Crystalline forms of her2 / mutegfr inhibitors and process for their preparation

Abstract

The present invention relates: to the crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy- anilino)-2-[3-[[(2S)-1,4-dioxan-2-yl]methoxy]-4-pyridyl]-1,5,6,7-tetrahydropyrrolo[3,2- c]pyridine-4-one of formula (A): 5 *x H 2 O (A), wherein the content of water is greater than 0 % (w / w) and ≤ 4.0 % (w / w); • to a method of preparing said crystalline Hydrate 1 Modification A form of said compound of formula (A) and to intermediate compounds used in said method;• to pharmaceutical compositions and combinations comprising said crystalline Hydrate 1 Modification A form of said compound of formula (A); and • to said crystalline Hydrate 1 Modification A form of the compound of formula (A), and to pharmaceutical compositions or combinations comprising same for use in the treatment or prevention of a cancer, such as lung cancer, particularly non-small cell lung carcinoma.

Description

[0001] BHC 243007 FOREIGN FILING 202508

[0002] CRYSTALLINE FORMS of HER2 / mutEGFR INHIBITORS and PROCESS FOR THEIR PREPARATION

[0003] FIELD OF THE INVENTION

[0004] The present invention relates:

[0005] • to the crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy- anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2- c]pyridine-4-one, of formula (A):

[0006] (A), wherein the content of water is greater than 0 % (w / w) and < 4.0 % (w / w), which is also referred to herein as the "crystalline Hydrate 1 Modification A compound of formula (A)";

[0007] • to a method of preparing said crystalline Hydrate 1 Modification A compound of formula (A) and to intermediate compounds used in said method;

[0008] • to pharmaceutical compositions comprising said crystalline Hydrate 1 Modification A compound of formula (A);

[0009] • to said crystalline Hydrate 1 Modification A compound of formula (A) for use in the treatment or prevention of a cancer, particularly lung cancer.

[0010] BACKGROUND TO THE INVENTION

[0011] 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridine-4-one, (which is hereinafter referred to as "compound (B)"), of structure: BHC 243007 FOREIGN FILING

[0012] 2025 08 is an oral, small molecule tyrosine kinase inhibitor under development as a potential new targeted therapy for patients with non-small cell lung carcinoma ("NSCLC") harbouring human epidermal growth factor receptor 2 ("HER2") activating mutations.

[0013] Compound (B) is published in international patent application PCT / EP2020 / 061176, published as WO 2020 / 216781 Al on October 29, 2020, (which is hereinafter incorporated by reference in its entirety), as the compound of Example 2 on pp. 154 to 155. Its synthesis is as described therein.

[0014] DESCRIPTION OF THE INVENTION

[0015] The present invention relates to a crystalline form of 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4- dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one which is the crystalline, pseudopolymorphic form Hydrate 1 Modification A of formula (A), which is herein referred to as the "crystalline Hydrate 1 Modification A form of compound 3-(3-chloro-2-methoxy- anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine- 4-one, of formula (A):

[0016] (A), wherein the content of water is greater than 0 % (w / w), which is herein also referred to as the "crystalline Hydrate 1 Modification A compound of formula (A)". BHC 243007 FOREIGN FILING 202508

[0017] In an embodiment, the present invention relates to a crystalline form of 3-(3-chloro-2-methoxy- anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine- 4-one which is the crystalline, pseudopolymorphic form Hydrate 1 Modification A of formula (A), which is herein referred to as the "crystalline Hydrate 1 Modification A form of compound 3-(3- chloro-2-methoxy-anilino)-2-[3-[[(2S)-l, 4-dioxan-2-yl]methoxy]-4-pyridyl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridine-4-one, of formula (A):

[0018] (A), wherein the content of water is greater than 0 % (w / w) and < 4.0 % (w / w), which is herein also referred to as the "crystalline Hydrate 1 Modification A compound of formula (A)".

[0019] It is to be understood that the crystalline Hydrate 1 Modification A compound of formula (A) is a nonstoichiometric hydrate, wherein „x" means a variable stoichiometric ratio of water molecules to the 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l, 4-dioxan-2-yl]methoxy]-4-pyridyl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridine-4-one molecule.

[0020] Said nonstoichiometric hydrate, the crystalline Hydrate 1 Modification A compound of formula (A), was selected as the most feasible form, although the water content in this form is not fixed.

[0021] The present invention further relates to processes for its preparation, to pharmaceutical compositions and combinations comprising it and to its use in the treatment and prevention of diseases, particularly cancer, in particular lung cancer, particularly non-small cell lung carcinoma.

[0022] 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydro- pyrrolo[3,2-c]pyridine-4-one (B), of structure: BHC 243007 FOREIGN FILING 2025 08

[0023] (B), demonstrates a surprisingly high tendency to solidify in various different crystalline lattices.

[0024] It is to be understood that the very high number of crystalline forms of said compound (B) is considered by the inventors of the present invention as defined in the appended claims to be really special and unique.

[0025] The following crystalline forms of the compound of formula (B) have been identified, which are Modification I, Modification II, Modification III, Modification IV, and the pseudopolymorphic forms which are the Hydrate 1 Modification A (herein described as "crystalline Hydrate 1 Modification A compound of formula (A)" of the present invention), Hydrate 1 Modification B and Hydrate 1 Modification C. Solvated forms were isolated from ethyl acetate, 2-propanol, 1-propanol, ethanol, 1-4 dioxane, toluene, THF, DMF and isopropanol. Especially the 1-propanol solvates show polymorphism (1-propanol solvate Modification A and 1-propanol solvate Modification B). Mixed solvate forms were characterized for ethanol / water, methanol / water and 1-propanol / water combinations.

[0026] The amorphous phase can exist at ambient conditions. The glass transition was not detected due to an overlay of an endothermic loss of water.

[0027] In this context, modifications, polymorphic forms and polymorphs have the same meaning. All together - the polymorphic forms, the pseudopolymorphic forms and the amorphous form - are different solid forms of the compound of formula (B).

[0028] It is to be understood that the surprisingly highly complex solid state landscape of the compound of the formula (B) makes it very difficult to select a crystalline form which show a beneficial behaviour in characterisation, storage stabilities with focus on humidity, crystallization, processability and formulation ability. Surprisingly, the pseudopolymorphic form Hydrate 1 Modification A of the compound of the formula (B), referred to herein as "crystalline Hydrate 1 Modification A compound of formula (A)", is the most suitable crystalline form. Surprisingly, pseudopolymorphic form Hydrate 1 of the compound of formula (B), ("crystalline Hydrate 1 Modification A compound of formula (A)"), BHC 243007 FOREIGN FILING

[0029] 2025 08 shows beneficial properties over the other solid forms of the compound of formula (B) with regard to hygroscopicity, storage stability, crystallization properties, processability and formulation ability.

[0030] It is to be understood that although the inventors of the present invention as defined in the appended claims had found anhydrous forms (Mod. I to Mod. IV), none of the anhydrous forms were used, because the nonstoichiometric hydrate, which additionally shows polymorphism on its own, is very surprisingly suitable for formulation, storage and chemical process. It is considered by the inventors of the present invention as defined in the appended claims that this finding is particularly unexpected, because nonstoichiometric hydrates normally loose and / or add water very easily by changes in the crystalline lattice.

[0031] Pseudopolymorphic form Hydrate 1 (the "crystalline Hydrate 1 Modification A compound of formula (A)") is therefore suitable and preferred over the other solid forms of the compound of formula (B) for use in the pharmaceutical field, in particular suitable for pharmaceutical compositions, such as tablets or other solid formulations, such as powders or cakes.

[0032] It is reiterated that it is considered by the inventors of the present invention as defined in the appended claims that the nonstoichiomentic hydrate, i.e. the crystalline Hydrate 1 Modification A compound of formula (A) as defined in the appended claims, is surprisingly stable during the formulation process (tableting), as the person skilled in the art could expect loss of water during such high energetic mechanical processes.

[0033] In particular, unexpectedly, pseudopolymorphic form Hydrate 1 of the compound of the formula (B), (the "crystalline Hydrate 1 Modification A compound of formula (A)"), ensures that an undesired conversion into another form of the compound of formula (B) and an associated change in the properties as described above is prevented. This increases the safety and quality of preparations and formulations comprising of the compound of the formula (B) and the risk to the patient is reduced, which is clearly advantageous.

[0034] A pharmaceutical composition according to the present invention comprises pseudopolymorphic form Hydrate 1 Modification A of the compound of formula (B), (the "crystalline Hydrate 1 Modification A compound of formula (A)"), and optionally further pharmaceutically acceptable excipients.

[0035] A preferred embodiment of the present invention is a pharmaceutical composition comprising pseudopolymorphic form Hydrate 1 Modification A of the compound of the formula (B), (the "crystalline Hydrate 1 Modification A compound of formula (A)"), mainly and no significant fractions of another form of the compound of the formula (B) and optionally further pharmaceutically acceptable excipients. More preferably, the pharmaceutical composition contains more than 85 percent by BHC 243007 FOREIGN FILING

[0036] 2025 08 weight, more preferably more than 90 percent by weight, most preferably more than 95 percent by weight, of the pseudopolymorphic form Hydrate 1 Modification A of the compound of the formula (B), (the "crystalline Hydrate 1 Modification A compound of formula (A)"), related to the total amount of all forms of the compound of the formula (B) present in the composition.

[0037] It is to be understood that the inventors of the present invention as defined in the appended claims that the nonstoichiomentic hydrate, i.e. the crystalline Hydrate 1 Modification A compound of formula (A) as defined in the appended claims, did not show any solid transformation into the additional modifications of Hydrate 1 during these mechanical formulation processes.

[0038] The different forms of the compound of formula (B) can be characterized by X-ray powder diffraction, differential scanning calorimetry (DSC), IR- and Raman-spectroscopy.

[0039] It is to be understood that although the inventors of the present invention as defined in the appended claims found so many forms, around 26 forms in all, all of which can be clearly characterized by XRPD, (which are given in the figures), it was the nonstoichiomentic hydrate, i.e. the crystalline Hydrate 1 Modification A compound of formula (A) as defined in the appended claims, which gave rise to the technically advantageous characteristics as described herein, and which was consequently selected for the formulation process. It is to be understood that normally, an anhydrous polymorph is selected for formulation development, but in this case, the crystalline Hydratel Modification A compound of formula (A) as defined in the appended claims was selected, due to its special and unexpected advantageous physico-chemical characteristics, because it did not display any transformation into any of the other hydrates. As such, the crystalline Hydrate 1 Modification A compound of formula (A) as defined in the appended claims surprisingly fulfills the requisites necessary for a formulated drug product.

[0040] It is to be understood that there are significant differences in the crystalline lattices of all the forms, which is considered to be highly surprising by the inventors.

[0041] The pseudopolymorphic form Hydrate 1 Modification A of the compound of formula (B), (the "crystalline Hydrate 1 Modification A compound of formula (A)"), can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 24.9; 6.5 and 19.7 preferably at least the following reflections: 24.9; 6.5; 19.7; 12.4 and 9.6; more preferably at least the following reflections: 24.9; 6.5; 19.7; 12.4; 9.6; 15.0 and 19.5, most preferably at least the following reflections: 24.9; 6.5; 19.7; 12.4; 9.6; 15.0; 19.5; 23.7; 13.0 and 14.0, each quoted as 2Q value ± 0.2°. The compound of formula (B) in the pseudopolymorphic form Hydrate 1 Modification A, (the "crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4- BHC 243007 FOREIGN FILING 2025 08 pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A)"), can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 4, which is the X-ray powder diffractogram of pseudopolymorphic form Hydrate 1 (the "crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)- 2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A)".

[0042] FIGURE 5 shows the FT Raman spectrum of pseudopolymorphic form Hydrate 1 (the "crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4- dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A)".

[0043] FIGURE 6 shows the IR spectrum of pseudopolymorphic form Hydrate 1 (the "crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2- yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A)".

[0044] FIGURE 7 shows the DSC- and TGA-thermogram of pseudopolymorphic form Hydrate 1 (the "crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3- [[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A)".

[0045] The pseudopolymorphic form Hydrate 1 Modification B of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 24.9; 11.4 and 23.6; preferably at least the following reflections: 24.9; 11.4; 23.6; 6.7 and 25.5; more preferably at least the following reflections: 24.9; 11.4; 23.6; 6.7; 25.5; 6.4 and 21.6; most preferably at least the following reflections: 24.9; 11.4; 23.6; 6.7; 25.5; 6.4; 21.6; 13.5; 12.4 and 8.5; each quoted as 20 value ± 0.2°. The compound of formula (B) in the pseudopolymorphic form Hydrate 1 Modification B can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 8, which is the X-ray powder diffractogram of pseudopolymorphic form Hydrate 1 Modification B.

[0046] FIGURE 9 shows the FT Raman spectrum of pseudopolymorphic form Hydrate 1 Modification B.

[0047] FIGURE 10 shows the IR spectrum of pseudopolymorphic form Hydrate 1 Modification B.

[0048] FIGURE 11 shows the DSC- and TGA-thermogram of pseudopolymorphic form Hydrate 1 Modification B. BHC 243007 FOREIGN FILING 2025 08

[0049] The pseudopolymorphic form Hydrate 1 Modification C of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 24.9; 6.4 and 18.4; preferably at least the following reflections: 24.9; 6.4; 18.4; 12.8 and 10.8; more preferably at least the following reflections: 24.9; 6.4; 18.4; 12.8; 10.8; 19.5 and 22.8 most preferably at least the following reflections: 24.9; 6.4; 18.4; 12.8; 10.8; 19.5; 22.8; 26.9; 13.5 and 18.2; each quoted as 20 value ± 0.2°. The compound of formula (B) in the pseudopolymorphic form Hydrate 1 Modification C can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 12, which is the X-ray powder diffractogram of pseudopolymorphic form Hydrate 1 Modification C.

[0050] FIGURE 13 shows the FT Raman spectrum of pseudopolymorphic form Hydrate 1 Modification C.

[0051] FIGURE 14 shows the IR spectrum of pseudopolymorphic form Hydrate 1 Modification C.

[0052] FIGURE 15 shows the DSc- and TGA-thermogram of pseudopolymorphic form Hydrate 1 Modification C.

[0053] The polymorphic form Modification I of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 16,8; 20,1 and 23,3; preferably at least the following reflections: 16.8; 20.1; 23.3; 27.2 and 14.8, more preferably at least the following reflections: 16.8; 20.1; 23.3; 27.2; 14.8; 24.5 and 20.7; most preferably at least the following reflections: 16.8; 20.1; 23.3; 27.2; 14.8; 24.5; 20.7; 16.0; 8.4 and 14.6 each quoted as 20 value ± 0.2°. The compound of formula (B) in the polymorphic form Modification I can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 16, which is the X-ray powder diffractogram of polymorphic form Modification I.

[0054] FIGURE 17 shows the FT Raman spectrum of polymorphic form Modification I.

[0055] FIGURE 18 shows the IR spectrum of polymorphic form Modification I.

[0056] FIGURE 19 shows the DSC- and TGA-thermogram of polymorphic form Modification I.

[0057] The polymorphic form Modification II of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 7.1; 19.9 and 11.5, preferably at least the following reflections: 7.1; 19.9; 11.5; 18.1 and 21.2; more preferably at least the following reflections: 7.1; 19.9; 11.5; 18.1; 21.2; 25.3 and 14.3; most preferably at least the following reflections: 7.1; 19.9; 11.5; 18.1; BHC 243007 FOREIGN FILING 2025 08

[0058] 21.2; 25.3; 14.3; 13.3; 14.1 and 23.5 each quoted as 2Q value ± 0.2°. The compound of formula (B) in the polymorphic form Modification II can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in FIGURE 20, which is the X-ray powder diffractogram of polymorphic form Modification II.

[0059] FIGURE 21 shows the FT Raman spectrum of polymorphic form Modification II.

[0060] FIGURE 22 shows the IR spectrum of polymorphic form Modification II.

[0061] FIGURE 23 shows the DSC- and TGA-thermogram of polymorphic form Modification II.

[0062] The polymorphic form Modification III of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at 180°C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 22.6; 8.4 and 16.3; preferably at least the following reflections: 22.6; 8.4; 16.3; 26.4 and 19.8, more preferably at least the following reflections: 22.6; 8.4; 16.3; 26.4; 19.8; 14.6 and 20.4; most preferably at least the following reflections: 22.6; 8.4; 16.3; 26.4; 19.8; 14.6; 20.4; 21.1; 16.1 and 18.2 each quoted as 2Q value ± 0.2°. The compound of formula (B) in the polymorphic form Modification III can also be characterized unambiguously by the X-Ray powder diffractogram (at 180°C and with Cu-K alpha 1 as radiation source) as shown in FIGURE 24, which is the X-ray powder diffractogram of polymorphic form Modification III.

[0063] The polymorphic form Modification IV of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C / 1 % RH and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 25.1; 6.4 and 19.6; preferably at least the following reflections: 25.1; 6.4; 19.6; 24.0 and 23.5, more preferably at least the following reflections: 25.1; 6.4; 19.6; 24.0; 23.5; 12.9 and 27.7; most preferably at least the following reflections: 25.1; 6.4; 19,6; 24.0; 23.5; 12.9; 27.7; 18.3; 12.5 and 20.4 each quoted as 2Q value ± 0.2°. The compound of formula (B) in the polymorphic form Modification IV can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C / 1 % RH and with Cu-K alpha 1 as radiation source) as shown in FIGURE 25, which is the X-ray powder diffractogram of polymorphic form Modification IV.

[0064] The pseudopolymorphic form Toluene Solvate of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 6.8; 11.2; 25.1; preferably at least the following reflections: 6.8; 11.2; 25.1; 13.2 and 19.8; more preferably at least the following reflections: 6.8; 11.2; 25.1; 13.2; 19.8; 20.4 and 21.1; most preferably at least the following reflections: 6.8; 11.2; 25.1; 13.2; 19.8; 20.4; 21.1; 18.0; 1.2 and 23.4 each quoted as 2Q value ± 0.2°. The compound of formula (B) in the pseudopolymorphic form Toluene Solvate can also be characterized unambiguously by BHC 243007 FOREIGN FILING 2025 08 the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 26, which is the X-ray powder diffractogram of pseudopolymorphic form Toluene Solvate.

[0065] FIGURE 27 shows the FT Raman spectrum of pseudopolymorphic form Toluene Solvate.

[0066] FIGURE 28 shows the IR spectrum of pseudopolymorphic form Toluene Solvate.

[0067] FIGURE 29 shows the DSC- and TGA-thermogram of pseudopolymorphic form Toluene Solvate.

[0068] The pseudopolymorphic form 1,4-Dioxane Solvate of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 24.4; 6.7 and 9.8; preferably at least the following reflections: 24.4; 6.7; 9.8; 13.2 and 21.5 ; more preferably at least the following reflections: 24.4; 6.7; 9.8; 13.2; 21.5; 20.9; 15.6; most preferably at least the following reflections 24.4; 6.7; 9.8; 13.2; 21.5; 20.9; 15.6; 20.0; 20.1 and 19.4; each quoted as 20 value ± 0.2°. The compound of formula (B) in the pseudopolymorphic form 1,4-Dioxane Solvate can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 30, which is the X-ray powder diffractogram of pseudopolymorphic form 1,4-Dioxane Solvate.

[0069] FIGURE 31 shows the FT Raman spectrum of pseudopolymorphic form 1,4-Dioxane Solvate.

[0070] FIGURE 32 shows the IR spectrum of pseudopolymorphic form 1,4-Dioxane Solvate.

[0071] FIGURE 33 shows the DSC- and TGA-thermogram of pseudopolymorphic form 1,4-Dioxane Solvate.

[0072] The pseudopolymorphic form Ethyl Acetate Solvate of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 8.3; 7.9 and 25.2; preferably at least the following reflections: 8.3; 7.9; 25.2; 16.6 and 23.9; more preferably at least the following reflections: 8.3; 7.9; 25.2; 16.6; 23.9; 18.9 and 16.8; most preferably at least the following reflections: 8.3; 7.9; 25.2; 16.6; 23.9; 18.9; 16.8; 13.2; 9.5 and 19.9; each quoted as 20 value ± 0.2°. The compound of formula (B) in the pseudopolymorphic form Ethyl Acetate Solvate can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 34, which is the X-ray powder diffractogram of pseudopolymorphic form Ethyl Acetate Solvate.

[0073] FIGURE 35 shows the FT Raman spectrum of pseudopolymorphic form Ethyl Acetate Solvate.

[0074] FIGURE 36 shows the IR spectrum of pseudopolymorphic form Ethyl Acetate Solvate. BHC 243007 FOREIGN FILING 2025 08

[0075] FIGURE 37 shows the DSC- and TGA-thermogram of pseudopolymorphic form Ethyl Acetate Solvate.

[0076] The pseudopolymorphic form 2-Propanol Solvate of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 19.9; 23.1 and 10.3; preferably at least the following reflections: 19.9; 23.1; 10.3; 9.2 and 17.2; more preferably at least the following reflections: 19.9; 23.1; 10.3; 9.2; 17.2; 22.2 and 20.3; most preferably at least the following reflections: 19.9; 23.1; 10.3; 9.2; 17.2; 22.2; 20.3; 19.3 and 18.7; each quoted as 2Q value ± 0.2°. The compound of formula (B) in the pseudopolymorphic form 2-Propanol Solvate can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 38, which is the X-ray powder diffractogram of pseudopolymorphic form 2-Propanol Solvate.

[0077] FIGURE 39 shows the FT Raman spectrum of pseudopolymorphic form 2-Propanol Solvate.

[0078] FIGURE 40 shows the IR spectrum of pseudopolymorphic form 2-Propanol Solvate.

[0079] FIGURE 41 shows the DSC- and TGA-thermogram of pseudopolymorphic form 2-Propanol Solvate.

[0080] The pseudopolymorphic form 1-Propanol Solvate Modification A of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 20.5; 9.1 and 10.3; preferably at least the following reflections: 20.5; 9.1; 10.3; 20.0 and 17.0; more preferably at least the following reflections: 20.5; 9.1; 10.3; 20.0; 17.0; 20.8 and 18.4; most preferably at least the following reflections: 20.5; 9.1; 10.3; 20.0; 17.0; 20.8; 18.4; 18.6; 14.0 and 16.4; 1 each quoted as 2Q value ± 0.2°. The compound of formula (B) in the pseudopolymorphic form 1-Propanol Solvate Modification A can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu- K alpha 1 as radiation source) as shown in FIGURE 42, which is the X-ray powder diffractogram of pseudopolymorphic form 1-Propanol Solvate Modification A.

[0081] FIGURE 43 shows the FT Raman spectrum of pseudopolymorphic form 1-Propanol Solvate Modification A.

[0082] FIGURE 44 shows the IR spectrum of pseudopolymorphic form 1-Propanol Solvate Modification A.

[0083] FIGURE 45 shows the DSC- and TGA-thermogram of pseudopolymorphic form 1-Propanol Solvate Modification A. BHC 243007 FOREIGN FILING

[0084] 2025 08

[0085] The pseudopolymorphic form 1-Propanol Solvate Modification B of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 5.5; 24.7 and 17.8; preferably at least the following reflections: 5.5; 24.7; 17.8; 10.6; and 23.7; more preferably at least the following reflections: 5.5; 24.7; 17.8; 10.6; 23.7; 12.6 and 17.4; most preferably at least the following reflections: 5.5; 24.7; 17.8; 10.6; 23.7; 12.6; 17.4; 20.7; 18.9 and 8.0 each quoted as 2Q value ± 0.2°. The compound of formula (B) in the pseudopolymorphic form 1-Propanol Solvate Modification B can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 46, which is the X-ray powder diffractogram of pseudopolymorphic form 1-Propanol Solvate Modification B.

[0086] FIGURE 47 shows the FT Raman spectrum of pseudopolymorphic form 1-Propanol Solvate Modification B.

[0087] FIGURE 48 shows the IR spectrum of pseudopolymorphic form 1-Propanol Solvate Modification B.

[0088] FIGURE 50 shows the DSC- and TGA-thermogram of pseudopolymorphic form 1-Propanol Solvate Modification B.

[0089] The pseudopolymorphic form 1-Propanol-Water Solvate of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at 110 K and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 7.2; 7.6 and 18.2; preferably at least the following reflections: 7.2; 7.6; 18.2; 9.7; and 22.1; more preferably at least the following reflections: 7.2; 7.6; 18.2; 9.7; 22.1; 17.2 and 19.0; most preferably at least the following reflections: 7.2; 7.6; 18.2; 9.7; 22.1; 17.2; 19.0; 21.4; 22.4 and 18.1 each quoted as 2Q value ± 0.2°. The compound of formula (B) in the pseudopolymorphic form 1-Propanol-Water SolvateModification can also be characterized unambiguously by the X-Ray powder diffractogram (at 110°C and with Cu-K alpha 1 as radiation source) as shown in FIGURE 49, which is the calculated X-ray powder diffractogram of the 1-Propanol-Water-Solvate at 110 K.

[0090] The pseudopolymorphic form Ethanol-Water Solvate of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 23.6; 12.0 and 23.9; preferably at least the following reflections: 23.6; 12.0; 23.9; 8.9 and 16.3; more preferably at least the following reflections: 23.6; 12.0; 23.9; 8.9; 16.3; 12.6 and 16.9; most preferably at least the following reflections: 23.6; 12.0; 23.9; 8.9; 16.3; 12.6; 16.9; 17.9; 12.3 and 21.9 each quoted as 2Q value ± 0.2°. The compound of formula (B) in the pseudopolymorphic form Ethanol-Water Solvate can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 BHC 243007 FOREIGN FILING

[0091] 2025 08 as radiation source) as shown in FIGURE 51, which is the X-ray powder diffractogram of pseudopolymorphic form Ethanol-Water Solvate.

[0092] BHC 243007 FOREIGN FILING

[0093] 2025 08

[0094] FIGURE 52 shows the FT Raman spectrum of pseudopolymorphic form Ethanol-Water Solvate.

[0095] FIGURE 53 shows the IR spectrum of pseudopolymorphic form Ethanol-Water Solvate.

[0096] FIGURE 54 shows the DSC- and TGA-thermogram of pseudopolymorphic form Ethanol-Water Solvate.

[0097] The pseudopolymorphic form Methanol-Water Solvate of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 23.8; 12.0 and 8.9; preferably at least the following reflections: 23.8; 12.0; 8.9; 24.0 and 12.5; more preferably at least the following reflections: 23.8; 12.0; 23.9; 8.9; 24.0; 12.5; 16.9; and 16.3; most preferably at least the following reflections: 23.8; 12.0; 23.9; 8.9; 24.0; 12.5; 16.9; 16.3; 12.7; 17.9 and 12.9; each quoted as 2Q value ± 0.2°. The compound of formula (B) in the pseudopolymorphic form Methanol-Water Solvate can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 55, which is the X-ray powder diffractogram of pseudopolymorphic form Methanol-Water Solvate

[0098] FIGURE 56 shows the FT Raman spectrum of pseudopolymorphic form Methanol-Water Solvate.

[0099] FIGURE 57 shows the IR spectrum of pseudopolymorphic form Methanol-Water Solvate.

[0100] FIGURE 58 shows the DSC- and TGA-thermogram of pseudopolymorphic form Methanol-Water Solvate.

[0101] The pseudopolymorphic Ethanol Form of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 24.9; 16.9 and 23.5; preferably at least the following reflections: 24.9; 16.9; 23.5; 19.7 and 9.6; more preferably at least the following reflections: 24.9; 16.9; 23.5; 19.7; 9.6; 12.0 and 19.4; most preferably at least the following reflections 24.9; 16.9; 23.5; 19.7; 9.6; 12.0; 19.4; 21.3; 17.1 and 12.4 each quoted as 2Q value ± 0.2°. The compound of formula (B) in the pseudopolymorphic Ethanol Form can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 59, which is the X-ray powder diffractogram of pseudopolymorphic form Ethanol Form.

[0102] FIGURE 60 shows the FT Raman spectrum of pseudopolymorphic form Ethanol Form.

[0103] FIGURE 61 shows the IR spectrum of pseudopolymorphic form Ethanol Form. BHC 243007 FOREIGN FILING 2025 08

[0104] FIGURE 62 shows the DSC- and TGA-thermogram of pseudopolymorphic form Ethanol Form.

[0105] The pseudopolymorphic 2-Propanol Form of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 19.9; 10.3 and 27.4; preferably at least the following reflections: 19.9; 10.3; 27.4; 28.6 and 19.3; more preferably at least the following reflections: 19.9; 10.3; 27.4; 28.6; 19.3; 16.5 and 22.2; most preferably at least the following reflections: 19.9; 10.3; 27.4; 28.6; 19.3; 16.5; 22.2; 17.2; 9.2 and 24.4; each quoted as 2Q value ± 0.2°. The compound of formula (B) in the pseudopolymorphic 2-Propanol Form can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 63, which is the X-ray powder diffractogram of pseudopolymorphic form 2-Propanol Form.

[0106] FIGURE 64 shows the FT Raman spectrum of pseudopolymorphic form 2-Propanol Form.

[0107] FIGURE 65 shows the IR spectrum of pseudopolymorphic form 2-Propanol Form.

[0108] FIGURE 66 shows the DSC- and TGA-thermogram of pseudopolymorphic form 2-Propanol Form.

[0109] The pseudopolymorphic DMF Form of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 24.6; 19.9 and 9.8; preferably at least the following reflections: 24.6; 19.9; 9.8; 18.5 and 25.2; more preferably at least the following reflections: 24.6; 19.9; 9.8; 18.5; 25.2; 24.0 and 5.7 most preferably at least the following reflections: 24.6; 19.9; 9.8; 18.5; 25.2; 24.0; 5.7; 22.3; 11.9 and 20.7; each quoted as 2Q value ± 0.2°. The compound of formula (B) in the pseudopolymorphic DMF Form can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 67, which is the X-ray powder diffractogram of pseudopolymorphic form DMF Form.

[0110] FIGURE 68 shows the FT Raman spectrum of pseudopolymorphic form DMF Form.

[0111] FIGURE 69 shows the IR spectrum of pseudopolymorphic form DMF Form.

[0112] FIGURE 70 shows the DSC- and TGA-thermogram of pseudopolymorphic form DMF Form.

[0113] The pseudopolymorphic THF Form 1 of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 5.5; 17.7 and 24.3; preferably at least the following reflections: 5.5; 17.7; 24.3; 10.5 and 23.2; more preferably at least the following reflections: 5.5; 17.7; 24.3; 10.5; 23.2; 20.3 and 12.5 most preferably at least the following reflections: 5.5; 17.7; 24.3; 10.5; BHC 243007 FOREIGN FILING 2025 08

[0114] 23.2; 20.3; 12.5; 17.4; 15.5 and 21.1 each quoted as 2Q value ± 0.2°. The compound of formula (B) in the pseudopolymorphic THF Form 1 can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 71, which is the X-ray powder diffractogram of pseudopolymorphic form THF Form 1.

[0115] FIGURE 72 shows the FT Raman spectrum of pseudopolymorphic form THF Form 1.

[0116] FIGURE 73 shows the IR spectrum of pseudopolymorphic form THF Form 1.

[0117] FIGURE 74 shows the DSC- and TGA-thermogram of pseudopolymorphic form THF Form 1.

[0118] The pseudopolymorphic THF Form 2 of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 5.5; 24.4 and 10.4; preferably at least the following reflections: 5.5; 24.4; 10.4; 17.9 and 23.4; more preferably at least the following reflections: 5.5; 24.4; 10.4; 17.9; 23.4; 20.8; 17.7; most preferably at least the following reflections: 5.5; 24.4; 10.4; 17.9; 23.4; 20.8; 17.7; 19.5; 19.0 and 16.0 each quoted as 2Q value ± 0.2°. The compound of formula (B) in the pseudopolymorphic THF Form 2 can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 75, which is the X-ray powder diffractogram of pseudopolymorphic form THF Form 2.

[0119] FIGURE 76 shows the FT Raman spectrum of pseudopolymorphic form THF Form 2.

[0120] FIGURE 77 shows the IR spectrum of pseudopolymorphic form THF Form 2.

[0121] FIGURE 78 shows the DSC- and TGA-thermogram of pseudopolymorphic form THF Form 2.

[0122] The pseudopolymorphic THF Form 3 of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 21.0; 9.8 and 20.6; preferably at least the following reflections: 21.0; 9.8; 20.6; 24.9 and 19.6; more preferably at least the following reflections: 21.0; 9.8; 20.5; 24.9; 19.6; 18.6; 15.5; most preferably at least the following reflections: 21.0; 9.8; 20.6; 24.9; 19.6; 18.6; 15.5; 12.3; 6.5 and 10.7 each quoted as 2Q value ± 0.2°. The compound of formula (B) in the pseudopolymorphic THF Form 3 can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 79, which is X-ray powder diffractogram of pseudopolymorphic form THF Form 3.

[0123] FIGURE 80 shows the FT Raman spectrum of pseudopolymorphic form THF Form 3.

[0124] FIGURE 81 shows the IR spectrum of pseudopolymorphic form THF Form 3. BHC 243007 FOREIGN FILING

[0125] 2025 08

[0126] FIGURE 82 shows the DSC- and TGA-thermogram of pseudopolymorphic form THF Form 3.

[0127] The pseudopolymorphic THF Form 4 of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 8.9; 23.9 and 20.1; preferably at least the following reflections: 8.9; 23.9; 20.1; 16.4 and 8.1; more preferably at least the following reflections: 8.9; 23.9; 20.1; 16.4; 8.1; 11.4 and 25.3; most preferably at least the following reflections: 8.9; 23.9; 20.1; 16.4; 8.1; 11.4; 25.3; 18.2; 24.3 and 15.9 each quoted as 2Q value ± 0.2°. The compound of formula (B) in the pseudopolymorphic THF Form 4 can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 83, which is the X-ray powder diffractogram of pseudopolymorphic form THF Form 4.

[0128] FIGURE 84 shows the FT Raman spectrum of pseudopolymorphic form THF Form 4.

[0129] FIGURE 85 shows the IR spectrum of pseudopolymorphic form THF Form 4.

[0130] FIGURE 86 shows the DSC- and TGA-thermogram of pseudopolymorphic form THF Form 4.

[0131] The pseudopolymorphic THF Form 5 of the compound of formula (B) can be characterized unambiguously by a X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 7.0; 6.6 and 20.0; preferably at least the following reflections: 7.0; 6.6; 20.0; 20.8 and 9.7; more preferably at least the following reflections: 7.0; 6.6; 20.0; 20.8; 9.7; 13.3 and 24.2 most preferably at least the following reflections: 7.0; 6.6; 20.0; 20.8; 9.7; 13.3; 24.2; 17.9; 7.4 and 18.9; each quoted as 2Q value ± 0.2°. The compound of formula (B) in the pseudopolymorphic THF Form 5 can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 87, which is the X-ray powder diffractogram of pseudopolymorphic form THF Form 5.

[0132] FIGURE 88 shows the FT Raman spectrum of pseudopolymorphic form THF Form 5.

[0133] FIGURE 89 shows the IR spectrum of pseudopolymorphic form THF Form 5.

[0134] FIGURE 90 shows the DSC- and TGA-thermogram of pseudopolymorphic form THF Form 5.

[0135] FIGURE 91 shows the X-ray powder diffractogram of the amorphous form.

[0136] FIGURE 92 shows the Raman spectrum of the amorphous form.

[0137] FIGURE 93 shows the IR spectrum of the amorphous form.

[0138] FIGURE 94 shows the DSC- and TGA-thermogram of the amorphous form. BHC 243007 FOREIGN FILING

[0139] 2025 08

[0140] The pseudopolymorphic form Hydrate 1 of 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2- yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one], ("crystalline Hydrate 1 Modification A compound of formula (A)"), can be characterized by Raman spectroscopy on the basis of the respective spectrum as shown in FIGURE 5, which is recorded at RT and with a laser wavelength of 1064 nm and a resolution of 2 cm1. The pseudopolymorphic form Hydrate 1, ("crystalline Hydrate 1 Modification A compound of formula (A)"), according to the present invention displays at least 3, often at least 5, in particular at least 7 , and especially all of the bands quoted in the following as peak maxima:

[0141] Table 1: Raman bands of form Hydrate 1 ("crystalline Hydrate 1 Modification A compound of formula (A)"):

[0142] The pseudopolymorphic form Hydrate 1 of 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2- yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one, ("crystalline Hydrate 1 Modification A compound of formula (A)"), can be characterized by infrared spectroscopy on the basis of the respective spectrum as shown in FIGURE 6, which is recorded at RT using an universal diamond ATR device and a resolution of 2 cm1. The pseudopolymorphic form Hydrate 1 according to the present invention displays at least 3, often at least 5, in particular at least 7 , and especially all of the bands quoted in the following as peak maxima: BHC 243007 FOREIGN FILING 2025 08

[0143] Table 2: IR bands of form Hydrate 1, ("crystalline Hydrate 1 Modification A compound of formula (A)"):

[0144] In addition to the pseudopolymorphic form Hydrate 1, ("crystalline Hydrate 1 Modification A compound of formula (A)"), further polymorphic forms Modification I, Modification 11, Modification III and Modification IV as well as pseudopolymorphic forms Hydrate 1 Modification B, Hydrate 1 Modification C, Toluene Solvate, 1,4-Dioxane Solvate, Ethyl Acetate Solvate, 2-Propanol Solvate, 1- Propanol Solvate Modification A, 1-Propanol Solvate Modification B, Ethanol-Water Solvate, Methanol-Water Solvate, Ethanol Form, 2-Propanol Form, DMF Form, THF Form 1, THF Form 2, THF Form 3, THF Form 4 and THF Form 5 have been identified, which are further characterized in the following.

[0145] The polymorphic forms Modification I and Modification II as well as pseudopolymorphic forms Hydrate 1 Modification B, Hydrate 1 Modification C, Toluene Solvate, 1,4-Dioxane Solvate, Ethyl Acetate Solvate, 2-Propanol Solvate, 1-Propanol Solvate Modification A, 1-Propanol Solvate Modification B, Ethanol-Water Solvate, Methanol-Water Solvate, Ethanol Form, 2-Propanol Form, DMF Form, THF Form 1, THF Form 2, THF Form 3, THF Form 4 and THF Form 5 of 3-(3-chloro-2- methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetra-hydropyrrolo[3,2- c]pyridine-4-one can be characterized by Raman spectroscopy on the basis of the respective spectrum, which are recorded at RT and with a laser wavelength of 1064 nm and a resolution of 2 cm1. The polymorphic forms Modification I and Modification II as well as pseudopolymorphic forms Hydrate BHC 243007 FOREIGN FILING 2025 08

[0146] 1 Modification B, Hydrate 1 Modification C, Toluene Solvate, 1,4-Dioxane Solvate, Ethyl Acetate Solvate, 2-Propanol Solvate, 1-Propanol Solvate Modification A, 1-Propanol Solvate Modification B, Ethanol-Water Solvate, Methanol-Water Solvate, Ethanol Form, 2-Propanol Form, DMF Form, THF Form 1, THF Form 2, THF Form 3, THF Form 4 and THF Form 5 displays at least 3, often at least 5, in particular at least 7, and especially all of the bands quoted in the following as peak maxima:

[0147] Table 3: Raman bands of forms Hydrate 1 Modification B, Hydrate 1 Modification C, Modification I, Modification II and Toluene Solvate

[0148] BHC 243007 FOREIGN FILING 2025 08

[0149] Table 4: Raman bands of forms 1,4-Dioxane Solvate, Ethyl Acetate Solvate, 2-Propanol Solvate, 1-

[0150] Propanol Solvate Modification A and 1- Propanol Solvate Modification B

[0151] BHC 243007 FOREIGN FILING 2025 08

[0152] Table 5: Raman bands of forms Ethanol-Water Solvate, Methanol-Water Solvate, Ethanol Form, 2-

[0153] Propanol Form and DMF Form

[0154] BHC 243007 FOREIGN FILING 2025 08

[0155] Table 6: Raman bands of forms THF Form 1, THF Form 1, THF Form 3, THF Form 4, THF Form 5, and the amorphous form

[0156] The polymorphic forms Modification I and Modification II as well as pseudopolymorphic forms Hydrate 1 Modification B, Hydrate 1 Modification C, Toluene Solvate, 1,4-Dioxane Solvate, Ethyl Acetate Solvate, 2-Propanol Solvate, 1-Propanol Solvate Modification A, 1-Propanol Solvate Modification B, Ethanol-Water Solvate, Methanol-Water Solvate, Ethanol Form, 2-Propanol Form, DMF Form, THF Form 1, THF Form 2, THF Form 3, THF Form 4 and THF Form 5 of [chemical name] can be characterized by infrared spectroscopy on the basis of the respective spectrum, which are recorded at RT using an universal diamond ATR device and a resolution of 2 cm1. The polymorphic forms Modification I and Modification II as well as pseudopolymorphic forms Hydrate 1 Modification B, Hydrate 1 Modification C, Toluene Solvate, 1,4-Dioxane Solvate, Ethyl Acetate Solvate, 2-Propanol Solvate, 1-Propanol Solvate Modification A, 1-Propanol Solvate Modification B, Ethanol-Water Solvate, Methanol-Water Solvate, Ethanol Form, 2-Propanol Form, DMF Form, THF Form 1, THF Form 2, THF Form 3, THF Form 4 and THF Form 5 displays at least 3, often at least 5, in particular at least 7, and especially all of the bands quoted in the following as peak maxima: BHC 243007 FOREIGN FILING 202508

[0157] Table 7: IR bands of forms Hydrate 1 Modification B, Hydrate 1 Modification C, Modification I,

[0158] Modification II and Toluene Solvate.

[0159] BHC 243007 FOREIGN FILING 202508

[0160] Table 8: IR bands of forms 1,4-Dioxane Solvate, Ethyl Acetate Solvate, 2-Propanol Solvate, 1- Propanol Solvate Modification A, and 1-Propanol Solvate Modification B.

[0161] BHC 243007 FOREIGN FILING 202508

[0162] Table 9: IR bands of forms Ethanol-Water Solvate, Methanol-Water Solvates, Ethanol Form, 2- Propanol Form and DMF Form.

[0163] BHC 243007 FOREIGN FILING 2025 08

[0164] Table 10: IR bands of forms THF Form 1, THF Form 2, THF Form 3, THF Form 4 and THF form 5.

[0165] BHC 243007 FOREIGN FILING 202508

[0166] SYNTHESIS SECTION: PROCESS CHEMISTRY

[0167] In an embodiment, the present invention relates to a method of preparing the crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2- yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A): wherein the content of water is greater than 0 % (w / w) and < 4.0 % (w / w), as defined in the claims, comprising the following step 9: wherein a crystalline compound of formula (XIII): is recrystallised from tetrahydrofuran and water, thereby providing said crystalline Hydrate 1 Modification A form of the compound of formula (A): BHC 243007 FOREIGN FILING

[0168] 202508

[0169] In an embodiment, the present invention relates to the above-mentioned method, wherein said crystalline compound of formula (XIII) is prepared by the following step 8: wherein a crystalline compound of formula (B):

[0170] (B), is: a) dissolved in a mixture of ethanol and water in the presence of p-toluenesulphonic acid monohydrate, b) filtered, thereby clarifying the solution provided in a), and c) crystallised by pH-shift crystallisation, by adding an aqueous solution of sodium hydroxide, thereby separating off impurities, thereby providing said crystalline compound of formula (XIII).

[0171] In an embodiment, the present invention relates to the above-mentioned method, wherein said crystalline compound of formula (B) is prepared by the following step 7: wherein a crystalline compound of formula (XI):

[0172] (XI), a) is allowed to react with sulphuric acid, in a solvent such as methanol for example, and is optionally heated, to a temperature of 45 degrees Celsius for example, b) a solution of hydrogen peroxide-urea in water is added to the resulting mixture in a), while maintaining the temperature of 45 degrees Celsius for example, BHC 243007 FOREIGN FILING 202508 c) an aqueous solution of sodium hydroxide is added to the resulting mixture, then, after cooling, the mixture is filtered, thereby providing said crystalline compound of formula (B) as a solid product.

[0173] In an embodiment, the present invention relates to the above-mentioned method, wherein said crystalline compound of formula (XI) is prepared by the following step 6: wherein a crystalline compound of formula (VI):

[0174] (VI), is allowed to react with a crystalline compound of formula (XVI):

[0175] (XVI), thereby providing said crystalline compound of formula (XI).

[0176] In an embodiment, the present invention relates to the above-mentioned method, wherein said crystalline compound of formula (XVI): is prepared by the following step 5: wherein a crystalline compound of formula (IX): , is allowed to react with hydrogen and ethanesulfonic acid in the presence of a suitable catalyst, such as Pd / C for example, thereby providing said crystalline compound of formula (XVI).

[0177] In an embodiment, the present invention relates to the above-mentioned method, wherein said crystalline compound of formula (IX) is prepared by the following step 4: BHC 243007 FOREIGN FILING

[0178] 202508 wherein a compound of formula (VIII):

[0179] (VIII), is allowed to react with a compound of formula (VII):

[0180] (VII), thereby providing said crystalline compound of formula (IX).

[0181] In an embodiment, the present invention relates to the above-mentioned method, wherein said crystalline compound of formula (VI) is prepared by the following step 3: wherein a crystalline compound of formula (XV (crystallised as salt with DBU)):

[0182] (XV), is allowed to react with an acid, such as hydrochloric acid, for example, thereby providing said crystalline compound of formula (VI).

[0183] In an embodiment, the present invention relates to the above-mentioned method, wherein said crystalline compound of formula (XV (crystallised as salt with DBU)) is prepared by the following step 2: wherein a compound of formula (III (telescoped in solution)):

[0184] (III (telescoped in solution)), is allowed to react with a compound of formula (IV): BHC 243007 FOREIGN FILING 202508 thereby providing said crystalline compound of formula (XV (crystallised as salt with DBU)). In an embodiment, the present invention relates to the above-mentioned method, wherein said compound of formula (III) is prepared by the following step 1: wherein a compound of formula (I): is allowed to react with a compound of formula (II): thereby providing said compound of formula (III (telescoped in solution)). In an embodiment, the present invention relates to the above-mentioned method, wherein said Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4- dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A) is prepared via the following steps shown in Reaction Scheme (II), infra:

[0185] BHC 243007 FOREIGN FILING

[0186] 202508

[0187] Reaction Scheme (II).

[0188] In an embodiment, the present invention relates to the crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]- l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A): BHC 243007 FOREIGN FILING 202508

[0189] (A), wherein the content of water is greater than 0 % (w / w) and < 4.0 % (w / w), as defined in the claims, which is prepared by the above-mentioned method as described herein and as defined in the claims.

[0190] Working Examples

[0191] Process

[0192] The synthesis of 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]- l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one (B), as described in PCT patent application WO 2020 / 216781 Al is outlined in Scheme (I). As indicated, several intermediates were obtained by means of complete solvent evaporation and purification by column chromatography or preparative HPLC, operations which are unfavourable for industrialization. Moreover, the low chemical stability of intermediate (X) is disadvantageous for manufacturing campaign planning as it disables any intermittent storage of this compound. Neither control of the polymorphic form of 3-(3-chloro-2- methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2- c]pyridin-4-one (B) in the final purification step by preparative HPLC, nor specific polymorphic forms are described in PCT patent application WO 2020 / 216781 Al. BHC 243007 FOREIGN FILING

[0193] 2025 08

[0194] Scheme (I)

[0195] In contrast, the inventive process of the present invention, as depicted in Scheme (II), below, avoids all complete solvent evaporations and chromatographic purifications, instead relying on processing of intermediate (III) in solution and otherwise suitable crystallization conditions either directly from the reaction mixture or after intermittent extractive workup, as depicted in Scheme (I). The limitedly stable free base amine X was replaced by the surprisingly stable hydroethanesulfonate analogue XVI, thus facilitating the handling and enabling storage of this key building block. The synthesis of said hydroethanesulfonate XVI turned out to work very well under mild reaction conditions using Pd catalysis, avoiding the previously established employment of large amounts of Raney-nickel and thereby increasing process safety. The employment of hydroethanesulfonate XVI instead of free base amine X in the subsequent condensation reaction yielding vinylogous thiourea XI required the addition of base to trigger conversion, with potassium phosphate identified as favourable for a clean reaction profile. Replacing the reported solvent acetonitrile by tetrahydrofuran enabled a controlled antisolvent crystallization with isopropyl acetate to afford the desired product as well isolable crystals.

[0196] Scheme (II) BHC 243007 FOREIGN FILING

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[0198] BHC 243007 FOREIGN FILING

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[0200] The inventive process for the manufacture of 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4- dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one hydrate (A), as depicted in Scheme (II), above, comprises several advantages:

[0201] Step 7: 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l, 4-dioxan-2-yl]methoxy]-4-pyridyl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridin-4-one crude (B):

[0202] • TFA was replaced by the superiorly performing sulphuric acid, thereby also avoiding utilization of a compound from the critically regarded PFAS group of chemicals.

[0203] • The employment of an aqueous solution of hydrogen peroxide-urea-adduct instead of plain aqueous hydrogen peroxide as oxidant unexpectedly improved the reaction profile by diminishing the amount of overoxidation of the target compound to pyridone XVII. Due to the close structural proximity of this side product to compound (B), separation of the two is intrinsically a major hurdle.

[0204] • Through addition of aqueous sodium hydroxide, the target compound was directly crystallized from the reaction mixture and readily isolated by filtration. This process purges aniline I, of which several percent are formed under the reaction conditions, to levels < 0.05 % (HPLC area %).

[0205] Step 8: 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l, 4-dioxan-2-yl]methoxy]-4-pyridyl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridin-4-one purified (XIII): Instead of a purification of compound (B) by preparative HPLC, a sequence of in situ formation of the corresponding hydrotosylate XIX with p- toluenesulfonic acid monohydrate in a mixture of ethanol and water, followed by a clarifying filtration and pH-shift crystallization to furnish compound XIII through addition of an aqueous solution of sodium hydroxide is performed and was identified capable of efficiently separating the following impurities from the target compound:

[0206] • Elemental sulphur: a byproduct in the synthesis of compound (B), initially isolated with that compound, is separated by a clarifying filtration of the transiently generated solution of compound (B) in the presence of p-toluenesulfonic acid monohydrate. BHC 243007 FOREIGN FILING 202508

[0207] • Benzothiazole XVIII: side-product in the synthesis of compound (B), resulting from an undesired alternative substrate oxidation and formed in several percent under the reaction conditions. Up to 2 % of this solid compound are frequently isolated together with compound (B) due to its low solubility in methanol / water, but serendipitously exhibited a significantly enhanced solubility in ethanol / water, allowing it to be purged during isolation of compound XIII.

[0208] Step 9: 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7- tetrahydropyrrolo[3,2-c]pyridin-4-one hydrate (A): Whereas compound XIII is typically formed in the desired hydrate I, Modification A form (A) during crystallization in the respective process, an inherent risk was identified of it converting into an undesired ethanol-water-solvate found to be more stable under the applied reaction conditions. This risk was mitigated by identification of a recrystallization procedure from tetrahydrofuran and water, in which the desired polymorphic form, hydrate I Modification A turned out not only to be the product of kinetic control, but also the thermodynamically preferred form. Furthermore, the formation of THF solvates was circumvented.

[0209] It is to be understood that in a polymorphic landscape like the present case, it is really difficult to not build any solvates during the recrystallization process. However, the process as described herein and as defined in the appended claims circumvented the formation of such solvates, which is critical.

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[0211] EXAMPLES

[0212] PREPARATION OF 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4- pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one hydrate (A) ("crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2- yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one of formula (A)" of the present invention. General information

[0213] IUPAC names of chemical compounds were generated with the software BIOVIA Draw from Dassault Systemes, version 19.1. Common trivial names of commercially available chemical compounds were used instead of their IUPAC names in some cases.

[0214] BHC 243007 FOREIGN FILING

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[0216] Table 11: List of abbreviations

[0217] CH2CI2Dichloromethane DBU 1,8-Diazabicyclo[5.4.0 ]undec-7-ene br s broad singlet (NMR spectroscopy) d doublet (NMR spectroscopy) dd doublet of doublet (NMR spectroscopy) d Chemical shift (in ppm; NMR spectroscopy) ent- [opposite] enantiomer ESI Electrospray ionization (mass spectrometry) EtOH Ethanol EtSO3H ethanesulfonic acid

[0218] H2Hydrogen H2O Water HCI Hydrogen chloride / hydrochloric acid HPLC High performance liquid chromatography (HR)MS (high resolution) mass spectrometry IC ion chromatography

[0219] ICP-OES inductively coupled plasma-optical emission spectroscopy / -PrOAc isopropyl acetate / -PrOH Isopropanol K3PO4 potassium phosphate KOt-Bu potassium tert-butoxide m Multiplet (NMR spectroscopy) MeCN Acetonitrile MeOH Methanol Me-THF Methyltetrahydrofuran

[0220] Mod. Modification MTBE tert-butyl methyl ether Na2SO4sodium sulphate NaHCOa sodium bicarbonate NMR Nuclear magnetic resonance Pd / C palladium on charcoal Phosphonics SEM26 2-Mercaptoethyl ethyl sulfide silica q Quartet (NMR spectroscopy) RRT relative retention time (HPLC) RT retention time (HPLC) s singlet (NMR spectroscopy) t triplet (NMR spectroscopy) THF Tetrahydrofuran BHC 243007 FOREIGN FILING 2025 08

[0221] Methods

[0222] NMR spectroscopy

[0223] 1H and13C NMR spectra were recorded in a suitable deuterated solvent. The solvent employed and respective measuring frequency are indicated for each experiment. Chemical shifts (d) are reported with Me4Si serving as a universal reference of all nuclides and with two or one digits after the comma. The resonance multiplicity is described as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad). All spectra were recorded at 298 K unless otherwise noted, and coupling constants are reported as observed. All spectra are broadband decoupled unless otherwise noted.

[0224] HPLC (method 1):

[0225] HPLC (method 2): BHC 243007 FOREIGN FILING

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[0227] HPLC (method 3): BHC 243007 FOREIGN FILING 2025 08

[0228] HPLC (method 4): BHC 243007 FOREIGN FILING 2025 08

[0229] HPLC (method 5):

[0230] HPLC (method 6): BHC 243007 FOREIGN FILING

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[0232] HPLC (method 7): BHC 243007 FOREIGN FILING 2025 08

[0233] HPLC (method 8):

[0234] HPLC (method 9): BHC 243007 FOREIGN FILING

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[0236] HPLC (method 10): BHC 243007 FOREIGN FILING

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[0238] DSC / TGA

[0239] DSC thermograms were recorded using Differential Scanning Calorimeters (models DSC 3 and DSC3+) from Mettler Toledo. The measurements were performed with a heating rate of 20 Kmin1using non- gastight aluminium pans. Flow gas was nitrogen. There was no sample preparation.

[0240] TGA thermograms were recorded using thermobalances (model TGA / DSC 3+) from Mettler Toledo. The measurements were performed with a heating rate of 10 Kmin1using non-gastight aluminium pans. Flow gas was nitrogen. There was no sample preparation.

[0241] XRPD

[0242] X-Ray diffraction patterns were recorded at room temperature using XRD diffractometers X'Pert PRO PANalytical and STOE STADI-P with Cu K alpha 1 radiation wavelength 1.5406 A, at generator settings of 40 kV and 40 mA, and no sample preparation. Samples were collected in transition geometry and the scanning range was between 2° and 40° 2 theta with a 0.013° step, except for compound XIX, which was measured with a 0.2° step at 15 sec / step. Two further measurements were conducted under nonambient conditions, these being Modification III which was measured at 180°C, and Modification IV which was measured at 25°C with 1 % relative humidity. Both of these non-ambient measurements were measured from 3.5° to 40° 2 theta in reflection geometry. All X-Ray reflections are quoted as °2Q (theta) values (peak maxima) with a resolution of ± 0.2°.

[0243] Raman

[0244] Raman spectra were recorded at room temperature using FT-Raman-spectrometers (model MultiRam) from Bruker. Range of Wavenumbers was 3500 to 100 cm1, number of scans were set to 64, resolution was 2 cm1. Measurements were performed in glass vials or aluminium discs. There was no sample preparation. BHC 243007 FOREIGN FILING 2025 08

[0245] IR

[0246] IR-ATR-spectra were recorded at room temperature using a FT-IR-spectrometer Lumos with universal diamond ATR device Alpha from Bruker. Number of scans were set to 64, resolution was 2 cm1. There was no sample preparation.

[0247] For compound XIX, IR measurements were performed with a Bruker alpha spectrometer in the attenuated total reflectance (ATR) geometry. Each individual measurement consisted of 32 scans, with the resolution set to 2 cm1.

[0248] EXAMPLE 1: Step 1: Preparation of l-chloro-3-isothiocvanato-2-methoxybenzene (III).

[0249] An agitator vessel was charged with water (60 kg), sodium hydrogen carbonate (25.6 kg) and dichloromethane (186 kg). The mixture was cooled to an inner temperature of 0 - 10°C and thiophosgene (II) (35.0 kg) was added within 1 h, followed by the addition of a solution of 3-chloro- 2-methoxyaniline (I) (23.3 kg) in dichloromethane (64.5 kg) within 3 h. After completion of the addition, the mixture was kept at 0 - 10°C for another 5.5 h. The layers were separated and the organic layer was washed with 5 % aqueous sodium sulphate solution (50.2 kg) at 15 - 25°C. The volume of the organic layer was reduced to 47 - 70 L by distillation under reduced pressure at an inner temperature < 45°C. The temperature of the vessel containing the distillation residue was adjusted to 20 - 30°C. Three cycles of solvent addition & distillation were applied, using dichloromethane (76 kg) and two times acetonitrile (each 100 kg), in each case reducing the volume of the distillation residue to 47 - 70 L. The temperature of the vessel containing the distillation residue was adjusted to 20 - 30°C and the obtained 63.4 kg solution of l-chloro-3-isothiocyanato- 2-methoxybenzene ((III); 45.5 % assay; 28.8 kg target compound; 98 %) was directly employed in step 2.

[0250] NMR (400 MHz, DMSO-d6): d 7.51 (dd, 1H), 7.35 (dd, 1H), 7.20 (t, 1H), 3.91 - 3.85 (m, 3H).1

[0251] HPLC (method 1): 99.7% purity (l-chloro-3-isothiocyanato-2-methoxybenzene, III; RT = 10.0 min), 45.5 % assay.

[0252] 1NMR data from WO 2020 / 216781, wherein said compound was prepared in an analogous manner to that described in example 1, step 1 above. BHC 243007 FOREIGN FILING 2025 08

[0253] EXAMPLE 2: Step 2: Preparation of 2,3,4,6,7,8,9,10-octahvdropyrimido[l,2-alazepin-l-ium 1-tert- butoxycarbonyl-5-[(3-chloro-2-methoxy-phenyl)carbamothioyll-6-oxo-2,3-dihvdropyridin-4- olate (XV).

[0254] An agitator vessel was charged with the solution of l-chloro-3-isothiocyanato-2-methoxybenzene (III) (63.4 kg, 45.5 % assay + 31.8 kg rinsing solution, 0.4 % assay), acetonitrile (84 kg) and tert-butyl 2,4-dioxopiperidine-l-carboxylate (IV) (32.5 kg). At an inner temperature of 15 - 25°C, 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine ("DBU") (25.3 kg) was added within 3 h. The inner temperature was raised to 20 - 30°C and the mixture was kept at that temperature for 14 h. Tert-butyl methyl ether (151 kg) was added within 4 h, the inner temperature was lowered to -5 to 5°C within 3 h and the mixture was kept at that temperature for 2 h. The solid product was isolated by centrifugation, washed with tert-butyl methyl ether (45 kg) and dried at 40 - 50°C and < 0.02 MPa, affording 67.8 kg (82 %) of 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepin-l-ium 1-tert- butoxycarbonyl-5-[(3-chloro-2-methoxy-phenyl)carbamothioyl]-6-oxo-2,3-dihydropyridin-4-olate (XV) as a yellow solid.

[0255] 2H NMR (600 MHz, CDCI3): d 14.23 (s, 1H), 10.63 (s, 1H), 8.45 (d, J = 8.1 Hz, 1H), 7.11 (dd, J = 8.1, 1.6 Hz, 1H), 6.98 (t, J = 8.1 Hz, 1H), 3.90 (s, 3H), 3.82 (dd, J = 6.8, 5.5 Hz, 2H), 3.50 (t, J = 5.9 Hz, 2H), 3.45 (m, 2H), 3.40 (t, J = 6.0 Hz, 2H), 2.92 (m, 2H), 2.50 (t, J = 6.2 Hz, 2H), 1.99 (tt, J = 7.1, 5.1 Hz, 2H), 1.76-1.74 (m, 4H), 1.67 (q, J = 5.2 Hz, 2H), 1.50 (s, 9H).2

[0256] 13C NMR (151 MHz, CDCI3): d 191.3, 188.7, 168.5, 166.3, 152.6, 149.3, 136.2, 127.4, 125.8, 125.4, 123.2, 108.8, 81.0, 61.1, 54.4, 48.7, 41.6, 38.7, 37.5, 32.6, 29.1, 28.3, 27.0, 24.0, 19.7 (3C).2

[0257] ESI-HRMS (method 1): calculated for CI8H20CIN2O5S ([compound V-H] ): 411.0787, found: 411.0788.

[0258] HPLC (method 2): 99.6 % purity (2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepin-l-ium 1-tert- butoxycarbonyl-5-[(3-chloro-2-methoxy-phenyl)carbamothioyl]-6-oxo-2,3-dihydropyridin-4-olate, XV; RT = 10.5 min).

[0259] Assay (HPLC, method 2; against external standard): 71.1 % (tert-butyl 5-[(3-chloro-2-methoxy- phenyl)carbamothioyl]-4-hydroxy-6-oxo-2,3-dihydropyridine-l-carboxylate, V).

[0260] DBU content (HPLC, method 10; against external standard): 27.8 % assay (2,3,4,6,7,8,9,10- octahydropyrimido[l,2-a]azepine, DBU).

[0261] 2NMR data from a different batch, manufactured analogously to the described procedure. BHC 243007 FOREIGN FILING 2025 08

[0262] EXAMPLE 3: Step 3: Preparation of N-(3-chloro-2-methoxy-phenyl)-4-hvdroxy-6-oxo-2,3-dihydro- lH-pyridine-5-carbothioamide (VI).

[0263] An agitator vessel was charged with 2-propanol (114 kg) and 2,3,4,6,7,8,9,10- octahydropyrimido[l,2-a]azepin-l-ium l-tert-butoxycarbonyl-5-[(3-chloro-2-methoxy- phenyl)carbamothioyl]-6-oxo-2,3-dihydropyridin-4-olate (XV; 67.0 kg). The inner temperature was adjusted to 20-30 °C and a solution of hydrochloric acid (34.4 kg) in 2-propanol (144 kg) was added within 3.5 h. The mixture was kept at that temperature for 14 h, water (300 kg) was added within 2 h and the resulting mixture was kept at 20 - 30°C for another 2 h. The solid product was isolated by centrifugation, washed with water (100 kg) and dried at 30 - 40°C and <0.015 MPa, affording

[0264] 33.7 kg (91 %) of N-(3-chloro-2-methoxy-phenyl)-4-hydroxy-6-oxo-2,3-dihydro-lH-pyridine-5- carbothioamide (VI) as a yellowish solid.

[0265] 3H NMR (400 MHz, DMSO-d6): d 16.45 (d, 1H), 14.69 (s, 1H), 14.33 (s, 1H), 9.37 (br s, 1H), 8.18 (br s, 1H), 7.87 - 7.76 (m, 1H), 7.45-7.37 (m, 1H), 7.23 - 7.15 (m, 1H), 3.76-3.73 (m, 3H), 3.43 (td, 1H), 3.32- 3.27 (m, 1H), 2.79 (t, 1H), 2.69 - 2.59 (m, 1H).3

[0266] HPLC (method 3): 99.57 % purity (N-(3-chloro-2-methoxy-phenyl)-4-hydroxy-6-oxo-2,3-dihydro-lH- pyridine-5-carbothioamide, VI; RT = 16.2 min).

[0267] EXAMPLE 4: Preparation of Step 4: 3-[[(2S)-l,4-dioxan-2-yllmethoxylpyridine-4-carbonitrile (IX).

[0268] An agitator vessel was charged with tetrahydrofuran (235.0 kg), 3-chloropyridine-4-carbonitrile (VII;

[0269] 25.8 kg) and [(2R)-l,4-dioxan-2-yl]methanol (VIII; 24.3 kg). The inner temperature was lowered to 0 - 10°C and a solution of potassium tert-butoxide in tetrahydrofuran (25 % VJ / VJ 93.2 kg) was added within 3 h. The inner temperature was raised to 15 - 25°C and the mixture was kept at that temperature for 5 h. The volatiles were distilled off at a pressure < 0.02 MPa and an inner temperature < 45°C until the volume of the distillation residue was lowered to 130 L. The distillation residue was adjusted to an inner temperature of 20 - 30°C and kept at that temperature for 0.5 h.

[0270] 3NMR data from WO 2020 / 216781. BHC 243007 FOREIGN FILING 2025 08

[0271] Water (615 kg) was added to the distillation residue within 3 h, its inner temperature was lowered to 3°C within 5 h and it was kept at that temperature for another 3 h. The formed solid product was isolated via centrifugation, washed with water (64.2 kg) and n-heptane (68.6 kg) and dried at a temperature of 40 - 50°C and a pressure < 0.02 MPa, affording 32.7 kg (80 %) of 3-[[(2S)-l,4-dioxan- 2-yl]methoxy]pyridine-4-carbonitrile (IX) as a grey solid.

[0272] 4H NMR (400 MHz, DMSO-d6): d 3.41 - 3.53 (m, 2 H), 3.59 - 3.72 (m, 2 H), 3.75 - 3.81 (m, 1 H), 3.82 - 3.87 (m, 1 H), 3.87 - 3.95 (m, 1 H), 4.27 - 4.37 (m, 2 H), 7.77 - 7.80 (m, 1 H), 8.38 - 8.41 (m, 1 H), 8.71 - 8.73 (m, 1 H).4

[0273] HPLC (method 4): 98.36 % purity (3-[[(2S)-l,4-dioxan-2-yl]methoxy]pyridine-4-carbonitrile, IX; RT = 12.3 min).

[0274] Assay (HPLC, method 4; against external standard): 98 %.

[0275] EXAMPLE 5: Step 5: [3-[[(2S)-l,4-dioxan-2-yllmethoxyl-4-pyridyllmethylammonium ethanesulfonate (XVI).

[0276] An agitator vessel was charged with 3-[[(2S)-l,4-dioxan-2-yl]methoxy]pyridine-4-carbonitrile (IX; 29.0 kg), methanol (326 kg), ethanesulfonic acid (16.5 kg) and palladium (10 % VJ / VJ on charcoal; 0.88 kg). Hydrogen was inserted into the vessel until a total pressure of 0.3 - 0.4 Mpa was reached. The inner temperature was raised to 45 - 55°C and the mixture was kept at that temperature for 35 h. The inner temperature was lowered to 30 - 40°C, the mixture was filtered through diatomite (10.0 kg) and the filter cake was washed with methanol (70.5 kg). In an agitator vessel, to the combined filtrates was added PhosphonicS™ SEM26 metal scavenger (2.90 kg) at an inner temperature of 15 - 25°C and the resulting mixture was kept at that temperature for 10 h. The mixture was filtered into an agitator vessel and the filter cake was washed with methanol (46.0 kg). The combined filtrate was distilled at a pressure < 0.02 Mpa and an inner temperature of the distillation residue < 45°C until the volume of the distillation residue was lowered to 170 L. The distillation residue was warmed to an inner temperature of 40 - 55°C and kept at that temperature for 1 h. Methyltetrahydrofuran (446 kg) was added within 4 h, the resulting mixture was cooled to an inner temperature of 0 - 10°C within 4 h and kept at that temperature for an additional 4 h. The solid product was isolated via centrifugation, washed with a mixture of methanol and methyltetrahydrofuran (3 : 1 v / v; 47.2 kg) and dried at a product temperature of 40 - 50°C at < 0.02

[0277] 4NMR data from WO 2020 / 216781. BHC 243007 FOREIGN FILING 2025 08

[0278] Mpa, affording 36.4 kg (81 %) of [3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]methylammonium ethanesulfonate (XVI) as a white solid.

[0279] 3H NMR (500 MHz, DMSO-d6) d 8.43 (s, 1H), 8.33 - 8.23 (d, J = 4.7 Hz, 4H), 7.41 (d, J = 4.8 Hz, 1H), 4.17 (d, J = 4.9 Hz, 2H), 4.05 (s, 2H), 3.96 - 3.91 (m, 1H), 3.88 (dd, J = 11.4, 2.6 Hz, 1H), 3.81 - 3.76 (m, 1H), 3.70 - 3.62 (m, 2H), 3.54 - 3.41 (m, 2H), 2.43 (q, J = 7.4 Hz, 2H), 1.07 (t, J = 7.4 Hz, 3H).5

[0280] 13C NMR (126 MHz, DMSO-d6) d 152.1, 142.4, 134.6, 130.3, 123.0, 73.0, 68.6, 67.3, 65.8, 65.7, 45.0, 36.3, 9.7.5

[0281] ESI-HRMS (method 2): calculated for C11H17N2O3 ([compound X+H]+): 225.1234, found: 225.1229.

[0282] HPLC (method 5): 99.79 % purity ([3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]methylammonium ethanesulfonate, XVI; RT = 7.6 min).

[0283] HPLC (method 6): > 99.0 % enantiomeric purity ([3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4- pyridyl]methylammonium ethanesulfonate, XVI; RT = 5.2 min); [3-[[(2R)-l,4-dioxan-2-yl]methoxy]- 4-pyridyl]methylammonium ethanesulfonate (ent-XVI) RRT = 0.81.

[0284] Assay (HPLC, method 5; against external standard): 99.2 % (1 : 1 salt).

[0285] Ethanesulfonate content (IC): 27.3 %.

[0286] EXAMPLE 6: Step 6: Preparation of N-(3-chloro-2-methoxy-phenyl)-4-[[3-[[(2S)-l,4-dioxan-2- yllmethoxyl-4-pyridyllmethylaminol-6-oxo-2,3-dihvdro-lH-pyridine-5-carbothioamide (XI).

[0287] An agitator vessel was charged with tetrahydrofuran (188.2 kg), N-(3-chloro-2-methoxy-phenyl)-4- hydroxy-6-oxo-2,3-dihydro-lH-pyridine-5-carbothioamide (VI, 10.5 kg), [3-[[(2S)-l,4-dioxan-2- yl]methoxy]-4-pyridyl]methylammonium ethanesulfonate (XVI, 12.5 kg) and potassium phosphate (14.4 kg). At 20°C, trimethylsilyl N-trimethylsilylethanimidate (20.6 kg) are added within 1 h. The inner temperature was raised to 50°C and the mixture was kept at that temperature for 5 h. The mixture was cooled to 20°C within 1.5 h and kept at that temperature for 12 h. Water (42,4 kg) was added within 1.7 h. The biphasic mixture was heated to an inner temperature of 40°C and the layers were separated. 150 kg of the solvents of the organic layer were distilled off at reduced pressure

[0288] 5NMR data from material generated from [3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]methanamine (X) and ethanesulfonic acid. BHC 243007 FOREIGN FILING

[0289] 2025 08 and a mantle temperature of 70°C. The inner temperature of the distillation residue was set to 50°C and isopropyl acetate (188 kg) was added within 1 h. The inner temperature was lowered to 20°C within 1 h and the mixture was kept at that temperature for another 1 h. The solid product was isolated via centrifugation, washed with isopropyl acetate and water and dried at a product temperature of > 65°C at < 40 mbar, affording 13.9 kg (80 % yield) of N-(3-chloro-2-methoxy- phenyl)-4-[[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]methylamino]-6-oxo-2,3-dihydro-lH- pyridine-5-carbothioamide (XI) as a yellowish solid. 14.79 (s, 1H), 13.69 (t, 1H), 8.39 (s, 1H), 8.24 (d, 1H), 7.81 (dd, 1H),

[0290] 7.73 (s, 1H), 7.33 - 7.26 (m, 2H), 7.11 (t, 1H), 4.67 (d, 2H), 4.16 (t, 2H), 3.95 - 3.84 (m, 2H), 3.79 -

[0291] 3.74 (m, 1H), 3.71 (s, 3H), 3.70 - 3.59 (m, 2H), 3.54 - 3.45 (m, 2H), 3.20 - 3.11 (m, 2H), 2.78 (t, 2H).6

[0292] HPLC (method 3): 99.9 % purity (N-(3-chloro-2-methoxy-phenyl)-4-[[3-[[(2S)-l,4-dioxan-2- yl]methoxy]-4-pyridyl]methylamino]-6-oxo-2,3-dihydro-lH-pyridine-5-carbothioamide, XI; RT = 9.1 min).

[0293] HPLC (method 9): > 99.0 % enantiomeric purity (N-(3-chloro-2-methoxy-phenyl)-4-[[3-[[(2S)-l,4- dioxan-2-yl]methoxy]-4-pyridyl]methylamino]-6-oxo-2,3-dihydro-lH-pyridine-5-carbothioamide, XI; RT = 5.7 min); N-(3-chloro-2-methoxy-phenyl)-4-[[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4- pyridyl]methylamino]-6-oxo-2,3-dihydro-lH-pyridine-5-carbothioamide (ent-XI) RRT = 0.73.

[0294] Assay (HPLC, method 3; against external standard): 98.3 %.

[0295] 6NMR data from WO 2020 / 216781. BHC 243007 FOREIGN FILING 2025 08

[0296] EXAMPLE 7: Step 7: Preparation of 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2- yllmethoxyl-4-pyridyll-l,5,6,7-tetrahvdropyrrolo[3,2-clpyridin-4-one crude (B).

[0297] A mixture of methanol (179 kg), N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-l, 2,5,6- tetrahydropyridine-3-carbothioamide (XI; 22.0 kg) and sulphuric acid (2.10 kg) in an agitator vessel was heated to an inner temperature of 45°C. A solution of hydrogen peroxide - urea (6.8 kg) in water (28.4 kg) was added within 2 h and the resulting mixture was kept at that temperature for an additional 14 h. A solution of sodium hydroxide (7.5 kg of a 45 % aqueous solution) was diluted with water (200 kg) and added within 1 h. The resulting mixture was cooled to an inner temperature of 20°C within 1 h and kept at that temperature for an additional 1 h. The solid product was isolated by filtration, washed with mixtures of methanol (60 kg) an water (63 kg) as well as water (86 kg) and dried at a product temperature of > 65°C at <40 mbar, affording 17.1 kg (83 %) of 3-(3-chloro- 2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2- c]pyridin-4-one crude (B) as a yellow solid.

[0298] 7H NMR (400 MHz, DMSO-d6): d 2.86 (t, 2H), 3.37-3.57 (m, 4H), 3.70 - 3.90 (m, 4H), 3.88 (s, 3H), 3.92 - 4.08 (m, 1H), 4.10 - 4.20 (m, 1H), 4.28 (dd, 1H), 6.15 (t, 1H), 6.68 (d, 2H), 7.16 (br s, 1H), 7.28 (d, 1H), 7.52 (s, 1H), 8.04 (d, 1H), 8.39 (s, 1H), 11.07 (s, 1H).7

[0299] HPLC (method 7): 97.9 % purity (3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2- yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one crude (B); RT = 9.6 min); 0.32 % 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5- dihydropyrrolo[3,2-c]pyridin-4-one (XVII, RRT = 0.97); <0.05 % 3-chloro-2-methoxyaniline (I, RRT = 0.85); 1.6 % 5-(5-chloro-4-methoxy-l,3-benzothiazol-2-yl)-4-[[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4- pyridyl]methylamino]-2,3-dihydro-lH-pyridin-6-one (XVIII, RRT = 1.10) and / or N-(3-chloro-2- methoxy-phenyl)-4-[[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]methylamino]-6-oxo-2,3- dihydro-lH-pyridine-5-carboxamide (XX, RRT = 1.10).

[0300] HPLC (method 8): > 99.0 % enantiomeric purity (3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4- dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one crude (B), RT = 6.5 min); 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2R)-l, 4-dioxan-2-yl]methoxy]-4-pyridyl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridin-4-one crude (ent-B) RRT = 1.42.

[0301] Assay (HPLC, method 7; against external standard): 95.8 %.

[0302] 7NMR data from WO 2020 / 216781. BHC 243007 FOREIGN FILING

[0303] 202508

[0304] Sulphur content (ICP-OES): 4.8 %.

[0305] Sulphate content (IC): 0.04 %.

[0306] EXAMPLE 8: Step 8: Preparation of 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2- yllmethoxyl-4-pyridyll-l,5,6,7-tetrahvdropyrrolo[3,2-clpyridin-4-one (purified) (XIII).

[0307] An agitator vessel was charged with ethanol denaturated with toluene (133 kg), water (42.2 kg), 3- (3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l, 4-dioxan-2-yl]methoxy]-4-pyridyl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridin-4-one crude (B; 21.0 kg) and p-toluenesulfonic acid monohydrate (8.0 kg). The mixture was heated to an inner temperature of 40°C, kept at that temperature for 0.5 h and filtered into another agitator vessel. At a mantle temperature of 40°C, a solution of sodium hydroxide (4.6 kg of a 45 % aqueous solution), diluted with water (29 kg) was added within 1 h. The inner temperature was lowered to 10°C within 1.5 h and stirring was continued at that temperature for another 1 h. The formed, solid product was isolated via centrifugation, washed with a 3 : 1 (w / w) mixture of ethanol denaturated with toluene / water (137 kg) and water (144 kg), and dried at a product temperature of > 65°C at < 40 mbar, affording 14.0 kg (67 %) of 3-(3-chloro- 2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2- c]pyridin-4-one purified (XIII) as a yellowish solid.

[0308] HPLC (method 7): 99.8 % purity (3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2- yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one purified, XIII; RT = 9.6 min); 0.22 % 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5- dihydropyrrolo[3,2-c]pyridin-4-one (XVII, RRT = 0.97); <0.05 % 3-chloro-2-methoxyaniline (I, RRT = 0.85); <0.05 % 5-(5-chloro-4-methoxy-l,3-benzothiazol-2-yl)-4-[[3-[[(2S)-l,4-dioxan-2-yl]methoxy]- 4-pyridyl]methylamino]-2,3-dihydro-lH-pyridin-6-one (XVIII, RRT = 1.10) and / or N-(3-chloro-2- methoxy-phenyl)-4-[[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]methylamino]-6-oxo-2,3- dihydro-lH-pyridine-5-carboxamide (XX, RRT = 1.10).8

[0309] 8Co-elution of compounds XVIII and XX. The predominant formation of compound XVIII under the reaction conditions was identified by isolation of the respective compound from the mother liquor after having isolated target compound (B), by partial solvent evaporation and crystallization of the respective compound. BHC 243007 FOREIGN FILING 202508

[0310] HPLC (method 8): > 99.0 % enantiomeric purity (3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4- dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one crude, XIII, RT = 6.7 min); 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2R)-l, 4-dioxan-2-yl]methoxy]-4-pyridyl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridin-4-one crude (ent-XII I) RRT = 1.40.

[0311] Assay (HPLC, method 7; against external standard): 98.3 %.

[0312] Sulphur content (ICP-OES): 13 ppm.

[0313] EXAMPLE 8': Preparation and characterization of 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4- dioxan-2-yllmethoxylpyridin-l-ium-4-yll-l,5,6,7-tetrahvdropyrrolo[3,2-clpyridin-4-one 4-

[0314] A mixture of 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]- l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one purified (XIII; 10.0 g) and p-toluenesulfonic acid monohydrate (3.9 g) was dissolved in a mixture of ethanol and water (4:1 v / v; 50 mL) at 40°C. After 10 min, the volatiles were evaporated under reduced pressure at 40°C, affording 21.4 g of a yellow to orange solid. 5 g of this solid were redissolved in ethanol (20 mL) and water (5 mL) at 50°C. The mixture was cooled to 20°C and kept at that temperature overnight. The resulting suspension was filtered, the filter cake was washed with a mixture of ethanol and water (4 : 1 v / v) and dried under air overnight to afford 1.66 g of solid 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2- yl]methoxy]pyridin-l-ium-4-yl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one 4- methylbenzenesulfonate (XIX).

[0315] NMR (DMSO-d6): d 11.31 (s, 1H), 8.60 (s, 1H), 8.30 (d, J = 6.3 Hz, 1H), 8.11 (s, 1H), 7.55 (d, J = 6.2 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.42 (br s, 1H), 7.11 (d, J = 7.9 Hz, 2H), 6.82 (dd, J = 8.1, 1.5 Hz, 1H), 6.79-6.74 (m, 1H), 6.17 (dd, J = 8.1, 1.5 Hz, 1H), 4.40 (dd, J = 10.6, 3.5 Hz, 1H), 4.30 (dd, J = 10.6, 6.7 Hz, 1H), 4.14 (tt, J = 6.5, 3.2 Hz, 1H), 3.93 (s, 3H), 3.89 (br d, J = 11.7 Hz, 1H), 3.84 (dd, J = 11.5, 2.5 BHC 243007 FOREIGN FILING 2025 08

[0316] Hz, 1H), 3.79 - 3.69 (m, 2H), 3.54 (td, J = 11.4, 2.7 Hz, 1H), 3.50 - 3.40 (m, 4H), 2.95 (t, J = 6.8 Hz, 2H), 2.28 (s, 3H).

[0317] 13C NMR (DMSO-d6): d 164.8, 149.8, 145.5, 143.8, 140.1, 137.8, 137.7, 135.01, 134.98, 130.7, 128.0 (2C), 127.4, 126.6, 125.4 (2C), 124.8, 120.6, 119.8, 114.0, 111.8, 107.9, 72.7, 69.9, 66.7, 65.72, 65.68, 59.9, 39.7, 22.1, 20.7.

[0318] 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]pyridin-l-ium-4-yl]-l,5,6,7- tetra-hydropyrrolo[3,2-c]pyridin-4-one 4-methylbenzenesulfonate (XIX) can be characterized unambiguously by a X-Ray powder diffractogram (with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 11.9, 21.8 and 25.7; preferably at least the following reflections: 7.2, 11.9, 21.8, 21.0 and 25.7, more preferably at least the following reflections: 7.2, 11.9, 13.9, 16.5, 21.0, 21.8 and 25.7; most preferably at least the following reflections: 7.2, 11.9, 13.9, 16.5, 18.2, 21.0, 21.8, 23.6, 25.7 and 28.3 each quoted as 2Q value ± 0.2°. The compound of formula (B) in the polymorphic form Modification I can also be characterized unambiguously by the X-Ray powder diffractogram (at RT and with Cu-K alpha 1 as radiation source) as shown in FIGURE 95, which is the X-ray powder diffractogram of 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]- methoxy]pyridin-l-ium-4-yl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one 4-methylbenzene- sulfonate (XIX).

[0319] 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l, 4-dioxan-2-yl]methoxy]pyridin-l-ium-4-yl]-l, 5,6,7- tetra-hydropyrrolo[3,2-c]pyridin-4-one 4-methylbenzenesulfonate (XIX), can be characterized by Raman spectroscopy on the basis of the respective FT Raman spectrum as shown in FIGURE 96, which is recorded at RT and with a laser wavelength of 1064 nm and a resolution of 2 cm1. 3-(3-chloro-2- methoxy-anilino)-2-[3-[[(2S)-l, 4-dioxan-2-yl]methoxy]pyridin-l-ium-4-yl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridin-4-one 4-methylbenzenesulfonate (XIX), according to the present invention displays at least 3, often at least 5, in particular at least 7, and especially all of the bands quoted in the following as peak maxima: BHC 243007 FOREIGN FILING 202508

[0320] Table 12: Raman bands of 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2- yl]methoxy]pyridin-l-ium-4-yl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one 4-methylbenzene- sulfonate (XIX). 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]pyridin-l-ium-4-yl]-l,5,6,7- tetra-hydropyrrolo[3,2-c]pyridin-4-one 4-methylbenzenesulfonate (XIX), can be characterized by infrared spectroscopy on the basis of the respective IR spectrum as shown in FIGURE 97 which is recorded at RT using an universal diamond ATR device and a resolution of 2 cm1. 3-(3-chloro-2- methoxy-anilino)-2-[3-[[(2S)-l, 4-dioxan-2-yl]methoxy]pyridin-l-ium-4-yl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridin-4-one 4-methylbenzenesulfonate (XIX) according to the present invention displays at least 3, often at least 5, in particular at least 7, and especially all of the bands quoted in the following as peak maxima: BHC 243007 FOREIGN FILING

[0321] 202508

[0322] Table 13: IR bands of 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]pyridin-l- ium-4-yl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one 4-methylbenzenesulfonate (XIX):

[0323] BHC 243007 FOREIGN FILING

[0324] 2025 08

[0325] Table 14: XRPD Reflections, IR and Raman bands of compound 3-(3-chloro-2-methoxy-anilino)-2-[3- [[(2S)-l,4-dioxan-2-yl]methoxy]pyridin-l-ium-4-yl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one 4-methylbenzenesulfonate (XIX). BHC 243007 FOREIGN FILING

[0326] 2025 08

[0327] FIGURE 98 shows the DSC- and TGA-thermogram of 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4- dioxan-2-yl]methoxy]pyridin-l-ium-4-yl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one 4- methylbenzenesulfonate (XIX). FIGURE 99 shows dynamic vapour sorption (hereinafter referred to as "DVS") curves measured on a sample from a similar technical batch, not on a sample of the same technical batch which was used to describe Hydrate 1 Mod. A of the present invention, which was also characterized via XRPD to be Hydrate 1 Mod. A.

[0328] As is well-known to the person skilled I the art, DVS is a gravimetric technique that measures how quickly and how much of a solvent is absorbed by a sample such as a dry powder absorbing water. BHC 243007 FOREIGN FILING 202508

[0329] The curves of FIGURE 99 show the sorption (lower line) and the desorption (upper line) of water starting with 0 % relative humidity and going up to 95 % relative humidity. The curves show the typical course of nonstoichiometric hydrates, with continuous uptake (sorption curve) and loss (desorption curve) of water during this measurement.

[0330] FIGURE 99 is a DVS with sorption higher than 4 % and is of a crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4- pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A):

[0331] (A), wherein the content of water is greater than 4.0% (w / w).

[0332] EXAMPLE 9: Step 9: Preparation of 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2- yllmethoxyl-4-pyridyll-l,5,6,7-tetrahvdropyrrolo[3,2-clpyridin-4-one hydrate (A) "crysta Hine Hydrate 1 Modification A compound of formula (A)" of the present invention^

[0333] An agitator vessel was charged with tetrahydrofuran (52.3 kg), water (6.4 kg) and 3-(3-chloro-2- methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2- c]pyridin-4-one purified (XIII; 13.8 kg). The inner temperature was raised to 60°C, the mixture was kept at that temperature for 0.5 h and filtered into another pre-heated (mantle temperature of 60°C) agitator vessel. The inner temperature of the filtrate was adjusted to 60°C for 15 min and water (167 kg) was added within 2 h. The inner temperature was lowered to 40°C within 1 h and the resulting mixture was kept at that temperature for another 1 h. The formed, solid product was isolated by filtration, washed with water (41.4 kg) and dried at a product temperature of 45 - 50°C at 64 - 67 mbar, affording 12.9 kg (93 %) of 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan- 2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one hydrate (A) as a white solid. BHC 243007 FOREIGN FILING 2025 08

[0334] HPLC (method 7): 99.8 % purity (3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2- yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one purified, XIII; RT = 9.6 min); 0.21 % 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5- dihydropyrrolo[3,2-c]pyridin-4-one (XVI I, RRT = 0.97); < 0.05 % 3-chloro-2-methoxyaniline (I, RRT = 0.85); < 0.05 % 5-(5-chloro-4-methoxy-l,3-benzothiazol-2-yl)-4-[[3-[[(2S)-l,4-dioxan-2- yl]methoxy]-4-pyridyl]methylamino]-2,3-dihydro-lH-pyridin-6-one (XVIII, RRT = 1.10) and / or N-(3- chloro-2-methoxy-phenyl)-4-[[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]methylamino]-6-oxo- 2,3-dihydro-lH-pyridine-5-carboxamide (XX, RRT = 1.10). HPLC (method 8): > 99.0 % enantiomeric purity (3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4- dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one crude, XIII, RT = 6.9 min); 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2R)-l, 4-dioxan-2-yl]methoxy]-4-pyridyl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridin-4-one crude (ent-XII I) RRT = 1.41. Assay (HPLC, method 7; against external standard): 94.2 %.

[0335] Water content (Karl Fischer titration)9: 3.0 % (VJ / VJ).

[0336] 9According to Ph. Eur. Chapter 2.5.32, Coulometric titration. BHC 243007 FOREIGN FILING 2025 08

[0337] Example 10: Manufacture of polymorphic and pseudopolymorphic forms of [3-(3-chloro-2- methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2- c]pyridine-4-one of formula (B)

[0338] Hydrate 1 Modification A

[0339] A mixture of 49 mg of the compound of formula (B) in the Modification I, produced as described below) and 50 mg of the compound of formula (B) in the Modification 11, produced as described below) was suspended in 0.5 ml ethanol / water (1:1) and the suspension was stirred at RT for seven days. The solid particles were isolated by filtration and dried at room temperature at ambient conditions.

[0340] Hydrate 1 Modification B

[0341] 513 mg of the compound Modification of formula (A) in the Hydrate 1 Modification A were suspended in 3 ml of acetonitrile and the suspension was stirred at room temperature. After 30 min 2 ml acetonitrile were added and the suspension was stirred for 11 days. The solid particles were isolated by filtration and dried at room temperature at ambient conditions.

[0342] Hydrate 1 Modification C

[0343] 511 mg of the compound of formula (A) in the Hydrate 1 Modification A Modification were suspended in 3 ml of acetone and the suspension was stirred at room temperature. After 30 min 2 ml acetone were added and the suspension was stirred for 11 days. The solid particles were isolated by filtration and dried at room temperature at ambient conditions.

[0344] Modification I

[0345] 3.140 g of the compound of formula (A) in the Hydrate 1 Modification A Modification were suspended in 20 ml of ethyl acetate and the suspension was stirred at room temperature for seven days. The solid particles were isolated by filtration and dried at room temperature at ambient conditions. BHC 243007 FOREIGN FILING

[0346] 2025 08

[0347] Modification II

[0348] 3.042 g of the compound of formula (A) in the Hydrate 1 Modification A Modification were suspended in 20 ml of 1,4 dioxane and the suspension was stirred at room temperature for seven days. The suspension was filtered and the residue dried at room temperature at ambient conditions. 2 g of the residue were tempered at 180°C in a drying cabinet for 1 h.

[0349] Toluene Solvate

[0350] 404 mg of the compound of formula (A) in the Hydrate 1 Modification A Modification were dissolved in 120 ml toluene at boiling temperature. The solution was filtered and quartered and one quarter was stored in a refrigerator until the solvent had evaporated.

[0351] 1,4-Dioxane Solvate

[0352] 3.042 g of the compound of formula (A) in the Hydrate 1 Modification A Modification were suspended in 20 ml of 1,4-dioxane and the suspension was stirred at room temperature for seven days. The solid particles were isolated by filtration and dried at room temperature at ambient conditions.

[0353] Ethyl acetate Solvate

[0354] A mixture of 52 mg of the compound of formula (B) in the Modification I Modification (produced as described above) and 53 mg of the compound of formula (B) in the Modification II (produced as described above) was suspended in 0.5 ml ethyl acetate and the suspension was stirred at 0°C. After one hour 0.5 ml ethyl acetate were added to the suspension. After seven days the solid particles were isolated by filtration and dried at room temperature at ambient conditions.

[0355] 2-Propanol Solvate

[0356] 105 mg of the compound of formula (B) in the amorphous form (produced as described below) were suspended in 0.5 ml of 2-propanol and the suspension was shaken in an Eppendorf Thermomixer at 25°C. After seven weeks and 5 days the substance was dried at room temperature and ambient conditions. BHC 243007 FOREIGN FILING

[0357] 2025 08

[0358] 1-Propanol Solvate Modification A

[0359] 3.001 g of the compound of formula (A) in the Hydrate 1 Modification A Modification were suspended in 20 ml of 1-propanol and the suspension was stirred at room temperature for seven days. The solid particles were isolated by filtration and dried at room temperature at ambient conditions.

[0360] 1-Propanol Solvate Modification B

[0361] 487 mg of the compound of formula (A) in the Hydrate 1 Modification A Modification were dissolved in 60 ml 1-propanol at boiling temperature. The solution was filtered and quartered, and one quarter was stored at room temperature until the solvent had evaporated.

[0362] Ethanol-Water-Solvate

[0363] 15 g of the compound of formula (A) in the Hydrate 1 Modification A Modification were mixed with 150 ml ethanol / water 4 : 1 (v / v) and 5.9 g 4- toluene sulfonic acid monohydrate and dissolved at 40°C. 17.8 g 2 N NaOH-solution were added within 30 min and it was stirred for a further 30 minutes at 40°C. Crystallization started at the end of the addition. The suspension was cooled to 10°C within 90 minutes.

[0364] After one hour post stirring the suspension was seeded with 500 mg the compound of formula (I) in the Ethanol-Water-Solvate and stirred overnight at 10°C. The next day 500 mg the compound of formula (I) in the Ethanol-Water-Solvate were added and the suspension was stirred further at 10°C for one night. The residue was isolated by suction and washed 3 times with 30 ml water each. The solid was dried overnight in a vacuum drying oven (50 mbar) at 45°C with nitrogen.

[0365] Ethanol-Water-Solvate

[0366] 3.088 g of the compound of formula (A) in the Hydrate 1 Modification A Modification were suspended in 20 ml of methanol and the suspension was stirred at room temperature for seven days. The solid particles were isolated by filtration and dried at room temperature at ambient conditions. BHC 243007 FOREIGN FILING

[0367] 202508

[0368] Ethanol Form

[0369] 408 mg of the compound of formula (A) in the Hydrate 1 Modification A Modification were dissolved in 60 ml ethanol at boiling temperature. The solution was filtered and quartered and one quarter was stored in a refrigerator until the solvent had evaporated.

[0370] 2-Propanol Form

[0371] 417 mg of the compound of formula (A) in the Hydrate 1 Modification A Modification were dissolved in 60 ml isopropanol at boiling temperature. The solution was filtered and quartered and one quarter was stored at room temperature until the solvent had evaporated.

[0372] DMF Form

[0373] 209 mg of the compound of formula (A) in the Hydrate 1 Modification A Modification were dissolved in 20 ml dimethylformamide at boiling temperature. The solution was filtered and divided in half and one half was stored at room temperature until the solvent had evaporated.

[0374] THF-Form 1

[0375] 410 mg of the compound of formula (A) in the Hydrate 1 Modification A Modification were dissolved in 40 ml tetrahydrofuran at boiling temperature. The solution was filtered and quartered and one quarter was stored at room temperature until the solvent had evaporated.

[0376] BHC 243007 FOREIGN FILING 2025 08

[0377] THF-Form 2

[0378] 3.002 g of the compound of formula (A) in the Hydrate 1 Modification A Modification were suspended in 20 ml of tetrahydrofuran and the suspension was stirred at room temperature for seven days. The suspension was filtered and the clear solution was stored at RT until the solvent had evaporated.

[0379] THF-Form 3

[0380] 518 mg of the compound of formula (A) in the Hydrate 1 Modification A Modification were suspended in 3 ml of tetrahydrofuran and the suspension was stirred at room temperature. After 30 min 2 ml tetrahydrofuran were added and the suspension was stirred for 11 days. The solid particles were isolated by filtration and dried at room temperature at ambient conditions.

[0381] THF-Form 4

[0382] 3.065 g of the compound of formula (A) in the Hydrate 1 Modification A Modification were suspended in 20 ml of tetrahydrofuran and the suspension was stirred at room temperature for seven days. The solid particles were isolated by filtration and dried at room temperature at ambient conditions.

[0383] THF-Form 5

[0384] 8.2 g of the compound of formula (A) in the Hydrate 1 Modification A Modification were dissolved in 82 ml tetrahydrofuran / water 9 : 1 (v / v). 0.6 g diatomaceous earth was added and the solution was filtered through a folded filter. The solution was added to 123 g of water at 15°C within 7 min, leading to precipitation of the substance. The suspension was stirred at 15°C for 2 days. The residue was isolated by suction and washed 3 times with 16 ml water each. The solid was dried overnight in a vacuum drying oven at 45°C (< 100 mbar) without nitrogen. BHC 243007 FOREIGN FILING

[0385] 2025 08

[0386] 1-Propanol-Water-Solvate

[0387] 487 mg of the compound of formula (A) in the Hydrate 1 Modification A were dissolved in 60 ml 1-propanol at boiling temperature. The solution was filtered and quartered and one quarter was mixed with double the amount of water. The clear solution was allowed to stand at RT until the solvent had evaporated.

[0388] Modification III

[0389] The compound of formula (A) in the Hydrate 1 Modification A was heated to 180°C in a PANalytical EMPYREAN diffractometer.

[0390] Modification IV

[0391] BAY 2927088 (Hydrate 1 Modification A) was stored at 1 % RH at 25°C in the humidity chamber of a PANalytical EMPYREAN diffractometer.

[0392] Amorphous form

[0393] A total of 5 g of the compound of formula (A) in the Hydrate 1 Modification A was amorphized in portions using a B-90 nano spray dryer from Buchi. For this purpose, 5 g of substance were dissolved in 250 ml acetone / water (90 vol. % 10 vol. %) at RT and sprayed at 60°C.

[0394] BHC 243007 FOREIGN FILING 2025 08

[0395] Example 11: Physical characterization of polymorphic forms of 3-(3-chloro-2-methoxy-anilino)- 2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2- c]pyridine-4-one of formula (B)

[0396] 11.1 XRPD X-Ray diffraction patterns were recorded at room temperature using XRD - diffractometers X'Pert PRO (PANalytical) and STOE STADI-P (radiation Cu K alpha 1, wavelength 1.5406 A). There was no sample preparation. All X-Ray reflections are quoted as °20 (theta) values (peak maxima) with a resolution of ±0.2°.

[0397] Table 15: XRPD reflections of forms Modification I, Modification ll7Modification III, Modification IV, Hydrate 1 Modification A, Hydrate 1 Modification B, Hydrate 1 Modification C and Ethanol-Water Solvate. BHC 243007 FOREIGN FILING

[0398] 2025 08 BHC 243007 FOREIGN FILING 2025 08

[0399] BHC 243007 FOREIGN FILING 2025 08

[0400] Table 16: XRPD reflections of forms Ethanol Form, Methanol-Water Solvate, THF Form 1, THF Form 2,

[0401] THF Form 3 and THF Form 4. BHC 243007 FOREIGN FILING

[0402] 2025 08 BHC 243007 FOREIGN FILING

[0403] 2025 08

[0404] BHC 243007 FOREIGN FILING 2025 08

[0405] Table 17: XRPD reflections of forms THF Form 5, 2-Propanol Solvate, 2-Propanol Form, 1-Propanol

[0406] Solvate Modification A, 1-Propanol Solvate Modification B, 1-Propanol-Water Solvate BHC 243007 FOREIGN FILING

[0407] 2025 08 BHC 243007 FOREIGN FILING 2025 08 BHC 243007 FOREIGN FILING

[0408] 2025 08

[0409] BHC 243007 FOREIGN FILING 2025 08

[0410] Table 18: XRPD reflections of forms Toluene Solvate, 1,4-Dioxane Solvate, Ethyl Acetate Solvate and

[0411] DMF Form. BHC 243007 FOREIGN FILING 2025 08 BHC 243007 FOREIGN FILING 2025 08

[0412] 11.2 Raman spectroscopy

[0413] Raman spectra were recorded at room temperature using FT-Raman-spectrophotometers (model MultiRam) from Bruker. Resolution was 2 cm1. Measurements were performed in glass vials or aluminium discs. There was no sample preparation. Table 19: Raman bands of forms Modification I, Modification ll7Hydrate 1 Modification A, Hydrate 1 Modification B, Hydrate 1 Modification C and Ethanol-Water Solvate. BHC 243007 FOREIGN FILING

[0414] 2025 08 BHC 243007 FOREIGN FILING

[0415] 2025 08

[0416] Table 20: Raman bands of forms Ethanol Form, Methanol-Water Form, THF Form 1, THF Form 2, THF Form 3, THF Form 4. BHC 243007 FOREIGN FILING

[0417] 2025 08 BHC 243007 FOREIGN FILING 2025 08

[0418] BHC 243007 FOREIGN FILING

[0419] 2025 08

[0420] Table 21: Raman bands of forms THF Form 5, 2-Propanol-Solvate, 2-Propanol Form and 1-Propanol Solvate Modification A. BHC 243007 FOREIGN FILING

[0421] 2025 08 BHC 243007 FOREIGN FILING

[0422] 2025 08

[0423] Table 22: Raman bands of forms Toluene Solvate, 1,4-Dioxane Solvate, Ethyl Acetate Solvate, DMF Form, Modification IV and the amorphous phase. BHC 243007 FOREIGN FILING

[0424] 2025 08 BHC 243007 FOREIGN FILING

[0425] 2025 08 BHC 243007 FOREIGN FILING 2025 08

[0426] 11.3 IR spectroscopy

[0427] IR-ATR-spectra were recorded at room temperature using a FT-IR-spectrophotometer Lumos with universal diamond ATR device Alpha from Bruker. Resolution was 2 cm1. There was no sample preparation. Table 23: IR bands of forms Modification I, Modification ll7Hydrate 1 Modification A, Hydrate 1 Modification B, Hydrate 1 Modification C and Ethanol-Water Solvate. BHC 243007 FOREIGN FILING

[0428] 2025 08 BHC 243007 FOREIGN FILING 2025 08

[0429] BHC 243007 FOREIGN FILING

[0430] 2025 08

[0431] Table 24: IR bands of forms Ethanol Form, Methanol-Water Solvate, THF Form 1, THF Form 2, THF Form 3 and THF Form 4. BHC 243007 FOREIGN FILING

[0432] 2025 08 BHC 243007 FOREIGN FILING 2025 08

[0433] BHC 243007 FOREIGN FILING

[0434] 2025 08

[0435] Table 25: IR bands of forms THF Form 5, 2-Propanol Solvate, 2-Propanol Form, 1-Propanol Solvate Modification A and 1-Propanol Solvate Modification B. BHC 243007 FOREIGN FILING

[0436] 2025 08 BHC 243007 FOREIGN FILING

[0437] 2025 08

[0438] BHC 243007 FOREIGN FILING 2025 08

[0439] Table 26: IR bands of forms Toluene Solvate, 1,4-Dioxane Solvate, Ethyl Acetate Solvate, DMF Form, and the amorphous phase. BHC 243007 FOREIGN FILING

[0440] 2025 08 BHC 243007 FOREIGN FILING 202508

[0441] Example 12: Properties of crystalline Hydrate 1 Modification A of compound 3-(3-chloro-2- methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7- tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A).

[0442] It was surprisingly found that Hydrate 1 Modification A of compound 3-(3-chloro-2-methoxy- anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine- 4-one of formula (A) has a highly complex crystalline structure including a 4 / 5 stoichiometry (compound of formula (A) / water). This crystalline lattice is able to overcome the effect of amorphization initiated by overdrying to some extent. Furthermore it can implement more water molecules to some extent and is therefore suitable for chemical processing, mechanical manufacturing procedures for drug product and storage at different conditions. depict the crystalline lattice of crystalline Hydrate 1 Modification A form of the compound 3-(3- chloro-2-methoxy-anilino)-2-[3-[[(2S)-l, 4-dioxan-2-yl]methoxy]-4-pyridyl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A) (X-ray single crystal structure analysis) from two different angles with focus on the water molecules included.

[0443] FIGURE 1: Depiction of the crystalline lattice of crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l, 4-dioxan-2-yl]methoxy]-4-pyridyl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A) (X-ray single crystal structure analysis) from two different angles with focus on the water molecules included.

[0444] FIGURE 2: Crystal packing from another angle.

[0445] Table 27, FIGURE 1 and FIGURE 2 depict the crystalline lattice of crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4- pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A) (X-ray single crystal structure analysis) from two different angles with focus on the water molecules included.

[0446] FIGURE 1: Depiction of the crystalline lattice of crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l, 4-dioxan-2-yl]methoxy]-4-pyridyl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A) (X-ray single crystal structure analysis) from two different angles with focus on the water molecules included.

[0447] FIGURE 2: Crystal packing from another angle. BHC 243007 FOREIGN FILING

[0448] 202508

[0449] Table 27; Crystal data and structure refinement for crystalline Hydrate 1 Modification A of compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l, 4-dioxan-2-yl]methoxy]-4-pyridyl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A)

[0450] Empirical formula C96 H110 CI4 N16 025

[0451] Formula weight 2029.79

[0452] Temperature 118 K

[0453] Wavelength 1.54178 A

[0454] Crystal system Triclinic

[0455] Space group Pl

[0456] Unit cell dimensions a = 11.7853(3) A a= 72.997(2)°. b = 14.8131(4) A b= 68.021(3)°. c = 15.4423(4) A g = 89.107(2)°.

[0457] Volume 2377.23(12) A3

[0458] Z 1

[0459] Density (calculated) 1.418 Mg / m3

[0460] Absorption coefficient 1.852 mm1

[0461] F(000) 1066

[0462] Crystal size 0.10 x 0.08 x 0.06 mm3

[0463] Theta range for data collection 3.753 to 63.661°.

[0464] Index ranges -13<=h<=13, -17<=k<=17, -17<=l<=17

[0465] Reflections collected 33934

[0466] Independent reflections 14609 [R(int) = 0.0531]

[0467] Completeness to theta = 63.661° 99.3 %

[0468] Absorption correction Semi-empirical from equivalents

[0469] Max. and min. transmission 0.92 and 0.84

[0470] Refinement method Full-matrix least-squares on F2

[0471] Data / restraints / parameters 14609 / 3 / 1274

[0472] Goodness-of-fit on F2 1.027

[0473] Final R indices [l>2sigma(l)] R1 = 0.0626, wR2 = 0.1643

[0474] R indices (all data) R1 = 0.0651, wR2 = 0.1679 BHC 243007 FOREIGN FILING

[0475] 202508

[0476] Absolute structure parameter -0.016(15)

[0477] Extinction coefficient n / a

[0478] Largest diff. peak and hole 0.475 and -0.540 e.A-3

[0479] FIGURE 3 is a depiction of independent molecules in the asymmetric unit of crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2- yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A) (X-ray single crystal structure analysis).

[0480] COMMERCIAL UTILITY

[0481] The crystalline forms of the compound of formula (B), preferably the crystalline Hydrate 1 Modification A compound of formula (A) according to the invention, may have useful pharmacological properties and may be employed for the prevention and treatment of disorders in humans and animals. The forms of the compound of formula (B), preferably the crystalline Hydrate 1 Modification A compound of formula (A) according to the invention, may open up a further treatment alternatives and may therefore be an enrichment of pharmacy.

[0482] The crystalline forms of the compound of formula (B), preferably the crystalline Hydrate 1 Modification A compound of formula (A) according to the invention, may be used in the treatment and / or prophylaxis of diseases of uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by mutant EGFR, such as, for example, benign and malignant neoplasia, more specifically haematological tumours, solid tumours, and / or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, BHC 243007 FOREIGN FILING 202508 and / or metastases thereof, especially haematological tumours, solid tumours, and / or metastases of breast, bladder, bone, brain, central and peripheral nervous system, cervix, colon, endocrine glands (e.g., thyroid and adrenal cortex), endocrine tumours, endometrium, esophagus, gastrointestinal tumours, germ cells, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, stomach, skin, testis, ureter, vagina and vulva as well as malignant neoplasias including primary tumours in said organs and corresponding secondary tumours in distant organs ("tumour metastases"). Haematological tumours can, e.g., be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia (CIVIL / AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, and cancers of unknown primary site, as well as AIDS related malignancies.

[0483] The crystalline forms of the compound of formula (B), preferably the crystalline Hydrate 1 Modification A compound of formula (A) according to the invention, may be used in the treatment and / or prophylaxis of hyperproliferative disorders or disorders responsive to induction of cell death, i.e., apoptosis.

[0484] By "hyperproliferative disease" is meant a disease, such as cancer, associated with inappropriately high levels of cell division, inappropriately low levels of apoptosis, or both. The term "inappropriate" within the context of the present invention, in particular in the context of "inappropriate cellular immune responses, or inappropriate cellular inflammatory responses", as used herein, is to be understood as generally meaning a response, which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases.

[0485] In particular embodiments, the use is in the treatment or prophylaxis of diseases, especially the treatment, wherein the diseases are haematological tumours, solid tumours and / or metastases thereof.

[0486] In some embodiments, the present invention further relates to a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the forms of the compound of formula (B), preferably the crystalline Hydrate 1 Modification A compound of formula (A) according to the invention.

[0487] In some embodiments, the present invention further relates to a method for the treatment and / or prophylaxis treatment or prevention of a disease, which is a cancer selected from leukaemia, myelodysplastic syndrome, malignant lymphoma, a head and neck tumour, a tumour of the thorax, such as lung cancer, particularly non-small cell lung carcinoma, a gastrointestinal tumour, an BHC 243007 FOREIGN FILING

[0488] 2025 08 endocrine tumour, a mammary or other gynaecological tumour, a urological tumour, a skin tumour, and a sarcoma, using an effective amount of at least one of the forms of the compound of formula (B), preferably the crystalline Hydrate 1 Modification A compound of formula (A) according to the invention.

[0489] The forms of the compound of formula (B), preferably the crystalline Hydrate 1 Modification A compound of formula (A) according to the invention, can be used alone or in combination with other active substances if necessary. The present invention further relates to medicinal products containing at least one of the forms of the compound of formula (B), preferably the crystalline Hydrate 1 Modification A compound of formula (A) according to the invention, and one or more further active substances, in particular for the treatment and / or prophylaxis of the aforementioned diseases. As suitable other active substances the following can be mentioned: 1311-metuximab, 1311-chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, aclarubicin, adalimumab, ado- trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alfaferone, alemtuzumab, alendronic acid, alitretinoin, almonertinib, alpelisib, alpharadin, monosodium alpha luminol, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, aminolevulinic acid, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, apalutamide, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, avapritinib, avelumab, axicabtagene ciloleucel, axitinib, azacitidine, basiliximab, beclomethasoone diproprionate, belantamab mafodotin, belinostat, belotecan, bendamustine, besilesomab, beta-elemene, bevacizumab, bexarotene, bicalutamide, binimetinib, bisantrene, bleomycin, blinatumomab, boanmycin hydrochloride, borofalan, bortezomib, bosutinib, budesonide, buserelin, brentuximab vedotin, brigatinib, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capmatenib, capromab, carbamazepine, carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, catequentinib, celecoxib, celmoleukin, cemiplimab, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dacomitinib, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, deferasirox, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, dupilumab, durvalumab, duvelisib, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, enasidenib, encorafenib, endostatin, enfortumab vedotin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, ensartinib, entrectinib, erdafitinib, esomeprazole, estradiol, BHC 243007 FOREIGN FILING

[0490] 2025 08 estramustine, estrone, ethinylestradiol, etoposide, everolimus, evocalcet, exemestane, fadrozole, famotidine, fentanyl, filgrastim, flumatinib, fluoxymesterone, fluticasone, fluticasone furoate, floxuridine, fludarabine, fluorouracil, flutamide, folinate, folinic acid, formestane, forodesine, fosaprepitant, fotemustine, fruquintinib, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, gendicine, gilteritinib, ginsenoside Rg3, glasdegib, glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, hematoporphyrin, histamine dihydrochloride, histrelin, holmium-166-chitosan complex, human menopausal gonadotrophin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, icotinib hydrochloride, idarubicin, idelalisib, iobenguane (1311), iodine(131l) tumor necrosis factor monoclonal antibody, ifosfamide, imatinib, imiquimod, improsulfan, immunocyanin, indisetron, incadronic acid, indole-3-carbinol + epigallocatechin-3-gallate, ingenol mebutate, inotuzumab ozogamicin, interferon alfa, interferon alpha lb, interferon-alpha 2, interferon alpha-2a, interferon alfa-2b, interferon beta, interferon gamma, interleukin-2, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, isatuximab, ivosidenib, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, lorlatinib, lurbinectedin, luspatercept, lutetium Lu 177 dotatate, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptamine, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, midostaurin, mifamurtide, mifepristone, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mometasone, mopidamol, morphine hydrochloride, morphine sulfate, mvasi, moxetumomab pasudotox, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, natalizumab, necitumumab, nedaplatin, nelarabine, neratinib, neridronic acid, netupitant / palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, niraparib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, olmutinib, omacetaxine mepesuccinate, omalizumab, omeprazole, ondansetron, oprelvekin, orelabrutinib, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymethoIone, ozogamicine, p53 gene therapy, paclitaxel, padeliporfin, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pemigatinib, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, phenoxybenzamine, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polatuzumab vedotin, polyestradiol phosphate, polyvinylpyrrolidone + sodium BHC 243007 FOREIGN FILING

[0491] 202508 hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, pralsetinib, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, quizartinib, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, relugolix, ribociclib, ripretinib, risedronic acid, rhenium-186 etidronate, rituximab, rivoceranib, rolapitant, romidepsin, romiplostim, romurtide, rucaparib, sacituzumab govitecan, samarium (153Sm) lexidronam, sargramostim, sarilumab, satumomab, secretin, selinexor, selpercatinib, selumetinib, siltuximab, sipuleucel-T, sirolimus, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sophoridine hydrochloride, sorafenib, stanozolol, streptozocin, Strontium 89, sunitinib, surufatinib, tagraxofusp, talaporfin, talazoparib, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, tazemetostat, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thrombopoietin, thymalfasin, thyrotropin alfa, tioguanine, tirabrutinib, tisagenlecleucel, tislelizumab, tivozanib, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, tryptophan, tucatinib, tucidinostat, recombinant tumor necrosis -factor of thymosine-1, ubenimex, ulipristal, umbralisib, valatinib, valrubicin, vandetanib, vapreotide, vemurafenib, venetoclax, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zanubrutinib, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

[0492] Combination Therapies

[0493] The crystalline forms of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. Those combined pharmaceutical agents can be other agents having antiproliferative effects such as for example for the treatment of haematological tumours, solid tumours and / or metastases thereof and / or agents for the treatment of undesired side effects. The present invention relates also to such combinations.

[0494] Other anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference, especially (chemotherapeutic) anti-cancer agents as defined supra. The combination can be a non-fixed combination or a fixed-dose combination as the case may be. BHC 243007 FOREIGN FILING

[0495] 202508

[0496] Pharmaceutical compositions:

[0497] It is possible for the crystalline forms of the compound of formula (B), preferably the crystalline Hydrate 1 Modification A compound of formula (A) according to the present invention, to have systemic and / or local activity. For this purpose, it can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.

[0498] For these administration routes, it is possible for the crystalline form of the compound of formula (B), preferably the crystalline Hydrate 1 Modification A compound of formula (A) according to the present invention, to be administered in suitable administration forms.

[0499] For oral administration, it is possible to formulate the crystalline form of the compound of formula (B), preferably the crystalline Hydrate 1 Modification A compound of formula (A) according to the present invention, to dosage forms known in the art that deliver the compounds of the invention rapidly and / or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films / wafers, films / lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compound according to the invention in crystalline and / or amorphised and / or dissolved form into said dosage forms. Parenteral administration can be affected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders. iExamples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets / films / wafers / capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents. iThe crystalline form of the compound of formula (B), preferably the crystalline Hydrate 1 Modification A compound of formula (A) according to the invention, can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia, BHC 243007 FOREIGN FILING 2025 08

[0500] • fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel*), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos*)),

[0501] • ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols),

[0502] • bases for suppositories (for example polyethylene glycols, cacao butter, hard fat),

[0503] • solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins),

[0504] • surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulphate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette ), sorbitan fatty acid esters (such as, for example, Span ), polyoxyethylene sorbitan fatty acid esters (such as, for

[0505] ® example, Tween ), polyoxyethylene fatty acid glycerides (such as, for example, ®

[0506] Cremophor ), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic*),

[0507] • buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),

[0508] • isotonicity agents (for example glucose, sodium chloride),

[0509] • adsorbents (for example highly-disperse silicas),

[0510] • viscosity-increasing agents, gel formers, thickeners and / or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for

[0511] ® example, Carbopol ); alginates, gelatine),

[0512] • disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch

[0513] ® glycolate (such as, for example, Explotab ), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol*)),

[0514] • flow regulators, lubricants, glidants and mould release agents (for example magnesium

[0515] ® stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil )),

[0516] • coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example

[0517] ® polyvinylpyrrolidones (such as, for example, Kollidon ), polyvinyl alcohol, BHC 243007 FOREIGN FILING 2025 08 hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit )),

[0518] • capsule materials (for example gelatine, hydroxypropylmethylcellulose),

[0519] • synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit ), polyvinylpyrrolidones (such as, for

[0520] ® example, Kollidon ), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),

[0521] • plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),

[0522] • penetration enhancers,

[0523] • stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate),

[0524] • preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

[0525] • colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide),

[0526] • flavourings, sweeteners, flavour- and / or odour-masking agents.

[0527] The present invention furthermore relates to a pharmaceutical composition which comprise at least the crystalline form of the compound of formula (B), preferably the crystalline Hydrate 1 Modification A compound of formula (A) according to the invention, according to the present invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.

[0528] BHC 243007 FOREIGN FILING

[0529] 2025 08

[0530] Dosage of the pharmaceutical compositions of the present invention:

[0531] Based upon laboratory techniques known to evaluate compounds useful for the treatment of disorders, by pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compound of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.

[0532] The total amount of the active ingredient to be administered will generally range from about 0.001 mg / kg to about 200 mg / kg body weight per day, and in particular embodiments from about 0.01 mg / kg to about 20 mg / kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will in other embodiments be from 0.01 to 200 mg / kg of total body weight. The average daily rectal dosage regimen will in particular embodiments be from 0.01 to 200 mg / kg of total body weight. The average daily vaginal dosage regimen will in other embodiments be from 0.01 to 200 mg / kg of total body weight. The average daily topical dosage regimen will in still other embodiments be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will in other embodiments be that required to maintain a daily dose of from 0.01 to 200 mg / kg. The average daily inhalation dosage regimen will in other embodiments be from 0.01 to 100 mg / kg of total body weight.

[0533] Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests. BHC 243007 FOREIGN FILING 2025 08

[0534] The weight data in the tests and examples which follow are, unless stated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on each case on the volume.

[0535] In accordance with an embodiment, the present invention relates to a pharmaceutical composition comprising the crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy- anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine- 4-one of formula (A) as defined in the claims, or as prepared by a method as described herein and as defined in the claims, optionally further pharmaceutically acceptable excipients.

[0536] In accordance with an embodiment, the present invention relates to the pharmaceutical composition mentioned above, comprising the crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l, 4-dioxan-2-yl]methoxy]-4-pyridyl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A) mainly and no significant fractions of other form of compound of formula (B): and optionally further pharmaceutically acceptable excipients.

[0537] In accordance with an embodiment, the present invention relates to a pharmaceutical combination comprising one or more first active ingredients selected from a crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4- pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A) as defined in the claims, or as prepared by a method as described herein and as defined in the claims, and one or more second active ingredients selected from a chemotherapeutic anti-cancer agent and a target-specific anticancer agent.

[0538] In accordance with an embodiment, the present invention relates to a crystalline Hydrate 1 Modification A form of the compound of formula (A) as defined in the claims, or as prepared according to a method as described herein or as defined in the claims, BHC 243007 FOREIGN FILING

[0539] 2025 08 or the pharmaceutical composition as defined in the claims, or the pharmaceutical combination as defined in the claims, for use in the treatment and / or prophylaxis of a disease, which is a cancer selected from leukaemia, myelodysplastic syndrome, malignant lymphoma, a head and neck tumour, a tumour of the thorax, such as lung cancer, particularly non-small cell lung carcinoma, a gastrointestinal tumour, an endocrine tumour, a mammary or other gynaecological tumour, a urological tumour, a skin tumour, and a sarcoma.

[0540] In accordance with an embodiment, the present invention relates to the use of a crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2- yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A) as defined in the claims, or as prepared by a method as described herein or as defined in the claims, for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease, which is a cancer selected from leukaemia, myelodysplastic syndrome, malignant lymphoma, a head and neck tumour, a tumour of the thorax, such as lung cancer, particularly non-small cell lung carcinoma, a gastrointestinal tumour, an endocrine tumour, a mammary or other gynaecological tumour, a urological tumour, a skin tumour, and a sarcoma.

[0541] In accordance with an embodiment, the present invention relates to a method of treating or preventing a disease in a mammal, which is a cancer selected from leukaemia, myelodysplastic syndrome, malignant lymphoma, a head and neck tumour, a tumour of the thorax, such as lung cancer, particularly non-small cell lung carcinoma, a gastrointestinal tumour, an endocrine tumour, a mammary or other gynaecological tumour, a urological tumour, a skin tumour, and a sarcoma, comprising administering to said mammal in need thereof a therapeutically effective amount of the crystalline Hydrate 1 Modification A form of the compound of formula (A) as defined in the claims, or as prepared according to a method as described herein or as defined in the claims, or the pharmaceutical composition as defined in the claims, or the pharmaceutical combination as defined in the claims.

[0542] In accordance with an embodiment, the present invention relates to the crystalline Hydrate 1 Modification A form of the compound of formula (A) for use in the treatment and / or prophylaxis of a disease as defined in the claims, or the pharmaceutical composition for use in the treatment and / or prophylaxis of a disease as defined in the claims, or the pharmaceutical combination for use in the treatment and / or prophylaxis of a disease as defined in the claims, or the use of the compound of BHC 243007 FOREIGN FILING 2025 08 formula (A) for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease as defined in the claims, or the method of treatment as defined in the claims, wherein said treatment is preceded by, made concomitantly with, or followed by, the administration of an anti-diarrhoeal medicine, such as loperamide, for example.

Claims

BHC 243007 FOREIGN FILING2025 08CLAIMS1. A crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A):wherein the content of water is greater than 0 % (w / w).

2. A crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2- [3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A):(A), wherein the content of water is greater than 0 % (w / w) and < 4.0% (w / w).

3. The crystalline Hydrate 1 Modification A form of the compound of formula (A) according to claim 1 or 2, characterized by an X-ray powder diffractogram measured at RT and with Cu-K alpha 1 as radiation source displaying at least the following reflections, quoted as 2Q value ± 0.2°: 24.9; 6.5 and 19.7.BHC 243007 FOREIGN FILING2025 084. The crystalline Hydrate 1 Modification A form of the compound of formula (A) according to any one of claims 1 to 3, characterized by a X-ray powder diffractogram measured at RT and with Cu-K alpha 1 as radiation source displaying at least the following reflections, quoted as 2Q value ± 0.2°: 24.9; 6.5; 19.7; 12.4 and 9.6.

5. The crystalline Hydrate 1 Modification A form of the compound of formula (A) according to any one of claims 1 to 4, characterized by a X-ray powder diffractogram measured at RT and with Cu-K alpha 1 as radiation source displaying at least the following reflections, quoted as 2Q value ± 0.2°: 24.9; 6.5; 19.7; 12.4; 9.6; 15.0 and 19.5.

6. The crystalline Hydrate 1 Modification A form of the compound of formula (A) according to any one of claims 1 to 5, characterized by a X-ray powder diffractogram measured at RT and with Cu-K alpha 1 as radiation source displaying at least the following reflections, quoted as 2Q value ± 0.2°: 24.9; 6.5; 19.7; 12.4; 9.6; 15.0; 19.5; 23.7; 13.0 and 14.0.

7. The crystalline Hydrate 1 Modification A form of the compound of formula (A) according to any one of claims 1 to 6, which in a Raman spectrum displays at least the following bands (peak maximum in cm1): 1516, 1591 and 1577.

8. The crystalline Hydrate 1 Modification A form of the compound of formula (A) according to any one of claims 1 to 7, which in a Raman spectrum displays at least the following bands (peak maximum in cm1): 1516, 1591, 1577, 1441 and 1469.

9. The crystalline Hydrate 1 Modification A form of the compound of formula (A) according to any one of claims 1 to 8, which in a Raman spectrum displays at least the following bands (peak maximum in cm’1): 1516, 1591, 1577, 1441, 1469, 1550 and 1248.

10. The crystalline Hydrate 1 Modification A form of the compound of formula (A) according to any one of claims 1 to 9, which in a Raman spectrum displays at least the following bands (peak maximum in cm’1): 1516, 1591, 1577, 1441, 1469, 1550, 1248, 844, 1404 and 1067.

11. The crystalline Hydrate 1 Modification A form of the compound of formula (A) according to any one of claims 1 to 10, which in an IR spectrum displays at least the following bands (peak maximum in cm’1): 1587, 1454 and 767.

12. The crystalline Hydrate 1 Modification A form of the compound of formula (A) according to any one of claims 1 to 11, which in an IR spectrum displays at least the following bands (peak maximum in cm’1): 1587, 1454, 767, 1230 and 1067.BHC 243007 FOREIGN FILING2025 0813. The crystalline Hydrate 1 Modification A form of the compound of formula (A) according to any one of claims 1 to 12, which in an IR spectrum displays at least the following bands (peak maximum in cm’1): 1587, 1454, 767, 1230, 1067, 1424 and 1654.

14. The crystalline Hydrate 1 Modification A form of the compound of formula (A) according to any one of claims 1 to 13, which in an IR spectrum displays at least the following bands (peak maximum in cm1): 1587, 1454, 767, 1230, 1067, 1424, 1654, 1518, 724, 737.

15. A method of preparing the crystalline Hydrate 1 Modification A form of the compound 3-(3- chloro-2-methoxy-anilino)-2-[3-[[(2S)-l, 4-dioxan-2-yl]methoxy]-4-pyridyl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A):wherein the content of water is greater than 0 % (w / w) and < 4.0% (w / w), according to any one of claims 1 to 14, comprising the following step 9: wherein a crystalline compound of formula (XIII):is recrystallised from tetrahydrofuran and water, thereby providing said crystalline Hydrate 1 Modification A form of the compound of formula (A):BHC 243007 FOREIGN FILING2025 08wherein the content of water is greater than 0 % (w / w) and < 4.0% (w / w).

16. The method according to claim 15, wherein said crystalline compound of formula (XIII) is prepared by the following step 8: wherein a crystalline compound of formula (B):d) dissolved in a mixture of ethanol and water in the presence of p-toluenesulphonic acid monohydrate, e) filtered, thereby clarifying the solution provided in a), and f) crystallised by pH-shift crystallisation, by adding an aqueous solution of sodium hydroxide, thereby separating off impurities, thereby providing said crystalline compound of formula (XIII).

17. The method according to claim 15 or 16, wherein said crystalline compound of formula (B) is prepared by the following step 7: wherein a crystalline compound of formula (XI):BHC 243007 FOREIGN FILING202508(XI), d) is allowed to react with sulphuric acid, in a solvent such as methanol for example, and is optionally heated, to a temperature of 45 degrees Celsius for example, e) a solution of hydrogen peroxide-urea in water is added to the resulting mixture in a), while maintaining the temperature of 45 degrees Celsius for example, f) an aqueous solution of sodium hydroxide is added to the resulting mixture, then, after cooling, the mixture is filtered, thereby providing said crystalline compound of formula (B) as a solid product.

18. The method according to any one of claims 15 to 17, wherein said crystalline compound of formula (XI) is prepared by the following step 6: wherein a crystalline compound of formula (VI):is allowed to react with a crystalline compound of formula (XVI):(XVI), thereby providing said crystalline compound of formula (XI).

19. The method according to any one of claims 15 to 18, wherein said crystalline compound of formula (XVI): is prepared by the following step 5: wherein a crystalline compound of formula (IX):BHC 243007 FOREIGN FILING 202508(IX), is allowed to react with hydrogen and ethanesulfonic acid in the presence of a suitable catalyst, such as Pd / C for example, thereby providing said crystalline compound of formula (XVI).

20. The method according to any one of claims 15 to 19, wherein said crystalline compound of formula (IX) is prepared by the following step 4: wherein a compound of formula (VIII):(VIII), is allowed to react with a compound of formula (VII):thereby providing said crystalline compound of formula (IX).

21. The method according to any one of claims 15 to 20, wherein said crystalline compound of formula (VI) is prepared by the following step 3: wherein a crystalline compound of formula (XV (crystallised as salt with DBU)):is allowed to react with an acid, such as hydrochloric acid, for example, thereby providing said crystalline compound of formula (VI).BHC 243007 FOREIGN FILING 20250822. The method according to any one of claims 15 to 21, wherein said crystalline compound of formula (XV (crystallised as salt with DBU)) is prepared by the following step 2: wherein a compound of formula (III (telescoped in solution)):lution)), is allowed to react with a compound of formula (IV):(IV), thereby providing said crystalline compound of formula (XV (crystallised as salt with DBU)).

23. The method according to any one of claims 15 to 22, wherein said compound of formula (III) is prepared by the following step 1: wherein a compound of formula (I):is allowed to react with a compound of formula (II):(ID, thereby providing said compound of formula (III (telescoped in solution)).

24. The method according to any one of claims 15 to 23, wherein said Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4- pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A) is prepared via the following steps shown in Reaction Scheme (II), infra:BHC 243007 FOREIGN FILING202508Reaction Scheme (II).

25. The crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A):BHC 243007 FOREIGN FILING2025 08(A), wherein the content of water is greater than 0 % (w / w) and < 4.0 % (w / w), according to any one of claims 1 to 14, which is prepared by a method according to any one of claims 15 to 24.

26. A pharmaceutical composition comprising the crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l, 4-dioxan-2-yl]methoxy]-4-pyridyl]-l, 5,6,7- tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A) according to any one of claims 1 to 14, or as prepared by a method according to any one of claims 15 to 24, and optionally further pharmaceutically acceptable excipients.

27. The pharmaceutical composition according to claim 26, comprising the crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2- yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A) mainly and no significant fractions of crystalline compound of formula (B):and optionally further pharmaceutically acceptable excipients.

28. A pharmaceutical combination comprising one or more first active ingredients selected from a crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy-anilino)-2-[3-BHC 243007 FOREIGN FILING2025 08[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one of formula (A) according to any one of claims 1 to 14, or as prepared by a method according to any one of claims 15 to 24, and one or more second active ingredients selected from a chemotherapeutic anti-cancer agent and a target-specific anti-cancer agent.

29. The crystalline Hydrate 1 Modification A form of the compound of formula (A) according to any one of claims 1 to 14, or as prepared according to a method according to any one of claims 15 to 24, or the pharmaceutical composition according to claim 26 or 27, or the pharmaceutical combination according to claim 28, for use in the treatment and / or prophylaxis of a disease, which is a cancer selected from leukaemia, myelodysplastic syndrome, malignant lymphoma, a head and neck tumour, a tumour of the thorax, such as lung cancer, particularly non-small cell lung carcinoma, a gastrointestinal tumour, an endocrine tumour, a mammary or other gynaecological tumour, a urological tumour, a skin tumour, and a sarcoma.

30. Use of a crystalline Hydrate 1 Modification A form of the compound 3-(3-chloro-2-methoxy- anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridine- 4-one of formula (A) according to any one of claims 1 to 14, or as prepared by a method according to any one of claims 15 to 24, for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease, which is a cancer selected from leukaemia, myelodysplastic syndrome, malignant lymphoma, a head and neck tumour, a tumour of the thorax, such as lung cancer, particularly non-small cell lung carcinoma, a gastrointestinal tumour, an endocrine tumour, a mammary or other gynaecological tumour, a urological tumour, a skin tumour, and a sarcoma.

31. A method of treating or preventing a disease in a mammal, which is a cancer selected from leukaemia, myelodysplastic syndrome, malignant lymphoma, a head and neck tumour, a tumour of the thorax, such as lung cancer, particularly non-small cell lung carcinoma, a gastrointestinal tumour, an endocrine tumour, a mammary or other gynaecological tumour, a urological tumour, a skin tumour, and a sarcoma, comprising administering to said mammal in need thereof a therapeutically effective amount of the crystalline Hydrate 1 Modification A form of the compound of formula (A) according to any one of claims 1 to 14, or as prepared according to a method according to any one of claims 15 to 24, or the pharmaceutical composition according to claim 26 or 27, or the pharmaceutical combination according to claim 28.BHC 243007 FOREIGN FILING2025 0832. The crystalline Hydrate 1 Modification A form of the compound of formula (A) for use in the treatment and / or prophylaxis of a disease according to claim 28, or the pharmaceutical composition for use in the treatment and / or prophylaxis of a disease according to claim 29, or the pharmaceutical combination for use in the treatment and / or prophylaxis of a disease according to claim 29, or the use of the compound of formula (A) for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease according to claim 30, or the method of treatment according to claim 31, wherein said treatment is preceded by, made concomitantly with, or followed by, the administration of an anti-diarrhoeal medicine, such as loperamide, for example.

33. A compound selected from:(VI),(IXLBHC 243007 FOREIGN FILING2025 08(IV), and(I).

34. Use of any compound according to claim 33, for preparing a crystalline Hydrate 1 Modification A form of the compound of formula (A):(A), wherein the content of water is greater than 0 % (w / w) and < 4.0 % (w / w), according to any one of claims 1 to 14, or as prepared according to a method according to any one of claims 15 to 24.

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