectedfrom (± 0.2) 4.5, 7.7, 9.2, 15.4, 20.6, 22.1, 26.0, 26.3, 27.5 and 28.8 degrees 2-theta.Suitably, the solid crystalline form of the substance of the invention which is the hydrochloricacid addition salt of the compound of formula (I) has the X-ray powder diffraction pattern substantially as shown in Fig.6A, such as the X-ray powder diffraction pattern comprises the same characteristic peaks as shown in Fig.6A. Preferably, the X-ray powder diffraction pattern comprises the same characteristic peaks as shown in Fig.6A under the same experimental conditions. More preferably, the X-ray powder diffraction pattern is as shown in Fig.6A.In an embodiment, the solid crystalline form of the substance of the invention which is thefumaric acid addition salt of the compound of formula (I) is characterised by a differentialscanning calorimetry (DSC) onset temperature of 215.39 (± 0.5) °C, such as 215.39 (± 0.2)°C, in particular 215.39 (± 0.1) °C, more particularly 215.39 °C, for example as shown in Fig. 4E.In an embodiment, the solid crystalline form of the substance of the invention which is thefumaric acid addition salt of the compound of formula (I) is characterised by a DSC peak temperature of 221.50 (± 0.5) °C, such as 221.50 (± 0.2) °C, in particular 221.50 (± 0.1) °C, more particularly 221.50 °C, for example as shown in Fig.4E.In an embodiment, the solid crystalline form of the substance of the invention which is thefumaric acid addition salt of the compound of formula (I) is characterised by a DSC peak withnormalized integral of -180.92 (± 0.5) J / g, such as -180.92 (± 0.2) J / g, in particular -180.92 (±0.1) J / g, more particularly -180.92 J / g, for example as shown in Fig.4E.Suitably, the solid crystalline form of the substance of the invention which is the fumaric acidaddition salt of the compound of formula (I) is characterised by a DSC thermogramsubstantially as shown in Fig.4E, such as the DSC thermogram is as shown in Fig.4E.In an embodiment, the solid crystalline form of the substance of the invention which is thefumaric acid addition salt of the compound of formula (I) is characterised by a thermogravimetric analysis (TGA) mass loss with onset at 213.28 (± 0.5) °C, such as 213.28AGO-P3287PCT Specification(± 0.2) °C, in particular 213.28 (± 0.1) °C, more particularly 213.28 °C, for example as shown in Fig.4E.Suitably, the solid crystalline form of the substance of the invention which is the fumaric acidaddition salt of the compound of formula (I) is characterised by a thermogravimetric analysis(TGA) thermogram substantially as shown in Fig.4E.An embodiment of the substance of the invention is referred to in the Examples section hereofas “crystalline Form 1 of the fumaric acid addition salt of the compound of formula (I)”.In an embodiment, the solid crystalline form of the substance of the invention which is thesuccinic acid addition salt of the compound of formula (I) is characterised by a differentialscanning calorimetry (DSC) onset temperature of 160.6 (± 0.5) °C, such as 160.6 (± 0.2) °C,in particular 160.6 (± 0.1) °C, more particularly 160.6 °C, for example as shown in Fig. 5C.In an embodiment, the solid crystalline form of the substance of the invention which is thesuccinic acid addition salt of the compound of formula (I) is characterised by a DSC peaktemperature of 165.4 (± 0.5) °C, such as 165.4 (± 0.2) °C, in particular 165.4 (± 0.1) °C, moreparticularly 165.4 °C, for example as shown in Fig.5C.In an embodiment, the solid crystalline form of the substance of the invention which is thesuccinic acid addition salt of the compound of formula (I) is characterised by a DSC peak withnormalized integral of -83 (± 0.5) J / g, such as -83 (± 0.2) J / g, in particular -83 (± 0.1) J / g, moreparticularly -83 J / g, for example as shown in Fig.5C.Suitably, the solid crystalline form of the substance of the invention which is the succinic acidaddition salt of the compound of formula (I) is characterised by a DSC thermogram substantially as shown in Fig.5C, such as the DSC thermogram is as shown in Fig.5C.In an embodiment, the solid crystalline form of the substance of the invention which is thesuccinic acid addition salt of the compound of formula (I) is characterised by a thermogravimetric analysis (TGA) mass loss with onset at 190.9 (± 0.5) °C, such as 190.9 (± 0.2) °C, in particular 190.9 (± 0.1) °C, more particularly 190.9 °C, for example as shown in Fig. 5C.AGO-P3287PCT SpecificationSuitably, the solid crystalline form of the substance of the invention which is the succinic acidaddition salt of the compound of formula (I) is characterised by a thermogravimetric analysis (TGA) thermogram substantially as shown in Fig.5C.An embodiment of the substance of the invention is referred to in the Examples section hereofas “crystalline Form 1 of the succinic acid addition salt of the compound of formula (I)”.In respect of the hydrochloric acid addition salt, the DSC trace as shown in Fig.6C comprisesa first broad endotherm containing two events, with an onset temperature of 36.9 °C and afirst peak centred at 62.4 °C (heat flow for this event: -79.8 J / g), and a second peak centredat 103.9 °C (heat flow for this event: -14.5 J / g). The total heat flow for the first broad endothermis -94.3 J / g.The DSC shown in Fig. 6C further comprises a second broad endotherm containing twoevents, with an onset temperature of 154.4 °C and a first peak centred at 178.0 °C (heat flowfor this event: -43.0 J / g) and a second peak centred at 194.1 °C (heat flow for this event: -39.8 J / g). The total heat flow for the second broad endotherm is -82.8 J / g.Thus, in an embodiment, the solid crystalline form of the substance of the invention which isthe hydrochloric acid addition salt of the compound of formula (I) is characterised by differentialscanning calorimetry (DSC) onset temperatures of 36.9 and 154.4 (± 0.5) °C, such as 36.9and 154.4 (± 0.2) °C, in particular 36.9 and 154.4 (± 0.1) °C, more particularly 36.9 and154.4 °C, for example as shown in Fig. 6C.In an embodiment, the solid crystalline form of the substance of the invention which is thehydrochloric acid addition salt of the compound of formula (I) is characterised by DSC peaktemperatures of 62.4, 103.9, 178.0 and 194.1 (± 0.5) °C, such as 62.4, 103.9, 178.0 and 194.1(± 0.2) °C, in particular 62.4, 103.9, 178.0 and 194.1 (± 0.1) °C, more particularly 62.4, 103.9, 178.0 and 194.1 °C, for example as shown in Fig.6C.In an embodiment, the solid crystalline form of the substance of the invention which is thehydrochloric acid addition salt of the compound of formula (I) is characterised by a differential scanning calorimetry (DSC) onset temperature of 36.9 (± 0.5) °C, such as 36.9 (± 0.2) °C, in particular 36.9 (± 0.1) °C, more particularly 36.9 °C, and DSC peak temperatures of 62.4 and 103.9 (± 0.5) °C, such as 62.4 and 103.9 (± 0.2) °C, in particular 62.4 and 103.9 (± 0.1) °C, more particularly 62.4 and 103.9 °C for example as shown in Fig.6C.AGO-P3287PCT SpecificationIn an embodiment, the solid crystalline form of the substance of the invention which is thehydrochloric acid addition salt of the compound of formula (I) is characterised by a differential scanning calorimetry (DSC) onset temperature of 154.4 (± 0.5) °C, such as 154.4 (± 0.2) °C, in particular 154.4 (± 0.1) °C, more particularly 154.4 °C, and DSC peak temperatures of 178.0 and 194.1 (± 0.5) °C, such as 178.0 and 194.1 (± 0.2) °C, in particular 178.0 and 194.1 (± 0.1) °C, more particularly 178.0 and 194.1 °C for example as shown in Fig.6C.In an embodiment, the solid crystalline form of the substance of the invention which is thehydrochloric acid addition salt of the compound of formula (I) is characterised by a DSC peakwith normalized integral of -79.8 and -14.5 (± 0.5) J / g, such as -79.8 and -14.5 (± 0.2) J / g, inparticular -79.8 and -14.5 (± 0.1) J / g, more particularly -79.8 and -14.5 J / g, for example asshown in Fig.6C. In an embodiment, the solid crystalline form of the substance of the inventionwhich is the hydrochloric acid addition salt of the compound of formula (I) is characterised bya DSC peak with normalized integral of -94.3 J / g.In an embodiment, the solid crystalline form of the substance of the invention which is thehydrochloric acid addition salt of the compound of formula (I) is characterised by a DSC peakwith normalized integral of -43.0 and -39.8 (± 0.5) J / g, such as -43.0 and -39.8 (± 0.2) J / g, inparticular -43.0 and -39.8 (± 0.1) J / g, more particularly -43.0 and -39.8 J / g, for example asshown in Fig.6C. In an embodiment, the solid crystalline form of the substance of the inventionwhich is the hydrochloric acid addition salt of the compound of formula (I) is characterised bya DSC peak with normalized integral of -82.8 J / g.In an embodiment, the solid crystalline form of the substance of the invention which is thehydrochloric acid addition salt of the compound of formula (I) is characterised by DSC peakswith normalized integrals of -94.3 J / g and -82.8 J / g.Suitably, the solid crystalline form of the substance of the invention which is the hydrochloricacid addition salt of the compound of formula (I) is characterised by a DSC thermogram substantially as shown in Fig.6C, such as the DSC thermogram is as shown in Fig.6C.In an embodiment, the solid crystalline form of the substance of the invention which is thehydrochloric acid addition salt of the compound of formula (I) is characterised by athermogravimetric analysis (TGA) with continual mass loss upon heating prior todecomposition with onset at 259.1 (± 0.5) °C, such as 259.1 (± 0.2) °C, in particular 259.1 (±0.1) °C, more particularly 259.1 °C, for example as shown in Fig.6C.AGO-P3287PCT SpecificationSuitably, the solid crystalline form of the substance of the invention which is the hydrochloricacid addition salt of the compound of formula (I) is characterised by a thermogravimetric analysis (TGA) thermogram substantially as shown in Fig.6C.An embodiment of the substance of the invention is referred to in the Examples section hereofas “crystalline Pattern 1 of the hydrochloric acid addition salt of the compound of formula (I)”. Pharmaceutical Compositions In any one of the below embodiments: in one embodiment, the substance of the invention is the fumaric acid addition salt of compound of formula (I). In another embodiment, the substance of the invention is the succinic acid addition salt of the compound of formula (I). In another embodiment, the substance of the invention is the hydrochloric acid addition salt of the compound of formula (I). In one embodiment, the present invention provides a pharmaceutical composition comprisingthe substance of the invention in combination with one or more pharmaceutically acceptablediluents or carriers. The pharmaceutical composition may, for example, be adapted for oraladministration or administration by inhalation.The pharmaceutical compositions may conveniently be administered in unit dosage form andmay be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, PA., (1985). The compositions may also conveniently be administered in unit dosageform, multiple unit dosage form or reservoir dosage form.In one embodiment, the substance of the invention (for example, formulated as a pharmaceutical composition as defined herein) is administered by the oral route. Thus, in one embodiment there is provided a pharmaceutical composition comprising the substance of theinvention optionally in combination with one or more pharmaceutically acceptable diluents,excipients, or carriers, wherein the pharmaceutical composition is suitable for oraladministration. The pharmaceutical composition comprising the substance of the invention can be formulatedfor oral administration as a liquid or solid, e.g. as a syrup, suspension, emulsion, tablet,capsule or lozenge.AGO-P3287PCT SpecificationA liquid formulation suitable for oral administration will generally consist of a suspension orsolution of the substance of the invention in a suitable liquid carrier(s). Suitably the carrier isnon-aqueous e.g. polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and / or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.Alternatively, the substance of the invention (for example, formulated as a pharmaceuticalcomposition as defined herein) is administered by inhalation such as topically to the lung ornose, particularly, topically to the lung. Thus, in an embodiment there is provided apharmaceutical composition comprising the substance of the invention optionally incombination with one or more topically acceptable diluents, excipients or carriers wherein thepharmaceutical composition is suitable administration by inhalation. Suitably the pharmaceutically acceptable (e.g. topically acceptable) diluent is an aqueousdiluent i.e. it is, or comprises, water.The pharmaceutical composition comprising the substance of the invention can be formulatedfor administration by inhalation as a liquid or solid and presented e.g. as a capsule,suspension, solution or powder.Topical administration by inhalation may be achieved by use of a pressurised aerosolformulation. Aerosol formulations typically comprise the active ingredient suspended ordissolved in a suitable aerosol propellant, such as a hydrofluorocarbon (HFC) orhydrofluoroolefin (HFO) propellant. Suitable HFC propellants include tetrafluoroethane (HFC-134a), heptafluoropropane (HFC-227) and 1,1-difluoroethane (HFC-152a). Suitably HFOpropellants include 1,3,3,3-tetrafluoropropene (HFO1234ze). The propellant typicallycomprises 40%-99.5%, e.g. 40%-90%, by weight of the total inhalation composition. Theformulation may comprise excipients including co-solvents (e.g. ethanol) and surfactants (e.g. lecithin, sorbitan trioleate and the like). Other possible excipients include polyethylene glycol,polyvinylpyrrolidone, glycerine and the like. Aerosol formulations are packaged in canistersand a suitable dose is delivered by means of a metering valve (e.g. as supplied by Bespak, Valois or 3M or alternatively by Aptar, Coster or Vari).AGO-P3287PCT SpecificationTopical administration by inhalation may also be achieved by use of a non-pressurisedformulation such as an aqueous solution or suspension.Thus, a pharmaceutical composition comprising the substance of the present disclosure mayalso be administered by inhalation using a nebuliser inhaler. Such nebuliser devices typically produce a stream of high velocity air that causes the pharmaceutical composition to spray as a mist that is carried into the patient's respiratory tract. Accordingly, when formulated for usein a nebuliser inhaler, the therapeutic agent can be dissolved in a suitable carrier to form asolution. Alternatively, the therapeutic agent can be micronized or nano-milled and combined with a suitable carrier to form a suspension. The formulation may comprise excipients such as water, buffers, tonicity adjusting agents (such as sodium chloride), pH adjusting agents, viscosity modifiers, surfactants (such as Lipoid S100) and co-solvents (such as ethanol or propylene glycol). A nebuliser inhaler may be hand-held and portable or for home or hospitaluse (i.e. non-portable). An example of such a device is a RESPIMAT inhaler.Suspension liquid and aerosol formulations (whether pressurised or unpressurised) will typically contain the compound of the invention in finely divided form, for example having a mass median aerodynamic diameter (MMAD) with a D50 of 0.5-10 μm e.g. around 1-6^m or around 1-5 μm.Administration by inhalation may also be achieved by use of a dry-powder formulation. A drypowder formulation will contain the substance of the invention in particulate form, typically withan mass median aerodynamic diameter (MMAD) of 1-10 µm or a D50 of 0.5-10 μm e.g. around1-5 μm. Powders of the substance of the invention in particulate form may be prepared by amicronisation process or similar size reduction process. Micronisation may be performed andmeasured as described above. The formulation will typically contain a pharmaceutically acceptable (e.g. a topically acceptable) diluent such as lactose, glucose or mannitol(preferably lactose), usually of comparatively large particle size e.g. an MMAD of 50 µm ormore, e.g.100 µm or more or a D50 of 40-150 µm. As used herein, the term “lactose” refers to a lactose-containing component, including α-lactose monohydrate, β-lactose monohydrate, α- lactose anhydrous, β-lactose anhydrous and amorphous lactose. Lactose components may be processed by micronisation, sieving, milling, compression, agglomeration or spray drying. Commercially available forms of lactose in various forms are also encompassed, for example Lactohale®(inhalation grade lactose; DFE Pharma), InhaLac®70 (sieved lactose for dry powder inhaler; Meggle), Pharmatose®(DFE Pharma) and Respitose®(sieved inhalation grade lactose; DFE Pharma) products. In one embodiment, the lactose component is selected from the group consisting of α-lactose monohydrate, α-lactose anhydrous and amorphousAGO-P3287PCT Specificationlactose. Preferably, the lactose is α-lactose monohydrate. Powders for inhalation can include spray dried powders (including blends of such). For some delivery devices the powders arepresented in a capsule.Dry powder formulations may also contain other excipients such as sodium stearate, calcium stearate or magnesium stearate. A dry powder formulation is typically delivered using a dry powder inhaler (DPI) device. Example dry powder delivery systems include SPINHALER, DISKHALER, TURBOHALER, DISKUS, SKYEHALER, ACCUHALER and CLICKHALER. Further examples of dry powder delivery systems include ECLIPSE, NEXT, ROTAHALER, HANDIHALER, AEROLISER, CYCLOHALER, BREEZHALER / NEOHALER, MONODOSE, FLOWCAPS, TWINCAPS, X- CAPS, TURBOSPIN, ELPENHALER, MIATHALER, TWISTHALER, NOVOLIZER, PRESSAIR, ELLIPTA, ORIEL dry powder inhaler, MICRODOSE, PULVINAL, EASYHALER, ULTRAHALER, TAIFUN, PULMOJET, OMNIHALER, GYROHALER, TAPER, CONIX, XCELOVAIR and PROHALER. A composition presented in the form of a capsule can be prepared using routine encapsulationprocedures, e.g. powders containing the active ingredient (such as the substance of theinvention) can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), e.g. aqueous gums, celluloses, silicates or oils and the dispersion or suspensionthen filled into a soft gelatin capsule. Capsules can also be made from HPMC.Liquid suspension and aerosol formulations (whether pressurised or unpressurised) willtypically contain the substance of the invention in particulate form, for example with a D50 of0.5 to 10 μm, suitably around 1 to 5 μm, such as 1 to 2 μm. Suitably, the substance of theinvention in particulate form has a D10 of 0.2 to 1 μm, such as 0.2 to 0.5 μm. Suitably, thesubstance of the invention in particulate form has a D90 of 2 to 6 μm such as 3 to 4 μm. Theparticulate form of the substance may, for example, be a micronised form. Micronisation may be performed using a jet mill such as those manufactured by Hosokawa Alpine. The resultant particle size distribution may be measured using laser diffraction (e.g. with a Malvern Mastersizer 2000S instrument). Particle size distributions may be represented using D10, D50 and D90 values. The D50 median value of particle size distributions is defined as the particle size in microns that divides the distribution in half. The measurement derived from laser diffraction is more accurately described as a volume distribution and consequently the D50value obtained using this procedure is more meaningfully referred to as a Dv50value (medianAGO-P3287PCT Specificationfor a volume distribution). As used herein Dv values refer to particle size distributions measured using laser diffraction. Similarly, D10and D90values, used in the context of laser diffraction, are taken to mean Dv10and Dv90values and refer to the particle size whereby 10% of the distribution lies below the D10value, and 90% of the distribution lies below the D90value, respectively. According to one embodiment of the invention there is provided a pharmaceutical compositioncomprising the substance of the invention as an aqueous suspension i.e. in particulate formsuspended in an aqueous medium or as an aqueous solution. The aqueous medium typicallycomprises water and one or more excipients selected from buffers, tonicity adjusting agents(such as sodium chloride), pH adjusting agents, viscosity modifiers, co-solvents (such aspropylene glycol) and surfactants (such as Lipoid S100).Suitably, the aqueous medium comprises at least about 40% water such as at least about 60% water, at least about 80% water, at least about 95% water, or at least about 99% water, such as at least about 99% water. Suitably, when the substance of the invention is administered as an aqueous suspension, thesubstance is in the form of crystalline Form 1 of the fumaric acid addition salt of the compoundof formula (I). Suitably, when the substance of the invention is administered as an aqueoussuspension, the substance is in the form of crystalline Form 1 of the succinic acid addition saltof the compound of formula (I). Suitably, when the substance of the invention is administered as an aqueous suspension, the substance is in the form of crystalline Pattern 1 of thehydrochloric acid addition salt of the compound of formula (I).Thus, according to one embodiment, there is provided a pharmaceutical compositioncomprising the substance of the invention in the form of crystalline Form 1 of the fumaric acidaddition salt of the compound of formula (I), in particulate form suspended in an aqueousmedium. In another embodiment, there is provided a pharmaceutical composition comprisingthe substance of the invention in the form of crystalline Form 1 of the fumaric acid addition saltof the compound of formula (I), dissolved in an aqueous medium.Thus, according to one embodiment, there is provided a pharmaceutical compositioncomprising the substance of the invention in the form of crystalline Form 1 of the succinic acidaddition salt of the compound of formula (I), in particulate form suspended in an aqueousmedium. In another embodiment, there is provided a pharmaceutical composition comprisingAGO-P3287PCT Specificationthe substance of the invention in the form of crystalline Form 1 of the succinic acid additionsalt of the compound of formula (I), dissolved in an aqueous medium.Thus, according to one embodiment, there is provided a pharmaceutical compositioncomprising the substance of the invention in the form of crystalline Pattern 1 of the hydrochloricacid addition salt of the compound of formula (I), in particulate form suspended in an aqueousmedium. In another embodiment, there is provided a pharmaceutical composition comprisingthe substance of the invention in the form of crystalline Pattern 1 of the hydrochloric acidaddition salt of the compound of formula (I), dissolved in an aqueous medium.The pharmaceutical compositions according to the present invention may also include variousother ingredients, including, but not limited to, tonicity agents, buffers, surfactants, stabilizing polymer, preservatives, co-solvents and viscosity building agents. Suitable pharmaceuticalcompositions of the present invention include the substance of the invention formulated witha tonicity agent and a buffer. The pharmaceutical compositions of the present invention may further optionally include a surfactant and / or a palliative agent and / or a stabilizing polymer. Various tonicity agents may be employed to adjust the tonicity of the composition. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, simple sugars such as dextrose, fructose, galactose, and / or simply polyols such as the sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, and hydrogenated starch hydrolysates may be added to the composition to approximate physiological tonicity. Such an amount of tonicity agent will vary, depending on the particular agent to be added. In general, however, the compositions will have a tonicity agent in an amount sufficient to cause the final composition to have an acceptable osmolality (generally about 150-450 mOsm, preferably 250-350 mOsm and most preferably at approximately 290 mOsm). In general, the tonicity agents of the invention will be present in the range of 2 to 4% w / w. Preferred tonicity agents of the invention include the simple sugars or the sugar alcohols, such as D-mannitol. An appropriate buffer system (e.g. sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid) may be added to the compositions to prevent pH drift under storage conditions. The particular concentration will vary, depending on the agent employed. The particular pH will depend on the route of administration. Preferably, for aqueous formulations intended for administration by inhalation, the buffer will be chosen to maintain a target pH within the range of pH 2 to 4, and more preferably to a target pH of pH 2.5-3.5 e.g.2.9-3.1.AGO-P3287PCT SpecificationSurfactants may optionally be employed to deliver higher concentrations of substance of thepresent invention. The surfactants function to solubilise the substance and stabilise colloiddispersion, such as micellar solution, microemulsion, emulsion and suspension. Examples of surfactants which may optionally be used include polysorbate, poloxamer, polyosyl 40 stearate, polyoxyl castor oil, tyloxapol, Triton, and sorbitan monolaurate. Preferred surfactants to be employed in the invention have a hydrophile / lipophile / balance "HLB" in the range of 12.4to 13.2, such as TritonX114 and tyloxapol.In further embodiments, the substance of the invention may be administered by other routes,such as parenteral or ocular routes. A pharmaceutical composition comprising the substanceof the invention may, for example, be adapted for parenteral administration or ocular administration. Pharmaceutical compositions for parenteral and ocular administration include aqueous formulations discussed above with adaptations appropriate for the route. For example, parenteral compositions will typically have an approximately neutral pH (e.g. pH 7.0- 7.4) and have an osmolarity in the range 100-300 mOsmol / L. The composition may contain from 0.1% to 100% by weight, for example from 10 to 60% by weight, of the substance of the invention, depending on the method of administration. The composition may contain from 0% to 99% by weight, for example 40% to 90% by weight, ofthe carrier, depending on the method of administration. In some cases, the formulation maycontain 100% by weight of the substance of the invention. The composition may contain from0.05mg to 1000mg, for example from 1.0 mg to 500 mg, such as from 1.0 mg to 50 mg, e.g. about 10 mg of the substance of the invention, depending on the method of administration. The composition may contain from 50 mg to 1000 mg, for example from 100mg to 400mg ofthe carrier, depending on the method of administration. The dose of the substance used in thetreatment of the aforementioned diseases and disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, asa general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 500 mg,such as from 1.0 mg to 50 mg, e.g. about 10 mg and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for anumber of weeks, months or years.The active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.AGO-P3287PCT SpecificationSecond or further active ingredientsIn a further embodiment, the substance of the invention is administered in combination with asecond or further active ingredient. Administration may be simultaneous, separate or sequential. Suitably, the second or further active ingredient is an agent useful for the treatmentof disease or pathological disorder that can be ameliorated by inhibition of ALK5 wherein thedisease or pathological disorder is defined elsewhere herein. Thus, the invention alsoprovides a combination therapy comprising the substance according to the invention and atherapeutic agent used for the prevention or treatment of a disease or pathological disorder that can be ameliorated by inhibition of ALK5, such as a disease selected from the group consisting of gastrointestinal diseases, lung diseases, fibrotic diseases, fibroproliferative disorders, cancer and graft vs. host disease (GVHD). For example, the second or furtheractive ingredient is an agent useful for the treatment of idiopathic pulmonary fibrosis (IPF) e.g.is selected from nintedanib and pirfenidone.The substance of the invention may be co-formulated with a second or further active ingredientor the second or further active ingredient may be formulated to be administered separately bythe same or a different route. For example, the substance of the invention may beadministered to patients already being treated systemically with the second or further activeingredient.In a further embodiment the invention provides a kit of parts comprising: (a) a pharmaceuticalcomposition comprising the substance of the invention optionally in combination with one ormore diluents, excipients, or carriers; (b) a pharmaceutical composition comprising a secondactive ingredient optionally in combination with one or more diluents, excipients, or carriers;(c) optionally one or more further pharmaceutical compositions each comprising a third orfurther active ingredient optionally in combination with one or more diluents, excipients, orcarriers and (d) instructions for the administration of the pharmaceutical compositions to a subject in need thereof. Medical uses The present invention provides the substance of the invention for use as a pharmaceutical.In particular, the invention provides a substance of the invention for use in the treatment orprevention of a disease or pathological disorder susceptible to amelioration by inhibition ofALK5. The invention also provides use of a substance of the invention the manufacture of amedicament for the treatment and / or prevention of a disease or pathological disorderAGO-P3287PCT Specificationsusceptible to amelioration by inhibition of ALK5. The invention also provides a method oftreating or preventing a disease or pathological disorder susceptible to amelioration byinhibition of ALK5 comprising the administration to a subject in need thereof a substance ofthe invention. In one embodiment, the substance of the invention is the fumaric acid addition salt of compound of formula (I). In another embodiment, the substance of the invention is the succinic acid addition salt of the compound of formula (I). In another embodiment, the substance of the invention is the hydrochloric acid addition salt of the compound of formula (I). The term "treatment" or "treating" as used herein includes the control, mitigation, reduction, or modulation of the disease state or its symptoms. The term "prevention" is used herein to mean preventing the disease state or disorder, or its symptoms, in a subject. Or preventing recurrence of symptoms of a disease or disorder in an afflicted subject and is not limited to complete prevention of an affliction. A subject will typically be a subject in need of treatment or prevention according to the invention. Suitably the subject is a human.Such a disease or pathological disorder may for example be selected from the groupconsisting of gastrointestinal diseases, lung diseases, fibrotic diseases, fibroproliferative disorders, cancer and graft vs. host disease (GvHD).The term “gastrointestinal diseases” refers to diseases which affect the gastro-intestinal tract,specifically the small and / or large intestine. The small intestine refers to the duodenum, jejunum, and ileum and the large intestine refers to the cecum (including the appendix), colon,rectum, and anal canal. In particular, the term gastrointestinal diseases includes inflammatorybowel diseases (IBD), post-radiation enteritis, complicated celiac disease and intestinalfibrosis. The term “inflammatory bowel diseases” or “IBD” refers to Crohn's disease (CD)(which includes inflammatory CD, fibrostenosing CD (FSCD), fistulizing CD, and perianal CD)and ulcerative colitis (UC). In particular, the term IBD includes fibrostenosing CD.The term “lung diseases” includes chronic obstructive pulmonary disease (COPD) and asthma. Also included are fibrotic lung diseases (discussed further below), interstitial lungdiseases (discussed further below), pulmonary arterial hypertension and lung cancer.AGO-P3287PCT SpecificationThe term “fibroproliferative disorders” refers to autoimmune diseases associated with fibroproliferative characteristics such as systemic lupus erythematosus (SLE) and rheumatoid arthritis and refers to myelofibrosis. The term “interstitial lung diseases” refers to lung disease of the pulmonary interstitium, e.g.as described in more detail in Wijsenbeek et al., (2022). Most interstitial lung diseases arecharacterised by inflammation or fibrosis of the interstitial space, the primary consequence of which is impaired gas exchange, resulting in breathlessness, diminished exercise tolerance and decreased quality of life. Specific example diseases of this type include sarcoidosis,systemic sclerosis associated interstitial lung disease, hypersensitivity pneumonitis,rheumatoid arthritis associated lung fibrosis and idiopathic pulmonary fibrosis.The term “fibrotic disease(s)” refers to diseases characterized by excessive scarring due toexcessive production, deposition, and contraction of extracellular matrix, and that are associated with the abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin,cornea, retina, musculoskeletal and digestive tract. The term fibrotic diseases includes (i)fibrosis of the digestive tract or intestinal fibrosis, such as fibrostenosing Crohn’s disease(FSCD); (ii) hepatic fibrosis, also known as liver fibrosis, such as cirrhosis, alcohol inducedliver fibrosis, toxic / drug induced liver fibrosis, hemochromatosis, non-alcoholic steatohepatitis(NASH) (in particular F4 NASH), biliary duct injury, primary biliary cirrhosis, primary sclerosing cholangitis, infection induced liver fibrosis, viral induced liver fibrosis, and autoimmune hepatitis; (iii) fibrotic skin diseases or fibrotic diseases with a skin component such as scleroderma, nephrogenic fibrosing dermopathy, mixed connective tissue disease,scleromyxedema, scleredema, and eosinophilic fasciitis; (iv) fibrotic renal diseases such asglomerulonephritis (GN) (e.g. mesangial proliferative GN, immune GN and crescentic GN), diabetic nephropathy, renal interstitial fibrosis and renal fibrosis in transplant patients; (v) fibrotic eye diseases such as dry eyes, age-related macular degeneration, scarring of the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy; and (vi) fibrotic lung diseases such as idiopathic pulmonary fibrosis, and upper airway stenosis including idiopathic subglottic stenosis, iatrogenic laryngotracheal stenosis, and autoimmune upper airway stenosis. The disease “non-alcoholic steatohepatitis (NASH)” is also known as metabolic dysfunction- associated steatohepatitis (MASH); the terms are interchangeable.AGO-P3287PCT SpecificationThe term “cancer” includes cancer of the breast, colon (including colorectal cancer),oesophagus, stomach, lung (including non-small cell lung cancer), pancreas, skin, prostate,liver (including hepatocellular carcinoma) and brain (including meningioma).In particular, the substance of invention is provided for use in the treatment or prevention of afibrotic disease selected from intestinal fibrosis, hepatic fibrosis, fibrotic skin diseases, fibrotic renal diseases, fibrotic eye diseases and fibrotic lung diseases. In particular, the fibrotic disease is intestinal fibrosis. In particular, the fibrotic disease is fibrostenosing Crohn’sdisease (FSCD). In particular, the fibrotic disease is a fibrotic lung disease. In particular thefibrotic disease is idiopathic lung fibrosis. Processes In a first aspect, the present invention provides a process for the preparing the substance of the invention, which comprises: a) preparing a solution comprising the compound of formula (I) as defined herein and an acid in a solvent, wherein the acid is selected from the group consisting of fumaric acid,succinic acid and hydrochloric acid; andb) crystallising the substance from the solution.In a second aspect, the present invention provides a process for the preparing the substanceof the invention which is the fumaric acid addition salt of the compound of formula (I), whichcomprises: a) preparing a solution comprising the compound of formula (I) as defined herein andfumaric acid in a solvent; andb) crystallising the substance from the solution. In a third aspect, the present invention provides a process for the preparing the substance ofthe invention which is the succinic acid addition salt of the compound of formula (I), whichcomprises: a) preparing a solution comprising the compound of formula (I) as defined herein and succinic acid in a solvent; and b) crystallising the substance from the solution.AGO-P3287PCT SpecificationIn a fourth aspect, the present invention provides a process for the preparing the substanceof the invention which is the hydrochloric acid addition salt of the compound of formula (I),which comprises: a) preparing a solution comprising the compound of formula (I) as defined herein and hydrochloric acid in a solvent; and b) crystallising the substance from the solution. Suitably, the solvent is selected from the group consisting of acetone, methanol, isopropanol, methyl t-butyl ether, ethanol, methyl ethyl ketone, 2-methyl tetrahydrofuran, tetrahydrofuran,ethyl acetate and N-methyl-2-pyrrolidone. More suitably, the solvent is selected from thegroup consisting of acetone, ethanol, methyl ethyl ketone, 2-methyl tetrahydrofuran, tetrahydrofuran, ethyl acetate and N-methyl-2-pyrrolidone. More suitably, the solvent isselected from the group consisting of acetone, methanol, isopropanol and methyl t-butyl ether.More suitably, the solvent is selected from the group consisting of acetone, isopropanol, methanol, 2-methyl tetrahydrofuran and ethyl acetate. More suitably, the solvent is selectedfrom acetone, 2-methyl tetrahydrofuran and ethyl acetate. More suitably, the solvent isselected from acetone, isopropanol and methanol.Suitably, when the substance of the invention is the fumaric acid addition salt of the compoundof formula (I), the solvent is selected from acetone, isopropanol and methanol. Suitably, whenthe substance of the invention is the succinic acid addition salt of the compound of formula (I),the solvent is ethyl acetate. Suitably, when the substance of the invention is the hydrochloricacid addition salt of the compound of formula (I), the solvent is selected from ethanol, acetone, methyl ethyl ketone, 2-methyl tetrahydrofuran, tetrahydrofuran, ethyl acetate and N-methyl-2- pyrrolidone. The substance of the invention may be prepared from a variety of reaction mixture stoichiometries. Thus the molar ratio of fumaric acid to compound of formula (I) in the solutionin step a) above is in the range 3:1 to 0.5:1, such as 2:1 to 0.8:1, such as 1.8:1 to 0.8:1, inparticular 1.5:1 to 1:1, more particularly 1.5:1 to 1.2, especially 1.5:1. The molar ratio ofsuccinic acid to compound of formula (I) in the solution in step a) above is in the range 3:1 to 0.5:1, such as 2:1 to 0.8:1, such as 1.8:1 to 0.8:1, in particular 1.5:1 to 1:1, more particularly 1.5:1 to 1.2, especially 1.5:1. The molar ratio of hydrochloric acid to compound of formula (I)in the solution in step a) above is in the range 4:1 to 0.95:1, such as 4:1 to 3:1, in particular4:1 to 3.4:1 especially 3.8:1 to 3.4:1.AGO-P3287PCT SpecificationThe substance of the invention is advantageously a crystalline solid form which may displayone or more of the following desirable properties: -High melting point;- Good polymorphic stability upon storage, for example under conditions of elevatedtemperature and presence of moisture; -Good chemical stability upon storage, for example under conditions of elevatedtemperature and presence of moisture; -Relatively low hygroscopicity; and- Adequate solubility in certain pharmaceutically acceptable buffers, particular at acidpH which is a suitable pH for formulations intended for inhalation. Abbreviations Any abbreviations not defined are intended to convey their generally accepted meaning. aq aqueousAUC area under the curveconc. concentrationDME 1,2-dimethoxyethaneDMSO dimethyl sulfoxideDTGS deuterated triglycine sulfateDSC differential scanning calorimetryDVS dynamic vapor sorptioneq equivalentsEt2O diethyl etherEtOH ethanolExp experimentEvap evaporation1H-NMR proton nuclear magnetic resonance (spectroscopy)HPLC high performance liquid chromatographyi-BuOH iso-butanol (2-methyl-1-propanol)IPA iso-propyl alcohol (2-propanol)K2EDTA dipotassium ethylenediaminetetraacetic acid2-ME 2-methoxyethanolMeCN acetonitrilemin minute(s)MTBE methyl tert-butyl etherno. numberAGO-P3287PCT Specificationppm parts per millionPrOAc propyl acetateRH relative humidityRSD relative standard deviationRT room temperatureRV reverse phasetemp temperatureTGA thermo-gravimetric analysisTHF tetrahydrofuranvol volume(s)SC single crystalTBME tert-butyl methyl ethersec second(s)VT variable temperatureXRPD x-ray powder diffraction (crystallography)ExamplesGeneral Methods for Examples 1 to 8X-ray Powder Diffraction (XRPD): Powder diffraction pattern was acquired on a Bruker D8 Advance Series 2Theta / Theta powder diffraction system using CuKα1-radiation in transmission geometry. The system is equipped with a VÅNTEC-1 single photon counting PSD, a Germanium monochromator, a ninety positions auto changer sample stage, fixed divergenceslits and a radial soller. Programs used: Data collection with DIFFRAC plus XRD CommanderV.2.5.1, and evaluation with EVA V.14.0.0.0 (Bruker-AXS 1996-2007). The samples weremeasured at room temperature in a range from 4˚ to 40˚ in 2θ in a 0.5 hours measurementusing an angular step of 0.049˚ and a time per step of 2787 s.Differential Scanning Calorimetry (DSC): Approximately 1-4 mg of sample were weighed (using a MX5 Mettler Toledo microbalance) into 40 μL aluminium crucibles with a pinhole lid. The samples were heated under dry nitrogen (flow rate: 50 mL / min) at 10 ˚C / min from 30 to300 ˚C. DSC analyses were recorded in a Mettler Toledo DSC822e calorimeter. Programsused: Data collection and evaluation with software STARe. Thermogravimetric analysis (TGA): Approximately 1-4 mg of sample were weighed (using a MX5 Mettler Toledo microbalance) into 40 μL aluminium crucibles with a pinhole lid. TheAGO-P3287PCT Specificationsamples were heated under dry nitrogen (flow rate: 10 mL / min) at 10 ˚C / min from 30 to 300˚C. Thermogravimetric analyses were recorded in a Mettler Toledo TGA / SDTA851 with abalance MT1 type. Programs used: Data collection and evaluation with software STARe.1H NMR Spectroscopy: Approximately 2-5 mg of sample were dissolved in 0.7 mL ofdeuterated solvent (DMSO-d6). Analyses were recorded in a Bruker 300 NMR spectrometer,equipped with a z-gradient 5 mm BBO (Broadband Observe) probe with ATM and anautomatic autosampler. The samples were analysed at room temperature.Dynamic Vapour Sorption (DVS): Approximately 10-20 mg of sample were weighed into 150μL platinum crucibles without lid. The samples of crystalline form 1 of the fumaric acid additionsalt were subjected to a moisture cycle from 10 to 90 and back to 10% relative humidity, in10% steps of 45 minutes, at a constant temperature of 25 ˚C. The samples of amorphous freebase were subjected to a moisture cycle from 10 to 90 and back to 10% relative humidity, in10% steps of variable time to ensure equilibrium during the adsorption stage in each step, ata constant temperature of 25 ˚C. The experiments were performed in a Mettler Toledo TGA / DSC 1 LF instrument equipped with a LF SDTA FRS2 sensor and coupled with a Modular Humidity Generator MHG 32. Data collection and evaluation was done with STARe software.Fourier Transformed Infrared spectroscopy analysis (FTIR): The FTIR spectra were recordedusing a Bruker Alpha spectrometer, equipped with a Bruker Diamond single reflection ATR system, a mid-infrared source as the excitation source and a DTGS detector. The spectra were acquired in 32 scans at a resolution of 4 cm-1in the range of 4000-400 cm-1.Fourier Transformed Raman spectroscopy analysis (FTR): FT-Raman measurements werecarried out on a NXR FT-Raman module added to the Thermo Nicolet FT-IR 5700 Nexus spectrometer equipped with a InGaAs detector, CaF2 beamsplitter and Nd:YVO4 laser operating at 1064 nm.Single Crystal X-ray Crystallography (SCXRD):Data collection: The measured crystals were prepared under inert conditions immersed inperfluoropolyether as protecting oil for manipulation. Crystal structure determination wascarried out using a Rigaku diffractometer equipped with a Pilatus 200K area detector, a Rigaku MicroMax-007HF microfocus rotating anode with MoKα radiation, Confocal Max Flux optics and an Oxford Cryosystems low temperature device Cryostream 700 plus (T = -173 °C). Full-sphere data collection was used with ω and φ scans.AGO-P3287PCT SpecificationPrograms used: Data collection and reduction with CrysAlisPro 1.171.39.12b V / .60A (RigakuOD, 2015) and absorption correction with Scale3 Abspack scaling algorithm. Empiricalabsorption correction using spherical harmonics implemented in Scale3 Abspack scaling algorithm.Structure solution and refinement: Crystal structure solution was achieved using directmethods as implemented in SHELXT (Sheldrick, 2015) and visualized using the programSHELXe (Huebschle et al., 2011). Missing atoms were subsequently located from differenceFourier synthesis and added to the atom list. Least-squares refinement on F2 using allmeasured intensities was carried out using the program SHELXL (Sheldrick, 2014). All non-hydrogen atoms were refined including anisotropic displacement parameters. General Methods for Examples 9 to 15 X-ray Powder Diffraction (XRPD): Malvern Panalytical Empyrean Alpha-1 XRPD diffractograms were collected on a Malvern Panalytical Empyrean Alpha-1diffractometer using Cu Ka radiation (45 kV, 40 mA) in reflection geometry with a θ-2θgoniometer fitted with a Ge (111) Johansson monochromator. A programmable divergenceslit in automatic mode with an observed length of 10 mm, with a 10 mm fixed incident beammask were used on the incident beam. A PIXcel1Ddetector, placed on the diffracted beam, was fitted with a programmable anti-scatter slit (in automatic mode with an observed length of10 mm) and 0.02 rad Soller slits. The data were collected with the detector in scanning linemode with an active length of 3.3482°. The software used for data collection was DataCollector and the data analysed and presented using HighScore Plus. Samples were run under ambient conditions as flat plate specimens using powder as received. The sample was prepared on a polished, zero-background (510) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane using 2 seconds per rotation. The details of the standard Pharmorphix data collection method are:Angular range: 2 to 42° 2θStep size: 0.013° 2θCollection time: 44.6 s / stepTotal collection time: 9 min 40 secAGO-P3287PCT SpecificationWhen required other methods for data collection are used with details as follows. The details of the screening data collection method are:Angular range: 2.5 to 32° 2θStep size: 0.013° 2θCollection time: 12.75 s / stepTotal collection time: 2 min 7 secPANalytical EmpyreanXRPD diffractograms were collected on a PANalytical Empyrean diffractometer using Cu Karadiation (45 kV, 40 mA) in transmission geometry with a θ-θ goniometer. A 0.5° slit, 4 mmmask and 0.04 rad Soller slits with a focusing mirror were used on the incident beam. APIXcel3D detector, placed on the diffracted beam, was fitted with a receiving slit and 0.04 radSoller slits. The software used for data collection was Data Collector using X’Pert Operator Interface. The data were analysed and presented using HighScore Plus. Samples were prepared and analysed in a 96 well-plate in transmission mode. X-ray transparent film was used between the sheets of the well-plate and powders (approximately1 – 2 mg) were used as received. The scan mode for a shallow well-plate used the gonio scanaxis, whereas a 2θ scan was utilised for a deeper well-plate. The details of the standard screening data collection method are:Angular range: 2.5 to 32.0° 2θStep size: 0.0130° 2θCollection time: 12.75 s / stepTotal collection time of 2 min 07 secNuclear Magnetic Resonance (NMR):1H NMR spectra were collected on a Bruker 400 MHz instrument equipped with anautosampler and controlled by a Avance NEO nanobay console. Samples were prepared in DMSO-d6 solvent, unless otherwise stated. Automated experiments were acquired using ICONNMR configuration within Topspin software, using standard Bruker-loaded experiments(1H). Experiments were performed at RT unless otherwise stated. Off-line analysis wasperformed using ACD Spectrus Processor.AGO-P3287PCT SpecificationDifferential Scanning Calorimetry (DSC): TA Instruments Discovery DSCDSC data were collected on a TA Instruments Discovery DSC equipped with a 50 positionauto-sampler. Typically, 0.5 - 3 mg of each sample, in a pin-holed aluminium pan, was heatedat 10 °C / min from 25 °C to typically 255 °C. A purge of dry nitrogen at 50 ml / min wasmaintained over the sample. The instrument control software was TRIOS and the data wereanalysed using TRIOS or Universal Analysis. TA Instruments DSC2500DSC data were collected on a TA Instruments DSC2500 equipped with a 54 positionauto-sampler. Typically, 0.5 - 3 mg of each sample, in a pin-holed aluminium pan, was heatedat 10 °C / min from 25 °C to typically 255 °C. A purge of dry nitrogen at 50 ml / min wasmaintained over the sample. Modulated temperature DSC (MDSC) was carried out using the following procedure: First cycle:ramp to 120 °C with an underlying heating rate of 2 °C / min and temperature modulationparameters of ±0.64 °C (amplitude) every 60 seconds (period)isothermal at 120°C for 10 minsequilibrate to -80 °CSecond cycle: isothermal at -80 °C for 10 minsramp to 225 °C with an underlying heating rate of 2 °C / min and temperature modulationparameters of ±0.64 °C (amplitude) every 60 seconds (period)The instrument control software was TRIOS and the data were analysed using TRIOS or Universal Analysis. Thermo-Gravimetric Analysis (TGA): TA Instruments Discovery TGATGA data were collected on a TA Instruments Discovery TGA, equipped with a 25 positionauto-sampler. Typically, 5 - 10 mg of each sample was loaded onto a pre-tared openaluminium standard DSC pan and heated at 10 °C / min from ambient temperature to 350 °C.A nitrogen purge at 25 ml / min was maintained over the sample.The instrument control software was TRIOS and the data were analysed using TRIOS or Universal Analysis.AGO-P3287PCT SpecificationTA Instruments TGA550TGA data were collected on a TA Instruments TGA550, equipped with a 25 positionautosampler. Typically, 5 - 10 mg of each sample was loaded onto a pre-tared pinholedaluminium Tzero DSC pan and heated at 10 °C / min from ambient temperature to 350 °C. Anitrogen purge at 60 ml / min was maintained over the sample.The instrument control software was TRIOS and the data were analysed using TRIOS or Universal Analysis. Gravimetric Vapour Sorption (GVS): SMS DVS Intrinsic Sorption isotherms were obtained using a SMS DVS Intrinsic moisture sorption analyser, controlled by DVS Intrinsic Control software. The sample temperature was maintained at25 °C by the instrument controls. The humidity was controlled by mixing streams of dry andwet nitrogen, with a total flow rate of 200 ml / min. The relative humidity was measured by acalibrated Rotronic probe (dynamic range of 1.0 – 100 %RH), located near the sample. Theweight change, (mass relaxation) of the sample as a function of %RH was constantlymonitored by a microbalance (accuracy ±0.005 mg).Typically, 5 - 30 mg of sample was placed in a tared mesh stainless steel basket underambient conditions. The sample was loaded and unloaded at 40 %RH and 25 °C (typical roomconditions). A moisture sorption isotherm was performed as outlined below (2 scans percomplete cycle). The standard isotherm was performed at 25 °C at 10 %RH intervals over a0 – 90 %RH range. Typically, a double cycle (4 scans) was carried out. Data analysis wascarried out within Microsoft Excel using the DVS Analysis Suite.Table 1: Method parameters for SMS DVS Intrinsic experimentsParameter ValueAdsorption – Scan 1 40 – 90Desorption, Adsorption – Scan 2 90 – 0, 0 – 40Intervals (%RH) 10Number of Scans 4Flow rate (ml / min) 200Temperature (°C) 25Stability (°C / min) 0.2AGO-P3287PCT SpecificationSorption Time (hours) 6 hour time outNumber of cycles 2Hiden IGASorp Sorption isotherms were obtained using a Hiden IGASorp moisture sorption analyser, controlled by Isochema HISorp software. The sample temperature was maintained at 25 °C by a Grant LT ecocool 150 re-circulating water bath. The humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 250 ml.min-1. The relative humiditywas measured by a calibrated Vaisala RH probe (dynamic range of 0 – 95 %RH), located nearthe sample. The weight change, (mass relaxation) of the sample as a function of %RH was constantly monitored by the microbalance (accuracy ±0.001 mg).Typically, 20 – 30 mg of sample was placed in a tared mesh stainless steel basket underambient conditions. The sample was loaded and unloaded at 40 %RH and 25 °C (typical room conditions). A moisture sorption isotherm was performed as outlined below (2 scans giving 1complete cycle). The standard isotherm was performed at 25 °C at 10 %RH intervals over a 0– 90 %RH range. Typically, a double cycle (4 scans) was carried out. Data analysis wascarried out within the Isochema HISorp 2019 software and exported into Microsoft Excel to present accordingly.Table 2: Method parameters for Hiden IGASorp experimentsParameters ValueAdsorption - Scan 1 40 - 90Desorption / Adsorption - Scan 2 90 - 0, 0 - 40Intervals (%RH) 10Number of Scans 2Flow rate (ml / min) 250Temperature (°C) 25Stability (˚C / min) 0.05Minimum Sorption Time (mins) 10Maximum Sorption Time (mins) 360Equilibration Mode Final RateAccuracy (tolerance) + / - 0.001 mg / min (over 600 s)AGO-P3287PCT SpecificationMaterials Unless otherwise stated, all starting materials are commercially available.Preparation of the amorphous form of the compound of formula (I) as free baseThe batches of amorphous form of the compound of formula (i) as free base employed in the studies described in the Examples were prepared either using the preparative method of Example 10 of WO2022 / 069509 or by a similar method. Example 1: First salt form investigationA range of possible salt forms prepared by different methodologies were investigated insearching for a novel solid crystalline form of the compound of formula (I) having enhancedproperties.The amorphous form of the compound of formula (I) as free base (20 mg) was mixed with 1equivalent of a corresponding acid. Crystallization attempts were performed in a set of 7solvents (acetone, acetonitrile, ethyl acetate, tetrahydrofuran, isopropanol, methyl t-butyl etherand n-heptane) according to one of the following crystallization methods as specified in Table3: cooling crystallization; short slurry at high temperature; and long slurry at either roomtemperature or high temperature.General methodologies for cooling crystallization and short slurry at high temperature:The amorphous form of the compound of formula (I) as free base (20 mg, 0.034 mmol) andthe corresponding acid (1 eq., 0.034 mmol) were placed in a tube, and solvent portions wereadded successively at reflux temperature or at a maximum of 75 ˚C up to complete solutionwas reached. If the solid did not dissolve completely, the suspension was slurried for 1 hour at high temperature and 72 hours at room temperature. Solutions were slowly cooled to room temperature to induce crystallization. If no solid was formed at room temperature, the solutionwas kept at 4 ˚C for a day. If no solid was formed at 4 ˚C, the solution was kept at -21 ˚C for aday. If no solid was formed at -21 ˚C, the solvent was left to evaporate at room temperature.The solids obtained were decanted, dried and analysed.General methodologies for long slurry experiments at room temperature or high temperature:The amorphous form of the compound of formula (I) as free base (20 mg, 0.034 mmol) andthe corresponding acid (1 eq., 0.034 mmol) were suspended at room temperature in 2 mL ofAGO-P3287PCT Specificationthe corresponding solvent. The mixture was stirred for 70 hours at room temperature or 18hours at 55 ˚C and afterwards the solid was separated by decantation.All solids obtained using the different crystallization methodologies were characterized byXRPD and classified according to the different XRPD patterns obtained. The results aresummarised in Table 3 below.Table 3: Methodologies Acid Solvent Method ResultCooling Hydrochloric acid AcetonitrileOil crystallization Cooling Hydrochloric acid Ethyl acetateOil crystallization Cooling Hydrochloric acid TetrahydrofuranAmorphous crystallization Cooling Hydrochloric acid AcetoneOil crystallization Solid formed, Cooling Hydrochloric acid Isopropanolwhich turned into crystallization oil Methyl tert-butyl Long slurry, room Amorphous Hydrochloric acidether temperature Long slurry, room Low crystalline Hydrochloric acid Heptanetemperature solid Methyl tert-butyl Long slurry, high Hydrochloric acidAmorphous ether temperature Long slurry, high Hydrochloric acid HeptaneAmorphous temperature Cooling Ascorbic acid AcetonitrileAmorphous crystallization Cooling Ascorbic acid Ethyl acetateOil crystallization Cooling Ascorbic acid TetrahydrofuranOil crystallization Cooling Ascorbic acid AcetoneAmorphous crystallizationAGO-P3287PCT SpecificationAcid Solvent Method ResultCoolingAscorbic acid IsopropanolOil crystallization Methyl tert-butyl Long slurry, room Ascorbic acid Amorphous ether temperature Long slurry, roomAscorbic acid HeptaneAmorphous temperature Methyl tert-butyl Long slurry, high Ascorbic acid Amorphous ether temperature Long slurry, highAscorbic acid HeptaneAmorphous temperature Cooling Citric acid AcetonitrileAmorphous crystallization Cooling Citric acid Ethyl acetateAmorphous crystallization Cooling Citric acid TetrahydrofuranAmorphous crystallization Cooling Citric acid AcetoneAmorphous crystallization Cooling Citric acid IsopropanolAmorphous crystallization Methyl tert-butyl Long slurry, room Citric acid Amorphous ether temperature Long slurry, room Citric acid HeptaneAmorphous temperature Methyl tert-butyl Long slurry, high Citric acid Amorphous ether temperature Long slurry, high Citric acid HeptaneAmorphous temperature CoolingFumaric acid AcetonitrileOil crystallization CoolingFumaric acid Ethyl acetateOil crystallization CoolingFumaric acid TetrahydrofuranOil crystallizationAGO-P3287PCT SpecificationAcid Solvent Method ResultShort slurry, high FA crystalline Fumaric acid Acetonetemperature form 1 Cooling FA crystalline Fumaric acid Isopropanolcrystallization form 1 Methyl tert-butyl Long slurry, room Fumaric acid Amorphous ether temperature Long slurry, room Fumaric acid HeptaneAmorphous temperature Amorphous and Methyl tert-butyl Long slurry, high Fumaric acid FA crystalline ether temperature form 1 Long slurry, high Fumaric acid HeptaneAmorphous temperature 1-Hydroxy-2- Cooling Acetonitrile Oil naphthoic acid crystallization 1-Hydroxy-2- Cooling Ethyl acetate Oil naphthoic acid crystallization 1-Hydroxy-2- Cooling Tetrahydrofuran Oil naphthoic acid crystallization 1-Hydroxy-2- Cooling Acetone Oil naphthoic acid crystallization 1-Hydroxy-2- Cooling Isopropanol Oil naphthoic acid crystallization 1-Hydroxy-2- Methyl tert-butyl Long slurry, room Amorphous naphthoic acid ether temperature 1-Hydroxy-2- Long slurry, room Heptane Amorphous naphthoic acid temperature 1-Hydroxy-2- Methyl tert-butyl Long slurry, high Amorphous naphthoic acid ether temperature 1-Hydroxy-2- Long slurry, high Heptane Amorphous naphthoic acid temperature CoolingL-tartaric acid AcetonitrileAmorphous crystallization CoolingL-tartaric acid Ethyl acetateAmorphous crystallizationAGO-P3287PCT SpecificationAcid Solvent Method ResultCoolingL-tartaric acid TetrahydrofuranAmorphous crystallization Short slurry, highL-tartaric acid AcetoneAmorphous temperature CoolingL-tartaric acid IsopropanolAmorphous crystallization Methyl tert-butyl Long slurry, room L-tartaric acid Amorphous ether temperature Long slurry, roomL-tartaric acid HeptaneAmorphous temperature Methyl tert-butyl Long slurry, high L-tartaric acid Amorphous ether temperature Long slurry, highL-tartaric acid HeptaneAmorphous temperature Cooling Saccharin AcetonitrileOil crystallization Cooling Saccharin Ethyl acetateOil crystallization Cooling Saccharin TetrahydrofuranOil crystallization Cooling Saccharin AcetoneOil crystallization Cooling Saccharin IsopropanolOil crystallization Methyl tert-butyl Long slurry, room Saccharin Amorphous ether temperature Long slurry, room Saccharin HeptaneAmorphous temperature Methyl tert-butyl Long slurry, high Saccharin Amorphous ether temperature Long slurry, high Saccharin HeptaneAmorphous temperature CoolingSuccinic acid AcetonitrileOil crystallizationAGO-P3287PCT SpecificationAcid Solvent Method ResultCooling Succinic acid Ethyl acetateOil crystallization Cooling Succinic acid TetrahydrofuranOil crystallization Cooling Succinic acid AcetoneOil crystallization Cooling Succinic acid IsopropanolOil crystallization Short slurry, highHBr crystallineHydrobromic acid Acetonitriletemperature form 1 Short slurry, highHBr crystallineHydrobromic acid Ethyl acetatetemperature form 3 Cooling Hydrobromic acid TetrahydrofuranOil crystallization Short slurry, highHBr crystallineHydrobromic acid Acetonetemperature form 2 Cooling Hydrobromic acid IsopropanolAmorphous crystallization Short slurry, high Sulfuric acid AcetonitrileAmorphous temperature Short slurry, high Sulfuric acid Ethyl acetateAmorphous temperature Short slurry, high Sulfuric acid TetrahydrofuranAmorphous temperature Short slurry, high Sulfuric acid AcetoneAmorphous temperature Short slurry, high Sulfuric acid IsopropanolAmorphous temperature Cooling Gentisic acid IsopropanolOil crystallization Based on these results, the salts formed with fumaric acid and hydrobromic acid were investigated further.AGO-P3287PCT SpecificationExample 2: Physical characterisation of the crystalline forms 1, 2 and 3 of the hydrobromicacid addition salt of the compound of formula (I)The crystalline forms 1, 2 and 3 of the hydrobromic acid addition salts of the compound of formula (I) were each characterised by XRPD,1H-NMR, DSC, and / or TGA.Crystalline form 1 of the hydrobromic acid addition salt of the compound of formula (I)Methodology:The compound of formula (I) (20 mg, 0.034 mmol) was dissolved in acetone (0.5 mL) andhydrobromic acid (39 μL of a 0.88 M solution in water, 0.034 mmol, 1 eq) was added. Theobtained solution was evaporated to dryness, and the residue was suspended in acetonitrile (3 mL) and stirred at room temperature for 24 hours. The suspension was decanted and a solid was obtained. XRPD XRPD was performed as described in General Methods. The XRPD pattern obtained is shownin Figure 1A. This pattern is characteristic of a crystalline product. The principal peakpositions are: 11.4, 14.5, 15.1, 16.4, 20.0, 20.9, 23.2, 24.6, 27.4, and 28.5 degrees 2-theta.Additional peaks positions are: 9.2, 14.1, 18.0, 21.6, and 27.8 degrees 2-theta.1H-NMR Proton NMR was performed as described in General Methods. The spectrum obtained is shown in Figure 1B. The spectrum is substantially the same as the1H-NMR spectrumobtained for the amorphous form of the compound of formula (I) as free base, with anadditional peak for acetonitrile suggesting that the crystalline form 1 of the hydrobromic acidaddition salt of the compound of formula (I) may be an acetonitrile solvate of the hydrobromic acid addition salt of the compound of formula (I). DSC DSC was performed as described in General Methods. The trace obtained is shown in Figure1C, characterised in having two endotherm events with onset around 34 ˚C and 201 ˚Crespectively. These events likely correspond to the loss of material from the crystalline form and suggest that the solid form is not temperature stable.AGO-P3287PCT SpecificationTGA TGA was performed as described in General Methods. The trace obtained is shown in Figure 1C, characterised by two broad, continuous peaks corresponding to weight loss of 5.5%between 35 ˚C and 220 ˚C, with weight loss due to decomposition of the material starting withonset around 271 ˚C. This result suggests the crystalline form 1 of the hydrobromic acidaddition salt of the compound of formula (I) loses a significant amount of material upon heatingat even low temperatures and would likely not be stable to storage at temperatures above room temperature.Crystalline form 2 of the hydrobromic acid addition salt of the compound of formula (I)Methodology:The compound of formula (I) (20 mg, 0.034 mmol) was dissolved in acetone (0.5 mL) andhydrobromic acid (39 μl of a 0.88 M solution in water, 0.034 mmol, 1 eq) was added. Theobtained solution was evaporated to dryness, and the residue was suspended in acetone (3ml) and stirred at 50 ˚C for 24 hours. A solid was obtained after decantation of the suspension.XRPD XRPD was performed as described in General Methods. The XRPD pattern obtained is shownin Figure 2A. This pattern is characteristic of a crystalline product. The principal peakpositions are: 11.2, 14.2, 14.7, 19.5, 20.3, 22.8, 24.2, 26.7, 27.5, and 28.3 degrees 2-theta. Additional peaks positions are: 13.3, 13.8, 14.3, 15.3, and 18.8 degrees 2-theta.1H-NMR Proton NMR was performed as described in General Methods. The spectrum obtained is shown in Figure 2B. The spectrum is substantially the same as the1H-NMR spectrumobtained for the amorphous form of the compound of formula (I) as free base, with anadditional peak for acetone suggesting that the solid may be an acetone solvate of thehydrobromic acid addition salt. DSC DSC was performed as described in General Methods. The trace obtained is shown in Figure2C, characterised in having two endotherm events with onset around 34 ˚C and 209 ˚Crespectively. These events likely correspond to the loss of material from the crystalline form and suggest that the solid form is not temperature stable.AGO-P3287PCT SpecificationTGA TGA was performed as described in General Methods. The trace obtained is shown in Figure 2C, characterised by two broad, continuous peaks corresponding to weight loss of 5.9%between 33 ˚C and 225 ˚C, with weight loss due to decomposition of the material startingaround 275 ˚C. This result suggests the product loses a significant amount of material uponheating at even low temperatures and would likely not be stable to storage at temperatures above room temperature. Crystalline form 3 of the hydrobromic acid addition salt of the compound of formula (I): Methodology: The compound of formula (I) (20 mg, 0.034 mmol) was dissolved in acetone (0.5 mL) andhydrobromic acid (39 μl of a 0.88 M solution in water, 0.034 mmol, 1 eq) was added. Theobtained solution was evaporated to dryness, and the residue was suspended in ethyl acetate(3 ml) and stirred at 50 ˚C for 24 hours. A solid was obtained after decantation of thesuspension. XRPD XRPD was performed as described in General Methods. The XRPD pattern obtained is shown in Figure 3. This figure is characteristic of a solid product with low crystallinity. This product was therefore not further characterized. In summary, the crystalline forms 1, 2 and 3 of the hydrobromic acid addition salt of thecompound of formula (I) were characterised by low thermal stability, low crystallinity, and / oran inability to be reproduced on a larger scale and were thus deemed not suitable for furtherdevelopment. Example 3: Alternative preparation of crystalline form 1 of fumaric acid addition salt on a larger scaleThe crystalline Form 1 of the fumaric acid addition salt of the compound of formula (I) wasprepared by another process, as follows.The amorphous form of the compound of formula (I) as free base (2.33 g) was dissolved inacetone (8 mL) and fumaric acid (0.466 g) was added. In this experiment the molar ratio ofthe compound of formula (I) as free base to fumaric acid used in the process was 1:1. Thesuspension was heated to 60 °C and stirred at this temperature overnight. The obtainedAGO-P3287PCT Specificationsuspension was slowly cooled to room temperature and stirred for 1 hour, and then stirred forhalf an hour in an ice bath. Afterwards, the solid was filtered off in a filter plate (N.4), washedwith cold acetone (2x2 mL), and dried in vacuum at 60 °C for 4 hours. Yield: 73%.Example 4: Preparation of crystalline Form 1 of fumaric acid addition salt on a larger scaleThe crystalline form 1 of the fumaric acid addition salt of the compound of formula (I) wasprepared at larger scale, as follows.The amorphous form of the compound of formula (I) as free base (100 g) was dissolved inmethanol (1000 mL) and fumaric acid (29.32 g) was added. The suspension was stirred atroom temperature overnight. The obtained suspension was filtered and the solid was washedwith methanol (200 ml) and dried in vacuum for 1-2 hr before being dried in an oven at 60 ˚Cfor 18 hr. Yield: 56%. Example 5: Physical characterisation of the crystalline Form 1 of the fumaric acid addition salt of the compound of formula (I)The crystalline Form 1 of the fumaric acid addition salt of the compound of formula (I)(prepared e.g., as described in Example 3 or Example 4) was characterised by XRPD, FTIR,FTR, 1H-NMR, DSC, TGA and DVS.XRPD XRPD was performed as described in General Methods. The XRPD pattern obtained is shown in Figure 4A. This figure is characteristic of a crystalline product. The principal peak positionsare: 9.3, 10.5, 17.7, 18.0, 18.5, 18.8, 20.4, 23.2, 23.7 and 24.0 degrees 2-theta. Additionalpeaks positions are: 16.5, 20.0, 20.9, 21.1, and 22.7 degrees 2-theta. Further additional peaks are observed at 7.5, 8.5, 9.8, 11.7, 12.3, 12.6, 13.4, 13.8, 14.9, 15.2, 16.9, 21.5, 21.8, 22.2, 24.7, 25.7, 26.0, 26.4, 27.6, 27.9, 28.5, 28.9, 29.8, 30.2, 30.5, 31.1, 31.8, 32.4, 34.7, 35.0,35.9, 36.8, 37.5, 38.1, and 39.1 degrees 2-theta.FTIR FTIR was performed as described in General Methods. The FTIR spectrum obtained is shownin Figure 4B. This spectrum is characteristic of a substance with numerous different carbonylbonding environments. The principal peak positions are: 1701, 1593, 1559, 1458, 1435, 1383,1340, 1312, 1288, 1252, 1166, 1140, 1102, 995, and 766 cm-1.AGO-P3287PCT SpecificationFTRFTR was performed as described in General Methods. The FTR spectrum obtained is shownin Figure 4C. This spectrum is characteristic of a substance with numerous different carbonyl bonding environments. This is consistent with the finding of several different carbonyl environments in the SCXRD pattern associated with the fumaric acid and fumarate moleculespresent in the co-crystal. as discussed below. The principal peak positions are: 3070, 2952,1702, 1592, 1556, 1493, 1451, 1366, 1352, 1271 and 1001 cm-1.1H-NMRProton NMR was performed as described in General Methods. The spectrum obtained isshown in Figure 4D: 1H NMR (300 MHz, DMSO-d6): δ (ppm) 11.14 (s, 1H), 8.86 (d, 1H), 8.17(s, 1H), 8.05 (m, 2H), 7.88 (dt, 1H), 7.70 (m, 2H), 7.59 (t, 1H), 7.50 (d, 1H), 7.40 (m, 3H), 6.98 (d, 1H), 6.52 (s, 3H), 5.29 (s, 2H), 4.41 (t, 2H), 4.08 (m, 4H), 2.76 (t, 2H), 2.65 (m, 4H), 1.84(s, 3H). The spectrum is substantially the same as the 1H-NMR spectrum obtained for theamorphous form of the compound of formula (I) as free base, with an additional singlet peakat 6.52 ppm attributable to fumaric acid and with shifts in the peak positions of the piperazinering protons consistent with formation of the fumarate salt. The integration of the peaks provides support for the number of equivalents of fumaric acid being 1.5. DSC DSC was performed as described in General Methods. The trace obtained is shown in Figure4E, characterised in having an endotherm with onset about 215 ˚C and a normalized peakintegral of -181 J / g. This result suggests the solid form is temperature stable up to around215 ˚C.TGA TGA was performed as described in General Methods. The trace obtained is shown in Figure4E, characterised by a weight loss of 1.2% between 35 ˚C and 191 ˚C, with weight loss dueto decomposition starting with onset at about 213 ˚C. This result suggests the product istemperature stable up to around 213 ˚C.DVSDVS analysis was performed as described in General Methods. The DVS results obtained areshown in Figure 4F. The DVS traces for sorption and desorption of the crystalline Form 1 ofthe fumaric acid addition salt of the compound of formula (I) are shown in Figure 4F. The traceis characterised in showing weight gain of 1.1% in the transition between 10 and 80% ofrelative humidity and weight gain of 1.2% in the transition between 10 and 90% of relativeAGO-P3287PCT Specificationhumidity. No changes in the crystalline form (observed by XRPD analysis) after the experimentwere observed. This result suggests that the substance is stable to moisture exposure and ischaracterised as being slightly hygroscopic.Figure 4F also shows the trace for a similar experiment performed on the amorphous form ofthe compound of formula (I) as free base, although the desorption stage was not performed.The DVS trace for this form is characterised in showing weight gain of 7% in the transitionbetween 10 and 80% of relative humidity and weight gain of 11.6% in the transition between10 and 90% of relative humidity and the substance is characterised as being moderatelyhygroscopic. Analysis of the crystalline Form 1 of the fumaric acid addition salt of the compound of formula(I) by Single Crystal X-ray Diffraction Spectroscopy (SCXRD)The molecular structure of the crystalline Form 1 of the fumaric acid addition salt of thecompound of formula (I) was investigated by SCXRD, performed as described in GeneralMethods. Parameters for data collection and structure refinement are summarised in Table 4. Table 4: SCXRD parameters for data collection and structure refinement Empirical formula C39 H38 F N7 O9Formula weight 767.76Temperature 100(2) KWavelength 0.71073 ÅCrystal system TriclinicSpace group P -1Unit cell dimensions a = 10.4561(9) Å α = 70.988(10)°b = 12.7689(14) Å β = 71.507(9)° c = 16.0863(18) Å γ = 66.738(9)° Volume 1821.0(4) Å3Z 2Density (calculated) 1.400 Mg / m3Absorption coefficient 0.105 mm-1F(000) 804Crystal size 0.200 x 0.020 x 0.010 mm3Theta range for data collection 2.200 to 27.559°.Index ranges -13≤h≤12, -14≤k≤16, -20≤l≤20AGO-P3287PCT SpecificationReflections collected 17722Independent reflections 6937[R(int) = 0.1059]Completeness to theta =27.559° 82.5%Absorption correction Multi-scanMax. and min. transmission 1.00 and 0.58Refinement method Full-matrix least-squares on F2Data / restraints / parameters 6937 / 0 / 508Goodness-of-fit on F2 0.937Final R indices [I>2sigma(I)] R1 = 0.0819, wR2 = 0.1710R indices (all data) R1 = 0.2270, wR2 = 0.2265Largest diff. peak and hole 0.22 and -0.277 e.Å-3The results of the SCXRD refinement process are summarised in Tables 5 to 7: Table 5: Bond lengths C17 C18 1.417(7) C25 C26 1.380(7)C17 H17 0.95 C25 C27 1.490(7)C18 C19 1.344(7) C26 H26 0.95C18 H18 0.95 C28 C29 1.500(7)C19 C20 1.412(6) C28 H28A 0.99C19 H19 0.95 C28 H28B 0.99O1B C1B 1.309(6) C29 H29A 0.99O1B H1B 1.1044 C29 H29B 0.99C1B O2B 1.229(6) C30 C31 1.513(7)C1B C2B 1.475(8) C30 H30A 0.99C1A O2A 1.195(6) C30 H30B 0.99C1A O1A 1.300(6) C2B C2B# 1.296(10)C1A C2A 1.510(7) C2B H2B 0.95O1A H1OA 0.8086 C2A C3A 1.292(7)C21 C22 1.401(6) C2A H2AA 0.95C21 C26 1.405(6) C31 H31A 0.99C22 C23 1.350(7) C31 H31B 0.99C22 H22 0.95 C32 C33 1.518(7)C23 C24 1.376(7) C32 H32A 0.99C24 C25 1.385(7) C32 H32B 0.99C24 H24 0.95 C33 H33A 0.99AGO-P3287PCT SpecificationC33 H33B 0.99 N6 C33 1.417(6)C3A C4A 1.529(7) N6 C30 1.473(6)C3A H3A 0.95 N6 C29 1.481(6)O3A C4A 1.248(6) C7 C8 1.352(7)O3A H1B 1.4313 C7 H7 0.95C4A O4A 1.238(6) N7 C31 1.463(6)F1 C23 1.372(5) N7 C32 1.475(7)O1 C1 1.229(5) N7 H7A 0.91C1 N1 1.349(6) N7 H7A 0.91C1 C2 1.524(7) N7 H7AB 0.91N1 C21 1.384(6) C8 C9 1.376(7)N1 H1N 0.9055 C8 H8 0.95O2 C27 1.340(6) C9 C10 1.412(7)O2 C28 1.461(6) C9 H9 0.95C2 N2 1.457(6) C10 C11 1.500(6)C2 H2A 0.99 C11 H11A 0.98C2 H2AB 0.99 C11 H11B 0.98N2 C5 1.335(5) C11 H11C 0.98N2 N3 1.347(5) C12 C13 1.371(6)O3 C27 1.195(6) C12 C20 1.399(7)C3 N3 1.362(6) C13 C14 1.403(6)C3 C4 1.422(7) C13 H13 0.95C3 C6 1.444(7) C14 H14 0.95C4 C5 1.356(7) C16 C17 1.361(7)C4 C12 1.506(6) C16 C15 1.381(7)N4 C10 1.328(6) C16 H16 0.95N4 C6 1.344(6) C15 C20 1.450(6)C5 H5 0.95N5 C14 1.316(6)N5 C15 1.371(6)C6 C7 1.415(6)Table 6: Bond angles O1 C1 N1 124.9(4) C1 N1 C21 127.2(4)O1 C1 C2 120.1(4) C1 N1 H1N 114.7N1 C1 C2 114.9(4) C21 N1 H1N 117.7AGO-P3287PCT SpecificationC27 O2 C28 117.8(4) H7A N7 H7AB 108.3N2 C2 C1 110.3(4) C7 C8 C9 120.2(5)N2 C2 H2A 109.6 C7 C8 H8 119.9C1 C2 H2A 109.6 C9 C8 H8 119.9N2 C2 H2AB 109.6 C8 C9 C10 118.2(5)C1 C2 H2AB 109.6 C8 C9 H9 120.9H2A C2 H2AB 108.1 C10 C9 H9 120.9C5 N2 N3 113.2(4) N4 C10 C9 122.3(4)C5 N2 C2 126.5(5) N4 C10 C11 117.2(4)N3 N2 C2 119.8(4) C9 C10 C11 120.5(5)N3 C3 C4 109.0(4) C10 C11 H11A 109.5N3 C3 C6 119.8(4) C10 C11 H11B 109.5C4 C3 C6 131.1(4) H11A C11 H11B 109.5N2 N3 C3 104.6(4) C10 C11 H11C 109.5C5 C4 C3 106.0(4) H11A C11 H11C 109.5C5 C4 C12 124.9(5) H11B C11 H11C 109.5C3 C4 C12 129.1(5) C13 C12 C20 119.5(4)C10 N4 C6 118.7(4) C13 C12 C4 118.5(4)N2 C5 C4 107.2(5) C20 C12 C4 122.0(4)N2 C5 H5 126.4 C12 C13 C14 119.6(5)C4 C5 H5 126.4 C12 C13 H13 120.2C14 N5 C15 119.0(4) C14 C13 H13 120.2N4 C6 C7 121.7(5) N5 C14 C13 123.2(4)N4 C6 C3 117.3(4) N5 C14 H14 118.4C7 C6 C3 121.1(4) C13 C14 H14 118.4C33 N6 C30 109.8(4) C17 C16 C15 121.4(5)C33 N6 C29 112.5(4) C17 C16 H16 119.3C30 N6 C29 108.7(4) C15 C16 H16 119.3C8 C7 C6 118.8(5) N5 C15 C16 119.6(4)C8 C7 H7 120.6 N5 C15 C20 120.9(5)C6 C7 H7 120.6 C16 C15 C20 119.5(4)C31 N7 C32 109.1(4) C16 C17 C18 120.2(5)C31 N7 H7A 109.9 C16 C17 H17 119.9C32 N7 H7A 109.9 C18 C17 H17 119.9C31 N7 H7AB 109.9 C19 C18 C17 119.5(5)C32 N7 H7AB 109.9 C19 C18 H18 120.2AGO-P3287PCT SpecificationC17 C18 H18 120.2 O2 C27 C25 111.8(5)C18 C19 C20 122.7(4) O2 C28 C29 108.5(5)C18 C19 H19 118.6 O2 C28 H28A 110C20 C19 H19 118.6 C29 C28 H28A 110C1B O1B H1B 116 O2 C28 H28B 110O2B C1B O1B 123.8(5) C29 C28 H28B 110O2B C1B C2B 123.0(5) H28A C28 H28B 108.4O1B C1B C2B 113.1(4) N6 C29 C28 109.9(5)O2A C1A O1A 125.6(5) N6 C29 H29A 109.7O2A C1A C2A 120.8(5) C28 C29 H29A 109.7O1A C1A C2A 113.6(5) N6 C29 H29B 109.7C1A O1A H1OA 152.6 C28 C29 H29B 109.7C12 C20 C19 125.8(4) H29A C29 H29B 108.2C12 C20 C15 117.6(4) N6 C30 C31 110.3(5)C19 C20 C15 116.6(4) N6 C30 H30A 109.6N1 C21 C22 118.7(4) C31 C30 H30A 109.6N1 C21 C26 123.6(4) N6 C30 H30B 109.6C22 C21 C26 117.7(5) C31 C30 H30B 109.6C23 C22 C21 119.9(4) H30A C30 H30B 108.1C23 C22 H22 120 C2B# C2B C1B 122.3(7)C21 C22 H22 120 C2B# C2B H2B 118.8C22 C23 F1 117.9(4) C1B C2B H2B 118.8C22 C23 C24 123.5(4) C3A C2A C1A 125.2(5)F1 C23 C24 118.5(5) C3A C2A H2AA 117.4C23 C24 C25 117.2(5) C1A C2A H2AA 117.4C23 C24 H24 121.4 N7 C31 C30 111.0(4)C25 C24 H24 121.4 N7 C31 H31A 109.4C26 C25 C24 121.2(4) C30 C31 H31A 109.4C26 C25 C27 120.4(5) N7 C31 H31B 109.4C24 C25 C27 118.2(5) C30 C31 H31B 109.4C25 C26 C21 120.5(4) H31A C31 H31B 108C25 C26 H26 119.7 N7 C32 C33 108.4(5)C21 C26 H26 119.7 N7 C32 H32A 110O3 C27 O2 123.8(5) C33 C32 H32A 110O3 C27 C25 124.3(5) N7 C32 H32B 110AGO-P3287PCT SpecificationTable 7: Torsion angles O1 C1 N1 C21 -4.6(9) C5 C4 C12 C20 122.4(6)C2 C1 N1 C21 174.2(5) C3 C4 C12 C20 -57.3(7)O1 C1 C2 N2 -37.2(6) C20 C12 C13 C14 2.6(8)N1 C1 C2 N2 143.9(4) C4 C12 C13 C14 -179.6(5)C1 C2 N2 C5 74.9(6) C15 N5 C14 C13 -0.7(8)C1 C2 N2 N3 -97.3(5) C12 C13 C14 N5 0.3(8)C5 N2 N3 C3 0.9(5) C14 N5 C15 C16 -179.9(5)C2 N2 N3 C3 174.1(4) C14 N5 C15 C20 -1.6(8)C4 C3 N3 N2 0.0(5) C17 C16 C15 N5 178.7(5)C6 C3 N3 N2 -179.3(4) C17 C16 C15 C20 0.4(8)N3 C3 C4 C5 -0.8(5) C15 C16 C17 C18 -2.4(9)C6 C3 C4 C5 178.3(5) C16 C17 C18 C19 2.3(8)N3 C3 C4 C12 178.9(4) C17 C18 C19 C20 -0.1(8)C6 C3 C4 C12 -2.0(8) C13 C12 C20 C19 176.3(5)N3 N2 C5 C4 -1.4(5) C4 C12 C20 C19 -1.4(8)C2 N2 C5 C4 -174.1(4) C13 C12 C20 C15 -4.8(7)C3 C4 C5 N2 1.3(5) C4 C12 C20 C15 177.5(5)C12 C4 C5 N2 -178.5(4) C18 C19 C20 C12 177.1(5)C10 N4 C6 C7 3.2(7) C18 C19 C20 C15 -1.8(8)C10 N4 C6 C3 -178.0(4) N5 C15 C20 C12 4.4(8)N3 C3 C6 N4 -23.5(6) C16 C15 C20 C12 -177.4(5)C4 C3 C6 N4 157.5(5) N5 C15 C20 C19 -176.6(5)N3 C3 C6 C7 155.3(4) C16 C15 C20 C19 1.6(7)C4 C3 C6 C7 -23.7(8) C1 N1 C21 C22 161.7(5)N4 C6 C7 C8 -3.8(7) C1 N1 C21 C26 -21.7(8)C3 C6 C7 C8 177.5(5) N1 C21 C22 C23 177.2(5)C6 C7 C8 C9 1.9(8) C26 C21 C22 C23 0.4(7)C7 C8 C9 C10 0.3(8) C21 C22 C23 F1 -179.4(4)C6 N4 C10 C9 -0.9(7) C21 C22 C23 C24 -1.1(8)C6 N4 C10 C11 -179.7(4) C22 C23 C24 C25 1.1(8)C8 C9 C10 N4 -0.9(8) F1 C23 C24 C25 179.3(5)C8 C9 C10 C11 177.9(5) C23 C24 C25 C26 -0.4(8)C5 C4 C12 C13 -55.3(7) C23 C24 C25 C27 -174.9(5)C3 C4 C12 C13 125.0(6) C24 C25 C26 C21 -0.2(8)AGO-P3287PCT SpecificationC27 C25 C26 C21 174.1(5) C29 N6 C30 C31 179.7(4)N1 C21 C26 C25 -176.4(5) O2B C1B C2B C2B -9.2(10)C22 C21 C26 C25 0.2(7) O1B C1B C2B C2B 169.4(7)C28 O2 C27 O3 1.2(8) O2A C1A C2A C3A -160.9(6)C28 O2 C27 C25 -177.9(5) O1A C1A C2A C3A 17.7(8)C26 C25 C27 O3 -162.7(6) C32 N7 C31 C30 58.6(6)C24 C25 C27 O3 11.9(9) N6 C30 C31 N7 -57.0(6)C26 C25 C27 O2 16.5(7) C31 N7 C32 C33 -58.5(5)C24 C25 C27 O2 -169.0(5) C30 N6 C33 C32 -58.9(6)C27 O2 C28 C29 -106.4(5) C29 N6 C33 C32 179.9(5)C33 N6 C29 C28 -68.1(6) N7 C32 C33 N6 60.4(6)C30 N6 C29 C28 170.1(4) C1A C2A C3A C4A 177.0(5)O2 C28 C29 N6 -161.9(4) C2A C3A C4A O4A -18.7(9)C33 N6 C30 C31 56.2(6) C2A C3A C4A O3A 161.1(6)An ORTEP Plot fitting the above data is shown in Figure 4G. The asymmetric unit contains one molecule of the protonated compound of formula (I), one molecule of monoanionic fumarate and a half molecule of fumaric acid. The position of the hydrogen atoms of the carboxylate groups at the fumaric acid and at the amine groups were confirmed in their positions by localizing them experimentally from the residual electron densities. The rest ofthe hydrogen atoms were calculated in their expected positions. Additionally, carboxylic acidgroups and carboxylates were distinguished by the distances between oxygen and carbon atoms (double bond and single bond in carboxylic acid group and equal short distances in the carboxylate). The half fumaric acid molecule shows Ci-symmetry and is shared with the neighbouring asymmetric unit. This structure corresponds to a co-crystal of the salt with half fumaric acid (molar ratio 2:1 salt / fumaric acid, which corresponds to a global 1:1.5 compound of formula (I) to fumaric acid).A XRPD pattern was simulated from the results of the SCXRD experiment. An overlay of theXRPD pattern obtained in Example 3 compared to the pattern simulated from the single crystalstructure is shown in Figure 4H. The comparison of the experimentally measured XRPDpattern and the XRPD pattern calculated from the single crystal X-ray structure determinationshows that they correspond to the same crystalline phase and confirms that the measured single crystal is the same as the bulk of the crystals available for the sample. Differences inthe peak position of the XRPD patterns are most probably due to the different measurementtemperatures (SCXRD: -173 ˚C, XRPD: 25 ˚C).AGO-P3287PCT SpecificationCounter ion stoichiometry investigation of the crystalline form 1 of the fumaric acid addition salt of the compound of formula (I) The stoichiometric ratio of the compound of formula (I) to fumaric acid in the fumaric acid addition salts of the compound of formula (I) was further investigated using the ratio of 1:1.5, during the synthetic process, as follows.The amorphous form of the compound of formula (I) as free base (1.27 g, 2.14 mmol) wasdissolved in acetone (5 mL) and fumaric acid (0.372 g, 3.21 mmol, 1.5 eq) was added. Thesuspension was seeded with the crystalline form (Form 1), heated to 60 ˚C and stirred at thistemperature overnight. The obtained suspension was slowly cooled to room temperature and stirred for 30 minutes at this temperature, and for additional 30 minutes in an ice bath. Afterwards, the solid was filtered off in a filter plate (N.3), washed with cold acetone (2x2 mL),and dried in vacuum at 55 ˚C for 3 hours. Yield: 1.29 g (85%).This fumaric acid addition salt was characterised by XRPD. The XRPD pattern obtained canbe seen in Fig. 4J. The pattern is substantially the same as the XRPD pattern of the productof Example 3, suggesting that the same crystalline form is produced using a range of acid stoichiometries. This experiment was repeating using the further ratios of compound of formula (I) to fumaricacid of 1:2, 1:1.3 and 1: 0.8 and the crystalline Form 1 of the fumaric acid addition salt of thecompound of formula (I) was obtained in all cases (data not shown). Evidently it is advantageous in the manufacturing process to be able to reproduce the samecrystalline form even with variation in certain parameters, such as the input compound:acidratio. It has thus been determined that crystalline Form 1 of the fumaric acid addition salt of thecompound of formula (I) is a co-crystal of hemifumarate and fumaric acid with a molar ratio of2:1 (hemifumarate:fumaric acid).Example 6: Solubility studies of the crystalline Form 1 of the fumaric acid addition salt of thecompound of formula (I)A basic solubility study of the crystalline Form 1 of the fumaric acid addition salt of thecompound of formula (I) was carried out.AGO-P3287PCT Specification10 mg of the salt were weighed, and portions of 0.1 mL of the corresponding buffer were addeduntil complete solution was produced, or up to a maximum of 3 mL were added. Buffersolutions of pH 3.2, 4.4, 6, and 8 were prepared as follows: Citrate buffer: sodium citrate dihydrate (0.419 g) and citric acid (1.647 g) were pH 3.2 dissolved in water (0.1 L) and the final desired pH was adjusted using HCl or NaOH solutions. Acetate buffer: sodium acetate (0.333 g) and acetic acid (0.357 g) were pH 4.4 dissolved in water (0.1 L) and the final desired pH was adjusted using HCl or NaOH solutions. Potassium phosphate buffer: K2HPO4 (1.628 g) and KH2PO4 (0.089 g) were pH 6 dissolved in water (0.1 L) and the final desired pH was adjusted using HCl or NaOH solutions. Potassium phosphate buffer: K2HPO4 (0.241 g) and KH2PO4 (1.173 g) were pH 8 dissolved in water (0.1 L) and the final desired pH was adjusted using HCl or NaOH solutions.The results of the solubility study are shown in Table 8 below.Table 8: Solubility of the crystalline Form 1 of the fumaric acid addition salt of the compoundof formula (I) at varying temperature and pH Room Temperature = pH temperature2 ˚C3.2 8-10 mg / mL ≈5 mg / mL4.4 Not soluble Not soluble6 Not soluble Not soluble8 Not soluble Not solubleThe results show that crystalline Form 1 of the fumaric acid addition salt of the compound of formula (I) is soluble in the pH 3.2 buffer, which is a suitable pH for administration by inhalation.A comparative solubility test between the crystalline Form 1 of the fumaric acid addition saltof the compound of formula (I) and the amorphous form of the compound of formula (I) as freebase was carried out.AGO-P3287PCT SpecificationStock solutions (10-2M) of the assayed compounds were diluted to decreased molarity, from 300 μM to 0.1μM, in 384 well transparent plate (Greiner 781801) with 1% DMSO: 99% PBSbuffer (pH around 7.4). The samples were incubated at 37 ˚C and read after 2 hours in aNEPHELOstar Plus (BMG LABTECH). The results were adjusted to a segmented regressionto obtain the maximum concentration in which compounds are soluble. The results aresummarised in Table 9 below.Table 9: Solubility of the amorphous form of the compound of formula (I) as free base and thecrystalline Form 1 of the fumaric addition salt of the compound of formula (I)Solubility / Form of the compound of formula (I)μM Amorphous form (free base) 31.2Crystalline form 1 of the fumarate addition salt 43.6The results surprisingly suggest that the crystalline Form 1 of the fumarate addition salt of the compound of formula (I) is more soluble than the amorphous form of the compound of formula(I) as free base in this buffer.Example 7: Polymorphic stability upon storage under various conditions of the crystalline Form1 of the fumaric acid addition salt of the compound of formula (I)Two samples of the crystalline Form 1 of the fumaric acid addition salt of the compound offormula (I) (open and closed vial) were stored in the climatic chamber at 25 ˚C and 75% RHfor 15 days. After this time, both samples were analysed by XRPD. The results aresummarized in Table 10 below.Table 10: Results of the moisture stability experiments Sample XRPD analysisOpen vial No changes observedClosed vial No changes observedA sample of the crystalline Form 1 of the fumaric acid addition salt of the compound of formula(I) was heated at 60 ˚C in a closed vial and stored, and the solid was analysed at differenttimes by XRPD. The results are summarized in Table 11 below.AGO-P3287PCT SpecificationTable 11: Results of the temperature stability experimentsTime XRPD analysis15 days No changes observed1 month No changes observedThe results suggest that the crystalline Form 1 of the fumaric acid addition salt of thecompound of formula (I) has polymorphic stability over extended periods of time when storedunder a range of conditions including presence of moisture and elevated temperature.Example 8: Long term chemical stability upon storage under various conditions of thecrystalline Form 1 of the fumaric acid addition salt of the compound of formula (I)A sample of the crystalline Form 1 of the fumaric acid addition salt of the compound of formula (I) was stored under various conditions and purity was measured by HPLC. The results aresummarised in Table 12 below:Table 12: Results of the temperature stability experiments Initial 33 months33 months7 months@ 5 + / - 3 oC @ 25 + / - 2 oC @ 40 + / - 2andoC and 60 + / - 5 RH 75 + / - 5 RHChromatographic purity by HPLC98.8% 98.5% 98.3% 98.3%(Area %) The results suggest that the crystalline Form 1 of the fumaric acid addition salt of the compound of formula (I) has very good chemical stability when stored under various conditions including accelerated stress conditions. Example 9: Second salt form investigation A range of possible salt forms prepared by different methodologies were investigated in searching for a novel solid crystalline form of the compound of formula (I) having enhanced properties.AGO-P3287PCT SpecificationThe amorphous form of the compound of formula (I) as free base (30 mg) was mixed with 2or 4 molar equivalents of a corresponding acid. An initial solvent screen was performed usingthe hydrochloric acid addition salt of the compound of formula (I). Subsequent crystallizationattempts were performed using a range of salts in a set of 3 solvents (acetone, 2-methyltetrahydrofuran, and ethyl acetate) according to one or more of the following crystallizationmethods as specified in Table 13: cooling crystallization; cooling crystallization plusmaturation; cooling crystallisation plus maturation plus sonication; liquid-assisted grinding; and extended maturation.General methodology for cooling crystallisation:The amorphous form of the compound of formula (I) as free base (30 mg) was dispensed anda magnetic stirrer added. A 2 volume aliquot of the selected solvent was added and themixture stirred (400 rpm) at 40 °C for 5 minutes. A further 2 volume solvent aliquot was addedif the solution remained turbid. The corresponding acid (2 mol. eq. or 4 mol. eq.) was addedand the samples were cooled to 5 °C at 0.1 °C / minute and stirred at 5 °C for ~ 17 hours. An aliquot was isolated by filtration or blot drying and analysed by XRPD.General methodology for cooling crystallisation plus maturation:The amorphous form of the compound of formula (I) as free base (30 mg) was dispensed anda magnetic stirrer added. An aliquot of the selected solvent (300 µl, 10 volumes) was addedand stirred (400 rpm) at 40 °C for 20 minutes resulting in light orange / brown solutions. Acorresponding acid was added (2.0 or 4.0 mol. eq.) and the samples were cooled to 5 °C at0.1 °C / minute and stirred at 5 °C overnight. An aliquot was isolated by filtration or blot drying and analysed by XRPD. Suspensions were then matured by 25 °C / 40 °C cycling (4 hours at each temperature) for 3 days. An aliquot was isolated by filtration or blot drying and analysed by XRPD.General methodology for cooling crystallisation plus maturation plus sonication:Suspensions were prepared and initially analysed as described above. Suspensions werethen sonicated for 1 hour at 5 °C and an aliquot was isolated by filtration or blot drying andanalysed by XRPD. General methodology for liquid-assisted grinding:The amorphous form of the compound of formula (I) as free base (30 mg) was dispensed and2.0 or 4.0 mol eq. of a corresponding acid was added. Two stainless steel grinding balls wereadded and a 5 µl solvent drop was added over one of the balls and the mixtures were groundAGO-P3287PCT Specificationfor 2 hours at 500 rpm using a planetary Fritsch Mill (Pulverisette 6) with an Automaxionadapter. An observation was made and if solids were observed, then a sample was analysedby XRPD. General methodology for extended maturation:The amorphous form of the compound of formula (I) as free base (30 mg) was dispensed toHPLC vials and a small magnetic stirrer added.2.0 or 4.0 mol eq. of a corresponding acid wasadded. The selected solvent (900 µl, 30 volumes) was added and the mixtures were stirred at 25 °C for 5 minutes then observations were recorded. Cycling between 25 °C / 40 °C was then started with 4 hours at each temperature.After 3 days, an aliquot was isolated by filtration or blot drying and analysed by XRPD. After afurther 2 days, a further aliquot was isolated by filtration or blot drying and analysed by XRPD.All solids obtained using the different crystallization methodologies were characterized byXRPD and classified according to the different XRPD patterns obtained. The results aresummarised in Table 13 below.Table 13: Methodologies Acid Solvent Method ResultCooling Hydrochloric acid Formic acidN / A crystallisation Cooling Hydrochloric acid EthanolHCl crystalline Pattern 1 crystallisation Cooling Hydrochloric acid AcetoneHCl crystalline Pattern 1 crystallisation A: HCl crystalline Pattern Cooling + Hydrochloric acid Acetone1, B: amorphous or low maturation signal Cooling Hydrochloric acid MEKHCl crystalline Pattern 1 crystallisation Cooling Hydrochloric acid 2-MeTHFHCl crystalline Pattern 1 crystallisation A: HCl crystalline Pattern Cooling + Hydrochloric acid 2-MeTHF1, B: HCl crystalline maturation Pattern 1AGO-P3287PCT SpecificationAcid Solvent Method ResultCooling Hydrochloric acid TetrahydrofuranHCl crystalline Pattern 1 crystallisation Cooling Hydrochloric acid DMSON / A crystallisation Cooling Hydrochloric acid Ethyl AcetateHCl crystalline Pattern 1 crystallisation A: HCl crystalline Pattern Cooling + 1 maturation B: HCl crystalline Pattern Hydrochloric acid Ethyl Acetate1 C: HCl crystalline Pattern 1 Cooling Hydrochloric acid NMPHCl crystalline Pattern 1 crystallisation Acetone / Water Cooling Hydrochloric acid HCl crystalline Pattern 1 9:1 v / v crystallisation Cooling + Succinic acid AcetoneNo recoverable solids maturation A: weak crystallinity B: Cooling + amorphous halo and Succinic acid 2-MeTHFmaturation weak crystalline reflections Cooling +A: SA crystalline Form 1,Succinic acid Ethyl Acetatematuration +B: SA crystalline Form 1,sonicationC: SA crystalline Form 1Key: “A” = after cooling to 5 °C; “B” = after 25 °C / 40 °C maturation cycle; “C” = after sonicationExample 10: Physical characterisation of the crystalline Form 1 of the succinic acid additionsalt of the compound of formula (I)The crystalline Form 1 of the succinic acid addition salt of the compound of formula (I) wereeach characterised by XRPD,1H-NMR, DSC, and / or TGA.AGO-P3287PCT SpecificationCrystalline Form 1 of the succinic acid addition salt of the compound of formula (I)Methodology: The amorphous form of the compound of formula (I) as free base (1.5 g) wasdispensed to a 100 ml round bottom flask and charged with ethyl acetate (45 ml, 30 volumes) and the sample stirred (500 rpm) at 40 °C for 10 minutes. Succinic acid (2527 µl, 1 mol eq.1 mol dm-3 in MeOH) was added. The sample was stirred for 30 minutes. A second portion of succinic acid (2527 µl, 1 mol eq.1 mol dm-3in MeOH) was added. The sample was stirred for 30 minutes and the residue persisted in a clear solution. The sample was cooled from 40 °Cto 5 °C at 0.1 °C / min and left at 5 °C for ~12 hrs. The sample was subjected to maturationcycling (4 hours at 5 °C, 4 hours at 25 °C, repeat cycles) for 5 days. The resulting whitesuspension was filtered and washed using ethyl acetate and the filter cake dried under a fullyopen vacuum line for 15 minutes. The filter cake was broken up with gentle application from a spatula and the filter cake dried at room temperature, ~5 mbar in a vacuum oven for 30 minutes. XRPD XRPD was performed as described in General Methods. The XRPD pattern obtained is shown in Figure 5A. This pattern is characteristic of a crystalline product. The principal peak positionsare: 4.1, 8.1, 11.7, 12.3, 12.8, 13.4, 14.4, 16.3, 17.7 and 23.4 degrees 2-theta. Additionalpeaks positions are: 9.9, 10.8, 11.0, 17.5, 18.2, 18.8, 19.1, 19.3, 19.5, 19.7, 20.1, 20.6, 21.1, 21.4, 22.5, 22.9, 23.9, 24.4, 24.8, 25.1, 25.4, 25.8, 26.2, 26.6, 27.1, 27.5, 28.5, 28.8, 29.1,29.6, 29.9 and 30.3 degrees 2-theta.1H-NMR Proton NMR was performed as described in General Methods. The spectrum obtained isshown in Figure 5B: 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.84 (s, 3 H) 2.55 - 2.65 (m, 4 H)2.70 - 2.79 (t, J=5.63 Hz, 2 H) 2.90 - 3.00 (m, 4 H) 4.35 - 4.47 (t, J=5.63 Hz, 2 H) 5.27 (s, 2 H)6.94 - 7.03 (d, J=7.38 Hz,1 H) 7.37 (d, J=4.38 Hz, 1 H) 7.39 - 7.46 (m, 2 H) 7.46 - 7.53 (m, 1H) 7.54 - 7.63 (m, 1 H) 7.65 - 7.75 (m, 2 H) 7.80 - 7.90 (td, J=10.63, Hz, 1 H) 8.00 - 8.06 (m,1 H) 8.08 (t, J=1.50 Hz, 1 H) 8.14 - 8.19 (s, 1 H) 8.82 - 8.90 (d, J=4.38 Hz, 1 H) 10.96 (s, 1 H).The spectrum is substantially the same as the1H-NMR spectrum obtained for the amorphousform of the compound of formula (I) as free base, with an additional singlet peak at 2.61 ppmattributable to succinic acid and with shifts in the peak positions of the piperazine ring protonsconsistent with formation of the succinic salt. The integration of the peaks provides support forthe number of equivalents of succinic acid being 1.5.AGO-P3287PCT SpecificationDSC DSC was performed as described in General Methods. The trace obtained is shown in Figure5C, characterised in having a single endotherm with onset at 160.6 °C (-83 J / g) which wasfollowed by a broad endotherm that overlaps with the decomposition in the TGA. This resultsuggests the solid form is temperature stable up to around 160 ˚C.TGA TGA was performed as described in General Methods. The trace obtained is shown in Figure5C, characterised by no weight loss prior to decomposition, starting with onset at about190.9 ˚C. This result suggests the product is temperature stable up to around 191 ˚C.Example 11: Solubility studies of the crystalline Form 1 of the succinic acid addition salt of thecompound of formula (I)A solubility study of the crystalline Form 1 of the succinic acid addition salt of the compoundof formula (I) was carried out.Sufficient salt was suspended in 0.5 ml of the buffer solution to achieve a maximum anticipatedconcentration of ca.20 mg / ml and the resulting suspensions were then shaken at 37 °C / 750rpm for 24 hours. Buffer solutions of pH 3, 4, and 5 were prepared as follows:Acetate buffer: Acetic acid (0.1 M, 196.5 ml) was mixed with sodium acetate pH 3 (0.1 M, 3.5 ml) in a 200 ml vessel. The final pH was recorded (pH 3.0). Acetate buffer: Acetic acid (0.1 M, 169.4 ml) was mixed with sodium acetate pH 4 (0.1 M, 30.6 ml) in a 200 ml vessel. The final pH was recorded (pH 4.0). Acetate buffer: Acetic acid (0.1 M, 71.4 ml) was mixed with sodium acetate (0.1 pH 5 M, 128.6 ml) in a 200 ml vessel. The final pH was recorded (pH 5.0).The results of the solubility study are shown in Table 14 below.Table 14: Solubility of the crystalline Form 1 of the succinic acid addition salt of the compound of formula (I) after 24 hrs at 37 °C pH Final Appearance3 Fine suspension4 Fine suspension5 Clear solutionAGO-P3287PCT SpecificationThe results show that crystalline Form 1 of the succinic acid addition salt of the compound offormula (I) is soluble in the pH 5 buffer, which is a suitable pH for administration by inhalation.Example 12: Polymorphic stability upon storage under various conditions of the crystallineForm 1 of the succinic acid addition salt of the compound of formula (I)Samples of the crystalline Form 1 of the succinic acid addition salt of the compound of formula(I) were stored in the climatic chamber at either (i) 25 ˚C and 11% RH, (ii) 25 ˚C and 97% RHor (iii) 40 ˚C and 75% RH for 7 days. After this time, the samples were analysed by XRPD andHPLC. The results are summarized in Table 15 below.Table 15: Results of the stability experiments Conditions XRPD analysis HPLC analysis25 °C / 11% RH No changes observed 99% purity25 °C / 97% RH No changes observed 99% purity40 °C / 75% RH No changes observed 99% purityThe results suggest that the crystalline Form 1 of the succinic acid addition salt of thecompound of formula (I) has polymorphic stability over extended periods of time when storedunder a range of conditions including presence of moisture and elevated temperature. GVS was performed as described in General Methods. The GVS isotherm plot is shown inFigure 5D. The results suggest that the crystalline Form 1 of the succinic acid addition salt ofthe compound of formula (I) is hygroscopic by GVS analysis with a reversible ~1.4% water uptake between 0 and 90% RH. The sample displayed physical stability being unchanged by XRPD for the post-GVS residue, as shown in the trace in Figure 5E.Example 13: Physical characterisation of the crystalline pattern 1 of the hydrochloric acidaddition salt of the compound of formula (I)The crystalline pattern 1 of the hydrochloric acid addition salt of the compound of formula (I)were each characterised by XRPD,1H-NMR, DSC, and / or TGA.AGO-P3287PCT SpecificationCrystalline pattern 1 of the hydrochloric acid addition salt of the compound of formula(I)Methodology: To 3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoic acid (Intermediate 17 as disclosed in WO 2022 / 069509 A1), t-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (1.2eq), EDC.HCl (1.5eq) and 4-pyrrolidinopyridine(1.5eq) in a reactor was added DCM and N,N-dimethylacetamide (2 vol). The reaction mixturewas agitated with heating at 30 to 40°C (Target 35°C) for 16 hours. The contents were thencooled 15 to 25°C (Target 20°C) and 5% aqueous acetic acid (5 vol) was added. The contentswere agitated at 15 to 25°C (Target 20°C) for 15 to 30 minutes and then the layers wereallowed to settle for 15 to 30 minutes. The lower organic layer [contains product] was collectedand the separation with 5% aqueous acetic acid (5 vol) was repeated twice more. The contentsof the reactor containing the combined organic layers was distilled to ~5 volumes andisopropanol (5 vol) was added. The contents of the reactor containing the combined organiclayers was distilled again to ~5 volumes.To the distilled contents was added 6N HCl in IPA (15 eq) maintaining temperature ≤50°C.The reaction mixture was then heated to 40 to 50°C (Target 45°C) for 4 hours. The contentswere then cooled 15 to 25°C (Target 20°C) and agitated at 15 to 25°C for at least 2 hours.The contents were filtered and the filter cake washed with isopropanol (4 vol). The filter cakewas allowed to dry under a flow of nitrogen for at least 1 hour and then recharged to thereactor. The filter cake was then further agitated, filtered and then dried two more times usingfirst ethanol (7.4 vol) and MTBE (2.5 vol). The resulting solid was transferred to an oven anddried under vacuum at 45 to 55°C for at least 12 hours to afford the amorphous HCl salt of thecompound of formula (I).The amorphous HCl salt of the compound of formula (I) (ca.1003.5 mg,) was weighed into a4 ml vial. MeOH / H2O 95:5 (2 vol, 2 ml) was added. The sample was stirred at 40 °C for ca. 5mins. A clear solution was obtained. The sample was stirred for a further 30 minutes thencooled to 5 °C at 0.1°C / min. Upon cooling, precipitation was observed (27 °C). After stirring at5 °C overnight, an aliquot of the suspension was analysed by XRPD. The suspension was toothick to filter, and the aliquot was blot dried with filter paper prior to XRPD analysis. MEK (2vol, 2 ml) was added to the vial to mobilise the suspension. The suspension was still thick. A portion of the suspension was poured onto a Buchner funnel equipped with PTFE filter paper.MEK (2 vol, 2 ml) was added to the remaining portion of the suspension and this was pouredonto the filter cake. A small amount of material was left in the vial and was washed with MEK(2 vol, 2 ml). This was added to the filter cake. The filter cake was dried under suction for 10AGO-P3287PCT Specificationmins then transferred to a pre-tared vial. The sample was then dried in-vacuo for 3 hours. Postdrying, the sample was subjected to characterisation.XRPD XRPD was performed as described in General Methods. The XRPD pattern obtained is shown in Figure 6A. This pattern is characteristic of a crystalline product. The principal peak positionsare: 4.5, 7.7, 9.2, 15.4, 20.6, 22.1, 26.0, 26.3, 27.5 and 28.8 degrees 2-theta. Additional peakspositions are: 10.9, 12.6, 12.7, 13.1, 13.4, 14.7, 17.4, 18.9, 23.4, 24.1, 27.0, 27.3, 28.0 and28.2 degrees 2-theta.1H-NMR Proton NMR was performed as described in General Methods. The spectrum obtained isshown in Figure 6B: 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.93 (s, 3 H) 4.63 - 4.74 (m, 2 H)5.43 (s, 2 H) 7.18 (d, J=7.75 Hz, 1 H) 7.17 (s, 1 H) 7.12 - 7.13 (m, 1 H) 7.19 (s, 1 H) 7.62 -7.72 (m, 2 H) 7.77 (td, J=7.50, 3.50 Hz, 2 H) 7.93 (d, J=5.50 Hz, 1 H) 7.96 (t, J=2.13 Hz, 1 H)8.00 (d, J=8.51 Hz, 1 H) 8.04 - 8.13 (m, 1 H) 8.09 (s, 1 H) 8.16 (t, J=1.50 Hz, 1 H) 8.40 (d,J=8.50 Hz, 1 H) 8.46 - 8.50 (m, 1 H) 9.22 (d, J=5.50 Hz, 1 H) 9.55 - 9.80 (m, 2 H) 11.53 (s, 1H) 11.49 - 11.57 (m, 1 H). The spectrum is substantially the same as the 1H-NMR spectrumobtained for the amorphous form of the compound of formula (I) as free base, with shifts inthe peak positions of the piperazine ring protons consistent with formation of the hydrochloricacid salt.DSC DSC was performed as described in General Methods. The trace obtained is shown in Figure6C, and is characterised in having four endothermic events occurring between 25 and 250 °C.TGA TGA was performed as described in General Methods. The trace obtained is shown in Figure 6C, characterised by having a weight loss of around 12.3% prior to decomposition, starting with onset at about 259.1 ˚C. This result suggests the product is temperature stable up to around 259.1 ˚C.Example 14: Solubility studies of the crystalline Pattern 1 of the hydrochloric acid addition saltof the compound of formula (I) A solubility study of the crystalline Pattern 1 of the hydrochloric acid addition salt of the compound of formula (I) was carried out.AGO-P3287PCT Specification6 mL solutions were prepared and HCl salt amounts were added as indicated in the column“API added” in Table 16. The solubility was evaluated at room temperature after stirring for24hours and 48hours by appearance and after stirring 24hours by analysing the supernatant by HPLC.Buffer solutions of pH 3, 4, 5 and 5.5 were prepared as follows:pH 3 Citrate buffer: 500 mMpH 4 Acetate buffer: 200 mMpH 5 Citrate buffer: 500 mMpH 5.5 Citrate buffer: 500 mMThe results of the solubility study are shown in Table 16 below.Table 16: Solubility of the crystalline Pattern 1 of the hydrochloric acid addition salt of thecompound of formula (I) ConcAppearance pH APISolubility (w / v%) added *** *** Wetting T24h* T48h** T24h (mg / m(mg / mL) L) T24h Purified- Good Solution Solution 2.0 76.2 70.68water pH 3 500 mM Good Solution Solution 2.7 61.4 60.90pH 4 200 mM Good Solution Solution 2.6 46.7 43.94pH 5 500 mM Poor Precipitation Solution 4.8 32.8 0.49pH 5.5 500 mM Poor Precipitation Solution 5.4 15.1 0.08* Initial test tube with saturated solution evaluated** Supernatant after 24h static evaluated *** Average of 2 replicatesThe results show that crystalline Pattern 1 of the hydrochloric acid addition salt of thecompound of formula (I) is soluble in purified water and at pH 3 and 4 buffer, which are suitablepHs for administration by inhalation. A solubility decrease was seen from pH 5.AGO-P3287PCT SpecificationExample 15: Polymorphic stability upon storage under various conditions of the crystallinePattern 1 of the hydrochloric acid addition salt of the compound of formula (I)Samples of the crystalline Pattern 1 of the hydrochloric acid addition salt of the compound offormula (I) were stored in the climatic chamber at either (i) 25 ˚C and 11% RH, (ii) 25 ˚C and97% RH, (iii) 40 ˚C and 75% RH or (iv) 60 ˚C and ambient RH for 7 days. After this time, thesamples were analysed by XRPD and HPLC. The results are summarized in Table 17 below.Table 17: Results of the stability experiments Conditions XRPD analysis HPLC analysis25 °C / 11% RH No changes observed 99% purity25 °C / 97% RH No changes observed 99% purity40 °C / 75% RH No changes observed 98% purity60 °C / ambient RH No changes observed 99% purityThe results suggest that the crystalline Pattern 1 of the hydrochloric acid addition salt of thecompound of formula (I) has polymorphic stability over extended periods of time when storedunder a range of conditions including presence of moisture and elevated temperature. Only aslight drop in purity from 99 % to 98.0 % was observed following storage at 40 °C / 75 % RH.GVS was performed as described in General Methods. The GVS isotherm plot is shown inFigure 6D. The results suggest that the crystalline Pattern 1 of the hydrochloric acid additionsalt of the compound of formula (I) is slightly hygroscopic by GVS analysis with a reversible ~14% water uptake between 0 and 90% RH. The sample displayed physical stability being unchanged by XRPD for the post-GVS residue, as shown in the trace in Figure 6E. References Akhurst R J, et al., Nat. Rev. Drug Discov., 2012, 11(10), 790-811. Aschner, Y. et al, Am. J. Respir. Cell Mol. Biol., 2016, 54(5), 647-55.Biernacka, A et al, Growth Factors, 2011, 29(5), 196-202.Bierie B et al, Nat. Rev. Cancer.2006, 6(7), 506-20. Heldin C H, et al, Cold Spring Harb. Perspect. Biol., 2016, 8(8), a022053.Huebschle, C B et al., J. Appl. Cryst. 2011, 44, 1281-1284.Saito A. et al, Int. J. Mol. Sci.2018, 19, 2460.Sheldrick, G M, Acta Cryst.2015, A71, 3-8.Wijsenbeek, M. et al., Lancet, 2022, 400, 769-786.AGO-P3287PCT SpecificationMiscellaneous All references referred to in this application, including patent and patent applications, are incorporated herein by reference to the fullest extent possible. Throughout the specification and the claims which follow, unless the context requiresotherwise, the word ‘comprise’, and variations such as ‘comprises’ and ‘comprising’, will beunderstood to imply the inclusion of a stated integer, step, group of integers or group of stepsbut not to the exclusion of any other integer, step, group of integers or group of steps.The application of which this description and claims forms part may be used as a basis forpriority in respect of any subsequent application. The claims of such subsequent applicationmay be directed to any feature or combination of features described herein. They may takethe form of product, composition, process, or use claims and may include, by way of exampleand without limitation, the following claims.

Claims

AGO-P3287PCT SpecificationCLAIMS1. A substance which is an acid addition salt of a compound of formula (I):wherein the acid addition salt is selected from the group consisting of a fumaric acid additionsalt, a succinic acid addition salt and a hydrochloric acid addition salt, and the substance is ina solid crystalline form.

2. The substance according to claim 1 which is a fumaric acid addition salt of a compoundof formula (I):wherein the substance is in a solid crystalline form.

3. The substance according to claim 2 wherein the fumaric acid addition salt of the compound of formula (I) is a monofumaric acid addition salt of the compound of formula (I).

4. The substance according to claim 2 or claim 3 wherein the crystalline form is the formof a cocrystal.

5. The substance according to claim 4 wherein the cocrystal is a cocrystal of the fumaricacid addition salt of the compound of formula (I) with fumaric acid.AGO-P3287PCT Specification6. The substance according to claim 4 or claim 5 wherein the molar ratio of fumarate and fumaric acid taken together to the compound of formula (I) in protonated form in the cocrystal is about 1.5:1.

7. The substance according to any one of claims 4 to 6 wherein the cocrystal is a cocrystalof (a) the monofumaric acid addition salt of the compound of formula (I) and (b) fumaric acid where (a) and (b) are in a molar ratio of about 2:

1.

8. The substance according to any one of claims 2 to 7 wherein the solid crystalline form has an X-ray powder diffraction pattern containing three, four, five, six, seven, eight, nine orten peaks selected from (± 0.2) 9.3, 10.5, 17.7, 18.0, 18.5, 18.8, 20.4, 23.2, 23.7 and 24.0degrees 2-theta.

9. The substance according to claim 8 wherein the solid crystalline form has the X-ray powder diffraction pattern substantially as shown in Fig.4A.

10. The substance according to any one of claims 2 to 9 wherein the solid crystalline formhas unit cell dimensions of about 10.46 Å, about 12.77 Å, about 16.09 Å, α angle of about71.0°, β angle of about 71.5°, and γ angle of about 66.7°.

11. The substance according to claim 1 which is a succinic acid addition salt of acompound of formula (I):wherein the substance is in a solid crystalline form.

12. The substance according to claim 11 wherein the succinic acid addition salt of thecompound of formula (I) is a monosuccinic acid addition salt of the compound of formula (I).AGO-P3287PCT Specification13. The substance according to claim 11 or claim 12 wherein the crystalline form is theform of a cocrystal.

14. The substance according to claim 13 wherein the cocrystal is a cocrystal of the succinicacid addition salt of the compound of formula (I) with succinic acid.

15. The substance according to claim 13 or claim 14 wherein the molar ratio of succinateand succinic acid taken together to the compound of formula (I) in protonated form in thecocrystal is about 1.5:1.

16. The substance according to any one of claims 13 to 15 wherein the cocrystal is acocrystal of (a) the monosuccinic acid addition salt of the compound of formula (I) and (b)succinic acid where (a) and (b) are in a molar ratio of about 2:1.

17. The substance according to any one of claims 11 to 16 wherein the solid crystalline form has an X-ray powder diffraction pattern containing three, four, five, six, seven, eight, nineor ten peaks selected from (± 0.2) 4.1, 8.1, 11.7, 12.3, 12.8, 13.4, 14.4, 16.3, 17.7 and 23.4degrees 2-theta measured using Cu Ka radiation.

18. The substance according to claim 17 wherein the solid crystalline form has the X-ray powder diffraction pattern substantially as shown in Fig.5A.

19. The substance according to claim 1 which is a hydrochloric acid addition salt of acompound of formula (I):wherein the substance is in a solid crystalline form.AGO-P3287PCT Specification20. The substance according to claim 19 wherein the hydrochloric acid addition salt of thecompound of formula (I) is a tri- or tetra-hydrochloric acid addition salt of the compound offormula (I).

21. The substance according to claim 19 or 20 wherein the solid crystalline form has an X- ray powder diffraction pattern containing three, four, five, six, seven, eight, nine or ten peaksselected from (± 0.2) 4.5, 7.7, 9.2, 15.4, 20.6, 22.1, 26.0, 26.3, 27.5 and 28.8 and 24.0 degrees2-theta measured using Cu Ka radiation.

22. The substance according to claim 21 wherein the solid crystalline form has the X-raypowder diffraction pattern substantially as shown in Fig.6A.

23. The substance according to any one of claims 1 to 22 for use as a pharmaceutical.

24. The substance for use as a pharmaceutical according to claim 23 for administration bythe oral route.

25. The substance for use as a pharmaceutical according to claim 23 for administration byinhalation.

26. A pharmaceutical composition comprising the substance according to any one ofclaims 1 to 22 in combination with one or more pharmaceutically acceptable diluents orcarriers.

27. A combination therapy comprising the substance according to any one of claims 1 to22 and a therapeutic agent used for the prevention or treatment of a disease or pathologicaldisorder that can be ameliorated by inhibition of ALK5, such as a disease selected from thegroup consisting of gastrointestinal diseases, lung diseases, fibrotic diseases, fibroproliferative disorders, cancer and graft vs. host disease (GvHD).

28. The substance according to any one of claims 1 to 22 or the pharmaceuticalcomposition according to claim 26 for use in the prevention or treatment of a disease orpathological disorder that can be ameliorated by inhibition of ALK5, such as a disease selected from the group consisting of gastrointestinal diseases, lung diseases, fibrotic diseases, fibroproliferative disorders, cancer and graft vs. host disease (GvHD).AGO-P3287PCT Specification29. A process for the preparing the substance of the invention according to any one ofclaims 1 to 22, which comprises: a) preparing a solution comprising the compound of formula (I):and an acid in a solvent, wherein the acid is selected from the group consisting of fumaricacid, succinic acid and hydrochloric acid; andb) crystallising the substance from the solution.

30. The process according to claim 29 wherein the acid is fumaric acid.

31. The process of claim 30 wherein the solvent is selected from the group consisting ofacetone, isopropanol and methyl t-butyl ether.

32. The process according to claim 29 wherein the acid is succinic acid.

33. The process of claim 32 wherein the solvent is ethyl acetate.

34. The process according to claim 29 wherein the acid is hydrochloric acid.

35. The process of claim 34 wherein the solvent is selected from the group consisting ofethanol, acetone, methyl ethyl ketone, 2-methyl tetrahydrofuran, tetrahydrofuran, ethyl acetate and N-methyl-2-pyrrolidone.

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