Crystalline phase forms of a benzylamide derivative

Abstract

There is provided inter alia a crystalline phase form of a compound of formula (I), wherein the crystalline phase form is the crystalline phase Form 1 polymorph.

Description

[0001] CRYSTALLINE PHASE FORMS OF A BENZYLAMIDE DERIVATIVE

[0002] Field of the Invention

[0003] The present invention relates inter alia to novel crystalline phase forms of a benzylamide derivative which is a potent inhibitor of transforming growth factor-p receptor I kinase, (also named activin receptor-like kinase 5) (TGFpRI) / ALK5.

[0004] State of the art

[0005] Transforming growth factor-p (TGF-P) belongs to the TGF-p superfamily, which comprises TGF-pi , TGF-P2, and TGF-P3, among other proteins. TGF-p is involved in many cellular processes, including cell proliferation, cell migration, invasion, epithelial-mesenchymal transition, extracellular matrix production and immune suppression. TGF-p and its receptors are often chronically overexpressed in various human diseases, including cancer, inflammation, tissue fibrosis and autoimmunity. Therefore, blockade of TGF-p signalling pathway is considered an attractive target for drug development. (Heldin C. H. et al.).

[0006] TGF-p signals via two related transmembrane type I and type II serine / threonine kinase receptors. Following TGF-p binding to the constitutively active type II receptor, the type I receptor (TGFPR1 , also called activin receptor-like kinase 5 (ALK5)) 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-p target genes involved in cell differentiation, proliferation, apoptosis, migration, and extracellular matrix production. (Akhurst R. J. et al.).

[0007] In most cell types, activin receptor-like kinase 5 (ALK5) is the predominant TGFp receptor I that is activated by TGF-p through TGFp receptor II. This interaction requires both extracellular and intracellular domains for signal transduction. ALK5 and TGFp 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.).

[0008] The functional TGFpRII-TGFpRI (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-p pathway, and which correlate with cancer occurrence and prognosis in many human tissues. The over expression of TGF-pi has been associated with breast, colon, oesophageal, gastric, hepatocellular, lung and pancreatic cancer. Importantly, the overexpression of TGF-p in human cancer correlates with tumour progression, metastasis, angiogenesis and poor prognostic outcome. Additionally, reports suggest that the combination of TGF-p blockade and immune checkpoint inhibitor strategies could be of interest in cancer treatments based on pre-clinical evidence (Tauriello DVF et al., 2022).

[0009] Extensive evidence also suggests that the canonical ALK5 / Smad3 pathway is critically involved in the pathogenesis of fibrosis in many tissues. In Crohn’s disease (CD) tissue TGF-p gene expression levels and phosphorylated SMAD2 / 3 (positive regulators of TGF-p signalling) are upregulated in myofibroblasts that overlie strictured (but not non-strictured) areas, while SMAD7 (negative regulator of TGF-pi) is downregulated in the same areas (Di Sabatino et al., 2009). TGF-pi upregulates a- SMA, collagen I and fibronectin in human fibroblasts, mesenchymal cells and smooth muscle cells. The role of TGF-pi in fibrosis is also underscored by the observation that vaccination against TGF- P1 attenuates fibrosis in a preclinical model for FSCD (Ma et al., 2010). A preclinical proof of concept for the efficacy of ALK5 inhibition in in vitro and in vivo models for intestinal fibrosis has been delivered with a systemic ALK5 inhibitor (Medina et al., 2011). Therefore, inhibition of the TGF-p signalling pathway is considered an attractive target for drug development for fibrotic diseases, in particular FSCD.

[0010] Oral administration of a small molecular weight selective inhibitor of the kinase activity of ALK5 inhibited fibrogenesis in a rat model of progressive TGF-pi -induced pulmonary fibrosis (D’Alessio et al., 2022). Furthermore, Smad3 null mice exhibit attenuated fibrosis in a wide range of experimental models and are resistant to bleomycin-induced pulmonary fibrosis. Similarly, dermal fibrosis following irradiation, renal interstitial fibrosis produced by unilateral ureteral obstruction and cardiac fibrosis are all attenuated in Smad3-deficient animals. (Biernacka, A. et al.).

[0011] Inhibitors of TGF-p intracellular signalling pathway are useful treatments for fibroproliferative diseases. Specifically, fibroproliferative diseases include kidney disorders associated with unregulated TGF-p activity and excessive fibrosis including glomerulonephritis (GN), such as mesangial proliferative GN, immune GN and crescentic GN. Other renal conditions include diabetic nephropathy, renal interstitial fibrosis, renal fibrosis in transplant patients. Collagen vascular disorders include progressive systemic sclerosis, polymyositis and scleroderma. Autoimmune disorders associated with fibroproliferative characteristics are systemic lupus erythematosus and rheumatoid arthritis.

[0012] Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in Janus Kinase 2 (JAK2), Myeloproliferative Leukemia Virus (MPL), and Calreticulin gene (CALR) have been identified in the pathogenesis of these diseases, inhibitors of the JAK2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-p family members are profibrotic cytokines and significant TGF-pi isoform over expression was observed in a large cohort of primary MF patient samples. It has been demonstrated that TGF-pi stimulates the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-p receptor I kinase (ALK5) / Smad3 pathway. The use of Galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in mouse models. The data demonstrate the role of malignant hematopoietic stem cell (HSC) / TGF-p / MSC axis in the pathogenesis of MF and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF. (Yue, L. et al.).

[0013] Additionally, there are studies that have investigated the therapeutic potential of TGF-p inhibitors in preventing postsurgical peritoneal adhesion band formation, and the results show that this kind of compounds significantly attenuates adhesion band formation by inhibiting inflammation, oxidative stress, downregulation of proinflam matory genes as well as suppression of fibrosis and profibrotic molecules. (Soleimani, A. et al.).

[0014] Several small molecules that inhibit ALK5 have been developed and demonstrate encouraging results in animal models of renal fibrosis. However, questions remain over the homeostatic role of ALK5 signaling, and therefore the safety implications of targeting this enzyme. A study showed that immunohistochemical analysis revealed that in the heart, ALK5 expression was unique to the valves. Two compounds (AZ12601011 and AZ12799734) were tested in rats. Microscopic evaluation revealed heart valve lesions in response to treatment with either compound. Both compounds induced histopathologic heart valve lesions characterized by haemorrhage, inflammation, degeneration, and proliferation of valvular interstitial cells. The pathology was observed in all animals, at all doses tested, and occurred in all four heart valves. Analysis of ALK5 in rat hearts revealed expression in the valves, but not in the myocardium. Compared to control animals, protein levels of ALK5 were unchanged in the heart valves of treated animals. These findings suggest that TGF-p signaling via ALK5 plays a critical role in maintaining heart valve integrity. (Anderton M.J. et al.).

[0015] In addition, another ALK-5 inhibitor, galunisertib, was tested in both rats and dogs. In both, the heart and great vessels were identified as the major target organs for toxicity. Cardiovascular findings in F344 rats treated with LY2157299 included degenerative and inflammatory valvular lesions (valvulopathy), myocardial degeneration and necrosis, aortitis with rupture, vasculitis / perivasculitis, and increased heart weights (Stauber A. et al.). In the gut, many immune and non-immune cells produce TGF-pi and almost all the mucosal cells are targeted by this cytokine. TGF-pi is secreted as part of a latent complex, which comprises latency-associated peptide (LAP) and latent TGF-p binding protein. Data emerging from recent studies indicate clearly that transforming growth factor pi is one of the key molecules involved in the regulation of the epithelial cell biology and immunity in the gut.

[0016] These studies underline the crucial role of TGF-pi in the maintenance of intestinal homeostasis and suggest that defective function of this cytokine can contribute to trigger and / or amplify detrimental signals in the gut (Troncone E. et al.).

[0017] Until now, researchers have studied the mechanisms of inflammation to alleviate and to inhibit intestinal fibrosis. However, anti-inflammatory agents have various problems and limitations to relieve or to treat fibrosis in inflammatory bowel disease (IBD). Therefore, in order to treat fibrotic diseases, new approaches for anti-fibrotic mechanisms should be explored. Numerous publications have displayed that molecules related to TGF-p signalling were implicated in fibrosis, so it is an important target in the progression of intestinal fibrosis because it correlates with the complex and diverse signalling pathways regulating the mechanism of the progression of intestinal fibrosis in IBD. Therefore, TGF-p signalling is a potential strategy to treat and alleviate fibrosis in several fibrotic diseases including IBD. (Yun S. M. et al.; Binabaj M.M et al.).

[0018] Potent inhibitors of TGFpRII-TGFpRI (ALK5) have been described in W02021 / 105317 including the compound ( / V-(2,6-difluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 / 7-pyrazol-1- yl)acetamide) which is the compound of formula (I) as shown below (see Example 24):

[0019] There remains a need in the art to identify new solid forms of the compound of formula (I) or a pharmaceutically acceptable salt thereof. SUMMARY OF THE INVENTION

[0020] In one aspect, the invention provides a crystalline phase form of a compound of formula (I): namely f / V-(2,6-difluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 / 7-pyrazol-1- yl)acetamide), wherein the crystalline phase form is the crystalline phase Form 1 polymorph.

[0021] In a further aspect the invention provides the crystalline phase Form 2 polymorph (1 ,4-dioxane solvate) of the compound of formula (I).

[0022] In further aspects, the invention provides crystalline phase forms of the compound of formula (I) with acids including salts and co-crystals thereof as described herein.

[0023] BRIEF DESCRIPTION OF THE FIGURES

[0024] Figure 1 shows the XRPD pattern of the crystalline phase Form 1 polymorph of the compound of formula (I).

[0025] Figure 2 shows the results of TGA and DSC on the crystalline phase Form 1 polymorph of the compound of formula (I).

[0026] Figure 3 shows the results of DVS analysis on the crystalline phase Form 1 polymorph of the compound of formula (I).

[0027] Figure 4 shows the sorption-desorption isotherm from DVS analysis on the crystalline phase Form 1 polymorph of the compound of formula (I).

[0028] Figure 5 shows a comparison of the XRPD pattern of the crystalline phase Form 1 polymorph of the compound of formula (I) before and after the DVS analysis experiment. Figure 6 shows a comparison of the XRPD pattern of the crystalline phase Form 1 polymorph of the compound of formula (I) before and after storage in an accelerated stability test.

[0029] Figure 7 shows the XRPD pattern of the crystalline phase Form 2 polymorph (1 ,4-dioxane solvate) of the compound of formula (I).

[0030] Figure 8 shows the results of TGA and DSC on the crystalline phase Form 2 polymorph (1 ,4-dioxane solvate) of the compound of formula (I).

[0031] Figure 9 shows the results of storage stability investigation of the crystalline phase Form 2 polymorph (1 ,4-dioxane solvate) of the compound of formula (I).

[0032] Figure 10 shows the XRPD pattern of the crystalline phase Form SC1 polymorph of the compound of formula (I) with succinic acid.

[0033] Figure 11 shows the XRPD pattern of the crystalline phase Form G1 polymorph of the compound of formula (I) with gentisic acid.

[0034] Figure 12 shows the XRPD pattern of the crystalline phase Form M1 polymorph of the compound of formula (I) with maleic acid.

[0035] Figure 13 shows the XRPD pattern of the crystalline phase Form M2 polymorph of the compound of formula (I) with maleic acid.

[0036] Figure 14 shows the XRPD pattern of the crystalline phase Form M3 polymorph of the compound of formula (I) with maleic acid.

[0037] Figure 15 shows the XRPD pattern of the crystalline phase Form M4 polymorph of the compound of formula (I) with maleic acid.

[0038] Figure 16 shows the XRPD pattern of the crystalline phase Form M5 polymorph of the compound of formula (I) with maleic acid.

[0039] Figure 17 shows the XRPD pattern of the crystalline phase Form M6 polymorph of the compound of formula (I) with maleic acid. Figure 18 shows the XRPD patters of the crystalline phase Form C1 of the compound of formula (I) with hydrochloric acid.

[0040] Figure 19 shows the XRPD pattern of the crystalline phase Form B1 polymorph of the compound of formula (I) with hydrobromic acid.

[0041] Figure 20 shows the XRPD pattern of the crystalline phase Form B2 polymorph of the compound of formula (I) with hydrobromic acid.

[0042] Figure 21 shows the XRPD pattern of the crystalline phase Form SF1 polymorph of the of the compound of formula (I) with sulfuric acid.

[0043] Figure 22 shows the XRPD pattern of the crystalline phase Form SF2 polymorph of the compound of formula (I) with sulfuric acid.

[0044] Figure 23 shows the XRPD pattern of the crystalline phase Form SF3 polymorph of the compound of formula (I) with sulfuric acid.

[0045] Figure 24 shows the XRPD pattern of the crystalline phase Form S1 polymorph of the compound of formula (I) with saccharine.

[0046] Figure 25 shows the XRPD pattern of the crystalline phase Form S2 polymorph of the compound of formula (I) with saccharine.

[0047] Figure 26 shows the XRPD pattern of the solid amorphous form of the compound of formula (I)

[0048] Figure 27 shows the results of storage stability investigation of the solid amorphous form of the compound of formula (I).

[0049] DETAILED DESCRIPTION OF THE INVENTION

[0050] Crystalline Phase Form 1 polymorph

[0051] In a first aspects the invention provides the compound of formula (I) in crystalline phase form wherein the crystalline phase form is the crystalline phase Form 1 polymorph.

[0052] The crystalline phase Form 1 polymorph of the compound of formula (I) suitably has an XRPD pattern substantially as shown in Figure 1. A table of peaks from Figure 1 is set out as Table 1 below: Table 1 : Peak listing for XRPD pattern of Form 1

[0053] The crystalline phase Form 1 polymorph of the compound of formula (I) suitably has an XRPD pattern comprising three, four, five, six, seven, eight, nine or ten peaks selected from 10.5, 14.3, 16.9, 18.6, 19.3, 21.1 , 22.3, 22.5, 26.6 and 28.6 (± 0.2) degrees 2-theta. For example, the crystalline phase Form 1 polymorph of the compound of formula (I) suitably has an XRPD pattern comprising all ten peaks selected from 10.5, 14.3, 16.9, 18.6, 19.3, 21.1 , 22.3, 22.5, 26.6 and 28.6 (± 0.2) degrees 2-theta. Suitably the XRPD pattern comprises three, four, five, six, seven, eight, nine or ten peaks (e.g. all ten peaks) as aforesaid wherein the said peaks are present with relative intensity of at least 20%, e.g. at least 30%. The crystalline phase Form 1 polymorph of the compound of formula (I) suitably has an XRPD pattern comprising one, two, three, four, or five further peaks selected from 6.1 , 13.4, 16.2, 24.4 and 25.1 (± 0.2) degrees 2-theta. For example, the crystalline phase Form 1 polymorph of the compound of formula (I) suitably has an XRPD pattern comprising all five peaks selected from 6.1 , 13.4, 16.2, 24.4 and 25.1 (± 0.2) degrees 2-theta. Suitably the XRPD pattern comprises three, four or five further peaks (e.g. all five further peaks) as aforesaid wherein the said peaks are present with relative intensity of at least 10%, e.g. at least 20%. Suitably the XRPD pattern of crystalline phase Form 1 polymorph of the compound of formula (I) comprises a peak at 6.1 (± 0.2) degrees 2-theta; a peak at this position is not found in the XRPD pattern of the crystalline phase Form 2 polymorph (1 ,4-dioxane solvate) of the compound of formula (I). Suitably the XRPD pattern of the Form 1 polymorph of the compound of formula (I) does not comprise a peak at 9.0 (± 0.2) degrees 2-theta; a prominent peak at this position is found in the XRPD pattern of the crystalline phase Form 2 polymorph (1 ,4- dioxane solvate) of the compound of formula (I).

[0054] In connection with the peak of an XRPD pattern, the term “relative intensity” means the intensity of said peak as a percentage of the intensity of the most intense peak in the pattern.

[0055] XRPD experiments will typically be performed using CuKal radiation as further described in General Methods.

[0056] The crystalline phase Form 1 polymorph of the compound of formula (I) suitably has unit cell dimensions as determined by SCXRD of about 14.71 Angstrom (dimension a), about 16.77 Angstrom (dimension b) and about 9.58 Angstrom (dimension c) in space group P2i / c, with a angle of 90 °C, angle of about 107.9 °C, and y angle of 90 °C.

[0057] XRPD pattern and unit cell dimension determinations may be made using the methods described in General Methods below.

[0058] As further explained in the Examples section, the Form 1 polymorph of the compound of formula (I) has a number of surprising properties which are favourable for its development as a pharmaceutical product. For example, the Form 1 polymorph is thermodynamically stable and has a high melting point, is not hygroscopic and is polymorphically stable on storage (see Figures 2-6) and under application of pressure.

[0059] The Form 1 polymorph of the compound of formula (I) may be prepared by a number of crystallisation methods including solvent evaporation, cooling crystallisation, antisolvent addition crystallisation (direct and inverse) and quench cooling.

[0060] In an exemplary solvent evaporation method, compound of formula (I) is dissolved in the minimum amount of solvent at room temperature (ca 20-25 °C) and the solution left to evaporate at room temperature (ca 20-25 °C). Crystals of Form 1 polymorph may be produced. Suitable solvents which may be used include acetone, chloroform, dichloromethane, 1 ,2-dimethoxyethane, N,N- dimethylformamide, ethanol, isobutanol, methyl acetate, methyl ethyl ketone, methanol, 3- pentanone, 1-propanol and tetrahydrofuran. Alternatively, the compound of formula (I) may be dissolved in the minimum amount of solvent at reflux or a maximum of 75 °C and the solution left to evaporate at that temperature. Crystals of Form 1 polymorph may be produced. Suitable solvents which may be used include acetone, acetonitrile, ethyl acetate, 2-butanol, dimethyl carbonate, chlorobenzene, chloroform, dichloromethane, N,N-dimethylacetamide, 1 ,2- dimethoxyethane, ethanol, ethyl formate, isobutanol, isopropanol, methyl acetate, methyl ethyl ketone, methyl isobutyl ketone, methanol, n-butanol, nitromethane, 3-pentanone, 1-propanol, tertbutanol and tetrahydrofuran. Alternatively, the compound of formula (I) may be dissolved in the minimum amount of solvent and the solution left to evaporate at around 4 °C. Crystals of Form 1 polymorph may be produced. Suitable solvents which may be used include chloroform, dichloromethane, methanol and tetrahydrofuran.

[0061] In an exemplary cooling crystallisation method, a hot concentrated (e.g. saturated) solution of the compound (I) in a solvent is slowly cooled. For example the solution is dissolved in the minimum amount of solvent at reflux or a maximum of 75 °C and slowly cooled to room temperature (ca 20- 25 °C). Crystals of Form 1 polymorph may be produced. Suitable solvents may be selected from acetone, acetonitrile, ethyl acetate, isopropyl acetate, propyl acetate, 2-butanol, dimethyl carbonate, chlorobenzene, dichloromethane, 1 ,2-dimethoxyethane, ethanol, ethyl formate, isobutanol, isopropanol, methyl acetate, methyl ethyl ketone, methyl isobutyl ketone, methanol, n-butanol, nitromethane, 3-pentanone, 1-propanol, tert-butanol, tetra hydrofuran and toluene.

[0062] In an exemplary direct antisolvent addition crystallisation method, compound of formula (I) is dissolved in the minimum amount of solvent at reflux or a maximum of 75 °C and antisolvent is slowly added until crystallisation starts (indicated by the presence of turbidity) and then the mixture is slowly cooled to room temperature (ca 20-25 °C). Crystals of Form 1 polymorph may be produced. Suitable antisolvents include heptane and diisopropyl ether. Suitable solvents which may be used include acetone, dimethylcarbonate, ethanol, isobutanol, isopropanol, methyl acetate, n-butanol and tetrahydrofuran.

[0063] In an exemplary inverse antisolvent addition crystallisation method, compound of formula (I) is dissolved in the minimum amount of solvent at reflux or a maximum of 75 °C and the solution is added at room temperature (ca 20-25 °C) over cold water (ca 4-10 °C). Crystals of Form 1 polymorph may be produced. Suitable solvents may be selected from acetone, dimethylcarbonate, ethanol, isobutanol and isopropanol.

[0064] In another exemplary inverse antisolvent addition crystallisation method, compound of formula (I) is dissolved in the minimum amount of solvent at reflux or a maximum of 75 °C and the solution is added dropwise over antisolvent at room temperature (ca 20-25 °C). Crystals of Form 1 polymorph may be produced. Suitable antisolvents include heptane and diisopropyl ether. Suitable solvents which may be used include acetone, dimethylcarbonate, ethanol, isobutanol, isopropanol, methyl acetate, methyl ethyl ketone, n-butanol and tetrahydrofuran.

[0065] In an exemplary quench cooling method, compound of formula (I) is dissolved in the minimum amount of solvent at reflux or a maximum of 75 °C and the solution is quickly cooled in an ice bath. Crystals of Form 1 polymorph may be produced. Suitable solvents may be selected from acetone, ethyl acetate, dimethylcarbonate, chlorobenzene, dichloromethane, 1 ,2- dimethoxyethane, methyl ethyl ketone, n-butanol and tetrahydrofuran.

[0066] The invention provides a process for preparing a crystalline phase form of a compound of formula (I): wherein the crystalline phase form is the crystalline phase Form 1 polymorph which comprises dissolving compound of formula (I) in a solvent e.g. selected from acetone, acetonitrile, ethyl acetate, isopropyl acetate, propyl acetate, 2-butanol, dimethylcarbonate, chlorobenzene, chloroform, dichloromethane, N,N-dimethylacetamide, 1 ,2-dimethoxyethane, ethanol, ethyl formate, isobutanol, isopropanol, methyl acetate, methyl ethyl ketone, methyl isobutyl ketone, methanol, n-butanol, nitromethane, 3-pentanone, 1 -propanol, tert-butanol, tetrahydrofuran and toluene and crystallising the crystalline phase Form 1 polymorph therefrom. In one aspect, the crystallising comprises cooling a hot solution of compound of formula (I) in a solvent (e.g. cooling a solution from reflux temperature or from a maximum temperature of around 75 °C). In one aspect, the crystallising comprises evaporating the solvent. In one aspect the crystallising comprises adding an antisolvent e.g. an antisolvent selected from water, n-heptane and diisopropyl ether to a solution of compound of formula (I) in a solvent. In one aspect the crystallising comprises adding a solution of compound of formula (I) in a solvent to an antisolvent e.g. an antisolvent selected from water, n-heptane and diisopropyl ether.

[0067] As used herein, by “reflux or a maximum of 75 °C” is meant a temperature which is the lesser of reflux temperature (i.e. solvent boiling point temperature) and 75 °C.

[0068] Crystalline phase Form 2 polymorph (1,4-dioxane solvate)

[0069] In a further aspect the invention provides the crystalline phase Form 2 polymorph (1 ,4-dioxane solvate) of the compound of formula (I). Suitably the stoichiometry is 2:1 (i.e. two molecules of compound of formula to one molecule of solvent i.e. 1 ,4-dioxane) i.e. suitably the solvate is a hemisolvate.

[0070] The crystalline phase Form 2 polymorph (1 ,4-dioxane solvate) may be prepared by anti-solvent addition crystallisation methods (direct or inverse) with n-heptane as antisolvent or by quench cooling.

[0071] In an exemplary direct antisolvent crystallisation method, compound of formula (I) is dissolved in the minimum amount of 1 ,4-dioxane at around 75 °C (e.g. 70-75 °C) and n-heptane is slowly added until crystallisation starts and then the mixture is slowly cooled to room temperature (ca 20-25 °C). Crystals of the Form 2 polymorph (1 ,4-dioxane solvate) may be produced.

[0072] In an exemplary inverse antisolvent addition crystallisation method, compound of formula (I) is dissolved in the minimum amount of 1 ,4-dioxane at around 75 °C (e.g. 70-75 °C) and added dropwise to n-heptane at room temperature (ca 20-25 °C). Crystals of the Form 2 polymorph (1 ,4-dioxane solvate) may be produced.

[0073] In an exemplary quench cooling method, compound of formula (I) is dissolved in the minimum amount of 1 ,4-dioxane at around 75 °C (e.g. 70-75 °C) and quickly cooled in an ice bath. Crystals of the Form 2 polymorph (1 ,4-dioxane solvate) may be produced.

[0074] The crystalline phase Form 2 polymorph (1 ,4-dioxane solvate) of the compound of formula (I) suitably has an XRPD pattern substantially as shown in Figure 7. The XRPD pattern of the crystalline phase Form 2 polymorph (1 ,4-dioxane solvate) of the compound of formula (I) comprises a peak at 9.0 (± 0.2) degrees 2-theta; a peak at this position is not found in the XRPD pattern of the crystalline phase Form 1 polymorph of the compound of formula (I). The XRPD pattern of the Form 2 polymorph (1 ,4-dioxane solvate) of the compound of formula (I) does not comprise a peak at 6.1 (± 0.2) degrees 2-theta; a prominent peak at this position is found in the XRPD pattern of the Form 1 polymorph of the compound of formula (I).

[0075] Crystalline phase forms of the compound of formula (I) with acids

[0076] The compound of formula (I) contains one basic nitrogen atom with a calculated pKa of 3.7. Accordingly, it is expected that the compound of formula (i) may form a salt with strong acids and said salt may crystallise. When the compound of formula (I) forms a crystalline phase form together with a weak acid (such as an acid with a pKa > 3.7), said crystalline form is unlikely to be a salt and alternatively may be a co-crystal. According to standard definition, in a salt, a proton from the acid is transferred to the base, creating a charge separation and an ionic interaction. In a co-crystal the proton is not transferred, therefore, there is no charge separation.

[0077] The invention also provides a crystalline phase form of a compound of formula (I): with an acid species wherein the crystalline phase form is a crystalline salt form or a co-crystal.

[0078] In a first embodiment, the acid is succinic acid. Succinic acid has an ionizable acid group with a pKa value of around 4.2 and a second ionizable group with a pKa of around 5.6. Suitably the stoichiometry is 2:1 (i.e. two molecules of compound of formula (I) to one molecule of succinic acid). In an embodiment the crystalline phase form is anhydrous and is not a solvate. In an embodiment the crystalline phase form is the crystalline phase Form SC1. Suitably the crystalline phase Form SC1 has an XRPD pattern substantially as shown in Figure 10.

[0079] In a second embodiment, the acid is gentisic acid. Gentisic acid has an ionizable acid group with a pKa value of around 2.5. Suitably the stoichiometry is 2:1 (i.e. two molecules of compound of formula (I) to one molecule of gentisic acid). In an embodiment, the crystalline phase form is a co-crystal. In an embodiment the crystalline phase form is anhydrous and is not a solvate. In an embodiment the crystalline phase form is the crystalline phase Form G1. Suitably the crystalline phase Form G1 has an XRPD pattern substantially as shown in Figure 11.

[0080] In a third embodiment, the acid is maleic acid. Maleic acid has an ionizable acid group with a pKa value of around 1.9 and a second ionizable group with pKa of around 6.9. Suitably the stoichiometry is 1 :1 (i.e. one molecule of compound of formula (I) to one molecule of maleic acid). In an embodiment, the crystalline phase form is a salt. In an embodiment the crystalline phase form is anhydrous and is not a solvate. In an embodiment the crystalline phase form is the crystalline phase Form M1 polymorph. Suitably the Form M1 polymorph has an XRPD pattern substantially as shown in Figure 12. In another embodiment the crystalline phase form is the crystalline phase Form M2 polymorph. Suitably the Form M2 polymorph has an XRPD pattern substantially as shown in Figure 13. In another embodiment the crystalline phase form is the crystalline phase Form M3 polymorph. Suitably the Form M3 polymorph has an XRPD pattern substantially as shown in Figure 14. In another embodiment the crystalline phase form is the crystalline phase Form M4 polymorph. Suitably the Form M4 polymorph has an XRPD pattern substantially as shown in Figure 15. In another embodiment the crystalline phase form is the crystalline phase Form M5 polymorph. Suitably the Form M5 polymorph has an XRPD pattern substantially as shown in Figure 16. In another embodiment the crystalline phase form is the crystalline phase Form M6 polymorph. Suitably the Form M6 polymorph has an XRPD pattern substantially as shown in Figure 17.

[0081] In a fourth embodiment, the acid is hydrochloric acid. Hydrochloric acid has an ionizable acid group with a pKa value of around -5.9. Suitably the stoichiometry is 1 :1 (i.e. one molecules of compound of formula (I) to one molecule of hydrochloric acid). In an embodiment, the crystalline phase form is a salt. In an embodiment the crystalline phase form is anhydrous and is not a solvate. In an embodiment the crystalline phase form is the crystalline phase Form C1 polymorph. Suitably the Form 01 polymorph has an XRPD pattern substantially as shown in Figure 18.

[0082] In a fifth embodiment, the acid is hydrobromic acid. Hydrobromic acid has an ionizable acid group with a pKa value of around -9. Suitably the stoichiometry is 1 :1 (i.e. one molecule of compound of formula (I) to one molecule of hydrobromic acid). In an embodiment, the crystalline phase form is a salt. In one embodiment the crystalline phase form is the crystalline phase Form B1 polymorph. Suitably the Form B1 polymorph has an XRPD pattern substantially as shown in Figure 19. In an embodiment the crystalline phase form is anhydrous and is not a solvate. In another embodiment the crystalline phase form is the crystalline phase Form B2 polymorph. Suitably the Form B2 polymorph has an XRPD pattern substantially as shown in Figure 20. In an embodiment the crystalline phase form is a hydrate.

[0083] In a sixth embodiment, the acid is sulfuric acid. Sulfuric acid has two ionizable acid groups with pKa values of around -2.8 and around 2.0. Suitably the stoichiometry is 2:1 (i.e. two molecules of compound of formula (I) to one molecule of sulfuric acid). In an embodiment, the crystalline phase form is a salt. In one embodiment the crystalline phase form is the crystalline phase Form SF1 polymorph. Suitably the Form SF1 polymorph has an XRPD pattern substantially as shown in Figure 21. In an embodiment the crystalline phase form is anhydrous and is not a solvate. In another embodiment the crystalline phase form is the crystalline phase Form SF2 polymorph. Suitably the Form SF2 polymorph has an XRPD pattern substantially as shown in Figure 22. In an embodiment the crystalline phase form is a solvate (hydrate). In another embodiment the crystalline phase form is the crystalline phase Form SF3 polymorph. Suitably the Form SF3 polymorph has an XRPD pattern substantially as shown in Figure 23. In an embodiment the crystalline phase form is anhydrous and is not a solvate.

[0084] In a seventh embodiment, the acid is saccharine. Saccharine has an ionizable acid group with a pKa value of around 1.6. Suitably the stoichiometry is 1 :1 (i.e. one molecules of compound of formula (I) to one molecule of saccharine). In an embodiment, the crystalline phase form is a salt. In an embodiment the crystalline phase form is a solvate (hydrate). In an embodiment the crystalline phase form is the crystalline phase Form S1 polymorph. Suitably the Form S1 polymorph has an XRPD pattern substantially as shown in Figure 24. In another embodiment the crystalline phase form is the crystalline phase Form S2 polymorph. Suitably the Form S2 polymorph has an XRPD pattern substantially as shown in Figure 25.

[0085] Crystalline phase forms of the compound of formula (I) with an acid may be prepared by mixing the desired equivalent of the corresponding acid (such as 1 equivalent, or 0.5 equivalent in the case of sulfuric acid or gentisic acid) with compound of formula (I) (as base). A range of conditions may be used to obtain crystalline phase forms as further described in the Examples section. In one method, a hot solution of the acid / base mixture in a solvent e.g. selected from acetone, acetonitrile, ethyl acetate, tetra hydrofuran and isopropanol is slowly cooled (“cooling crystallisation method”). Crystallisation of a salt or co-crystal form may occur. In another method, a slurry may be prepared of the acid / base mixture in a solvent in which it is not fully soluble at high temperature (reflux or a maximum of 75 °C) which was held for 1 hour. Crystallisation of a salt or co-crystal form may occur. In a variation on these conditions, the slurry may be held at room temperature (ca 20-25 °C) for 7 days. Crystallisation of a salt or co-crystal form may occur. In another method, a solution of the acid / base mixture in a solvent e.g. selected from acetone, acetonitrile, ethyl acetate, tetra hydrofuran and isopropanol is prepared and the solvent allowed to evaporate at room temperature (ca 20-25 °C). Crystallisation of a salt or co-crystal form may occur.

[0086] Compound of formula (I)

[0087] The compound of formula (I) may be prepared as described in W02021 / 105317 (see general synthesis and Example 24 in particular), the contents of which patent publication are herein incorporated by reference in their entirety.

[0088] Compositions and uses

[0089] As used herein, the crystalline phase Form 1 polymorph, the crystalline phase Form 2 polymorph (1 ,4-dioxane solvate) and the crystalline phase forms of the compound of formula (I) with acids including polymorphs described herein are referred to as “crystalline phase forms of the invention”. As used herein the compound of formula (I) is sometimes referred to as the “active ingredient of the invention”.

[0090] The invention provides a pharmaceutical composition comprising a crystalline phase form of the invention and a pharmaceutically acceptable diluent or carrier.

[0091] The compound of the invention has a low systemic exposure after oral, topical or ocular administration, due to its low metabolic stability, so the solid forms of the invention are especially suited for the prevention or treatment of diseases as further described herein.

[0092] The crystalline phase forms of the invention may be administered by any convenient method, e.g. by oral, parenteral, buccal, sublingual, nasal, rectal, transdermal administration, intratympanic and intracochlear, and the pharmaceutical compositions adapted accordingly. Oral administration may be particularly convenient. Topical and ocular administration may also be convenient.

[0093] Compositions for oral administration can be formulated as liquids or solids, e.g. as elixirs, syrups, suspensions, emulsions, tablets, capsules or lozenges.

[0094] A liquid composition will generally consist of a suspension or solution of the crystalline phase form of the invention in a suitable liquid carrier(s) e.g. an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also comprise 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.

[0095] A composition in the form of a capsule can be prepared using routine encapsulation procedures, e.g. pellets comprising the crystalline phase form of the invention 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 suspension then filled into a soft gelatin capsule.

[0096] Typical parenteral compositions consist of a solution or suspension of a crystalline phase form of the invention in a sterile aqueous carrier or parenterally acceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. In an embodiment, parenteral compositions are suitable for injection.

[0097] Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of a crystalline phase form of the invention in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container which can take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container may be a disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve. Where the dosage form comprises an aerosol dispenser, it will comprise a propellant which can be a compressed gas e.g. air, or an organic propellant such as a fluorochlorohydrocarbon or hydrofluorocarbon. Aerosol dosage forms can also take the form of pump-atomisers.

[0098] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles where the crystalline phase form of the invention is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

[0099] Compositions for rectal administration are conveniently in the form of suppositories comprising a conventional suppository base such as cocoa butter.

[0100] Compositions suitable for transdermal administration include ointments, gels and patches. In one embodiment the composition is in unit dose form such as a tablet, capsule or ampoule. The composition may comprise from 0.001% to 99.9% by weight, preferably 0.01% to 90% by weight e.g. 10% to 60% by weight of the active ingredient of the invention (i.e. , the compound of formula (I)), depending on the method of administration. The composition may comprise from 0.1 % to 99.999% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration. The composition may comprise from 0.05 mg to 1000 mg, for example from 2.0 mg to 500 mg or from 1.0 mg to 500 mg of the active ingredient of the invention, depending on the method of administration. The composition may comprise from 50 mg to 1000 mg, for example from 100 mg to 400 mg of the carrier, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide, suitable unit doses may be 0.05 mg to 1000 mg, more suitably 1.0 mg to 500 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.

[0101] The dose provided to a subject will typically be a safe and effective dose, i.e. an amount providing an acceptable balance of desired benefits and undesired side effects. A “safe and effective amount" is intended to include an amount of a compound that is effective to achieve a desirable effect in treatment and / or prophylaxis of a disease-state. A desirable effect is typically clinically significant and / or measurable, for instance in the context of (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., slowing or arresting its development; and / or (c) relieving the disease-state, i.e., causing regression of the disease state or a reduction in associated symptoms. The safe and effective amount may be one that is sufficient to achieve the desirable effect either when the crystalline phase form of the invention is administered alone, or alternatively when it is administered in combination with one or more further active ingredients which are not the same as the compound of formula (I).

[0102] For avoidance of doubt, a “safe and effective amount” as recited herein can be achieved by any suitable dosage regimen, including but not limited to exemplary dosage regimens described elsewhere herein. Hence, for example, references herein to administering a safe and effective amount of a compound, such as by a particular administration route, include achieving the safe and effective amount via a single dose or by plural doses, such as administered by the specified administration route. For instance, orally administering a safe and effective amount includes both orally administering a single dose and orally administering any plural number of doses, provided that a safe and effective amount is thereby achieved by oral administration. The invention provides, in a further aspect, a combination comprising a crystalline phase form of the invention e.g. a combination comprising a crystalline phase form of the invention together with a further pharmaceutically acceptable active ingredient or ingredients.

[0103] The invention provides a crystalline phase form of the invention for use in combination with a further pharmaceutically acceptable active ingredient or ingredients.

[0104] When crystalline phase form of the invention is used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route. Alternatively, the compounds may be administered separately.

[0105] The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. The individual components of combinations may also be administered separately, through the same or different routes.

[0106] When a crystalline phase form of the invention is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.

[0107] Suitably, a crystalline phase form of the invention is administered orally.

[0108] Suitably, a crystalline phase form of the invention is administered at 2 to 2000 mg per day such as 2 to 1200 mg per day, such as 2 to 800 mg per day, in particular 2 to 400 mg per day, especially 2 to 300 mg per day, for example 5 to 250 mg per day.

[0109] Suitably, a crystalline phase form of the invention is administered 1-4 times per day e.g. once or twice per day.

[0110] Suitably, a crystalline phase form of the invention is administered for a period of at least three months. Desirably, a crystalline phase form of the invention is administered orally, once or twice per day, 2 to 1200 mg per day, such as 2 to 800 mg per day, in particular 2 to 400 mg per day, especially 2 to 300 mg per day, for example 5 to 250 mg per day.

[0111] A human subject may be an adult, such as aged 18 to 65. Alternatively, a human subject may be 66 years old or older. A crystalline phase form of the invention may be administered to a human subject of less than 18 years of age, such as 4 to 17 years old.

[0112] The invention provides a crystalline phase form of the invention for use in the treatment or prevention of a disease or pathological condition susceptible to ameliorate by inhibition of transforming growth factor-p receptor I (TGFPRI / ALK5). The invention also provides use of a crystalline phase form of the invention the manufacture of a medicament for the treatment and / or prevention of a disease or pathological condition susceptible to ameliorate by inhibition of transforming growth factor-p receptor I (TGFPRI / ALK5). The invention also provides a method for the treatment or prevention of a disease or pathological condition susceptible to ameliorate by inhibition of transforming growth factor-p receptor I (TGFPRI / ALK5) comprising the administration to a subject in need thereof of a crystalline phase form of the invention.

[0113] Such a disease or pathological condition may for example be selected from the group consisting of gastrointestinal diseases, fibrotic diseases, cancer and graft vs. host disease (GVHD).

[0114] The invention also provides a combination comprising a crystalline phase form of the invention and a therapeutic agent used for the treatment or prevention of a disease selected from the group consisting of gastrointestinal diseases, fibrotic diseases, cancer and graft vs. host disease (GVHD).

[0115] As used herein the term “fibrotic disease(s)” refers to diseases characterized by excessive scarring due to excessive 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. In particular, the term fibrotic diseases refers to fibrosis of the digestive tract or intestinal fibrosis, such as fibrostenosing Crohn’s disease (FSCD). In particular, the term fibrotic diseases refers to hepatic fibrosis, also known as liver fibrosis, such as cirrhosis, alcohol induced liver fibrosis, toxic / drug induced liver fibrosis, hemochromatosis, nonalcoholic 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. In particular, the term fibrotic diseases refers to 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. In particular, the term fibrotic diseases refers to fibrotic renal diseases such as glomerulonephritis (GN) (e.g. mesangial proliferative GN, immune GN and crescentic GN), diabetic nephropathy, renal interstitial fibrosis and renal fibrosis in transplant patients. In particular, the term fibrotic diseases refers to 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. In particular, the term fibrotic diseases refers to fibrotic lung diseases such as idiopathic pulmonary fibrosis, and upper airway stenosis including idiopathic subglottic stenosis, iatrogenic laryngotracheal stenosis, and autoimmune upper airway stenosis.

[0116] The disease “non-alcoholic steatohepatitis (NASH)” is also known as metabolic dysfunction- associated steatohepatitis (MASH); the terms are interchangeable.

[0117] As used herein, the term “gastrointestinal diseases” refers to diseases which affect the gastrointestinal 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 refers to inflammatory bowel diseases (IBD), post-radiation enteritis, complicated celiac disease and intestinal fibrosis.

[0118] 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 refers to fibrostenosing CD.

[0119] The commonly used Montreal classification system categorizes CD patients into non-stricturing [B1], stricturing [B2], or penetrating [B3] sub-types. Stricturing disease is characterised by the narrowing of the intestinal lumen caused by the fibrosis developing in the submucosal layer. The penetrating phenotype is characterised by the formation of fistulae (abnormal communications between two epithelialized surfaces). They can be defined anatomically; those arising internally and those involving the perineum. Internal fistulae may be further classified into those forming an internal communication with another bowel layer (ie, enteroenteric) or a communication between the intestine and other organs (ie, enterocutaneous or enterovesical). Therefore, in specific embodiments, the term CD refers to non-stricturing CD, stricturing CD or penetrating CD. As used herein, the term “cancer” includes, and refers in particular to, breast, colon, oesophageal, gastric, colorectal, hepatocellular, lung or pancreatic cancer. In particular, the term refers to cancers which affects the oesophagus or the gastrointestinal tract, such as gastric cancer, oesophageal cancer or colorectal cancer.

[0120] Therefore, the present invention provides a crystalline phase form of the invention for use in the treatment or prevention of a fibrotic 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’s disease (FSCD).

[0121] Therefore, the present invention provides a crystalline phase form of the invention for use in the treatment or prevention of inflammatory bowel diseases. In particular, the inflammatory bowel disease is selected from Crohn’s disease and ulcerative colitis. In particular, the inflammatory bowel disease is fibrostenosing CD.

[0122] Examples

[0123] General methods

[0124] XRPD analysis

[0125] Sample preparation: 20 mg of non-manipulated sample were prepared in standard sample holders using two foils of polyacetate.

[0126] Data acquisition: Powder diffraction patterns were acquired on a Bruker D8 Advance Series 2Theta / Theta powder diffraction system using CuKal -radiation operated at 40 kV and 40 mA in transmission geometry. The system is equipped with a VANTEC-1 single photon counting PSD, a Germanium monochromator, a ninety positions auto changer sample stage, fixed divergence slits and a radial soller. Programs used: Data collection with DIFFRAC plus XRD Commander V.2.5.1 , and evaluation with High Score Plus 4.9 (Malvern PANalytical B.V.).

[0127] Measurement conditions: The samples were measured in a range from 4 to 40° in 20 in a 6 or 30 minutes measurement using an angular step of 0.05° and a time per step of 432 or 2198 s.

[0128] SCXRD analysis

[0129] Data collection: The measured crystals were prepared under inert conditions immersed in perfluoropolyether as protecting oil for manipulation. Crystal structure determination was carried out using a Rigaku diffractometer equipped with a Pilatus 200K area detector, a Rigaku MicroMax- 007HF microfocus rotating anode with MoKa 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 co and (p scans. Programs used: Data collection and reduction with CrysAlisPro V / .60A (CrysAlisPro 1.171.39.12b (Rigaku OD, 2015)). Empirical absorption correction using spherical harmonics with Scale3 Abspack scaling algorithm (CrysAlisPro 1.171.39.12b (Rigaku OD, 2015)).

[0130] Structure Solution and Refinement: Crystal structure solution was achieved using the computer program SHELXT (Sheldrick, G.M. Acta Cryst. 2015 A71 , 3-8). Visualization was performed with the program SHELXle (C.B. Huebschle, G.M. Sheldrick & B. Dittrich; J.Appl.Cryst. 2011 44, 1281- 1284). Missing atoms were subsequently located from difference Fourier synthesis and added to the atom list. Least-squares refinement on F2using all measured intensities was carried out using the program SHELXL 2015 (Sheldrick, G.M. Acta Cryst. 2015 C71 , 3-8). All non- hydrogen atoms were refined including anisotropic displacement parameters.

[0131] DSC analysis

[0132] Sample preparation: Approximately 1-4 mg of sample were weighed (using a MX5 Mettler Toledo microbalance) into 40 pL aluminium crucibles with a pinhole lid.

[0133] Data acquisition: DSC analyses were recorded in a Mettler Toledo DSC822e calorimeter. Programs used: Data collection and evaluation with software STARe.

[0134] Measurement conditions: The samples were heated under dry nitrogen (flow rate: 50 mL / min) at 10 °C / min from 30 to 300 °C.

[0135] TGA analysis

[0136] Sample preparation: Approximately 1-4 mg of sample were weighed (using a MX5 Mettler Toledo microbalance) into 40 pL aluminium crucibles with a pinhole lid.

[0137] Data acquisition: Thermogravimetric analyses were recorded in a Mettler Toledo TGA / SDTA851 with a balance MT1 type. Programs used: Data collection and evaluation with software STARe.

[0138] Measurement conditions: The samples were heated under dry nitrogen (Flow rate: 10 mL / min) at 10 °C / min from 30 to 300 °C.

[0139] DVA analysis

[0140] Sample preparation’. Approximately 5-10 mg of sample were weighed (using a MX5 Mettler Toledo microbalance) into 150 pL platinum crucibles without lid.

[0141] Data acquisition’. 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.

[0142] Measurement conditions’. The samples were analysed following a humidity cycle from 10%RH up to 80%RH and down to 10%RH in 10% steps of 60 minutes at 25 °C. Preparation and evaluation of crystalline phase forms of the invention

[0143] Example 1

[0144] Crystalline phase Form 1 polymorph of the compound of formula (I)

[0145] Preparation

[0146] The crystalline phase Form 1 polymorph may be prepared by a number of methods.

[0147] (1) Solvent evaporation

[0148] (A) Compound of formula (I) (20 mg) was dissolved in the minimum amount of the corresponding solvent at room temperature. The solutions were left to evaporate at room temperature. All solids obtained were analysed by XRPD. The results are summarized in Table 2A.

[0149] Table 2A: Forms of compound of formula (I) obtained by solvent evaporation at room temperature

[0150] (B) Compound of formula (I) (20 mg) was dissolved at reflux or at a maximum of 75 °C in 2 mL of the corresponding solvent. The solutions were left to evaporate at 75°C in an open flask. All solids obtained were analysed by XRPD. The results are summarized in Table 2B.

[0151] Table 2B: Forms of compound of formula (I) obtained by solvent evaporation at reflux or at a maximum of 75 °C

[0152] (C) Compound of formula (I) (20 mg) was dissolved in the minimum amount of the corresponding solvent. The solutions were left to evaporate at around 4 °C. All solids obtained were analysed by XRPD. The results are summarized in Table 2C.

[0153] Table 2C: Forms of compound of formula (I) obtained by solvent evaporation at around 4 °C (2) Cooling crystallisation

[0154] Compound of formula (I) (20 mg) was dissolved in the minimum amount of the corresponding solvent at reflux or at a maximum of 75 °C. The solution was slowly cooled to room temperature. The solid was separated by decantation, dried in vacuum (2-5 mbar) for 2 hours at room temperature. All solids obtained were analysed by XRPD. The results are summarized in Table 3.

[0155] Table 3: Forms of compound of formula (I) obtained by cooling crystallization. (3) Antisolvent crystallisation

[0156] Compound of formula (I) (20 mg) was dissolved in the minimum amount of the dissolving solvent at reflux or at a maximum of 75°C. Then the antisolvent was slowly added until the crystallization started (indicated by the presence of turbidity), and then the mixture was slowly cooled to room temperature. The solid was separated by decantation, dried in vacuum (2- 5 mbar) for 2 hours at room temperature. All solids obtained were analysed by XRPD. The results are summarized in Table 4.

[0157] Table 4: Forms of compound of formula (I) obtained by direct antisolvent addition.

[0158] (4) Inverse antisolvent crystallisation

[0159] Compound of formula (I) (20 mg) was dissolved in the minimum amount of the dissolving solvent at reflux or a maximum of 75°C, and the solution was added over cold water (1 mL) or other antisolvent (1 mL) at room temperature. The solid was separated by decantation, dried in vacuum (2-5 mbar) for 2 hours at room temperature. All solids obtained were analysed by XRPD. The results are summarized in Tables 5A and 5B.

[0160] Table 5A: Forms of compound of formula (I) obtained by inverse antisolvent addition with water as antisolvent. Table 5B: Forms of compound of formula (I) obtained by inverse antisolvent addition with n- heptane or diisopropyl ether as antisolvent. (5) Quench cooling

[0161] Compound of formula (I) (20 mg) was dissolved in the minimum amount of the dissolving solvent at reflux or a maximum of 75°C, and the solution was quickly cooled in an ice bath. The solid was separated by decantation, dried in vacuum (2-5 mbar) for 2 hours at room temperature. All solids obtained were analysed by XRPD. The results are summarized in Table 6.

[0162] Table 6: Forms of compound of formula (I) obtained by quench cooling Characterisation

[0163] The XRPD pattern of the crystalline phase Form 1 polymorph is shown in Figure 1 . The material appears to be crystalline.

[0164] The crystalline phase Form 1 polymorph was evaluated by SCXRD.

[0165] SCXRD showed that Form 1 crystallizes in the monoclinic space group P2i / c with one molecule in the asymmetric unit. The unit cell dimensions were about 14.71 Angstrom (dimension a), about 16.77 Angstrom (dimension b) and about 9.58 Angstrom (dimension c), with a angle of 90 °C, p angle of about 107.9 °C, and y angle of 90 °C. The structure is of good quality (no A- or B- alerts) refining to a R1 of 5.9 %.

[0166] The crystalline phase Form 1 polymorph was evaluated by DSC. The results of the DSC experiment are shown in Figure 2. There was a single eendothermic melting peak with an onset at 190°C (-105 J / g).

[0167] The crystalline phase Form 1 polymorph was evaluated by TGA. The results of the TGA experiment are shown in Figure 2. The TGA analysis revealed mass loss of 0.29% between 147°C and 229°C. This implies that the material is anhydrous.

[0168] The crystalline phase Form 1 polymorph was evaluated by DVS. The results of the DVS experiment are shown in Figures 3 and 4. The relative humidity was raised from 10% to 80% and then decreased back to 10% in 10% steps of 60 minutes at25°C. In Figure 4 the desorption curve is initially below the sorption curve, then rises above it at 50% RH, is coincident at 60% RH and 80% RH, and is slightly above it at 70% RH. The moisture adsorption between 10% and 80%RH was 0.089%. The Form 1 polymorph was thus assessed to be non-hygroscopic. The form of the material after completion of the DVS experiment was investigated by XRPD. The material remained as the crystalline phase Form 1 polymorph (see Figure 5).

[0169] A sample of the crystalline phase Form 1 polymorph was kept in a climatic chamber at 25°C and 80%RH. After 4 days, the solid was analysed by XRPD. The material remained as the crystalline phase Form 1 polymorph (see Figure 6).

[0170] Pressure was applied to a sample of the crystalline phase Form 1 polymorph for 5 minutes with a tableting press (pressure of 9 tonnes). The solid was analysed afterwards by XRPD and it remained as Form 1. From these experiments it may be concluded that the crystalline phase Form 1 polymorph is a thermodynamically stable high melting point solid which is not hygroscopic and is polymorphically stable on storage and under application of pressure. The crystalline phase Form 1 polymorph therefore has a number of properties which are favourable for its development as a pharmaceutical product.

[0171] Example 2

[0172] Crystalline phase Form 2 polymorph (1 ,4-dioxane solvate) of the compound of formula (I) Preparation

[0173] The crystalline phase Form 2 polymorph (1 ,4-dioxane solvate) of the compound of formula (I) may be prepared by a number of methods.

[0174] (1) Direct antisolvent addition

[0175] A sample of the compound of formula (I) (20 mg) was dissolved in 0.3 mL of dioxane at a maximum of 75 °C. n-Heptane (antisolvent) was slowly added until crystallisation started, which was indicated by the presence of turbidity, and then the mixture was slowly cooled to room temperature. The solid was separated by decantation and dried in vacuum (2-5 mbar) for 2 hours at room temperature.

[0176] (2) Inverse antisolvent addition

[0177] Compound of formula (I) (20 mg) was dissolved in the minimum amount of 1 ,4-dioxane at a maximum of 75°C, and the solution was added to n-heptane (antisolvent, 1 mL) at room temperature. The solid was separated by decantation, dried in vacuum (2-5 mbar) for 2 hours at room temperature.

[0178] (3) Quench cooling

[0179] Compound of formula (I) (20 mg) was dissolved in the minimum amount of 1 ,4-dioxane at a maximum of 75°C, and the solution was quickly cooled in an ice bath. The solid was separated by decantation, dried in vacuum (2-5 mbar) for 2 hours at room temperature.

[0180] Characterisation

[0181] The XRPD pattern of the crystalline phase Form 2 polymorph (1 ,4-dioxane solvate) is shown in Figure 7.

[0182] DSC analysis (figure not shown) showed two endothermic peaks with onsets at 81 °C (-72 J / g) and at 191 °C (-100 J / g) (melting). The crystalline phase Form 2 polymorph (1 ,4-dioxane solvate) was evaluated by TGA. The results of the TGA experiment are shown in Figure 8. TGA analysis showed weight loss of 8.3% between 40 °C and 150 °C. In a separate experiment, in order to study the desolvation process based on the weight loss observed in the TGA, a sample of the crystalline dioxane solvate was heated to 120°C and cooled down to room temperature. The solid obtained was found to be the crystalline phase Form 1 polymorph by XRPD analysis (figure not shown). From TGA it may be inferred that the crystalline phase Form 2 polymorph (1 ,4-dioxane solvate) is a hemisolvate although this has not been determined.

[0183] The storage stability of the crystalline phase Form 2 polymorph (1 ,4-dioxane solvate) was evaluated. The results are shown in Figure 9. The crystalline phase Form 2 polymorph (1 ,4- dioxane solvate) was kept in a climatic chamber at 25°C and 80% RH. After 4 days, the solids were analysed by XRPD. The crystalline sample of the Form 2 polymorph (1 ,4-dioxane solvate) had transformed into the Form 1 polymorph in the climatic chamber conditions.

[0184] Example 3

[0185] Crystalline phase Form SC1 of the compound of formula (I) with succinic acid

[0186] Preparation

[0187] Compound of formula (I) (0.5 g, 1.06 mmol) was suspended in ethyl acetate (5 mL) and succinic acid (125 mg, 1.06 mmol, 1 eq) was added. The obtained suspension was heated to 75°C. Ethyl acetate was added up to complete dissolution (20 mL), and the clear solution obtained was slowly cooled to room temperature, seeded with crystalline phase Form SC1 and stirred overnight. Seed crystals of the crystalline phase Form SC1 were obtained by a small scale cooling crystallisation method using acetonitrile or ethyl acetate or acetone or isopropanol as solvent. Afterwards, the solid was filtered off in a filter plate (N. 3), washed with ethyl acetate (2.5 mL), and dried in vacuum at 35 °C for 3 hours. Yield: 0.425 g (68%).

[0188] Characterisation

[0189] The XRPD pattern of the crystalline phase Form SC1 of the compound of formula (I) with succinic acid is shown in Figure 10. Stoichiometry (compound of formula (I) to succinic acid) is assumed to be 2:1 although this has not been determined.

[0190] DSC analysis (figure not shown) showed endotherms with onsets at 136 °C (-9 J / g) and 159 °C (-84 J / g) TGA analysis (figure not shown) showed weight loss due to decomposition at ca 160 °C. This implies that the material is most likely anhydrous and is not a solvate.

[0191] DVS analysis (figure not shown) was performed from 10 to 90 to 10% of RH at 25 °C in 10% steps of 30 min. A weight gain of 0.40% between 10 and 80% of RH was recorded. The form of the material after completion of the DVS experiment was investigated by XRPD and no change in form was observed.

[0192] Example 4

[0193] Crystalline phase Form G1 of the compound of formula (I) with gentisic acid

[0194] Preparation

[0195] Compound of formula (I) (0.5 g, 1.06 mmol) was suspended in ethyl acetate (5 mL) and gentisic acid (83 mg, 0.53 mmol, 0.5 eq) was added. The obtained suspension was heated to 75°C. Ethyl acetate was additionally added up to complete dissolution (20 mL), and the clear solution obtained was slowly cooled to room temperature, seeded with the crystalline phase Form G1 and stirred overnight. Seed crystals of the crystalline phase Form G1 were obtained by a small scale cooling crystallisation method using acetonitrile or ethyl acetate or acetone as solvent. Afterwards, the solid was filtered off in a filter plate (N. 3), washed with ethyl acetate (2.5 mL), and dried in vacuum at 35°C for 3 hours. Yield: 0.390 g (67%).

[0196] Characterisation

[0197] The XRPD pattern of the crystalline phase Form G1 of the compound of formula (I) with gentisic acid is shown in Figure 11 .

[0198] DSC analysis (figure not shown) showed endotherms with onset at 181 °C (-93 J / g).

[0199] TGA analysis (figure not shown) showed weight loss due to decomposition at ca 180 °C. This implies that the material is anhydrous and is not a solvate.

[0200] DVS analysis (figure not shown) was performed from analysis from 10 to 90 to 10% of relative humidity at 25 °C, in 10% steps of 30 minutes. Weight gain of 0.76% between 10 and 80% of relative humidity. The form of the material after completion of the DVS experiment was investigated by XRPD and no change in form was observed.

[0201] SCXRD showed that the crystalline phase Form G1 of the compound of formula (I) with gentisic acid is a co-crystal with stoichiometry of 2:1 (compound of formula (I) to gentisic acid). Example 5A

[0202] Crystalline phase form of the compound of formula (I) with maleic acid (Form M1 polymorph) Preparation

[0203] Compound of formula (I) (20 mg, 0.106 mmol) was suspended in methanol (1 mL) and maleic acid (4.9 mg, 1 eq) was added. The mixture was stirred for 15 minutes and evaporated. The obtained residue was dissolved in isopropanol (0.2 mL) at 75°C, and the solution was slowly cooled to room temperature. When crystallization was produced, the mother liquors were decanted, and the solid was dried in vacuum at 35°C for 3 hours.

[0204] Characterisation

[0205] The XRPD pattern of the Form M1 polymorph of the compound of formula (I with maleic acid is shown in Figure 12. Stoichiometry (compound of formula (I) to maleic acid) is assumed to be 1 :1 , although this has not been determined.

[0206] DSC analysis (figure not shown) showed endotherm with onset at 117 °C (-6 J / g).

[0207] TGA analysis (figure not shown) showed weight loss of 2.9% below 122°C. Weight loss due to decomposition starting at ca. 130°C.

[0208] Example 5B

[0209] Crystalline phase form of the compound of formula (I) with maleic acid (Form M2 polymorph) Preparation

[0210] Compound of formula (I) (20 mg, 0.106 mmol) was suspended in methanol (1 mL) and maleic acid (4.9 mg, 1 eq) was added. The mixture was stirred for 15 minutes and evaporated. The obtained residue was dissolved in acetonitrile (0.2 mL) at 75°C, and the solution was slowly cooled to room temperature. When crystallization was produced, the mother liquors were decanted, and the solid was dried in vacuum at 35°C for 3 hours.

[0211] Characterisation

[0212] The XRPD pattern of the Form M2 polymorph of the crystalline phase form with maleic acid is shown in Figure 13. Stoichiometry (compound of formula (I) to maleic acid) is assumed to be 1 :1 , although this has not been determined.

[0213] DSC analysis (figure not shown) showed endotherm with onset at 117 °C (-71 J / g).

[0214] TGA analysis (figure not shown) showed weight loss due to decomposition starting at ca. 130°C. This implies that the material is anhydrous and is not a solvate. Example 5C

[0215] Crystalline phase form of the compound of formula (I) with maleic acid (Form M3 polymorph) Preparation

[0216] Compound of formula (I) (20 mg, 0.106 mmol) was suspended in methanol (1 mL) and maleic acid (4.9 mg, 1 eq) was added. The mixture was stirred for 15 minutes and evaporated. The obtained residue was dissolved in tetrahydrofuran (0.2 mL) at reflux, and the solution was slowly cooled to room temperature. When crystallization was produced, the mother liquors were decanted, and the solid was dried in vacuum at 35°C for 3 hours.

[0217] Characterisation

[0218] The XRPD pattern of the Form M3 polymorph of the crystalline phase form with maleic acid is shown in Figure 14. Stoichiometry (compound of formula (I) to maleic acid) is assumed to be 1 :1 , although this has not been determined.

[0219] DSC analysis (figure not shown) showed endotherms with onsets at 35 °C (wide, -10 J / g) and 80 °C (-40 J / g).

[0220] TGA analysis (figure not shown) showed weight loss of 1 % below 100 °C. Weight loss due to decomposition starting at ca. 110 °C.

[0221] Example 5D

[0222] Crystalline phase form of the compound of formula (I) with maleic acid (Form M4 polymorph) Preparation

[0223] Compound of formula (I) (50 mg, 0.106 mmol) was suspended in methanol (1 mL) and maleic acid (12.3 mg, 0.106 mmol, 1 eq) was added. The mixture was stirred for 15 minutes and evaporated. The obtained residue was dissolved in acetonitrile at 75°C (0.5 mL), and the obtained solution was slowly cooled to room temperature, seeded with maleic acid crystalline phase Form M2 and stirred overnight. Seed crystals of the Form M2 polymorph were obtained by a small scale cooling crystallisation method using acetonitrile or acetone as solvent. Afterwards, the mother liquors were decanted, and the solid was dried in vacuum at 35°C for 3 hours. Note that although the attempt was aimed at obtaining form M2, the new form M4 was obtained.

[0224] Characterisation

[0225] The XRPD pattern of the Form M4 polymorph of the crystalline phase form with maleic acid is shown in Figure 15. Stoichiometry (compound of formula (I) to maleic acid) is assumed to be 1 :1 , although this has not been determined. DSC analysis (figure not shown) showed endotherms with onsets at 33 °C (wide, -15 J / g), 113 °C (-53 J / g) and 144 °C (-9 J / g).

[0226] TGA analysis (figure not shown) showed weight loss of 0.6% below 85 °C. Weight loss due to decomposition starting at ca. 120 °C.

[0227] Example 5E

[0228] Crystalline phase form of the compound of formula (I) with maleic acid (Form M5 polymorph) Preparation

[0229] Compound of formula (I) (50 mg, 0.106 mmol) was suspended in methanol (1 mL) and maleic acid (12.3 mg, 0.106 mmol, 1 eq) was added. The mixture was stirred for 15 minutes and evaporated. The obtained residue was dissolved in tetra hydrofuran at reflux (0.2 mL), and the obtained solution was slowly cooled to room temperature, seeded with maleic acid crystalline phase Form M3 and stirred overnight. Seed crystals of the Form M3 polymorph were obtained by a small scale cooling crystallisation method using tetra hydrofuran as solvent. Afterwards, the mother liquors were decanted, and the solid was dried in vacuum at 35°C for 3 hours. Note that although the attempt was aimed at obtaining form M3, the new form M5 was obtained.

[0230] Characterisation

[0231] The XRPD pattern of the Form M5 polymorph of the crystalline phase form with maleic acid is shown in Figure 16. Stoichiometry (compound of formula (I) to maleic acid) is assumed to be 1 :1 , although this has not been determined.

[0232] DSC analysis (figure not shown) showed endotherms with onsets at 32 °C (wide, -28 J / g) and 78°C (wide, -53 J / g). Exotherm with an onset at 108 °C (96 J / g).

[0233] TGA analysis (figure not shown) showed weight loss of 1.3% below 100 °C. Weight loss due to decomposition starting at ca. 110 °C.

[0234] Example 5F

[0235] Crystalline phase form of the compound of formula (I) with maleic acid (Form M6 polymorph) Preparation

[0236] Compound of formula (I) (50 mg, 0.106 mmol) was suspended in methanol (1 mL) and maleic acid (12.3 mg, 0.106 mmol, 1 eq) was added. The mixture was stirred for 15 minutes and evaporated. The obtained residue was dissolved in isopropanol at 75°C (0.2 mL), and the obtained solution was slowly cooled to room temperature, seeded with maleic acid crystalline phase Form M1 and stirred overnight. Seed crystals of the Form M1 polymorph were obtained by a small scale cooling crystallisation method using tetra hydrofuran as solvent. Afterwards, the mother liquors were decanted, and the solid was dried in vacuum at 35°C for 3 hours. Note that although the attempt was aimed at obtaining form M1 the new form M6 was obtained.

[0237] Characterisation

[0238] The XRPD pattern of the Form M6 polymorph of the crystalline phase form with maleic acid is shown in Figure 17. Stoichiometry (compound of formula (I) to maleic acid) is assumed to be 1 :1 , although this has not been determined.

[0239] DSC analysis (figure not shown) showed endotherms with onsets at 33 °C (wide, -28 J / g) and 87°C (-32 J / g) and 113 °C (-22 J / g).

[0240] TGA analysis (figure not shown) showed weight loss of 1.5% below 80 °C. Weight loss due to decomposition starting at ca. 120 °C.

[0241] Example 6

[0242] Crystalline phase Form C1 of the compound of formula (I) with hydrochloric acid

[0243] Preparation

[0244] Compound of formula (I) (0.5 g, 1.06 mmol) was suspended in isopropanol (5 mL) and hydrochloric acid (1.2 mL, 1 N in diisopropyl ether, 1.1 eq) was added. The obtained suspension was heated to 75°C and stirred at this temperature for one hour, and slowly cooled to room temperature and stirred overnight. Afterwards, the solid was filtered off in a filter plate (N. 3), washed with isopropanol (2 mL), and dried in vacuum at 35°C for 3 hours. Yield: 0.46 g (85%).

[0245] Characterisation

[0246] The XRPD pattern of the crystalline phase Form C1 of the compound of formula (I) with hydrochloric acid is shown in Figure 18. Stoichiometry (compound of formula (I) to HCI) is assumed to be 1 :1 , although this has not been determined.

[0247] DSC analysis (figure not shown) showed endotherm with onset at 236 °C (-168 J / g).

[0248] TGA analysis (figure not shown) showed weight loss due to decomposition at ca 210 °C. This implies that the material is anhydrous and is not a solvate.

[0249] DVS analysis (figure not shown) was performed from 10 to 90 to 10% of RH at 25 °C in 10% steps of 30 min. A weight gain of 0.55% between 10 and 80% of RH was recorded. The form of the material after completion of the DVS experiment was investigated by XRPD and no change in form was observed.

[0250] Example 7A

[0251] Crystalline phase form of the compound of formula (I) with hydrobromic acid (Form B1 polymorph) Preparation

[0252] Compound of formula (I) (50 mg, 0.106 mmol) was suspended in methanol (1 mL) and hydrobromic acid (122.5 pL, 0.88N in water, 1 eq) was added. The mixture was stirred for 15 minutes and evaporated. The obtained residue was dissolved in acetonitrile at 75°C (0.5 mL), slowly cooled to room temperature and stirred overnight. Afterwards, the mother liquors were decanted, and the solid was dried in vacuum at 35°C for 3 hours.

[0253] Characterisation

[0254] The XRPD pattern of the Form B1 polymorph of the crystalline phase form with hydrobromic acid is shown in Figure 19. Stoichiometry (compound of formula (I) to HBr) is assumed to be 1 :1 , although this has not been determined.

[0255] DSC analysis (figure not shown) showed endotherm with onset at 229 °C (-94 J / g).

[0256] TGA analysis (figure not shown) showed weight loss of 0.13% below 65 °C. Weight loss due to decomposition starting at ca. 230 °C. This implies that the material is anhydrous and is not a solvate.

[0257] Example 7B

[0258] Crystalline phase form of the compound of formula (I) with hydrobromic acid (Form B2 polymorph) Preparation

[0259] Compound of formula (I) (0.5 g, 1.06 mmol) was suspended in acetonitrile (2.5 mL) and hydrobromic acid (0.36 mL, 3N in water, 1 eq) was added. The obtained suspension was heated to 75°C. A clear solution was obtained, which was slowly cooled to room temperature and stirred overnight. Afterwards, the solid was filtered off in a filter plate (N. 3), washed with acetonitrile (1 mL), and dried in vacuum at 35°C for 3 hours. Yield: 0.2 g (34%).

[0260] Characterisation

[0261] The XRPD pattern of the Form B2 polymorph of the crystalline phase form with hydrobromic acid is shown in Figure 20. Stoichiometry (compound of formula (I) to HBr) is assumed to be 1 :1 , although this has not been determined. DSC analysis (figure not shown) showed endotherms with onset at 124 °C (-118 J / g) and 170 °C (-21 J / g).

[0262] TGA analysis (figure not shown) showed weight loss 5.1 % below 170 °C. Weight loss due to decomposition starting at ca. 220 °C. This implies that the material is a solvate (hydrate).

[0263] DVS analysis (figure not shown) was performed from 10 to 90 to 10% of RH at 25 °C in 10% steps of 30 min. A weight gain of 0.25% between 10 and 80% of RH was recorded. The form of the material after completion of the DVS experiment was investigated by XRPD and no change in form was observed.

[0264] Example 8A

[0265] Crystalline phase form of the compound of formula (I) with sulfuric acid (Form SF1 polymorph) Preparation

[0266] Compound of formula (I) (50 mg, 0.106 mmol) was suspended in methanol (1 mL) and sulfuric acid (55 pL, 1 M in water, 0.5 eq) was added. The mixture was stirred for 15 minutes and evaporated. The obtained residue was slurried in acetone (3 mL) at reflux for 2 hours, slowly cooled to room temperature, and stirred overnight. Afterwards, the mother liquors were decanted, and the solid was dried in vacuum at 35°C for 3 hours.

[0267] Characterisation

[0268] The XRPD pattern of the Form SF1 polymorph of the crystalline phase form with sulfuric acid is shown in Figure 21. Stoichiometry (compound of formula (I) to sulfuric acid) is assumed to be 2:1 , although this has not been determined.

[0269] DSC analysis (figure not shown) showed endotherm with onset at 208 °C (-62 J / g).

[0270] TGA analysis (figure not shown) showed weight loss due to decomposition starting at ca. 200 °C. This implies that the material is anhydrous and is not a solvate.

[0271] Example 8B

[0272] Crystalline phase form of the compound of formula (I) with sulfuric acid (Form SF2 polymorph) Preparation

[0273] Compound of formula (I) (20 mg, 0.043 mmol) was suspended in methanol (1 mL) and sulfuric acid (22 pL, 1 M in water, 0.5 eq) was added. The mixture was stirred for 15 minutes and evaporated. The obtained residue was slurried in tetra hydrofuran (3 mL) at reflux for 2 hours, slowly cooled to room temperature, and stirred for 7 days. Afterwards, the mother liquors were decanted, and the solid was dried in vacuum at 35°C for 3 hours.

[0274] Characterisation

[0275] The XRPD pattern of the Form SF2 polymorph of the crystalline phase form with sulfuric acid is shown in Figure 22. Stoichiometry (compound of formula (I) to sulfuric acid) is assumed to be 2: 1 , although this has not been determined.

[0276] DSC analysis (figure not shown) showed wide endotherms with onsets at 62 °C (-33 J / g), 150 °C (-28 J / g) and 172 °C (-4 J / g).

[0277] TGA analysis (figure not shown) showed weight loss 3.7% below 136 °C. Weight loss due to decomposition starting at ca. 230 °C. This implies that the material is a solvate (hydrate).

[0278] Example 8C

[0279] Crystalline phase form of the compound of formula (I) with sulfuric acid (Form SF3 polymorph) Preparation

[0280] Compound of formula (I) (20 mg, 0.043 mmol) was suspended in methanol (1 mL) and sulfuric acid (22 pL, 1 M in water, 0.5 eq) was added. The mixture was stirred for 15 minutes and evaporated. The obtained residue was dissolved in isopropanol (0.2 mL) at 75°C, and the solution was slowly cooled to room temperature. An oil was formed when cooling, which crystallizes after standing at ambient conditions for an undetermined time.

[0281] Characterisation

[0282] The XRPD pattern of the Form SF3 polymorph of the crystalline phase form with sulfuric acid is shown in Figure 23. Stoichiometry (compound of formula (I) to sulfuric acid) is assumed to be 2:1 , although this has not been determined.

[0283] DSC analysis (figure not shown) showed wide endotherms with onsets at 159 °C (-46 J / g) and 175 °C (-18 J / g).

[0284] TGA analysis (figure not shown) showed weight loss due to decomposition starting at ca. 210 °C. This implies that the material is most likely anhydrous and is not a solvate. Example 9A

[0285] Crystalline phase form of the compound of formula (I) with saccharine (Form S1 polymorph) Preparation

[0286] Compound of formula (I) (50 mg, 0.106 mmol) was suspended in methanol (1 mL) and saccharine (19.5 mg, 0.106 mmol, 1 eq) was added. The mixture was stirred for 15 minutes and evaporated. The obtained residue was slurried in acetone at reflux (5 mL) for 2 hours, slowly cooled to room temperature and stirred overnight. Afterwards, the mother liquors were decanted, and the solid was dried in vacuum at 35°C for 3 hours.

[0287] Characterisation

[0288] The XRPD pattern of the Form S1 polymorph of the crystalline phase form with saccharine is shown in Figure 24. Stoichiometry (compound of formula (I) to saccharine) was determined as 1 :1 by NMR.

[0289] DSC analysis (figure not shown) showed endotherm with onset at 198 °C (-126 J / g).

[0290] TGA analysis (figure not shown) showed weight loss of 0.3% below 86 °C and 1.5% between 110 and 210 °C. Weight loss due to decomposition starting at ca. 210 °C. This implies that the material is possibly a solvate (hydrate).

[0291] Example 9B

[0292] Crystalline phase form of the compound of formula (I) with saccharine (Form S2 polymorph) Preparation

[0293] Compound of formula (I) (50 mg, 0.106 mmol) was suspended in methanol (1 mL) and saccharine (19.5 mg, 0.106 mmol, 1 eq) was added. The mixture was stirred for 15 minutes and evaporated. The obtained residue was dissolved in tetra hydrofuran at reflux (3 mL), and the obtained solution was slowly cooled to room temperature, seeded with saccharine crystalline phase form S2 and stirred overnight. A seed crystal was obtained by a small scale cooling crystallisation method using tetrahydrofuran as solvent. Afterwards, the mother liquors were decanted, and the solid was dried in vacuum at 35°C for 3 hours.

[0294] Characterisation

[0295] The XRPD pattern of the Form S2 polymorph of the crystalline phase form with saccharine is shown in Figure 25. Stoichiometry (compound of formula (I) to saccharine) was determined as 1 :1 by NMR.

[0296] DSC analysis (figure not shown) showed endotherm with onset at 198 °C (-117 J / g). TGA analysis (figure not shown) showed weight loss 5.3% between 110 and 210 °C. Weight loss due to decomposition starting at ca. 220 °C. This implies that the material is possibly a solvate (hydrate).

[0297] Example 10 (comparator)

[0298] Solid amorphous form of compound of formula (I)

[0299] Preparation

[0300] A sample of the compound of formula (I) was heated until melt using a Kofler bench and then quickly cooled in an ice bath. An amorphous product resulted.

[0301] Characterisation

[0302] The XRPD pattern of the amorphous form is shown in Figure 26.

[0303] DSC analysis (figure not shown) showed an exothermic peak with onset at 99 °C (55 J / g (crystallisation) and an endothermic peak with onset at 190 °C (-107 J / g) (melting).

[0304] TGA analysis (figure not shown) showed weight loss of 1 .6% between 40°C and 120°C.

[0305] The storage stability of the solid amorphous form was evaluated. The results are shown in Figure 27. The amorphous form was kept in a climatic chamber at 30°C and 75% RH and at ambient conditions (room temperature in an open vial in the fume hood). After 4 days, the solids were analysed by XRPD. The amorphous sample had started to crystallize to Form 1 in ambient conditions but remained amorphous in the climatic chamber conditions.

[0306] Abbreviations

[0307] °C Degrees Celsius

[0308] A Angstrom

[0309] DSC Differential scanning calorimetry

[0310] DVS Dynamic vapour sorption eq equivalent

[0311] J / g Joules per gram kV Kilovolt

[0312] M Molar concentration mA Milliamp mbar Millibar mg Milligram min minute mmol Millimole

[0313] N Equivalent concentration

[0314] NMR nuclear magnetic resonance

[0315] RH Relative humidity

[0316] SCXRD Single crystal X-ray diffraction

[0317] TGA Thermogravimetric analysis

[0318] XRPD X-ray powder diffraction

[0319] 0 Theta pL Microlitre

[0320] References

[0321] Akhurst R. J. et al. Targeting the TGF / 3 signalling pathway in disease, Nat Rev Drug Discov, 2012 11(10), 790-811.

[0322] Anderton M.J. et al. Induction of Heart Valve Lesions by Small-Molecule ALK5 Inhibitors, Toxicologic Pathology, 2011 , 39(6), 916-924.

[0323] Bierie B. et al. TGF-fi: the molecular Jekyll and Hyde of cancer, Nature Reviews Cancer, 2006, 6, 506-520.

[0324] Biernacka, A. et al. TGF- / 3 signaling in fibrosis, Growth Factors, 2011, 29(5), 196-202.

[0325] Binabaj M.M et al. EW-7197 prevents ulcerative colitis -associated fibrosis and inflammation, J Cell Physiol. 2019, 234(7), 11654-11661.

[0326] D'Alessio S. et al., Revisiting fibrosis in inflammatory bowel disease: the gut thickens. Nat Rev Gastroenterol Hepatol., 2022, 19(3), 169-184.

[0327] Di Sabatino A. et al., Transforming growth factor beta signalling and matrix metalloproteinases in the mucosa overlying Crohn's disease strictures. Gut, 2009, 58(6), 777-89.

[0328] Heldin C. H. et al. Signaling Receptors for TGF-b Family Members, Cold Spring Harb Perspect Biol, 2016, 8(8), 1-33.

[0329] Ma Y. et al., Targeting TGF-beta1 by employing a vaccine ameliorates fibrosis in a mouse model of chronic colitis. Inflamm Bowel Dis., 2010, 16(6), 1040-50.

[0330] Medina C. et al., Transforming growth factor-beta type 1 receptor (ALK5) and Smad proteins mediate TIMP-1 and collagen synthesis in experimental intestinal fibrosis. J Pathol., 2011, 224(4), 461-72.

[0331] Soleimani, A. et al. Novel oral transforming growth factor- / 3 signaling inhibitor potently inhibits postsurgical adhesion band formation, J Cell Physiol. 2020, 235(2), 1349-1357.

[0332] Stauber A. et al. Nonclinical Safety Evaluation of a Transforming Growth Factor / 3 Receptor I Kinase Inhibitor in Fischer 344 Rats and Beagle Dogs, J Clin Tox. 2014, 4, 1-10.

[0333] Tavares de Sousa H. et al. J Crohns Colitis. 2024, 18(11), 1741-1752. Tauriello D.V.F. et al., Overcoming TGFp-mediated immune evasion in cancer. Nat Rev Cancer, 2022, 22(1), 25-44.

[0334] Troncone E. et al., Transforming Growth Factor- / 31 / Smad7 in intestinal immunity, inflammation, and Cancer, Front. Immunol. 2018, 9, 1407.

[0335] Yue, L. et al. Efficacy ofALK5 inhibition in myelofibrosis, JCI Insight. 2017, 2(7):e90932.

[0336] Yun S. M. et al. The Molecular Mechanism of Transforming Growth Factor- / 3 Signaling for Intestinal Fibrosis: A Mini-Review, Frontiers in Pharmacology, 2019, 10(162), 1-9.

[0337] Miscellaneous

[0338] All references referred to in this application, including patent and patent applications, are incorporated herein by reference to the fullest extent possible.

[0339] Throughout the specification and the claims which follow, unless the context requires otherwise, the word ‘comprise’, and variations such as ‘comprises’ and ‘comprising’, will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.

[0340] The application of which this description and claims form part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims.

Claims

CLAIMS1 . A crystalline phase form of a compound of formula (I):wherein the crystalline phase form is the crystalline phase Form 1 polymorph.

2. The crystalline phase form of the compound of formula (I) according to claim 1 wherein the crystalline phase form has an XRPD pattern substantially as shown in Figure 1.

3. The crystalline phase form according to claim 1 wherein the crystalline phase form has an XRPD pattern comprising three, four, five, six, seven, eight, nine or ten peaks selected from 10.5, 14.3, 16.9, 18.6, 19.3, 21.1 , 22.3, 22.5, 26.6 and 28.6 (± 0.2) degrees 2-theta.

4. The crystalline phase form according to claim 3 wherein the crystalline phase form has an XRPD pattern comprising ten peaks at 10.5, 14.3, 16.9, 18.6, 19.3, 21.1 , 22.3, 22.5, 26.6 and 28.6 (± 0.2) degrees 2-theta.

5. The crystalline phase form according to claim 3 or claim 4 wherein the said peaks are present with relative intensity of at least 20% e.g. at least 30%.

6. The crystalline phase form according to claim 1 wherein the crystalline phase form has unit cell dimensions as determined by SCXRD of about 14.71 A (dimension a), about 16.77 A (dimension b) and about 9.58 A (dimension c) in space group P2i / c, with a angle of 90 °C, angle of about 107.9 °C, and y angle of 90 °C.

7. A pharmaceutical composition comprising the crystalline phase form as defined in any one of claims 1 to 6 and a pharmaceutically acceptable diluent or carrier.

8. The crystalline phase form as defined in any one of claims 1 to 6 for use in the treatment or prevention of a disease or pathological condition susceptible to ameliorate by inhibition of transforming growth factor-p receptor I (TGFPRI / ALK5).

9. The crystalline phase form for use according to claim 8 wherein the disease or pathological condition is selected from the group consisting of gastrointestinal diseases, fibrotic diseases, cancer and graft vs. host disease (GVHD).

10. A combination comprising the crystalline phase form as defined in any one of claims 1 to 6 and a therapeutic agent used for the treatment or prevention of a disease selected from the group consisting of gastrointestinal diseases, fibrotic diseases, cancer and graft vs. host disease (GVHD).11 . Use of the crystalline phase form as defined in any one of claims 1 to 6 for the manufacture of a medicament for the treatment and / or prevention of a disease or pathological condition susceptible to ameliorate by inhibition of transforming growth factor-p receptor I (TGFPRI / ALK5).

12. Use according to claim 11 wherein the disease or pathological condition is selected from the group consisting of gastrointestinal diseases, fibrotic diseases, cancer and graft vs. host disease (GVHD).

13. A method for the treatment or prevention of a disease or pathological condition susceptible to ameliorate by inhibition of transforming growth factor-p receptor I (TGFPRI / ALK5) comprising the administration to a subject in need thereof of the crystalline phase form as defined in any one claims 1 to 6.

14. A method according to claim 13 wherein the disease or pathological condition is selected from the group consisting of gastrointestinal diseases, fibrotic diseases, cancer and graft vs. host disease (GVHD).

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