Crystalline phase forms of benzamide derivatives

Abstract

In particular, there is provided a crystalline phase form of a compound of formula (I): (I), wherein the crystalline phase form is crystalline phase form 1 polymorph.

Description

Technical Field

[0001] This invention relates in particular to a novel crystalline form of a benzamide derivative, which is an effective inhibitor of transforming growth factor-β receptor I kinase (also known as activin receptor-like kinase 5) (TGFβRI) / ALK5. Background Technology

[0002] Transforming growth factor-β (TGF-β) belongs to the TGF-β superfamily, which includes proteins such as TGF-β1, TGF-β2, and TGF-β3. TGF-β is involved in many cellular processes, including cell proliferation, cell migration, invasion, epithelial-mesenchymal transition, extracellular matrix production, and immunosuppression. TGF-β and its receptor are typically overexpressed long-term in various human diseases, including cancer, inflammation, tissue fibrosis, and autoimmunity. Therefore, blocking the TGF-β signaling pathway is considered an attractive target for drug development (Heldin CH et al.).

[0003] TGF-β signals via two associated transmembrane type I and type II serine / threonine kinase receptors. Upon binding of TGF-β to the constitutively active type II receptor, the type I receptor (TGFβR1, also known as activin receptor-like kinase 5 (ALK5)) is phosphorylated, creating binding sites for Smad2 and Smad3 proteins, which are further phosphorylated. The phosphorylated Smad2 / Smad3 proteins form a heteropolymeric complex with Smad4, which translocates to the nucleus, assembles with specific DNA-binding cofactors and co-regulators, and binds to the promoters of TGF-β target genes involved in cell differentiation, proliferation, apoptosis, migration, and extracellular matrix production (Akhurst RJ et al.).

[0004] In most cell types, activin receptor-like kinase 5 (ALK5) is the major TGFβ receptor I, activated by TGF-β via TGFβ receptor II. This interaction requires both extracellular and intracellular domains for signal transduction. ALK5 and TGFβ receptor II proteins can also form active heterooligomeric complexes in the absence of ligands. When both receptors are co-expressed, these complexes can transduce basal signals due to their intrinsic affinity for the interaction (Bierie B. et al.).

[0005] The functional TGFβRII-TGFβRI (ALK5) heteropolymer signaling complex is frequently associated with human cancers and regulates the activation of downstream Smad-dependent and Smad-independent pathways. Indeed, numerous studies have identified mutations in components associated with the TGF-β pathway and relevant to cancer development and prognosis in many human tissues. Overexpression of TGF-β1 is associated with breast cancer, colon cancer, esophageal cancer, gastric cancer, hepatocellular carcinoma, lung cancer, and pancreatic cancer. Importantly, overexpression of TGF-β in human cancers is associated with tumor progression, metastasis, angiogenesis, and poor prognostic outcomes. Furthermore, reports suggest that, based on preclinical evidence, the combination of TGF-β blockade and immune checkpoint inhibitor strategies may be of interest in cancer treatment (Tauriello DVF et al., 2022).

[0006] Extensive evidence also indicates that the classical ALK5 / Smad3 pathway is closely related to the pathogenesis of fibrosis in many tissues. In Crohn's disease (CD) tissues, TGF-β gene expression levels and phosphorylated SMAD2 / 3 (positive regulators of TGF-β signaling) are upregulated in myofibroblasts covering narrow (but not non-narrow) regions, while SMAD7 (a negative regulator of TGF-β1) is downregulated in the same regions (Di Sabatino et al., 2009). TGF-β1 upregulates α-SMA, collagen I, and fibronectin in human fibroblasts, mesenchymal cells, and smooth muscle cells. Observations of TGF-β1-targeted vaccination attenuating fibrosis in preclinical models of FSCD also highlight the role of TGF-β1 in fibrosis (Ma et al., 2010). Systemic ALK5 inhibitors have provided preclinical proof of concept for the efficacy of ALK5 inhibition in in vitro and in vivo models of intestinal fibrosis (Medina et al., 2011). Therefore, inhibiting the TGF-β signaling pathway is considered an attractive target for drug development in fibrotic diseases (FSCD in particular).

[0007] In a rat model of progressive TGF-β1-induced pulmonary fibrosis, oral administration of a low-molecular-weight selective inhibitor of ALK5 kinase activity suppressed fibrosis (D'Alessio et al., 2022). Furthermore, Smad3-deficient mice exhibited reduced fibrosis in multiple experimental models and were resistant to bleomycin-induced pulmonary fibrosis. Similarly, post-radiation skin fibrosis, renal interstitial fibrosis due to unilateral ureteral obstruction, and cardiac fibrosis were all reduced in Smad3-deficient animals (Biernacka, A. et al.). Inhibitors of the TGF-β intracellular signaling pathway are useful treatments for fibroproliferative disorders. Specifically, fibroproliferative disorders include kidney conditions associated with unregulated TGF-β activity and excessive fibrosis, including glomerulonephritis (GN), such as mesangial proliferative GN, immune GN, and crescentic GN. Other kidney disorders include diabetic nephropathy in transplant recipients, renal interstitial fibrosis, and renal fibrosis. Collagen vascular disorders include progressive systemic sclerosis, polymyositis, and scleroderma. Autoimmune diseases associated with fibroproliferative features are systemic lupus erythematosus and rheumatoid arthritis.

[0008] Myelofibrosis (MF) is a bone marrow disorder characterized by clonal bone marrow proliferation, aberrant cytokine production, extramedullary hematopoiesis, and myelofibrosis. 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 yet shown efficacy in improving MF in patients. Members of the TGF-β family are pro-fibrotic cytokines, and significant overexpression of the TGF-β1 isoform has been observed in a large number of primary MF patient samples. TGF-β1 has been shown to stimulate excessive collagen deposition in mesenchymal stromal cells (MSCs) by activating the TGF-β receptor I kinase (ALK5) / Smad3 pathway. The clinically active ALK5 inhibitor galunisertib significantly improved MF in a mouse model. The data suggest the role of the malignant hematopoietic stem cell (HSC) / TGF-β / MSC axis in the pathogenesis of MF and provide a preclinical basis for ALK5 blockade as a therapeutic strategy for MF. (Yue, L. et al.).

[0009] In addition, studies have investigated the therapeutic potential of TGF-β inhibitors in preventing postoperative peritoneal adhesions, and the results show that these compounds significantly reduce adhesion formation by inhibiting inflammation, oxidative stress, downregulating pro-inflammatory genes, and inhibiting fibrotic and pro-fibrotic molecules (Soleimani, A. et al.).

[0010] Several small molecules that inhibit ALK5 have been developed and have shown encouraging results in animal models of renal fibrosis. However, questions remain regarding the homeostatic role of ALK5 signaling and the safety implications of targeting this enzyme. One study showed that immunohistochemical analysis revealed ALK5 expression in the heart to be valve-specific. Two compounds (AZ12601011 and AZ12799734) were tested in rats. Microscopic evaluation revealed valvular lesions in response to treatment with either compound. Both compounds induced histopathological valvular lesions characterized by hemorrhage, inflammation, degeneration, and proliferation of valvular interstitial cells. Lesions were observed in all animals at all tested doses and in all four heart valves. Analysis of ALK5 in the rat heart revealed expression in the valves, not the myocardium. ALK5 protein levels were not altered in the heart valves of the treated animals compared to control animals. These findings suggest that TGF-β signaling via ALK5 plays a crucial role in maintaining valvular integrity. (Anderton MJ et al.)

[0011] Additionally, another ALK-5 inhibitor, galusette, was tested in rats and dogs. In both, the heart and major blood vessels were identified as the primary target organs for toxicity. Cardiovascular findings in F344 rats treated with LY2157299 included degenerative and inflammatory valvular disease (valvular disease), myocardial degeneration and necrosis, aortitis with rupture, vasculitis / perivascularitis, and increased cardiac weight (Stauber A. et al.).

[0012] In the gut, numerous immune and non-immune cells produce TGF-β1, and almost all mucosal cells target this cytokine. TGF-β1 is secreted as part of a latent complex that includes a latent period-related peptide (LAP) and a latent TGF-β binding protein. Recent data clearly demonstrate that transforming growth factor β1 is one of the key molecules involved in regulating intestinal epithelial cell biology and immunity.

[0013] These studies highlight the crucial role of TGF-β1 in maintaining intestinal homeostasis and suggest that functional defects in this cytokine can help trigger and / or amplify harmful signals in the gut (Troncone E. et al.).

[0014] To date, researchers have investigated the inflammatory mechanisms that reduce and suppress intestinal fibrosis. However, anti-inflammatory agents have various problems and limitations in reducing or treating fibrosis in inflammatory bowel disease (IBD). Therefore, new approaches to anti-fibrotic mechanisms should be explored for the treatment of fibrotic diseases. Numerous publications have shown that molecules associated with TGF-β signaling are involved in fibrosis and are therefore important targets in the progression of intestinal fibrosis, as they are associated with complex and diverse signaling pathways that regulate the mechanisms of intestinal fibrosis progression in IBD. Therefore, TGF-β signaling is a potential strategy for treating and reducing fibrosis in several fibrotic diseases, including IBD (Yun SM et al.; Binabaj MM et al.).

[0015] Effective inhibitors of TGFβRII–TGFβRI (ALK5) have been described in WO2021 / 105317, including compounds ( N -(2,6-Difluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H (-pyrazole-1-yl)acetamide), which is a compound of formula (I) as shown below (see Example 24): (I) There is still a need in the art for new solid forms of compounds of formula (I) or pharmaceutically acceptable salts thereof. Summary of the Invention

[0016] In one aspect, the present invention provides the crystalline phase form of compounds of formula (I): (I), Right now( N -(2,6-Difluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H -pyrazole-1-yl)acetamide), wherein the crystalline phase is a polymorph of crystalline phase form 1.

[0017] In another aspect, the present invention provides a polymorph of the crystalline phase form 2 of the compound of formula (I) (1,4-dioxane solvate).

[0018] In other respects, the present invention provides crystalline phase forms of compounds of formula (I) as described herein with acids, including their salts and eutectics. Attached Figure Description

[0019] Figure 1 The XRPD diagram of the polymorph of the crystalline phase form of compound (I) is shown.

[0020] Figure 2The results of TGA and DSC show the crystalline phase form of the polymorph of compound (I) 1.

[0021] Figure 3 The results of DVS analysis of the polymorph of the crystalline phase form of compound (I) are shown.

[0022] Figure 4 Adsorption-desorption isotherms of DVS analysis of polymorphs of compound (I) showing the crystalline phase form 1.

[0023] Figure 5 Comparison of XRPD plots of polymorphs of compound (I) before and after DVS analysis experiments.

[0024] Figure 6 The comparison of XRPD plots of the polymorph of compound (I) before and after storage in accelerated stability testing shows the crystalline phase form 1.

[0025] Figure 7 The XRPD plot of the crystalline phase form 2 polymorph (1,4-dioxane solvate) of compound (I) is shown.

[0026] Figure 8 The results of TGA and DSC show the crystalline phase form 2 polymorph (1,4-dioxane solvate) of compound (I).

[0027] Figure 9 Results of a storage stability study of the crystalline phase form 2 polymorph (1,4-dioxane solvate) of compound (I) were presented.

[0028] Figure 10 The XRPD diagram shows the crystalline phase form of the (I) compound and the polymorph of succinic acid in the form of SC1.

[0029] Figure 11 The XRPD diagram shows the crystalline phase form of compound (I) and gentian acid in polymorph G1.

[0030] Figure 12 The XRPD diagrams of the crystalline phase form M1 polymorph of compound (I) and maleic acid are shown.

[0031] Figure 13 The XRPD diagrams of the crystalline phase form M2 polymorph of compound (I) and maleic acid are shown.

[0032] Figure 14 The XRPD diagrams of the crystalline phase form M3 polymorph of compound (I) and maleic acid are shown.

[0033] Figure 15The XRPD diagrams of the crystalline phase form M4 polymorph of compound (I) and maleic acid are shown.

[0034] Figure 16 The XRPD diagrams of the crystalline phase form M5 polymorph of compound (I) and maleic acid are shown.

[0035] Figure 17 The XRPD diagrams of the crystalline phase form M6 polymorph of compound (I) and maleic acid are shown.

[0036] Figure 18 The XRPD diagram of compound (I) in crystalline form C1 with hydrochloric acid is shown.

[0037] Figure 19 The XRPD diagram shows the crystalline phase form B1 polymorph of compound (I) with hydrobromic acid.

[0038] Figure 20 The XRPD diagram shows the crystalline phase form B2 polymorph of compound (I) and hydrobromic acid.

[0039] Figure 21 The XRPD diagrams of the polymorph of SF1, the crystalline phase of compound (I) and sulfuric acid, are shown.

[0040] Figure 22 The XRPD diagram of compound (I) and the crystalline phase form of sulfuric acid, SF2 polymorph, is shown.

[0041] Figure 23 The XRPD diagram of compound (I) and the crystalline phase form of sulfuric acid, SF3 polymorph, is shown.

[0042] Figure 24 The XRPD diagrams of the crystalline phase form S1 polymorph of compound (I) and saccharin are shown.

[0043] Figure 25 The XRPD diagrams of the crystalline phase form S2 polymorph of compound (I) and saccharin are shown.

[0044] Figure 26 XRPD diagram of the solid amorphous form of compound (I) Figure 27 Results of a study on the storage stability of the solid amorphous form of compound (I). Detailed Implementation

[0045] Crystallization phase form 1 polymorph In a first aspect, the present invention provides a compound of formula (I) in the form of a crystalline phase, wherein the crystalline phase is a polymorph of crystalline phase form 1.

[0046] The crystalline phase form of the compound of formula (I) 1 Polymorph appropriately has essentially the following characteristics: Figure 1 The XRPD diagram shown. Figure 1 The peaks in the peaks are shown in Table 1 below: Table 1: Peak List of XRPD Plot in Form 1 The polymorph of crystalline phase form 1 of the compound of formula (I) suitably has an XRPD plot containing three, four, five, six, seven, eight, nine or ten peaks selected from the following: 10.5, 14.3, 16.9, 18.6, 19.3, 21.1, 22.3, 22.5, 26.6 and 28.6 (± 0.2) °2θ. For example, the polymorph of crystalline phase form 1 of the compound of formula (I) suitably has an XRPD plot containing all ten peaks selected from the following: 10.5, 14.3, 16.9, 18.6, 19.3, 21.1, 22.3, 22.5, 26.6 and 28.6 (± 0.2) °2θ. Suitably, the XRPD plot contains three, four, five, six, seven, eight, nine, or ten peaks (e.g., all ten peaks) as described above, wherein said peaks are present with a relative intensity of at least 20%, for example, at least 30%. The crystalline phase form 1 polymorph of the compound of formula (I) suitably has an XRPD plot containing one, two, three, four, or five other peaks selected from the following: 6.1, 13.4, 16.2, 24.4, and 25.1 (± 0.2) °2θ. For example, the crystalline phase form 1 polymorph of the compound of formula (I) suitably has an XRPD plot containing all five peaks selected from the following: 6.1, 13.4, 16.2, 24.4, and 25.1 (± 0.2) °2θ. Suitably, the XRPD plot contains three, four, or five other peaks as described above (e.g., all five other peaks), wherein said peaks are present with a relative intensity of at least 10%, for example, at least 20%. Suitablely, the XRPD plot of the polymorph of crystalline phase 1 of compound (I) contains a peak at 6.1 (± 0.2) °2θ; a peak at this position is not found in the XRPD plot of the polymorph of crystalline phase 2 of compound (I) (1,4-dioxane solvate). Suitablely, the XRPD plot of the polymorph of form 1 of compound (I) does not contain a peak at 9.0 (± 0.2) °2θ; a prominent peak at this position is found in the XRPD plot of the polymorph of crystalline phase 2 of compound (I) (1,4-dioxane solvate).

[0047] In relation to the peaks in an XRPD plot, the term "relative intensity" refers to the intensity of the peak as a percentage of the intensity of the strongest peak in the pattern.

[0048] XRPD experiments are typically performed using CuKα1 radiation, as further described in the General Methods section.

[0049] The crystalline phase form 1 polymorph of the compound of formula (I) suitably has cell sizes of about 14.71 Å (size a), about 16.77 Å (size b) and about 9.58 Å (size c) in space group P21 / c as determined by SCXRD, wherein the α angle is 90 °C, the β angle is about 107.9 °C and the γ angle is 90 °C.

[0050] XRPD plots and unit cell size determinations can be performed using the methods described in the general methods section below.

[0051] As further explained in the Examples section, the Form 1 polymorph of the compound (I) possesses many surprising properties that are advantageous for its development into a pharmaceutical product. For example, the Form 1 polymorph is thermodynamically stable and has a high melting point, is non-hygroscopic, and is suitable for storage (see [link to documentation]). Figures 2 to 6 It is polymorphic and stable under applied pressure.

[0052] The polymorph of compound (I) can be prepared by a variety of crystallization methods, including solvent evaporation, cooling crystallization, antisolvent addition crystallization (direct and reverse) and quenching.

[0053] In an exemplary solvent evaporation method, the compound of formula (I) is dissolved in a minimal amount of solvent at room temperature (about 20-25°C), and the solution is evaporated at room temperature (about 20-25°C). Crystals of the form 1 polymorph are produced. Suitable solvents that can 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) can be dissolved in a minimal amount of solvent under reflux or at a maximum of 75°C, and the solution can be evaporated at said temperature. Crystals of the form 1 polymorph are produced. Suitable solvents that can 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, tert-butanol, and tetrahydrofuran. Alternatively, the compound of formula (I) can be dissolved in a minimal amount of solvent and the solution evaporated at about 4°C. Crystals of the polymorph of form 1 can be produced. Suitable solvents that can be used include chloroform, dichloromethane, methanol, and tetrahydrofuran.

[0054] In an exemplary cooling crystallization method, a thermally concentrated (e.g., saturated) solution of compound (I) in a solvent is slowly cooled. For example, the solution is dissolved in a minimal amount of solvent under reflux or at a maximum of 75°C and slowly cooled to room temperature (about 20-25°C). Crystals of the polymorph of form 1 are 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, tetrahydrofuran, and toluene.

[0055] In an exemplary direct antisolvent addition crystallization method, the compound of formula (I) is dissolved in a minimal amount of solvent under reflux or at a maximum temperature of 75°C, and the antisolvent is slowly added until crystallization begins (indicated by the presence of turbidity), and the mixture is then slowly cooled to room temperature (about 20-25°C). Crystals of the polymorph of form 1 are produced. Suitable antisolvents include heptane and diisopropyl ether. Suitable solvents that can be used include acetone, dimethyl carbonate, ethanol, isobutanol, isopropanol, methyl acetate, n-butanol, and tetrahydrofuran.

[0056] In an exemplary reverse antisolvent addition crystallization method, the compound of formula (I) is dissolved in a minimal amount of solvent under reflux or at a maximum temperature of 75°C, and the solution is added to cold water (about 4-10°C) at room temperature (about 20-25°C). Crystals of the polymorph of form 1 are produced. Suitable solvents may include acetone, dimethyl carbonate, ethanol, isobutanol, and isopropanol.

[0057] In another exemplary reverse antisolvent addition crystallization method, the compound of formula (I) is dissolved in a minimal amount of solvent under reflux or at a maximum temperature of 75°C, and the solution is added dropwise to the antisolvent at room temperature (about 20-25°C). Crystals of the polymorph of form 1 are produced. Suitable antisolvents include heptane and diisopropyl ether. Suitable solvents that can be used include acetone, dimethyl carbonate, ethanol, isobutanol, isopropanol, methyl acetate, methyl ethyl ketone, n-butanol, and tetrahydrofuran.

[0058] In an exemplary quenching method, the compound of formula (I) is dissolved in a minimal amount of solvent under reflux or at a maximum temperature of 75°C, and the solution is rapidly cooled in an ice bath. Crystals of the polymorph of form 1 are produced. Suitable solvents may include acetone, ethyl acetate, dimethyl carbonate, chlorobenzene, dichloromethane, 1,2-dimethoxyethane, methyl ethyl ketone, n-butanol, and tetrahydrofuran.

[0059] This invention provides a method for preparing a crystalline phase form of a compound of formula (I), wherein the crystalline phase form is a polymorph of crystalline phase form 1, comprising dissolving the compound of formula (I) in a solvent selected from, for example, acetone, acetonitrile, ethyl acetate, isopropyl acetate, propyl 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, tert-butanol, tetrahydrofuran, and toluene, and crystallizing the polymorph of crystalline phase form 1 therefrom. In one aspect, crystallization comprises cooling the hot solution of the compound of formula (I) in the solvent (e.g., cooling the solution from reflux temperature or from a maximum temperature of about 75°C). In another aspect, crystallization comprises evaporating the solvent. In one aspect, crystallization involves adding an antisolvent, such as an antisolvent selected from water, n-heptane, and diisopropyl ether, to a solution of the compound of formula (I) in a solvent. In another aspect, crystallization involves adding a solution of the compound of formula (I) in a solvent to an antisolvent, such as an antisolvent selected from water, n-heptane, and diisopropyl ether.

[0060] As used in this article, "reflux or up to 75°C" means the lower of the reflux temperature (i.e., the solvent boiling point temperature) and 75°C.

[0061] Crystalline phase 2 polymorph (1,4-dioxane solvate) In another aspect, the present invention provides a polymorph of the crystalline phase form 2 of the compound of formula (I) (a 1,4-dioxane solvate). Suitably, the stoichiometry is 2:1 (i.e., two molecules of the compound of formula : one molecule of the solvent, i.e., 1,4-dioxane), i.e., suitably, the solvate is a semi-solvate.

[0062] The crystalline phase 2 polymorph (1,4-dioxane solvate) can be prepared by antisolvent addition crystallization (direct or reverse) using n-heptane as the antisolvent or by quenching.

[0063] In an exemplary direct antisolvent crystallization method, the compound of formula (I) is dissolved in a minimal amount of 1,4-dioxane at about 75°C (e.g., 70-75°C) and n-heptane is slowly added until crystallization begins, and then the mixture is slowly cooled to room temperature (about 20-25°C). Crystals of the form 2 polymorph (1,4-dioxane solvate) are produced.

[0064] In an exemplary reverse antisolvent addition crystallization method, the compound of formula (I) is dissolved in a minimum amount of 1,4-dioxane at about 75°C (e.g., 70-75°C) and added dropwise to n-heptane at room temperature (about 20-25°C). Crystals of the polymorph of form 2 (1,4-dioxane solvate) are produced.

[0065] In an exemplary quenching method, the compound of formula (I) is dissolved in a minimal amount of 1,4-dioxane at about 75°C (e.g., 70-75°C) and rapidly cooled in an ice bath. Crystals of the polymorph of form 2 (1,4-dioxane solvate) are produced.

[0066] The crystalline phase form of compound (I) 2, a polymorph (1,4-dioxane solvate), suitably possesses essentially the following characteristics: Figure 7 The XRPD diagrams are shown. The XRPD diagram of the polymorph of crystalline phase form 2 (1,4-dioxane solvate) of compound (I) contains a peak at 9.0 (± 0.2) °2θ; a peak at this position is not found in the XRPD diagram of the polymorph of crystalline phase form 1 of compound (I). The XRPD diagram of the polymorph of form 2 (1,4-dioxane solvate) of compound (I) does not contain a peak at 6.1 (± 0.2) °2θ; a prominent peak at this position is found in the XRPD diagram of the polymorph of form 1 of compound (I).

[0067] Crystallization phases of compounds of formula (I) and acids Compound (I) contains a basic nitrogen atom and has a calculated pKa of 3.7. Therefore, it is expected that compound (i) can form a salt with a strong acid and that the salt is crystallizable. When compound (I) forms a crystalline phase with a weak acid (e.g., an acid with a pKa > 3.7), the crystalline form is unlikely to be a salt and may instead be a eutectic. In a salt, by standard definition, protons from the acid are transferred to the base, resulting in charge separation and ionic interactions. In a eutectic, no protons are transferred, and therefore no charge separation occurs.

[0068] The present invention also provides compounds of formula (I): (I) The crystalline phase form of the acidic substance, wherein the crystalline phase form is a crystalline salt form or a eutectic.

[0069] In a first embodiment, the acid is succinic acid. Succinic acid has an ionizable acid group with a pKa of about 4.2 and a second ionizable group with a pKa of about 5.6. Suitably, the stoichiometry is 2:1 (i.e., two molecules of compound (I) : one molecule of succinic acid). In one embodiment, the crystalline phase is anhydrous and not a solvate. In one embodiment, the crystalline phase is crystalline phase form SC1. Suitably, crystalline phase form SC1 has substantially the following characteristics: Figure 10 The XRPD diagram shown.

[0070] In a second embodiment, the acid is gentianic acid. Gentianic acid has an ionizable acid group with a pKa value of about 2.5. Suitably, the stoichiometry is 2:1 (i.e., two molecules of compound (I) : one molecule of gentianic acid). In one embodiment, the crystalline phase is a eutectic. In one embodiment, the crystalline phase is anhydrous and not a solvate. In one embodiment, the crystalline phase is crystalline phase G1. Suitably, crystalline phase G1 has substantially the following characteristics: Figure 11 The XRPD diagram shown.

[0071] In a third embodiment, the acid is maleic acid. Maleic acid has an ionizable acid group with a pKa of about 1.9 and a second ionizable group with a pKa of about 6.9. Suitably, the stoichiometry is 1:1 (i.e., one molecule of compound (I) : one molecule of maleic acid). In one embodiment, the crystalline phase is a salt. In one embodiment, the crystalline phase is anhydrous and not a solvate. In one embodiment, the crystalline phase is a polymorph of crystalline phase form M1. Suitably, the polymorph of form M1 has substantially the following characteristics: Figure 12 The XRPD diagram is shown. In another embodiment, the crystalline phase is a polymorph of crystalline phase M2. Suitably, the polymorph of form M2 has substantially the following characteristics: Figure 13 The XRPD diagram is shown. In another embodiment, the crystalline phase is a polymorph of crystalline phase M3. Suitably, the polymorph of form M3 has substantially the following characteristics: Figure 14 The XRPD diagram is shown. In another embodiment, the crystalline phase is a polymorph of crystalline phase M4. Suitably, the polymorph of form M4 has substantially the following characteristics: Figure 15 The XRPD diagram is shown. In another embodiment, the crystalline phase is a polymorph of crystalline phase M5. Suitably, the polymorph of form M5 has substantially the following characteristics: Figure 16 The XRPD diagram is shown. In another embodiment, the crystalline phase is a polymorph of form M6. Suitably, the polymorph of form M6 has substantially the following characteristics: Figure 17 The XRPD diagram shown.

[0072] In a fourth embodiment, the acid is hydrochloric acid. Hydrochloric acid has an ionizable acid group with a pKa value of about -5.9. Suitably, the stoichiometry is 1:1 (i.e., one molecule of compound (I) : one molecule of hydrochloric acid). In one embodiment, the crystalline phase is a salt. In one embodiment, the crystalline phase is anhydrous and not a solvate. In one embodiment, the crystalline phase is a C1 polymorph. Suitably, the C1 polymorph has substantially the following characteristics: Figure 18 The XRPD diagram shown.

[0073] In a fifth embodiment, the acid is hydrobromic acid. Hydrobromic acid has an ionizable acid group with a pKa value of approximately -9. Suitably, the stoichiometry is 1:1 (i.e., one molecule of compound (I) : one molecule of hydrobromic acid). In one embodiment, the crystalline phase is a salt. In one embodiment, the crystalline phase is a polymorph of crystalline phase form B1. Suitably, the polymorph of form B1 has substantially the following characteristics: Figure 19 The XRPD diagram is shown. In one embodiment, the crystalline phase is anhydrous and not a solvate. In another embodiment, the crystalline phase is a polymorph of crystalline phase B2. Suitably, the polymorph of form B2 has substantially the following characteristics: Figure 20 The XRPD diagram is shown. In one embodiment, the crystalline phase is in the form of a hydrate.

[0074] In a sixth embodiment, the acid is sulfuric acid. Sulfuric acid has two ionizable acid groups with pKa values ​​of approximately -2.8 and approximately 2.0. Suitably, the stoichiometry is 2:1 (i.e., two molecules of compound (I) : one molecule of sulfuric acid). In one embodiment, the crystalline phase is a salt. In one embodiment, the crystalline phase is a crystalline SF1 polymorph. Suitably, the SF1 polymorph has substantially the following characteristics: Figure 21 The XRPD diagram is shown. In one embodiment, the crystalline phase is anhydrous and not a solvate. In another embodiment, the crystalline phase is a crystalline SF2 polymorph. Suitably, the SF2 polymorph has substantially the following characteristics: Figure 22 The XRPD diagram is shown. In one embodiment, the crystalline phase is a solvate (hydrate). In another embodiment, the crystalline phase is a polymorph of SF3. Suitably, the polymorph of SF3 has substantially the following characteristics: Figure 23 The XRPD diagram is shown. In one embodiment, the crystalline phase is anhydrous and not a solvate.

[0075] In a seventh embodiment, the acid is saccharin. Saccharin has an ionizable acid group with a pKa value of about 1.6. Suitably, the stoichiometry is 1:1 (i.e., one molecule of compound (I) : one molecule of saccharin). In one embodiment, the crystalline phase is a salt. In one embodiment, the crystalline phase is a solvate (hydrate). In one embodiment, the crystalline phase is a polymorph of crystalline phase form S1. Suitably, the polymorph of form S1 has substantially the following characteristics: Figure 24 The XRPD diagram is shown. In another embodiment, the crystalline phase is a polymorph of form S2. Suitably, the polymorph of form S2 has substantially the following characteristics: Figure 25 The XRPD diagram shown.

[0076] The crystalline phase form of the compound of formula (I) with an acid can be prepared by mixing the desired equivalent of the corresponding acid (e.g., 1 equivalent, or 0.5 equivalent in the case of sulfuric acid or gentianic acid) with the compound of formula (I) (as a base). A range of conditions can be used to obtain the crystalline phase form 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, tetrahydrofuran, and isopropanol) is slowly cooled (“cooling crystallization method”). Crystallization in either the salt or eutectic form can occur. In another method, a slurry of the acid / base mixture in a solvent in which it is not completely dissolved can be prepared at a high temperature (reflux or up to 75°C) maintained for 1 hour. Crystallization in either the salt or eutectic form can occur. In variations of these conditions, the slurry can be maintained at room temperature (about 20-25°C) for 7 days. Crystallization in either the salt or eutectic form can occur. In another method, an acid / base mixture is prepared as a solution in a solvent (e.g., selected from acetone, acetonitrile, ethyl acetate, tetrahydrofuran, and isopropanol), and the solvent is evaporated at room temperature (approximately 20-25°C). Crystallization may occur in the form of a salt or a eutectic.

[0077] Compound of formula (I) Compounds of formula (I) can be prepared as described in WO2021 / 105317 (see in particular General Synthesis and Example 24), the contents of which are incorporated herein by reference in their entirety.

[0078] Composition and Use 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 compounds of formula (I) with acids (including the polymorphs described herein) are referred to as “the crystalline phase forms of the present invention”. As used herein, compounds of formula (I) are sometimes referred to as “the active ingredient of the present invention”.

[0079] The present invention provides a pharmaceutical composition comprising the crystalline phase form of the present invention and a pharmaceutically acceptable diluent or carrier.

[0080] The compounds of the present invention have low systemic exposure after oral, topical or ocular administration due to their low metabolic stability, and therefore the solid form of the present invention is particularly suitable for the prevention or treatment of diseases as further described herein.

[0081] The crystalline form of the present invention can be administered by any convenient method, such as oral, parenteral, buccal, sublingual, nasal, rectal, transdermal, intratympanic, and intracochlear administration, and the pharmaceutical composition may be adjusted accordingly. Oral administration may be particularly convenient. Topical and ocular administration may also be convenient.

[0082] Compositions for oral administration may be formulated as liquids or solids, such as elixirs, syrups, suspensions, emulsions, tablets, capsules, or sugar tablets.

[0083] Liquid compositions typically consist of a suspension or solution of the crystalline phase of the invention in a suitable liquid carrier, such as an aqueous solvent like water, ethanol, or glycerol, or a non-aqueous solvent like polyethylene glycol or oil. Formulations may also contain suspending agents, preservatives, flavoring agents, and / or coloring agents.

[0084] Compositions in tablet form can be prepared using any suitable pharmaceutical carrier commonly used to prepare solid dosage forms, such as magnesium stearate, starch, lactose, sucrose, and cellulose.

[0085] The capsule-form composition can be prepared using conventional encapsulation procedures. For example, pellets containing the crystalline phase of the present invention can be prepared using a standard carrier and then filled into hard gelatin capsules; alternatively, any suitable pharmaceutical carrier (e.g., aqueous gum, cellulose, silicate, or oil) can be used to prepare a dispersion or suspension, and then the dispersion or suspension can be filled into soft gelatin capsules.

[0086] Typical parenteral compositions consist of a solution or suspension of the crystalline phase of the invention in a sterile aqueous carrier or a parenteral-acceptable oil (e.g., polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil). Alternatively, the solution may be lyophilized and then reconstituted with a suitable solvent just before administration. In one embodiment, the parenteral composition is suitable for injection.

[0087] Compositions for nasal administration can be conveniently formulated as aerosols, drops, gels, and powders. Aerosol formulations typically comprise a solution or fine suspension of the crystalline phase of the invention in a pharmaceutically acceptable aqueous or non-aqueous solvent, and are typically presented aseptically in single or multiple doses in a sealed container that may be used with a nebulizer or refill. Alternatively, the sealed container may be a disposable dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metering valve. When the dosage form includes an aerosol dispenser, it will contain a propellant, which may be a compressed gas such as air, or an organic propellant such as chlorofluorocarbons (CFCs) or hydrofluorocarbons (HFCs). Aerosol dosage forms may also be in the form of a pump nebulizer.

[0088] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and soft tablets, wherein the crystalline phase of the invention is formulated with a carrier (e.g., sugar and gum arabic, tragacanth, or gelatin and glycerin).

[0089] Compositions for rectal administration are conveniently available in suppository form and contain a conventional suppository base such as cocoa butter.

[0090] Compositions suitable for transdermal application include ointments, gels, and patches. In one embodiment, the composition is in unit dosage form such as tablets, capsules, or ampoules.

[0091] The composition may contain 0.001% to 99.9% by weight, preferably 0.01% to 90% by weight, for example 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 contain 0.1% to 99.999% by weight, for example 40% to 90% by weight, of a carrier, depending on the method of administration. The composition may contain 0.05 mg to 1000 mg, for example 2.0 mg to 500 mg or 1.0 mg to 500 mg, of the active ingredient of the invention, depending on the method of administration. The composition may contain 50 mg to 1000 mg, for example 100 mg to 400 mg, of a carrier, depending on the method of administration. The dosage of the compound for treating the aforementioned conditions will vary in a generally consistent manner depending on the severity of the condition, patient weight, and other similar factors. However, as a general guideline, suitable unit doses can range from 0.05 mg to 1000 mg, more preferably from 1.0 mg to 500 mg, and such unit doses can be administered more than once a day, such as twice or three times a day. Such therapy can continue for several weeks or months.

[0092] The dose provided to the subject will generally be a safe and effective dose, i.e., an amount that provides an acceptable balance between the desired benefit and the undesirable side effects. "Safe and effective dose" is intended to include the amount of a compound that effectively achieves the desired effect in the treatment and / or prevention of a disease state. The desired effect is generally clinically significant and / or measurable, for example, in cases where: (a) disease state is prevented in mammals, specifically when the mammal is susceptible to the disease state but has not yet been diagnosed with it; (b) disease state is inhibited, i.e., its development is slowed or halted; and / or (c) disease state is alleviated, i.e., the disease state is induced to regress or associated symptoms are reduced. A safe and effective dose may be an amount sufficient to achieve the desired effect when the crystalline form of the invention is administered alone, or when it is administered in combination with one or more other active ingredients different from those of formula (I).

[0093] For the avoidance of doubt, a “safe and effective amount” as described herein can be achieved by any suitable dosing regimen (including, but not limited to, exemplary dosing regimens described elsewhere herein). Thus, for example, references herein to compounds for example to be administered in a safe and effective amount via a specific route of administration include administration via a single dose or via multiple doses, such as via a specified route of administration. For example, a safe and effective amount administered orally includes administration of a single dose or any multiple doses orally, provided that the safe and effective amount is achieved through oral administration.

[0094] In another aspect, the present invention provides combinations comprising the crystalline phase form of the present invention, such as combinations comprising the crystalline phase form of the present invention and one or more other pharmaceutically acceptable active ingredients.

[0095] This invention provides a crystalline phase form of the invention for use in combination with one or more other pharmaceutically acceptable active ingredients.

[0096] When the crystalline form of the present invention is used in combination with other therapeutic agents, the compounds may be administered sequentially or simultaneously via any convenient route. Alternatively, the compounds may be administered alone.

[0097] The combinations mentioned above are conveniently presented for use in the form of pharmaceutical formulations, and therefore pharmaceutical formulations comprising the combinations as defined above, as well as pharmaceutically acceptable carriers or excipients, constitute another aspect of the invention. Individual components of such combinations may be administered individually or as a combination of pharmaceutical formulations, sequentially or simultaneously. Individual components of a combination may also be administered individually via the same or different routes.

[0098] When the crystalline form of the present invention is used in combination with a second therapeutic agent that is active against the same disease state, the dosage of each compound may differ from the dosage when the compound is used alone. Those skilled in the art will readily understand the appropriate dosage.

[0099] Suitablely, the crystalline phase form of the present invention is for oral application.

[0100] Suitablely, the crystalline phase of the present invention is administered at a dose of 2 to 2000 mg per day, for example 2 to 1200 mg per day, for example 2 to 800 mg per day, particularly 2 to 400 mg per day, especially 2 to 300 mg per day, for example 5 to 250 mg per day.

[0101] Suitablely, the crystalline phase of the present invention is applied 1-4 times daily, for example once or twice daily.

[0102] Suitablely, the crystalline phase form of the present invention is applied for a period of at least three months.

[0103] Ideally, the crystalline phase of the present invention is to be administered orally once or twice daily, at a dose of 2 to 1200 mg daily, for example 2 to 800 mg daily, particularly 2 to 400 mg daily, especially 2 to 300 mg daily, for example 5 to 250 mg daily.

[0104] Human subjects may be adults, for example, aged 18 to 65 years. Alternatively, human subjects may be 66 years of age or older. The crystalline phase form of the present invention may be administered to human subjects younger than 18 years of age, for example, aged 4 to 17 years.

[0105] This invention provides a crystalline form of the invention for treating or preventing diseases or pathological conditions that are readily improved by inhibiting transforming growth factor-β receptor I (TGFβRI / ALK5). This invention also provides the use of the crystalline form of the invention for manufacturing a medicament for treating or preventing diseases or pathological conditions that are readily improved by inhibiting transforming growth factor-β receptor I (TGFβRI / ALK5). This invention further provides a method for treating or preventing diseases or pathological conditions that are readily improved by inhibiting transforming growth factor-β receptor I (TGFβRI / ALK5), the method comprising administering the crystalline form of the invention to a subject in need.

[0106] Such diseases or pathological conditions may be selected from, for example, the following groups: gastrointestinal diseases, fibrotic diseases, cancer, and graft-versus-host disease (GVHD).

[0107] The present invention also provides a combination comprising the crystalline phase form of the present invention and a therapeutic agent for the treatment or prevention of diseases selected from the group consisting of: gastrointestinal diseases, fibrotic diseases, cancer, and graft-versus-host disease (GVHD).

[0108] As used herein, the term "fibrotic disease" refers to a disease characterized by excessive scarring due to the overproduction, deposition, and contraction of the extracellular matrix and associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased recruitment of fibroblasts, and includes, but is not limited to, fibrosis of individual organs or tissues (e.g., heart, kidneys, liver, joints, lungs, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal system, and digestive tract). Specifically, the term fibrotic disease refers to gastrointestinal fibrosis or intestinal fibrosis, such as fibrotic stenotic Crohn's disease (FSCD). Specifically, the term fibrotic disease refers to liver fibrosis, also known as hepatic fibrosis, such as cirrhosis, alcohol-induced liver fibrosis, toxic / drug-induced liver fibrosis, hemochromatosis, nonalcoholic steatohepatitis (NASH) (especially F4NASH), bile duct injury, primary biliary cirrhosis, primary sclerosing cholangitis, infection-induced liver fibrosis, virus-induced liver fibrosis, and autoimmune hepatitis. Specifically, the term fibrotic disease refers to fibrotic skin diseases or fibrotic diseases with skin components, such as scleroderma, nephrotic fibrotic skin disease, mixed connective tissue disease, sclerosing myxedema, sclerosing edema, and eosinophilic fasciitis. Specifically, the term fibrotic disease refers to fibrotic kidney diseases in transplant recipients, such as glomerulonephritis (GN) (e.g., mesangial proliferative GN, immune GN, and crescentic GN), diabetic nephropathy, renal interstitial fibrosis, and renal fibrosis. Specifically, the term fibrotic disease refers to fibrotic eye diseases, such as dry eye syndrome, age-related macular degeneration, corneal and conjunctival scarring, postcataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy. Specifically, the term fibrotic disease 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.

[0109] The disease “non-alcoholic steatohepatitis (NASH)” is also known as metabolic dysfunction-associated steatohepatitis (MASH); the terms are interchangeable.

[0110] As used herein, the term "gastrointestinal disease" refers to a disease affecting the gastrointestinal tract, specifically the small intestine and / or large intestine. The small intestine includes the duodenum, jejunum, and ileum, and the large intestine includes the cecum (including the appendix), colon, rectum, and anal canal. Specifically, the term gastrointestinal disease includes inflammatory bowel disease (IBD), post-radiation enteritis, complicated celiac disease, and intestinal fibrosis.

[0111] The terms "inflammatory bowel disease" or "IBD" refer to Crohn's disease (CD), which includes inflammatory CD, fibrous stricture CD (FSCD), fistula CD, and perianal CD, and ulcerative colitis (UC). Specifically, the term IBD refers to fibrous stricture CD.

[0112] The commonly used Montreal classification system categorizes CD patients into non-stenotic [B1], stenotic [B2], or penetrating [B3] subtypes. Stenotic diseases are characterized by narrowing of the intestinal lumen caused by fibrosis occurring in the submucosa. The penetrating phenotype is characterized by the formation of fistulas (abnormal communication between two epithelialized surfaces). These can be anatomically defined; those that originate internally and those that involve the perineum. Fistulas can be further classified as those that form an internal communication with another intestinal layer (i.e., the intestine-to-intestine) or a communication between the intestine and other organs (i.e., the intestinal lining or the enterobladder). Therefore, in a particular implementation, the term CD refers to non-stenotic CD, stenotic CD, or penetrating CD.

[0113] As used herein, the term "cancer" includes, and in particular refers to, breast cancer, colon cancer, esophageal cancer, stomach cancer, colorectal cancer, hepatocellular carcinoma, lung cancer, or pancreatic cancer. Specifically, the term refers to cancers affecting the esophagus or gastrointestinal tract, such as stomach cancer, esophageal cancer, or colorectal cancer.

[0114] Therefore, the present invention provides a crystalline phase form for treating or preventing fibrotic diseases selected from intestinal fibrosis, liver fibrosis, fibrotic skin diseases, fibrotic kidney diseases, fibrotic eye diseases, and fibrotic lung diseases. Specifically, the fibrotic disease is intestinal fibrosis. Specifically, the fibrotic disease is fibrotic stenotic Crohn's disease (FSCD).

[0115] Therefore, the present invention provides a crystalline phase form of the invention for the treatment or prevention of inflammatory bowel disease. Specifically, inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis. Specifically, inflammatory bowel disease is fibrotic stricture CD.

[0116] Example General methods XRPD Analysis Sample preparation: 20 mg of untreated sample was prepared in a standard sample holder using two polyacetate foils.

[0117] Data collection:Powder diffraction patterns were obtained in transmission geometry using CuKα1 radiation operated at 40 kV and 40 mA on a Bruker D8 Advance series 2θ / θ powder diffraction system. The system was equipped with a VÅNTEC-1 single-photon counting PSD, a germanium monochromator, a 90-position automatic sample changing stage, a fixed divergence slit, and a radial Soler. The procedures used were: data acquisition with DIFFRAC plus XRD Commander V.2.5.1 and evaluation with High Score Plus 4.9 (Malvern PANalytical BV).

[0118] Measurement conditions: In measurements lasting 6 or 30 minutes, samples are measured in a 2θ range of 4 to 40° using an angular step size of 0.05° and a step time of 432 or 2198 s.

[0119] SCXRD Analysis Data collection The crystals measured were prepared under inert conditions and immersed in perfluoropolyether as a handling protective oil. Crystal structure determination was performed using a Rigaku diffractometer equipped with a Pilatus 200K area detector, a Rigaku MicroMax-007HF microfocus rotating anode with MoKα radiation, confocal maximum flux optics, and an Oxford Cryosystems Cryostream 700 plus cryogenic system (T = -173℃). Global data collection and ω and Used together with scans. Procedure used: Data collection and reduction were performed using CrysAlisPro V / .60A (CrysAlisPro 1.171.39.12b (Rigaku OD, 2015)). Empirical absorption correction was performed using spherical harmonics with the Scale3 Abspack scaling algorithm (CrysAlisPro 1.171.39.12b (Rigaku OD, 2015)).

[0120] Structural solution and refinement: Crystal structure solving was performed using the computer program SHELXT (Sheldrick, GM). Acta Cryst.2015A71, 3-8). Visualization was performed using the program SHELXle (CB Huebschle, GMSheldrick and B. Dittrich; J.Appl.Cryst.201144, 1281-1284). Missing atoms were then located using differential Fourier synthesis and added to the atom list. The missing atoms were then visualized using the program SHELXL 2015. 2 Least-squares refinement was performed using all measured intensities (Sheldrick, GM Acta Cryst. 2015 C71, 3-8). All non-hydrogen atoms were refined, including anisotropic displacement parameters.

[0121] DSC analysis Sample preparation: Weigh approximately 1–4 mg of sample (using an MX5 Mettler Toledo microbalance) into a 40 μL aluminum crucible with a pinhole cap.

[0122] Data collection: DSC analysis was recorded in a Mettler Toledo DSC822e calorimeter. The program used was STARE software for data collection and evaluation.

[0123] Measurement conditions: The sample was heated from 30°C to 300°C at a rate of 10°C / min under dry nitrogen (flow rate: 50 mL / min).

[0124] TGA Analysis Sample preparation: Weigh approximately 1–4 mg of sample (using an MX5 Mettler Toledo microbalance) into a 40 μL aluminum crucible with a pinhole cap.

[0125] Data collection: Thermogravimetric analysis was recorded in a Mettler Toledo TGA / SDTA851 balance equipped with an MT1 type balance. The software used for data collection and evaluation was STARE.

[0126] Measurement conditions: The sample was heated from 30°C to 300°C at a rate of 10°C / min under dry nitrogen (flow rate: 10 mL / min).

[0127] DVA analysis Sample preparation Weigh approximately 5-10 mg of sample (using an MX5 Mettler Toledo microbalance) into a 150 μL uncovered platinum crucible.

[0128] Data collection: Experiments were conducted on a Mettler Toledo TGA / DSC 1 LF instrument equipped with an LF SDTA FRS2 sensor coupled to a modular humidity generator MHG 32. Data collection and evaluation were performed using STARe software.

[0129] Measurement conditions Samples were analyzed at 25°C after 60-minute, 10% humidity cycles from 10% RH to 80% RH and then back down to 10% RH.

[0130] Preparation and evaluation of the crystalline phase form of the present invention Example 1 Crystallization form of compound (I) 1 Polymorph preparation Polymorphs of crystalline phase 1 can be prepared by a variety of methods.

[0131] (1) Solvent evaporation (A) The compound of formula (I) (20 mg) was dissolved in a minimal amount of the corresponding solvent at room temperature. The solution was then evaporated at room temperature. All solids obtained were analyzed by XRPD. The results are summarized in Table 2A.

[0132] Table 2A: Forms of compounds of formula (I) obtained by solvent evaporation at room temperature

[0133] (B) Dissolve 20 mg of compound (I) in 2 mL of the appropriate solvent under reflux or at a maximum temperature of 75 °C. Evaporate the solution in an open flask at 75 °C. Analyze all solids obtained by XRPD. The results are summarized in Table 2B.

[0134] Table 2B: Forms of compounds of formula (I) obtained by solvent evaporation under reflux or at a maximum temperature of 75°C

[0135] (C) The compound of formula (I) (20 mg) was dissolved in a minimal amount of the corresponding solvent. The solution was evaporated at approximately 4 °C. All solids obtained were analyzed by XRPD. The results are summarized in Table 2C.

[0136] Table 2C: Forms of compounds of formula (I) obtained by solvent evaporation at approximately 4°C

[0137] (2) Cooling crystallization The compound of formula (I) (20 mg) was dissolved in a minimal amount of the corresponding solvent under reflux or at a maximum temperature of 75 °C. The solution was slowly cooled to room temperature. The solids were separated by decantation and dried under vacuum (2–5 mbar) for 2 hours at room temperature. All solids obtained were analyzed by XRPD. The results are summarized in Table 3.

[0138] Table 3: Forms of compounds of formula (I) obtained by cooling crystallization.

[0139] (3) Antisolvent crystallization The compound of formula (I) (20 mg) was dissolved in a minimal amount of solvent under reflux or at a maximum temperature of 75 °C. The antisolvent was then slowly added until crystallization began (indicated by the presence of turbidity), and the mixture was then slowly cooled to room temperature. The solids were separated by decantation and dried under vacuum (2–5 mbar) for 2 hours at room temperature. All obtained solids were analyzed by XRPD. The results are summarized in Table 4.

[0140] Table 4: Forms of compounds of formula (I) obtained by direct antisolvent addition.

[0141] (4) Reverse antisolvent crystallization Compound (I) (20 mg) was dissolved in a minimal amount of solvent under reflux or at a maximum temperature of 75 °C, and the solution was added at room temperature with cold water (1 mL) or other antisolvent (1 mL). The solids were separated by decantation and dried under vacuum (2–5 mbar) for 2 h at room temperature. All solids obtained were analyzed by XRPD. The results are summarized in Tables 5A and 5B.

[0142] Table 5A: Forms of compounds of formula (I) obtained by adding a reverse antisolvent using water as the antisolvent.

[0143] Table 5B: Forms of compounds of formula (I) obtained by adding a reverse antisolvent using n-heptane or diisopropyl ether as the antisolvent.

[0144] (5) Sudden cooling Compound (I) (20 mg) was dissolved in a minimal amount of solvent under reflux or at a maximum temperature of 75 °C, and the solution was rapidly cooled in an ice bath. The solids were separated by decantation and dried under vacuum (2–5 mbar) for 2 h at room temperature. All solids obtained were analyzed by XRPD. The results are summarized in Table 6.

[0145] Table 6: Forms of Compounds of Formula (I) Obtained by Quenching

[0146] Characterization XRPD diagram of polymorphic form 1 is shown in Figure 1. Figure 1 The material appears to be crystalline.

[0147] The polymorph of crystalline phase 1 was evaluated by SCXRD.

[0148] SCXRD shows form 1 crystallized in monoclinic space group P21 / c, with one molecule in an asymmetric unit cell. The cell sizes are approximately 14.71 Å (size a), 16.77 Å (size b), and 9.58 Å (size c), with an α angle of 90 °C, a β angle of approximately 107.9 °C, and a γ angle of 90 °C. The structure exhibits good quality (no A- or B- alarms) and is refined to 5.9% R1.

[0149] The polymorph of crystalline phase 1 was evaluated by DSC. The results of the DSC experiment are shown in... Figure 2 There is a single endothermic melting peak, with an onset temperature of 190℃ (-105 J / g).

[0150] The polymorph of crystalline phase 1 was evaluated by TGA. The results of the TGA experiments are shown in... Figure 2 TGA analysis revealed a mass loss of 0.29% between 147°C and 229°C. This indicates that the material is anhydrous.

[0151] The polymorph of crystalline phase 1 was evaluated by DVS. The results of the DVS experiment are shown in... Figure 3 and Figure 4 In the middle. Relative humidity at 25°C increased from 10% to 80% in 10% increments over 60 minutes, and then decreased back to 10%. Figure 4 In the desorption curve, the initial value was lower than the adsorption curve, then rose above the adsorption curve at 50% RH, coincided at 60% and 80% RH, and was slightly higher than the adsorption curve at 70% RH. Moisture adsorption between 10% and 80% RH was 0.089%. Therefore, the form 1 polymorph was assessed as non-hygroscopic. The material form was investigated by XRPD after the DVS experiment. The material remained as the crystalline form 1 polymorph (see [link to study]). Figure 5 ).

[0152] Samples of the crystalline phase 1 polymorph were stored in a climate chamber at 25°C and 80% RH. After 4 days, solids were analyzed by XRPD. The material remained as the crystalline phase 1 polymorph (see [link to relevant documentation]). Figure 6 ).

[0153] The sample of polymorphic crystalline phase 1 was pressurized for 5 minutes using a tablet press (9 tons of pressure). The solid was then analyzed by XRPD and remained in phase 1.

[0154] These experiments demonstrate that the crystalline phase 1 polymorph is a thermodynamically stable high-melting-point solid, non-hygroscopic, and polymorphically stable during storage and under pressure. Therefore, the crystalline phase 1 polymorph possesses many properties advantageous for its development into pharmaceutical products.

[0155] Example 2 The crystalline phase form of compound (I) is a polymorph (1,4-dioxane solvate). preparation The crystalline phase form 2 polymorph (1,4-dioxane solvate) of compound (I) can be prepared by various methods.

[0156] (1) Direct addition of antisolvent A sample (20 mg) of compound (I) was dissolved in 0.3 mL of dioxane at a maximum temperature of 75 °C. Heptane (antisolvent) was slowly added until crystallization began, indicated by the presence of turbidity, and the mixture was then slowly cooled to room temperature. The solid was separated by decantation and dried under vacuum (2–5 mbar) for 2 hours at room temperature.

[0157] (2) Addition of reverse antisolvent Compound (I) (20 mg) was dissolved in a minimum amount of 1,4-dioxane at a maximum temperature of 75 °C, and the solution was added to n-heptane (antisolvent, 1 mL) at room temperature. The solid was separated by decantation and dried under vacuum (2–5 mbar) for 2 hours at room temperature.

[0158] (3) Sudden cooling The compound of formula (I) (20 mg) was dissolved in a minimum amount of 1,4-dioxane at a maximum temperature of 75 °C, and the solution was rapidly cooled in an ice bath. The solid was separated by decantation and dried under vacuum (2-5 mbar) for 2 hours at room temperature.

[0159] Characterization XRPD illustration of polymorph 2 (1,4-dioxane solvate) in crystalline phase form 2 is shown in Figure 7 middle.

[0160] DSC analysis (not shown in the figure) revealed two endothermic peaks with onset temperatures of 81 °C (-72 J / g) and 191 °C (-100 J / g) (melting).

[0161] The polymorph of crystalline phase 2 (1,4-dioxane solvate) was evaluated by TGA. The results of the TGA experiments are shown in… Figure 8 In the first experiment, TGA analysis showed a weight loss of 8.3% between 40°C and 150°C. In another experiment, to investigate the desolvation process based on the weight loss observed in TGA, a sample of the crystalline dioxane solvate was heated to 120°C and then cooled to room temperature. XRPD analysis revealed that the obtained solid was a polymorph of crystalline phase 1 (not shown). Based on TGA, it can be inferred that the polymorph of crystalline phase 2 (1,4-dioxane solvate) is a hemisolvate, but this has not yet been confirmed.

[0162] The storage stability of the polymorph of crystalline phase 2 (1,4-dioxane solvate) was evaluated. The results are shown in... Figure 9 The crystalline form 2 polymorph (1,4-dioxane solvate) was maintained in a climate chamber at 25°C and 80% RH. After 4 days, the solids were analyzed by XRPD. The crystalline sample of form 2 polymorph (1,4-dioxane solvate) had transformed into form 1 polymorph under the climate chamber conditions.

[0163] Example 3 The crystalline phase form of compound (I) and succinic acid is SC1. preparation Compound (I) (0.5 g, 1.06 mmol) was suspended in ethyl acetate (5 mL) and succinic acid (125 mg, 1.06 mmol, 1 equivalent) was added. The resulting suspension was heated to 75 °C. Ethyl acetate was added until completely dissolved (20 mL), and the resulting clear solution was slowly cooled to room temperature. Seeds were added to the crystalline form SC1 and stirred overnight. Seeds of the crystalline form SC1 were obtained by small-scale cooling crystallization using acetonitrile, ethyl acetate, acetone, or isopropanol as solvents. The solid was then filtered through a filter plate (N. 3), washed with ethyl acetate (2.5 mL), and dried under vacuum at 35 °C for 3 h. Yield: 0.425 g (68%).

[0164] Characterization The XRPD diagram of the crystalline phase SC1 of compound (I) and succinic acid is shown in Figure 1. Figure 10 In the middle. It is assumed that the stoichiometry (compound of formula (I) and succinic acid) is 2:1, but this has not yet been determined.

[0165] DSC analysis (figure not shown) showed endothermic reaction at initial temperatures of 136 °C (-9 J / g) and 159 °C (-84 J / g). TGA analysis (figure not shown) revealed weight loss due to decomposition at approximately 160°C. This suggests that the material is likely anhydrous and not a solvate.

[0166] DVS analysis was performed at 25°C in 30-minute intervals of 10% to 90% to 10% RH (figure not shown). A weight gain of 0.40% was recorded between 10% and 80% RH. The material morphology after the DVS experiment was investigated by XRPD, and no morphological changes were observed.

[0167] Example 4 The crystalline phase form of compound (I) and gentianic acid is G1. preparation Compound (I) (0.5 g, 1.06 mmol) was suspended in ethyl acetate (5 mL) and gentian acid (83 mg, 0.53 mmol, 0.5 equivalent) was added. The resulting suspension was heated to 75 °C. Ethyl acetate was added again until completely dissolved (20 mL), and the resulting clear solution was slowly cooled to room temperature. Seeds were added to the crystalline phase G1 and stirred overnight. Seeds of the crystalline phase G1 were obtained by small-scale cooling crystallization using acetonitrile, ethyl acetate, or acetone as solvents. The solid was then filtered through a filter plate (N. 3), washed with ethyl acetate (2.5 mL), and dried under vacuum at 35 °C for 3 hours. Yield: 0.390 g (67%).

[0168] Characterization XRPD diagram of the crystalline phase G1 of compound (I) and gentianic acid is shown in Figure 1. Figure 11 middle.

[0169] DSC analysis (figure not shown) showed endothermic reaction with an initial temperature of 181 °C (-93 J / g).

[0170] TGA analysis (figure not shown) revealed weight loss due to decomposition at approximately 180°C. This indicates that the material is anhydrous and not a solvate.

[0171] DVS analysis was performed at 25°C and at relative humidity ranging from 10% to 90% with a step size of 10% over 30 minutes (figure not shown). The weight increased by 0.76% between 10% and 80% relative humidity. The material morphology after the DVS experiment was investigated by XRPD, and no morphological changes were observed.

[0172] SCXRD shows that the crystalline phase G1 of compound (I) and gentic acid is a co-crystal with a stoichiometric ratio of 2:1 (compound (I) and gentic acid).

[0173] Example 5A The crystalline phase form of compound (I) and maleic acid (form M1 polymorph) preparation The compound of formula (I) (20 mg, 0.106 mmol) was suspended in methanol (1 mL) and maleic acid (4.9 mg, 1 equivalent) was added. The mixture was stirred for 15 minutes and evaporated. The resulting residue was dissolved in isopropanol (0.2 mL) at 75 °C, and the solution was slowly cooled to room temperature. When crystals formed, the mother liquor was decanted, and the solid was dried under vacuum at 35 °C for 3 hours.

[0174] Characterization The XRPD diagram of the polymorph of compound (I) M1 and maleic acid is shown in Figure 1. Figure 12 In the middle. It is assumed that the stoichiometry (compound of formula (I) and maleic acid) is 1:1, but this has not yet been determined.

[0175] DSC analysis (figure not shown) showed endothermic reaction with an initial temperature of 117 °C (-6 J / g).

[0176] TGA analysis (figure not shown) showed a weight loss of 2.9% below 122°C. Weight loss due to decomposition began at approximately 130°C.

[0177] Example 5B The crystalline phase form of compound (I) and maleic acid (form M2 polymorph) preparation The compound of formula (I) (20 mg, 0.106 mmol) was suspended in methanol (1 mL) and maleic acid (4.9 mg, 1 equivalent) was added. The mixture was stirred for 15 minutes and evaporated. The resulting residue was dissolved in acetonitrile (0.2 mL) at 75 °C, and the solution was slowly cooled to room temperature. When crystals formed, the mother liquor was decanted, and the solid was dried under vacuum at 35 °C for 3 hours.

[0178] Characterization The XRPD diagram of the M2 polymorph of maleic acid in its crystalline phase form is shown in the figure. Figure 13 In the middle. It is assumed that the stoichiometry (compound of formula (I) and maleic acid) is 1:1, but this has not yet been determined.

[0179] DSC analysis (figure not shown) showed endothermic reaction with an initial temperature of 117 °C (-71 J / g).

[0180] TGA analysis (figure not shown) shows weight loss due to decomposition that began at approximately 130°C.

[0181] This means that the material is anhydrous and not a solvate.

[0182] Example 5C The crystalline phase form of compound (I) and maleic acid (form M3 polymorph) preparation The compound of formula (I) (20 mg, 0.106 mmol) was suspended in methanol (1 mL) and maleic acid (4.9 mg, 1 equivalent) was added. The mixture was stirred for 15 minutes and evaporated. The resulting residue was dissolved in tetrahydrofuran (0.2 mL) under reflux, and the solution was slowly cooled to room temperature. When crystals formed, the mother liquor was decanted, and the solid was dried under vacuum at 35 °C for 3 hours.

[0183] Characterization The XRPD diagram of the M3 polymorph of maleic acid in its crystalline phase form is shown in the figure. Figure 14 In the middle. It is assumed that the stoichiometry (compound of formula (I) and maleic acid) is 1:1, but this has not yet been determined.

[0184] DSC analysis (figure not shown) showed endothermic activity at initial temperatures of 35°C (wide, -10 J / g) and 80°C (-40 J / g).

[0185] TGA analysis (figure not shown) showed a 1% weight loss below 100°C. Weight loss due to decomposition began at approximately 110°C.

[0186] Example 5D The crystalline phase form of compound (I) and maleic acid (form M4 polymorph) preparation Compound (I) (50 mg, 0.106 mmol) was suspended in methanol (1 mL) and maleic acid (12.3 mg, 0.106 mmol, 1 equivalent) was added. The mixture was stirred for 15 minutes and evaporated. The resulting residue was dissolved in acetonitrile (0.5 mL) at 75 °C, and the resulting solution was slowly cooled to room temperature. Seeds were added to the crystalline maleic acid form M2 and stirred overnight. Seeds of the polymorph of form M2 were obtained by small-scale cooling crystallization using acetonitrile or acetone as solvent. The mother liquor was then decanted, and the solid was dried under vacuum at 35 °C for 3 hours. It should be noted that although the attempt was aimed at obtaining form M2, a new form M4 was obtained.

[0187] Characterization The XRPD diagram of the M4 polymorph of maleic acid in its crystalline phase form is shown in the figure. Figure 15 In the middle. It is assumed that the stoichiometry (compound of formula (I) and maleic acid) is 1:1, but this has not yet been determined.

[0188] DSC analysis (figure not shown) showed endothermic activity at initial temperatures of 33°C (wide, -15 J / g), 113°C (-53 J / g), and 144°C (-9 J / g).

[0189] TGA analysis (figure not shown) showed a weight loss of 0.6% below 85°C. Weight loss due to decomposition began at approximately 120°C.

[0190] Example 5E The crystalline phase form of compound (I) and maleic acid (form M5 polymorph) preparation Compound (I) (50 mg, 0.106 mmol) was suspended in methanol (1 mL) and maleic acid (12.3 mg, 0.106 mmol, 1 equivalent) was added. The mixture was stirred for 15 minutes and evaporated. The resulting residue was dissolved in tetrahydrofuran (0.2 mL) under reflux, and the resulting solution was slowly cooled to room temperature. Seeds were added to the crystalline phase of maleic acid, form M3, and stirred overnight. Seeds of polymorphs of form M3 were obtained by small-scale cooling crystallization using tetrahydrofuran as a solvent. The mother liquor was then decanted, and the solid was dried under vacuum at 35 °C for 3 hours. It should be noted that although the attempt was aimed at obtaining form M3, a new form M5 was obtained.

[0191] Characterization The XRPD diagram of the M5 polymorph of maleic acid in its crystalline phase form is shown in the figure. Figure 16 In the middle. It is assumed that the stoichiometry (compound of formula (I) and maleic acid) is 1:1, but this has not yet been determined.

[0192] DSC analysis (figure not shown) showed endothermic reaction at temperatures of 32°C (wide, -28 J / g) and 78°C (wide, -53 J / g). Exothermic reaction was observed at 108°C (96 J / g).

[0193] TGA analysis (figure not shown) showed a weight loss of 1.3% below 100°C. Weight loss due to decomposition began at approximately 110°C.

[0194] Example 5F The crystalline phase form of compound (I) and maleic acid (form M6 polymorph) preparation Compound (I) (50 mg, 0.106 mmol) was suspended in methanol (1 mL) and maleic acid (12.3 mg, 0.106 mmol, 1 equivalent) was added. The mixture was stirred for 15 minutes and evaporated. The resulting residue was dissolved in isopropanol (0.2 mL) at 75 °C, and the resulting solution was slowly cooled to room temperature. Seeds were added to the crystalline phase of maleic acid, form M1, and stirred overnight. Seeds of the polymorph of form M1 were obtained by small-scale cooling crystallization using tetrahydrofuran as a solvent. The mother liquor was then decanted, and the solid was dried under vacuum at 35 °C for 3 hours. It should be noted that although the attempt was aimed at obtaining form M1, a new form M6 was obtained.

[0195] Characterization The XRPD diagram of the M6 ​​polymorph of maleic acid in its crystalline phase form is shown in the figure. Figure 17 In the middle. It is assumed that the stoichiometry (compound of formula (I) and maleic acid) is 1:1, but this has not yet been determined.

[0196] DSC analysis (figure not shown) showed endothermic activity at initial temperatures of 33°C (wide, -28 J / g), 87°C (-32 J / g), and 113°C (-22 J / g).

[0197] TGA analysis (figure not shown) showed a weight loss of 1.5% below 80°C. Weight loss due to decomposition began at approximately 120°C.

[0198] Example 6 The crystalline phase form of compound (I) with hydrochloric acid is C1. preparation Compound (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 equivalence) was added. The resulting suspension was heated to 75 °C and stirred at this temperature for 1 hour, then slowly cooled to room temperature and stirred overnight. The solid was then filtered through a filter plate (N. 3), washed with isopropanol (2 mL), and dried under vacuum at 35 °C for 3 hours. Yield: 0.46 g (85%).

[0199] Characterization The XRPD diagram of the crystalline phase C1 of compound (I) with hydrochloric acid is shown in Figure 1. Figure 18 In the middle. It is assumed that the stoichiometry (compound of formula (I) and HCl) is 1:1, but this has not yet been determined.

[0200] DSC analysis (figure not shown) showed endothermic reaction with an initial temperature of 236 °C (-168 J / g).

[0201] TGA analysis (figure not shown) revealed weight loss due to decomposition at approximately 210°C. This means that the material is anhydrous and not a solvate.

[0202] DVS analysis was performed at 25°C in 30-minute intervals of 10% to 90% to 10% RH (figure not shown). A weight gain of 0.55% was recorded between 10% and 80% RH. The material morphology after the DVS experiment was investigated by XRPD, and no morphological changes were observed.

[0203] Example 7A The crystalline phase form of compound (I) and hydrobromic acid (form B1 polymorph) preparation The compound of formula (I) (50 mg, 0.106 mmol) was suspended in methanol (1 mL), and hydrobromic acid (122.5 μL, 0.88 N in water, 1 equivalent) was added. The mixture was stirred for 15 minutes and evaporated. The resulting residue was dissolved in acetonitrile (0.5 mL) at 75 °C, slowly cooled to room temperature, and stirred overnight. The mother liquor was then decanted, and the solid was dried under vacuum at 35 °C for 3 hours.

[0204] Characterization The XRPD diagram of the B1 polymorph of hydrobromic acid in its crystalline phase form is shown in the figure. Figure 19 In the middle. It is assumed that the stoichiometry (compound of formula (I) and HBr) is 1:1, but this has not yet been determined.

[0205] DSC analysis (figure not shown) showed endothermic reaction with an initial temperature of 229 °C (-94 J / g).

[0206] TGA analysis (figure not shown) showed a weight loss of 0.13% below 65°C. Weight loss due to decomposition begins at approximately 230°C. This means that the material is anhydrous and not a solvate.

[0207] Example 7B The crystalline phase form of compound (I) and hydrobromic acid (form B2 polymorph) preparation Compound (I) (0.5 g, 1.06 mmol) was suspended in acetonitrile (2.5 mL) and hydrobromic acid (0.36 mL, 3N in water, 1 equivalent) was added. The resulting suspension was heated to 75 °C. A clear solution was obtained, which was slowly cooled to room temperature and stirred overnight. The solid was then filtered through a filter plate (N. 3), washed with acetonitrile (1 mL), and dried under vacuum at 35 °C for 3 hours. Yield: 0.2 g (34%).

[0208] Characterization The XRPD diagram of the B2 polymorph of hydrobromic acid in its crystalline phase form is shown in the figure. Figure 20 In the middle. It is assumed that the stoichiometry (compound of formula (I) and HBr) is 1:1, but this has not yet been determined.

[0209] DSC analysis (figure not shown) showed endothermic reaction at initial temperatures of 124 °C (-118 J / g) and 170 °C (-21 J / g).

[0210] TGA analysis (figure not shown) revealed a 5.1% weight loss below 170°C. Weight loss due to decomposition begins at approximately 220°C. This implies that the material is a solvate (hydrate).

[0211] DVS analysis was performed at 25°C in 30-minute intervals of 10% to 90% to 10% RH (figure not shown). A weight gain of 0.25% was recorded between 10% and 80% RH. The material morphology after the DVS experiment was investigated by XRPD, and no morphological changes were observed.

[0212] Example 8A The crystalline phase form of the compound of formula (I) with sulfuric acid (form SF1 polymorph) preparation The compound of formula (I) (50 mg, 0.106 mmol) was suspended in methanol (1 mL), and sulfuric acid (55 μL, 1 M in water, 0.5 equivalents) was added. The mixture was stirred for 15 minutes and evaporated. The resulting residue was slurried in acetone (3 mL) under reflux for 2 hours, slowly cooled to room temperature, and stirred overnight. The mother liquor was then decanted, and the solid was dried under vacuum at 35 °C for 3 hours.

[0213] Characterization The XRPD diagram of the polymorph of SF1 in the crystalline phase form of sulfuric acid is shown in the figure. Figure 21 In the middle. It is assumed that the stoichiometry (compound of formula (I) and sulfuric acid) is 2:1, but this has not yet been determined.

[0214] DSC analysis (figure not shown) showed endothermic reaction with an initial temperature of 208 °C (-62 J / g).

[0215] TGA analysis (figure not shown) revealed weight loss due to decomposition that began at approximately 200°C. This means that the material is anhydrous and not a solvate.

[0216] Example 8B The crystalline phase form of compound (I) with sulfuric acid (form SF2 polymorph) preparation The compound of formula (I) (20 mg, 0.043 mmol) was suspended in methanol (1 mL), and sulfuric acid (22 μL, 1 M in water, 0.5 equivalents) was added. The mixture was stirred for 15 minutes and evaporated. The resulting residue was slurried in tetrahydrofuran (3 mL) under reflux for 2 hours, slowly cooled to room temperature, and stirred for 7 days. The mother liquor was then decanted, and the solid was dried under vacuum at 35 °C for 3 hours.

[0217] Characterization The XRPD diagram of the polymorph of SF2 in the crystalline phase form of sulfuric acid is shown in the figure. Figure 22 In the middle. It is assumed that the stoichiometry (compound of formula (I) and sulfuric acid) is 2:1, but this has not yet been determined.

[0218] DSC analysis (figure not shown) showed a wide endothermic range with onset temperatures of 62°C (-33 J / g), 150°C (-28 J / g), and 172°C (-4 J / g).

[0219] TGA analysis (figure not shown) revealed a weight loss of 3.7% below 136°C. Weight loss due to decomposition begins at approximately 230°C. This implies that the material is a solvate (hydrate).

[0220] Example 8C The crystalline phase form of the compound of formula (I) with sulfuric acid (form SF3 polymorph) preparation The compound of formula (I) (20 mg, 0.043 mmol) was suspended in methanol (1 mL), and sulfuric acid (22 μL, 1 M in water, 0.5 equivalents) was added. The mixture was stirred for 15 minutes and then evaporated. The resulting residue was dissolved in isopropanol (0.2 mL) at 75 °C, and the solution was slowly cooled to room temperature. An oily substance formed upon cooling, which crystallized after standing for an indeterminate time under ambient conditions.

[0221] Characterization The XRPD diagram of the polymorph of SF3 in the crystalline phase form of sulfuric acid is shown in the figure. Figure 23 In the middle. It is assumed that the stoichiometry (compound of formula (I) and sulfuric acid) is 2:1, but this has not yet been determined.

[0222] DSC analysis (figure not shown) showed a wide endothermic range with onset temperatures of 159 °C (-46 J / g) and 175 °C (-18 J / g).

[0223] TGA analysis (figure not shown) revealed weight loss due to decomposition that began at approximately 210°C. This suggests that the material is likely anhydrous and not a solvate.

[0224] Example 9A The crystalline phases of compound (I) and saccharin (form S1 polymorph) preparation Compound (I) (50 mg, 0.106 mmol) was suspended in methanol (1 mL) and saccharin (19.5 mg, 0.106 mmol, 1 equivalent) was added. The mixture was stirred for 15 minutes and evaporated. The resulting residue was slurried in acetone (5 mL) under reflux for 2 hours, slowly cooled to room temperature, and stirred overnight. The mother liquor was then decanted, and the solid was dried under vacuum at 35 °C for 3 hours.

[0225] Characterization The XRPD diagram of the S1 polymorph of saccharin in crystalline form is shown in the figure. Figure 24 The stoichiometry (compound of formula (I) and saccharin) was determined to be 1:1 by NMR.

[0226] DSC analysis (figure not shown) showed endothermic reaction with an initial temperature of 198 °C (-126 J / g).

[0227] TGA analysis (figure not shown) showed a weight loss of 0.3% below 86°C and a weight loss of 1.5% between 110°C and 210°C. The weight loss due to decomposition begins at approximately 210°C. This suggests that the material may be a solvate (hydrate).

[0228] Example 9B The crystalline phases of compound (I) and saccharin (form S2 polymorph) preparation Compound (I) (50 mg, 0.106 mmol) was suspended in methanol (1 mL) and saccharin (19.5 mg, 0.106 mmol, 1 equivalent) was added. The mixture was stirred for 15 minutes and evaporated. The resulting residue was dissolved in tetrahydrofuran (3 mL) under reflux, and the resulting solution was slowly cooled to room temperature. Seeds were added in the saccharin crystalline phase S2 and stirred overnight. Seeds were obtained by small-scale cooling crystallization using tetrahydrofuran as a solvent. The mother liquor was then decanted, and the solid was dried under vacuum at 35 °C for 3 hours.

[0229] Characterization The XRPD diagram of the S2 polymorph of saccharin in crystalline form is shown in the figure. Figure 25 The stoichiometry (compound of formula (I) and saccharin) was determined to be 1:1 by NMR.

[0230] DSC analysis (figure not shown) showed endothermic reaction with an initial temperature of 198 °C (-117 J / g).

[0231] TGA analysis (figure not shown) revealed a weight loss of 5.3% between 110°C and 210°C. Weight loss due to decomposition began at approximately 220°C. This suggests that the material may be a solvate (hydrate).

[0232] Example 10 (Comparative Example) The solid amorphous form of compound (I) preparation The sample of compound (I) was heated using a Kofler stage until it melted, and then rapidly cooled in an ice bath. This produced an amorphous product.

[0233] Characterization The amorphous form of XRPD is illustrated in Figure 26 middle.

[0234] DSC analysis (figure not shown) shows an exothermic peak (crystallization) starting at 99 °C (55 J / g) and an endothermic peak (melting) starting at 190 °C (-107 J / g).

[0235] TGA analysis (figure not shown) showed a weight loss of 1.6% between 40°C and 120°C.

[0236] The storage stability of amorphous solids was evaluated. Results are shown in... Figure 27The amorphous form was stored in a climate chamber at 30°C and 75% RH under ambient conditions (room temperature, in an open vial within a fume hood). Solids were analyzed by XRPD after 4 days. The amorphous sample began to crystallize into form 1 under ambient conditions but remained amorphous under climate chamber conditions.

[0237] abbreviation

[0238] References Miscellaneous All references (including patents and patent applications) mentioned in this application are incorporated herein by reference in the most comprehensive manner possible.

[0239] Throughout this specification and the appended claims, unless the context otherwise requires, the word 'comprise' and variations such as 'comprises' and 'comprising' shall be understood to imply inclusion of the said integer, step, group of integers or set of steps, but not to exclude any other integer, step, group of integers or set of steps.

[0240] An application to which this specification and claims form a part may serve as the basis for priority with respect to any subsequent application. The claims of such a subsequent application may relate to any feature or combination of features described herein. They may take the form of product, composition, method, or use claims and may include, for example, but not limited to, the appended claims.

Claims

1. The crystalline phase form of a compound of formula (I): (I)； The crystalline phase form is a polymorph of crystalline phase form 1.

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 FIG1.

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 the following: 10.5, 14.3, 16.9, 18.6, 19.3, 21.1, 22.3, 22.5, 26.6 and 28.6 (± 0.2) °2θ.

4. The crystalline phase form according to claim 3, wherein the crystalline phase form has an XRPD plot containing 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) °2θ.

5. The crystalline phase form according to claim 3 or claim 4, wherein the peak is present with a relative intensity of at least 20%, for example at least 30%.

6. The crystalline phase form according to claim 1, wherein the crystalline phase form has cell sizes of about 14.71 Å (size a), about 16.77 Å (size b), and about 9.58 Å (size c) in space group P21 / c as determined by SCXRD, wherein the α angle is 90°, the β angle is about 107.9°, and the γ angle is 90°.

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

8. The crystalline phase form according to any one of claims 1 to 6, said crystalline phase form being used to treat or prevent diseases or pathological conditions that are easily improved by inhibiting transforming growth factor-β receptor I (TGFβRI / 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-versus-host disease (GVHD).

10. A combination comprising the crystalline phase form of any one of claims 1 to 6 and a therapeutic agent, said combination for treating or preventing diseases selected from the group consisting of: gastrointestinal diseases, fibrotic diseases, cancer, and graft-versus-host disease (GVHD).

11. The use of the crystalline phase form as described 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 that is readily improved by inhibiting transforming growth factor-β receptor I (TGFβRI / ALK5).

12. The 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-versus-host disease (GVHD).

13. A method for treating or preventing a disease or pathological condition that is readily improved by inhibiting transforming growth factor-β receptor I (TGFβRI / ALK5), the method comprising administering to a subject in need the crystalline form of any one of claims 1 to 6.

14. The method of claim 13, wherein the disease or pathological condition is selected from the group consisting of: gastrointestinal diseases, fibrotic diseases, cancer, and graft-versus-host disease (GVHD).

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