Stable solid pharmaceutical dosage form comprising crystalline form of her2 / mutegfr inhibitor and process for its preparation

Abstract

The present invention relates: to a tablet formulation comprising 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]-1, 5,6,7- tetrahydropyrrolo[3,2-c]pyridine-4-one, of formula (A): wherein the content of water is greater than 0% (w / w), particularly greater than 0% and less than or equal to 4%, of the total weight of said compound of formula (A); to methods of preparing said tablet formulation, and to uses of said tablet formulation in the prophylaxis and / or treatment of diseases.

Description

[0001] BHC 243008 FOREIGN FILING 202508

[0002] Stable solid pharmaceutical dosage form comprising crystalline form of HER2 / mutEGFR inhibitor and process for its preparation.

[0003] The present invention relates:

[0004] • to a tablet formulation comprising crystalline Hydrate 1 Modification A form of the compound

[0005] 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), particularly greater than 0% and less than or equal to 4%, of the total weight of said compound of formula (A),

[0007] • to methods of preparing said tablet formulation, and

[0008] • to uses of said tablet formulation in the prophylaxis and / or treatment of diseases.

[0009] 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: 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") habouring human epidermal growth factor receptor 2 ("HER2") activating mutations. BHC 243008 FOREIGN FILING

[0010] 2025 08

[0011] 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.

[0012] There are several specific technical problems associated with: a) the manufacture of solid dosage forms, particularly immediate release tablets, comprising said compound (A); and b) the solid dosage forms, particularly immediate release tablets, comprising said compound (A).

[0013] Specifically, said technical problems are: a) In re. the manufacture of solid dosage forms, particularly immediate release tablets comprising said compound (A):

[0014] • commonly used sieving techniques, such as rough sieving (0.8 mm), is not sufficient for the deagglomeration of the compound (A) of all compound (A) batches; b) In re. solid dosage forms, particularly immediate release tablets, comprising said compound (A):

[0015] • solid dosage forms comprising compound (A) with a high tendency for agglomeration (or "clumping together"), which are produced in the form of tablets by a typical manufacturing process involving mixing, sieving, mixing, granulating and tabletting, has an incomplete dissolution behaviour of the solid dosage form comprising compound (A);

[0016] • tablets made from compound (A) batches after storage can have worse dissolution.

[0017] The technical problems described in the preceding paragraph under a) and b) were surprisingly successfully all solved together by the present invention, which provides the following technical solutions:

[0018] • establishing a robust manufacturing process by identification of crucial manufacturing steps such as pre-processing of the compound (A) pre-blend with fine sieving and / or processing with a twin screw granulator in a standard batch or continuous process in order to reduce the amount of compound (A) agglomerates, or to mitigate the risk of agglomeration and its impact on dissolution behaviour ;

[0019] • establishing said continuous process as a time- and cost-efficient alternative; and

[0020] • roller compaction (dry granulation) was identified as more favourable than wet processing (e.g. wet granulation) regarding the stability profile of the resulting compound (A) in the final solid dosage form. BHC 243008 FOREIGN FILING

[0021] 2025 08

[0022] Within the context of the present text and the present invention the term "complete" dissolution, is to be interpreted as dissolution of the tablets of the present invention of greater than 80% at 30 minutes.

[0023] Hence, in accordance with a first aspect, the present invention, as described herein and as defined in the claims herein, relates to pharmaceutical compositions comprising: a) 0.1 to 30%, by weight of the total composition, 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): wherein the content of water is greater than 0% (w / w) of the total weight of said compound of formula (A) ; b) 30 to 80%, particularly 35 to 70%, by weight of the total composition, of a bulking agent (which is also referred to in the present text as "fil ler / binder"), such as microcrystalline cellulose; c) 30 to 80%, particularly 35 to 70%, by weight of the total composition, of a filler, such as lactose monohydrate; d) 0.1 to 20%, by weight of the total composition, of a disintegrant, such as cross-linked polyvinylpyrrolidone, such as crospovidone, or croscarmellose sodium; e) 0 to 5%, by weight of the total composition, of a binder , such as hypromellose, such as hypromellose 3 cP for example; f) 0.1 to 5%, by weight of the total composition, of a lubricant, such as magnesium stearate; and g) 0 to 1%, by weight of the total composition, of a glidant, such as anhydrous colloidal silica. BHC 243008 FOREIGN FILING

[0024] 2025 08

[0025] In an embodiment, said pharmaceutic compositions comprise said 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):

[0026] (A), wherein the content of water of greater than 0 % (w / w) and < 4.0% (w / w) of the total weight of said compound of formula (A).

[0027] It is to be understood that said 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.

[0028] 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.

[0029] In an embodiment, the pharmaceutical compositions comprise: a) 5 to 30%, particularly 20 to 30%, more particularly 10 to 25%, even more particularly 10 to 15%, by weight of the total composition, 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):

[0030] (A), BHC 243008 FOREIGN FILING

[0031] 2025 08 wherein the content of water is greater than 0% and less than or equal to 4% of the total weight of said compound of formula (A).

[0032] In an embodiment, the pharmaceutical compositions comprise: b) 30 to 45%, particularly 35 to 45%, more particularly 40 to 45%, by weight of the total composition, of a bulking agent (or "f il ler / binder").

[0033] In an embodiment, said bulking agent (or "filler / binder") is microcrystalline cellulose.

[0034] In an embodiment, the pharmaceutical compositions comprise: c) 30 to 45%, particularly 35 to 45%, more particularly 40 to 45%, by weight of the total composition, of a filler.

[0035] In an embodiment, said filler is lactose monohydrate.

[0036] In an embodiment, the pharmaceutical compositions comprise: d) 0.1 to 20%, particularly 1 to 10%, more particularly 2 to 6%, by weight of the total composition, of a disintegrant.

[0037] In an embodiment, said disintegrant is cross-linked polyvinylpyrrolidone, such as crospovidone.

[0038] In an embodiment, the pharmaceutical compositions comprise: e) 0 to 5%, by weight of the total composition, of a binder.

[0039] In an embodiment, said binder is hydroxypropylmethylcellulose.

[0040] In an embodiment, the pharmaceutical compositions comprise: f) 0.1 to 5%, particularly 0.2 to 3%, more particularly 0.5 to 2.5%, by weight of the total composition, of a lubricant.

[0041] In an embodiment, said lubricant is magnesium stearate.

[0042] In an embodiment, the pharmaceutical compositions comprise: g) 0 to 1%, by weight of the total composition, of a glidant.

[0043] In an embodiment, said glidant is anhydrous colloidal silica.

[0044] In accordance with a second aspect, the present invention, as described herein and as defined in the claims herein, relates to a method of preparing the pharmaceutical composition according to any one of claims 1 to 14, which comprises the following Steps: BHC 243008 FOREIGN FILING

[0045] 2025 08

[0046] Step A : blending a mixture of: i) micronized, optionally sieved, 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% and less than or equal to 4% of the total weight of said compound of formula (A); ii) a bulking agent (or „filler / binder"), as defined in any one of claims 1 to 14, such as microcrystalline cellulose; iii) a disintegrant, as defined in any one of claims 1 to 14, such as cross-linked polyvinylpyrrolidone, such as crospovidone; and iv) a filler, as defined in any one of claims 1 to 14, such as lactose monohydrate; thereby producing a blended mixture;

[0047] Step B : sieving the thus-produced blended mixture from Step A, thereby producing a sieved, blended mixture;

[0048] Step C : blending the thus-produced sieved, blended mixture from Step B with excipients, such as in pre-blend containing compound (A)) with a small sieve, such as with a 0.5 mm, particularly 0.3 mm, sieve, thereby producing a pre-blend;

[0049] Step D : dry processing the thus-produced pre-blend from Step C in a twin screw granulator, thereby producing a final pre-blend;

[0050] Step E : dry granulating the final pre-blend from Step D by roller compaction, BHC 243008 FOREIGN FILING

[0051] 2025 08 thereby producing dry granules;

[0052] Step F : post-blending the thus-produced dry granules from Step E with a sieved lubricant, such as magnesium stearate, thereby producing a ready-to-press blend.

[0053] In an embodiment, the pharmaceutical composition according to any one of claims 1 to 14 is prepared by a method according to claim 15.

[0054] In an embodiment, the pharmaceutical composition according to claim 16 is obtainable by dry granulating by roller compaction.

[0055] In an embodiment, the pharmaceutical composition according to any one of claims 1 to 14, 16 or 17 is in the form of a tablet.

[0056] In an embodiment, the method according to claim 15 comprises the following additional step:

[0057] Step G : tableting the thus-produced ready-to-press blend, thereby producing a pharmaceutical composition in the form of a tablet with a complete dissolution.

[0058] In an embodiment, the pharmaceutical composition according to claim 18 is prepared by a method according to claim 19.

[0059] In an embodiment, the pharmaceutical composition according to claim 20 contains said compound of formula (A) which is contaminated with less than 1.50 %, particularly 1.10 %, more particularly 1.01%, by weight of the total pharmaceutical composition, of degradation products.

[0060] In an embodiment, the pharmaceutical composition according to claim 18 or 20 is a coated pharmaceutical composition in the form of a tablet coated with a coating.

[0061] In an embodiment, the coated pharmaceutical composition according to claim 22 has a coating wherein said coating is 0.5 to 10%, by weight of said coated pharmaceutical composition.

[0062] In an embodiment, the coated pharmaceutical composition according to claim 22 or 23, has a coating wherein said coating comprises: h) 0.5 to 10%, by weight of said coated pharmaceutical composition, of a film-forming agent, such as hydroxypropylmethylcellulose, such as Hypromellose 5 cP, or polyethylene glycol, such as polyethylene glycol 3350, such as macrogol 3350; and i) 0.5 to 10%, by weight of the coated pharmaceutical composition, of a colourant / pigment a colourant / pigment, such as ferric oxide red. BHC 243008 FOREIGN FILING

[0063] 2025 08

[0064] In an embodiment, the coated pharmaceutical composition according to any one of claims 22 to 24 has a coating wherein said coating comprises: h) 0.5 to 10%, particularly 0.5 to 4.5%, more particularly 1.5 to 4.5%, by weight of said coated pharmaceutical composition, of a film-forming agent.

[0065] In an embodiment, the coated pharmaceutical composition according to claim 25 has a coating wherein said film-forming agent is hydroxypropylmethylcellulose, such as Hypromellose 5 cP.

[0066] In an embodiment, the coated pharmaceutical composition according to claim 25 has a coating wherein said film-forming agent is polyethylene glycol, such as polyethylene glycol 3350, such as macrogol 3350.

[0067] In an embodiment, the coated pharmaceutical composition according to any one of claims 22 to 27 has a coating wherein said coating comprises: i) 0.01 to 6.0%, particularly 0.05 to 3.0%, more particularly 0.1 to 2.0%, by weight of the coated pharmaceutical composition, of a colourant or pigment.

[0068] In an embodiment, the coated pharmaceutical composition according to claim 28 has a coating wherein said colourant or pigment is ferric oxide red.

[0069] In an embodiment, the method according to claim 19 comprises the following additional step:

[0070] Step H : coating the thus-produced uncoated tablets with a coating suspension comprising mixture of: v) a pigment, such as ferric oxide red; vi) a film-forming agent, such as a mixture of hydroxypropylmethylcellulose, such as Hypromellose 5 cP, and polyethylene glycol 3350, such as macrogol 3350; and vii) purified water in bulk; thereby producing coated tablets.

[0071] In an embodiment, the method according to any one of claims 15, 19 and 30 is performed in an operation selected from the group consisting of:

[0072] - a batch operation,

[0073] - a fully integrated continuous manufacturing operation, and

[0074] - a combination of a batch operation and a fully integrated continuous manufacturing operation.

[0075] In an embodiment, the coated pharmaceutical composition according to any one of claims 22 to 29 is prepared by a method according to claim 30 or 31. BHC 243008 FOREIGN FILING

[0076] 2025 08

[0077] In an embodiment, the coated pharmaceutical composition according to claim 32 contains 10 mg of said compound (A).

[0078] In an embodiment, the pharmaceutical composition according to any one of claims 1 to 14, 16 to 18, or 20, comprises: a) 10 to 15%, by weight of the total composition, 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): wherein the content of water is greater than 0% and less than or equal to 4% of the total weight of said compound of formula (A); b) 40 to 45%, by weight of the total composition, of a bulking agent (or "filler / binder"); c) 40 to 45%, by weight of the total composition, of a filler; d) 2 to 6%, by weight of the total composition, of a disintegrant; e) 0 to 5%, by weight of the total composition, of a binder; f) 0.5 to 2.5%, by weight of the total composition, of a lubricant; and g) 0 to 1%, by weight of the total composition, of a glidant.

[0079] In an embodiment, the pharmaceutical composition according to claim 34 further comprises: a coating, said coating being 0.5 to 10%, by weight of said coated pharmaceutical composition.

[0080] In an embodiment, the pharmaceutical composition according to claim 35 has a coating which comprises: h) 1.5 to 4.5%, by weight of said coated pharmaceutical composition, of a film-forming agent; and i) 0.1 to 2.0%, by weight of said coated pharmaceutical composition, of a colourant or pigment. BHC 243008 FOREIGN FILING

[0081] 2025 08

[0082] In an embodiment, the pharmaceutical composition according to any one of claims 1 to 14, 16 to 18 comprises: a) 10 to 15%, by weight of the total composition, 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): wherein the content of water is greater than 0% and less than or equal to 4% of the total weight of said compound of formula (A); b) 40 to 45%, by weight of the total composition, of microcrystalline cellulose; c) 40 to 45%, by weight of the total composition, of lactose monohydrate; d) 2 to 6%, by weight of the total composition, of crospovidone; e) 0 to 5%, by weight of the total composition, of hydroxypropylmethylcellulose; f) 0.5 to 2.5%, by weight of the total composition, of magnesium stearate; and g) 0 to 1%, by weight of the total composition, of anhydrous colloidal silica.

[0083] In an embodiment, the pharmaceutical composition according to claim 37 further comprises: a coating, said coating being 0.5 to 10%, by weight of said coated pharmaceutical composition.

[0084] In an embodiment, the pharmaceutical composition according to claim 36 has a coating, wherein said coating comprises: h) 1.5 to 4.5%, by weight of the coated pharmaceutical composition, of hydroxypropylmethylcellulose, such as Hypromellose 5 cP, and polyethylene glycol 3350, such as macrogol 3350; and i) 0.1 to 2.0%, by weight of the coated pharmaceutical composition, of ferric oxide red. BHC 243008 FOREIGN FILING

[0085] 2025 08

[0086] In the context of the present disclosure, "excipients" are surfactants, fillers, binders, lubricants, glidants, disintegrants, sweeteners, flavouring agents and colourants. It may come to happen that a person skilled in the art assigns similar or even identical substances to be member of more than one of the above-mentioned groups of substances. Within the context of the present disclosure, the functional descriptions of the substances are however intentionally filled with specific substances to clarify their respective property assigned to them.

[0087] The expression "pharmaceutically acceptable" refers to those excipients, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0088] The solid pharmaceutical composition may optionally contain one or more further pharmaceutically acceptable excipients. In one embodiment pharmaceutically acceptable excipients are selected from the group consisting of surfactants, fillers, binders, lubricants, glidants, disintegrants, sweeteners, flavouring agents, and colourants; or mixtures thereof.

[0089] Surfactants (or "surface active agents") are organic compounds containing a hydrophilic "waterseeking" group, and a hydrophobic "water-avoiding" group. Depending on the ionic type of the hydrophilic group surfactants are classified as anionic, cationic, amphoteric, and non-ionic surfactants. Surfactants in the solid pharmaceutical composition according to the present disclosure in one embodiment are selected from the sodium dodecylsulphate (also referred to as "sodium laurylsulphate") or group of polysorbates or poloxamer.

[0090] In accordance with an embodiment, said surfactant is sodium dodecylsulphate.

[0091] It will be understood by those of ordinary skill in the art that excipients may be added to provide for different properties. Depending on the context, an excipient may serve, e.g. as a binder or a filler or may serve to provide for both.

[0092] As used in the present text, the term "bulking agent (or "filler / binder")" refers to one or more pharmaceutically acceptable excipient(s) which in its filling role adds bulkiness to a pharmaceutical composition and which in its binding role imparts enhanced cohesion by binding the active ingredient(s) and the excipient(s) together in a mixture. It is to be understood that said bulking agent (or "filler / binder") has an explicit double function where both filler properties and binder properties are added to the tablet. BHC 243008 FOREIGN FILING

[0093] 2025 08

[0094] As used in the present text, the term "filler" refers to one or more pharmaceutically acceptable excipient(s) which adds bulkiness or diluteness to a pharmaceutical composition, improving content uniformity.

[0095] As used in the present text, the term "binder" refers to one or more pharmaceutically acceptable excipient(s) which imparts enhanced cohesion and the plasticity, by binding the active ingredient(s) and the excipient(s) together in a mixture. Binders improve the tablet's mechanical properties of the powder mixture, which enhances the processability of the tablet and reduces the risk of tablet breakage during manufacture. It is to be understood that said binder is a material that would typically not be used as a filler, i.e. has a strictly binder function.

[0096] In the solid pharmaceutical composition according to the present invention as described herein and as defined in the claims herein, said bulking agent (or "filler / binder") or said filler or said binder is, independently from each other, selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins, polyvinylpyrrolidone (PVP), hydroxypropylcellulose or hypromellose (e.g. hypromellose 3 cP), acacia, copovidone, carbomer, STARCH 1500, calcium carboxymethylcellulose, calcium cellulose glycolate, carmellosum calcium, carboxymethylcellulose sodium, carmellose sodium, ceratonia, chitosan hydrochloride, dextrates, ethylcellulose, liquid glucose, guar galactomannan, guar gum, hydroxyethyl cellulose, or hydroxyethylmethyl cellulose, or a mixture thereof.

[0097] Such excipients can be found here: https: / / wjbphs.com / sites / default / files / WJBPHS-2024-0142.pdf.

[0098] In an embodiment, in the solid pharmaceutical composition according to the present invention as described herein and as defined in the claims herein, said bulking agent (or "filler / binder") is selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate; or a mixture thereof.

[0099] In an embodiment, in the solid pharmaceutical composition according to the present invention as described herein and as defined in the claims herein, said filler is selected from the group consisting of mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins; or a mixture thereof. BHC 243008 FOREIGN FILING

[0100] 2025 08

[0101] In an embodiment, in the solid pharmaceutical composition according to the present invention as described herein and as defined in the claims herein, said binder is selected from the group consisting of polyvinylpyrrolidone (PVP), hydroxypropylcellulose or hypromellose (e.g. hypromellose 3 cP), acacia, copovidone, carbomer, STARCH 1500, calcium carboxymethylcellulose, calcium cellulose glycolate, carmellosum calcium, carboxymethylcellulose sodium, carmellose sodium, ceratonia, chitosan hydrochloride, dextrates, ethylcellulose, liquid glucose, guar galactomannan, guar gum, hydroxyethyl cellulose, or hydroxyethylmethyl cellulose; or a mixture thereof.

[0102] In an embodiment, in the solid pharmaceutical composition according to the present invention as described herein and as defined in the claims herein, said binder is selected from the group consisting of polyvinylpyrrolidone (PVP), hydroxypropylcellulose or hypromellose (e.g. hypromellose 3 cP); or a mixture thereof.

[0103] In one embodiment the solid pharmaceutical composition comprises one or more bulking agent (or "filler / binder") selected from those disclosed herein above.

[0104] In accordance with a particular embodiment, said bulking agent (or "filler / binder") is a mixture of lactose monohydrate and microcrystalline cellulose.

[0105] In a further embodiment the binder is selected from the group consisting of microcrystalline cellulose or silicified microcrystalline cellulose; or a mixture thereof.

[0106] In accordance with an embodiment, said bulking agent (or "filler / binder") is microcrystalline cellulose.

[0107] In accordance with an embodiment, said bulking agent (or "filler / binder") is maltitol.

[0108] In accordance with an embodiment, said bulking agent (or "filler / binder") is anhydrous lactose.

[0109] In accordance with an embodiment, said bulking agent (or "filler / binder") is lactose monohydrate.

[0110] In accordance with an embodiment, said bulking agent (or "filler / binder") is hypromellose, such as Hypromellose 3 cP for example.

[0111] In accordance with an embodiment, said filler is anhydrous lactose.

[0112] In accordance with an embodiment, said filler is a lactose hydrate, such as lactose monohydrate for example.

[0113] In accordance with an embodiment, said filler is lactose monohydrate. BHC 243008 FOREIGN FILING

[0114] 2025 08

[0115] In accordance with an embodiment, said binder is hypromellose, such as Hypromellose 3 cP for example.

[0116] The hypromellose 3 cP used as binder in Example 1A was purchased from Nutrition & Biosciences as Methocel E3 Premium LV from Nutrition & Biosciences : https: / / www.answercenter.iff.com / products / methocel-e3-premium-lv-hpmc .

[0117] In a yet further embodiment, the solid pharmaceutical composition comprises microcrystalline cellulose and lactose monohydrate.

[0118] In some embodiments, the concentration of the bulking agent (or "filler / binder") ranges from about 10% w / w to about 90% w / w, from about 30% w / w to about 80% w / w, from about 50% w / w to about 70% w / w.

[0119] In some embodiments, the concentration of the filler ranges from about 10% w / w to about 90% w / w, from about 30% w / w to about 80% w / w, from about 50% w / w to about 70% w / w.

[0120] In some embodiments, the concentration of the binder ranges from about 10% w / w to about 90% w / w, from about 30% w / w to about 80% w / w, from about 50% w / w to about 70% w / w.

[0121] Depending on the context, an excipient may serve, e.g. as a disintegrant. Without being bound by hypothesis, disintegrants expand and dissolve when wet and thereby facilitate disintegration of a solid pharmaceutical composition, such as a tablet, releasing the active ingredients.

[0122] In the solid pharmaceutical composition according to the present invention as described herein and as defined in the claims herein, said disintegrant is selected from the group consisting of alginic acid, cross-linked polyvinylpyrrolidone, maize starch, modified starch, and starch derivatives such as sodium carboxymethyl starch, cellulose derivatives such as carmellose calcium (carboxymethylcellulose calcium) and croscarmellose sodium (which is also referred to as "cross-linked polymer of carboxymethylcellulose sodium"); or a mixture thereof.

[0123] In one embodiment the solid pharmaceutical composition comprises one or more disintegrant selected from those disclosed herein above.

[0124] In a particular embodiment, said disintegrant is croscarmellose sodium (which is also referred to as "cross-linked polymer of carboxymethylcellulose sodium") or cross-linked polyvinylpyrrolidone (which is also referred to as "crospovidone"); or a mixture thereof. BHC 243008 FOREIGN FILING

[0125] 2025 08

[0126] In accordance with an embodiment, said disintegrant is croscarmellose sodium (which is also referred to as "cross-linked polymer of carboxymethylcellulose sodium").

[0127] In accordance with an embodiment, said disintegrant is cross-linked polyvinylpyrrolidone (which is also referred to as "crospovidone").

[0128] In a further embodiment the one or more disintegrant is selected from the group consisting of croscarmellose sodium and cross-linked polyvinylpyrrolidone; or a mixture thereof.

[0129] In a yet further embodiment the solid pharmaceutical composition comprises croscarmellose sodium.

[0130] In some embodiments, the concentration of the disintegrant ranges from about 0.1% w / w to about 20% w / w, from about 1% w / w to about 10% w / w, from about 2% w / w to about 6% w / w.

[0131] Depending on the context, an excipient may serve, e.g. as lubricant. Lubricants prevent ingredients from sticking, e.g., to production equipment, or which reduces friction, heat and wear when introduced between solid surfaces.

[0132] In the solid pharmaceutical composition according to the present invention as described herein and as defined in the claims herein, said lubricant is selected from the group consisting of magnesium stearate, sodium stearylfumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydrogenated vegetable fat or oil, polyethylenglycol and talcum; or a mixture thereof. In one embodiment of the present disclosure lubricants according to the present disclosure are selected from the group consisting of magnesium stearate, stearic acid and talcum, or mixtures thereof.

[0133] In accordance with an embodiment, said lubricant is magnesium stearate.

[0134] In one embodiment of the present disclosure the solid pharmaceutical composition comprises a lubricant.

[0135] In one embodiment the lubricant of the present disclosure is magnesium stearate.

[0136] In some embodiments, the concentration of the lubricant ranges from about 0.1% w / w to about 5% w / w, from about 0.2% w / w to about 3% w / w, from about 0.5% w / w to about 2.5% w / w.

[0137] Depending on the context, an excipient may serve, e.g. as glidant. Glidants are used to enhance the flowability of a powder. The key difference between a "lubricant" and a "glidant" is that a lubricant reduces the friction while the glidant promotes the flowability of a powder. BHC 243008 FOREIGN FILING

[0138] 2025 08

[0139] In the solid pharmaceutical composition according to the present invention as described herein and as defined in the claims herein, said glidant is selected from the group consisting of ascorbyl palmitate, calcium palmitate, magnesium stearate, colloidal silicon dioxide or (which is also referred to as "colloidal silica"), starch and talc.

[0140] In accordance with an embodiment, said glidant is anhydrous colloidal silica.

[0141] To provide for a pharmaceutical composition with desirable taste or to cover undesired taste, the pharmaceutical composition may contain agents that provide for a certain taste, such as sweeteners or flavouring agents.

[0142] Sweeteners suitable in the solid pharmaceutical composition according to the present invention as described herein and as defined in the claims herein are those selected from the group consisting of sucralose, saccharin, sodium-, potassium- or calcium saccharin, potassium acesulfame, neotame, alitame, glycyrrhizin or thaumatin, or sugars such as glucose, mannitol, fructose, saccharose, maltose, maltitol, galactose, sorbitol or xylitol. In the context of the present disclosure sweeteners are added in amounts to achieve the desired grade of sweetness and may be adapted by those skilled in the art. Flavouring agents in the context of the present disclosure are natural flavouring substances obtained from plant or animal raw materials, nature-identical flavouring substances obtained by synthesis or isolated through chemical processes, which are chemically and organoleptically identical to flavouring substances naturally present in products intended for human consumption and artificial flavouring substances. In a particular embodiment, the flavouring agent is selected from the group consisting of synthetic / artificial flavouring agents such as amyl acetate (banana flavouring), benzaldehyde (cherry or almond flavour), ethyl butyrate (pineapple), methyl anthranilate (grape), natural flavouring agents such as essential oils and oleoresins, herbs and spices, and natural-identical flavouring agents which are flavouring substances that are obtained by synthesis or are isolated through chemical processes and whose chemical make-up is identical to their natural counterpart. In the context of the present disclosure, flavouring agents may be added in amounts to achieve the desired taste and grade of taste.

[0143] The solid pharmaceutical composition may optionally contain colourants. Colourants are commonly used to color an uncolored pharmaceutical composition or to enhance its color, to minimize batch-to- batch variations or to replace a color already present to complement its effect and also to provide for a desirable appearance. Colourants in context with the present disclosure may be selected from the group consisting of dyes or pigment such as indigo carmine, riboflavin, titanium dioxide, rice starch, calcium sulfate and calcium carbonate. In the context of the present disclosure colourants may be added in amounts to achieve the desired color and / or grade of color. BHC 243008 FOREIGN FILING

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[0145] In one embodiment the one or more further pharmaceutically acceptable excipient optionally comprises a flow regulator, such as silicon dioxide.

[0146] In some embodiments, the concentration of the flow regulator ranges from about 0.1% w / w to about 5% w / w, from about 0.1% w / w to about 2% w / w, from about 0.1% w / w to about 1.0% w / w.

[0147] Coating

[0148] In one embodiment, the solid pharmaceutical composition is coated.

[0149] In the context of the present invention, the optional coating is carried out with addition of customary coating and film-forming agents familiar to the person skilled in the art, such as hydroxy-propylcellulose, hydroxypropylmethylcellulose (which is also referred to as "hypromellose" or "HPMC", for example Hypromellose 5 cP), ethylcellulose, polyvinyl-pyrrolidone, vinylpyrrolidone-vinyl acetate copolymers (for example Kollidon® VA64, BASF), shellac, acrylic and / or methacrylic acid ester copolymers with trimethylammonium methylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, ethyl acrylate-methyl methacrylate copolymers, methacrylic acid-methyl acrylate copolymers, propylene glycol, polyethylene glycol (e.g. polyethylene glycol 3350), glycerol triacetate or triethyl citrate, and / or colourants / pigments such as, for example, titanium dioxide, rice starch, calcium sulfate, calcium carbonate, iron oxide (e.g. red iron oxide (also referred to as "ferric oxide red"), yellow iron oxide, black iron oxide), indigotin or suitable color lakes, and / or anti-tacking agents such as talc, and / or opacifiers such as titanium dioxide, rice starch, calcium sulfate, calcium carbonate. An optional coating may comprise HPMC and polyethylene glycol, and iron oxide, such as iron oxide red and / or iron oxide yellow. Optionally the coating may comprise an opacifier, such titanium dioxide or rice starch or calcium sulfate. A mixture of the coating substances mentioned herein may also be used as a ready-to-use coating system such as commercially available coatings.

[0150] The hypromellose 5 cP used in said coating was purchased from Nutrition & Biosciences as Methocel E5 Premium LV : https: / / www.answercenter.iff.com / products / methocel-specialty-lv-hpmc .

[0151] The Macrogol 3350 used in said coating was purchased from Dow Chemical Company as Polyethylene Glycol 3350 : https: / / www.dow.com / en-us / pdp.carbowax-sentry-polyethylene-glycol-3350-usp-powder-inhibited- macrogol-3350-ph-eur.446418z.html#overview . BHC 243008 FOREIGN FILING

[0152] 2025 08

[0153] In one embodiment, the coating is about 0.5% to 10% by weight of the coated tablet, preferably 0.5% to 4.5% by weight of the coated tablet formulation, more preferably about 1.5% to 4.5% by weight of the coated tablet.

[0154] In an embodiment the solid pharmaceutical composition is coated with a lacquer containing HPMC and polyethylene glycol, and iron oxide, such as iron oxide red, iron oxide yellow and titanium dioxide.

[0155] Continuous processing and usage / application / purpose of twin screw granulator are described in supplier publications by e.g. GEA (ConsiGma TM) and also by e.g. M. Verstraeten et al., International Journal of Pharmaceutics 529 (2017): In-depth experimental analysis of pharmaceutical twin-screw wet granulation in view of detailed process understanding or e.g. in WO 2004 / 0479774 Process and apparatus for continuous wet granulation of powder material. Twin screw granulation is normally used for granulation of fine powder into granules, which are then compressed into tablets. But in our case twin screw granulator is not used in wet processing, but in dry processing. Twin screw granulator was used in addition to the sieving for deagglomeration and roller compaction for granulation.

[0156] The above-mentioned technical solution to the above-mentioned technical problem was not at all obvious, because the selection of the manufacturing process (fluid bed wet granulation vs. roller compaction) was unclear with regards to tablet quality attributes and stability profile.

[0157] Due to agglomeration tendency of the compound (A) resulting solid dosage forms (tablets) from roller compacted granules, a variable and non-reliable dissolution behaviour was observed, depending on compound (A) batches used for manufacturing though applying same manufacturing process. Even the same compound (A) batch resulted in tablets showing variable dissolution behaviour. An influence of storage conditions as well as manufacturing equipment was also observed.

[0158] The present invention is exemplified by the following Examples:

[0159] BHC 243008 FOREIGN FILING

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[0161] EXAMPLES

[0162] 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: 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. 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):

[0163] (A), wherein the content of water is greater than 0% and less than or equal to 4% of the total weight of said compound of formula (A), which is referred to herein as "compound (A)" and which is used in the preparation of the pharmaceutical composition according to the present invention as defined in the claims of the present text and as described and exemplified in the present text, was prepared for example from compound (B) by the following steps: BHC 243008 FOREIGN FILING 2025 08

[0164] Step 1: 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).

[0165] 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) BHC 243008 FOREIGN FILING 2025 08 as a yellowish solid. 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).1

[0166] HPLC (method 8): > 99.0 % enantiomeric purity (3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-

[0167] 2-yl]methoxy]-4-pyridyl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one crude, XIII, RT = 6.7 min); 3-(3-

[0168] 1Co-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 243008 FOREIGN FILING 202508 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.

[0169] Assay (HPLC, method 7; against external standard): 98.3 %.

[0170] Sulphur content (ICP-OES): 13 ppm. Step 2: 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-methylbenzene- sulfonate (XIX).

[0171] 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). BHC 243008 FOREIGN FILING

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[0173] 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 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).

[0174] 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,

[0175] 59.9, 39.7, 22.1, 20.7.

[0176] 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,

[0177] 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 1, which is an X-ray powder diffractogram of 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]-methoxy]pyridin-l-ium-

[0178] 4-yl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one 4-methylbenzene-sulfonate (XIX).

[0179] 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 spectrum as shown in Figure 2, which is an FT Raman spectrum 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), 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 243008 FOREIGN FILING 2025 08

[0180] Table 1: 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).

[0181] 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 spectrum as shown in Figure 3, which is an IR spectrum 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), 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 243008 FOREIGN FILING 202508

[0182] Table 2: IR bands of 3-(3-chloro-2-methoxy-anilino)-2-[3-[[(2S)-l,4-dioxan-2-yl]methoxy]pyridin-l-ium-

[0183] 4-yl]-l,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one 4-methylbenzenesulfonate (XIX):

[0184] BHC 243008 FOREIGN FILING

[0185] 2025 08

[0186] Table 3: 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 243008 FOREIGN FILING

[0187] 2025 08 BHC 243008 FOREIGN FILING 202508

[0188] FIGURE 4 is a 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-methylbenzene- sulfonate (XIX). 1-4- crystalline Hydrate 1

[0189] Modification A compound of formula (A)".

[0190] 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.

[0191] 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- BHC 243008 FOREIGN FILING

[0192] 2025 08 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).

[0193] 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.

[0194] Assay (HPLC, method 7; against external standard): 94.2 %.

[0195] Water content (Karl Fischer titration)2: 3.0 % (w / w). 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.

[0196] Figure 5 depicts 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.

[0197] Figure 6 depicts crystal packing from another angle.

[0198] Table 4, Figure 5 and Figure 6 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]-

[0199] 2According to Ph. Eur. Chapter 2.5.32, Coulometric titration. BHC 243008 FOREIGN FILING 2025 08 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.

[0200] Figure 5 depicts the crystalline lattice of crystalline Hydrate 1 Modification A form of the compound 3-

[0201] (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.

[0202] Figure 6 depicts crystal packing from another angle.

[0203] Table 4; Crystal data and structure refinement for crystalline Hydrate 1 Modification A of compound

[0204] 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)

[0205] Empirical formula C96 H110 CI4 N16 O25

[0206] Formula weight 2029.79

[0207] Temperature 118 K

[0208] Wavelength 1.54178 A

[0209] Crystal system Triclinic

[0210] Space group Pl

[0211] Unit cell dimensions a = 11.7853(3) A a= 72.997(2)°. BHC 243008 FOREIGN FILING

[0212] 2025 08 b = 14.8131(4) A b= 68.021(3)°. c = 15.4423(4) A g = 89.107(2)°.

[0213] Volume 2377.23(12) A3

[0214] Z 1

[0215] Density (calculated) 1.418 Mg / m3

[0216] Absorption coefficient 1.852 mm1

[0217] F(000) 1066

[0218] Crystal size 0.10 x 0.08 x 0.06 mm3

[0219] Theta range for data collection 3.753 to 63.661°.

[0220] Index ranges -13<=h<=13, -17<=k<=17, -17<=l<=17

[0221] Reflections collected 33934

[0222] Independent reflections 14609 [R(int) = 0.0531]

[0223] Completeness to theta = 63.661° 99.3 %

[0224] Absorption correction Semi-empirical from equivalents

[0225] Max. and min. transmission 0.92 and 0.84

[0226] Refinement method Full-matrix least-squares on F2

[0227] Data / restraints / parameters 14609 / 3 / 1274

[0228] Goodness-of-fit on F2 1.027

[0229] Final R indices [l>2sigma(l)] R1 = 0.0626, wR2 = 0.1643

[0230] R indices (all data) Rl = 0.0651, wR2 = 0.1679

[0231] Absolute structure parameter -0.016(15)

[0232] Extinction coefficient n / a

[0233] Largest diff. peak and hole 0.475 and -0.540 e.A3 BHC 243008 FOREIGN FILING

[0234] 2025 08

[0235] Figure 7 depicts 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).

[0236] It is to be understood that the X-Ray powder diffractogram of the pseudopolymorphic form Hydrate 1 Modification A of the compound of formula (B), (the "crystalline Hydrate 1 Modification A compound of formula (A)") is given in Figure 8, which is described as follows:

[0237] 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-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 8, which is an 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)".

[0238] Figure 9 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)".

[0239] Figure 10 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)".

[0240] Figure 11 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)". BHC 243008 FOREIGN FILING

[0241] 202508

[0242] EXAMPLE 1: MANUFACTURING PROCESS FOR THE PREPARATION of UNCOATED TABLETS

[0243] COMPRISING COMPOUND (A)

[0244] EXAMPLE 1A: Selection of the manufacturing process: roller compaction (Formulation A) or fluid bed granulation (Formulation B)

[0245] Composition Function 20 mg tablet 20 mg tablet

[0246] Amount Amount mg (% by weight mg (% by weight of of total) total)

[0247] Formulation A Formulation B

[0248] Drug substance

[0249] Compound (A) micronized drug substance 20.00 (24) 20.00 (22,9)

[0250] Excipients

[0251] Cellulose microcrystalline filler / binder 28.34 (34) 34.07 (39)

[0252] Lactose monohydrate filler 28.76 (34,5) 26.8 (30,69)

[0253] Crospovidone disintegrant 4.16 (5)

[0254] Croscarmellose Sodium disintegrant - 2.94 (3,37)

[0255] Hypromellose 3 cP binder - 2.94 (3,37)

[0256] Post-blend

[0257] Magnesium stearate lubricant 1.66 (2) 0.58 (0,66)

[0258] Silica colloidal anhydrous glidant 0.42 (0,5)

[0259] Weight 83,34 87,33

[0260] (uncoated tablet)

[0261] The hypromellose 3 cP used as binder in Example 1A was purchased from Nutrition & Biosciences as

[0262] Methocel E3 Premium LV from Nutrition & Biosciences : https: / / www.answercenter.iff.com / products / methocel-e3-premium-lv-hpmc . BHC 243008 FOREIGN FILING 2025 08

[0263] For information, cP is the abbreviation for centipoise, (which are old units which are still commonly used), the new units being mPas (milliPascalseconds (SI unit equivalent)).

[0264] Flow diagram of the manufacturing process of compound (A) tablet 20 mg by roller compaction (Formulation A) BHC 243008 FOREIGN FILING

[0265] 2025 08

[0266] Flow diagram of the manufacturing process of compound (A) tablet 20 mg by fluid bed (Formulation B)

[0267] Ingredients Manufacture

[0268] BHC 243008 FOREIGN FILING 2025 08

[0269] EXAMPLE 2: STRESS TESTS PERFORMED ON UNCOATED TABLETS COMPRISING COMPOUND (A)

[0270] The common manufacturing process is fluid bed granulation. To investigate if this manufacturing process is suitable for the compound (A), which has a variable water content which is greater than 0% and less than or equal to 4%, i.e. x = >0>4% by weight, of the total weight of said compound of formula (A), and which is also referred to as the "variable occupancy hydrate 1", accelerated stress tests have been performed. For this purpose, tablets manufactured with fluid bed granulation (Formulation B) as well as roller compaction (Formulation A) were stressed for 4 weeks at 60 °C und 90 °C. The degradation products were analyzed. Analyses have shown that tablets manufactured by roller compaction are superior to tablets manufactured with fluid bed granulation regarding their degradation products. The results are shown following table:

[0271] EXAMPLE 3: MANUFACTURING PROCESS FOR THE PREPARATION of UNCOATED TABLETS COMPRISING COMPOUND (A)

[0272] The manufacture of uncoated tablets comprising compound (A), the composition of which is as shown in the following TABLE, is described below. The manufacture can be performed in a batch operation or in a fully integrated continuous manufacturing or in a combination of both.

[0273] BHC 243008 FOREIGN FILING

[0274] 2025 08

[0275] TABLE

[0276] Composition Function 10 mg tablet 10 / 15 mg

[0277] Amount tablet core

[0278] [mg] I%1

[0279] Formulation C, D

[0280] Drug substance

[0281] Compound (A) micronized drug substance 10.00 11.8

[0282] Excipients

[0283] Cellulose microcrystalline bulking agent 34.79 40.9

[0284] (or

[0285] "filler / binder")

[0286] Crospovidone Disintegrant 4.17 4.9

[0287] Lactose monohydrate Filler 34.79 40.9

[0288] Post-blend

[0289] Magnesium stearate Lubricant 1.25 1.5

[0290] Silica colloidal anhydrous Glidant

[0291] Weight 85.00 100

[0292] (uncoated tablet)

[0293] Examples were produced under the following conditions:

[0294] Process description:

[0295] Pre-blend preparation: Blending, sieving and blending Compound (A) micronized, cellulose microcrystalline, crospovidone and lactose monohydrate are blended in a turbula or in a bin-blender (volumes from 100 ml - 300 I; 10 min; Rotating speed 15 rpm for bin blender and 29 rpm for the turbula blender). The mixture is sieved with a hand sieve or a mechanical sieve such as oscillating or conical shaped sieving unit. Hereby mesh sizes of 0,3 - 1,0 mm are used. The process is followed by an additional blending step with the same equipment as used in the first blending step. Mixing step for compound (A) with excipients. BHC 243008 FOREIGN FILING

[0296] 2025 08

[0297] Dry processing by twin screw

[0298] Continuous line (Commercial scale): Pre-blend is fed and a fixed throughput of approx. 12kg / h using powderfeeder. Furthertransportation of the powder blend is conducted by a twin screw granulator by using conveying elements with optional kneading or size exclusion elements with 25 mm screw diameter.

[0299] Variant (Lab scale): Twin screw granulator with diameter of 11 mm (various configurations containing only transport elements, and in combination with size controlling elements or kneading elements).

[0300] Dry Granulation

[0301] The powder blend is compacted on a roller compactor with a specific compaction force of 3- 13 kN / cm and a gap of 2-4 mm and grinded with 0.8 or 1 mm square wire sieve.

[0302] Variant (Lab scale): this step is sometimes done using briquetting using a tablet press for smaller batches

[0303] Post-blending

[0304] The dry granules are lubricated with magnesium stearate by blending with a turbula- (5 min, 29 rpm), bin- (15 rpm, 5 min TBC) or ribbon blender (100 rpm, 1 min) resulting in the ready- to-press blend.

[0305] Tableting

[0306] 10 mg tablets: The ready-to-press blend is compressed into 85 mg tablets with a diameter of 6 mm using a rotary press using compaction forces of 3 - 16 kN.

[0307] Optional coating

[0308] Ferric oxide red, hypromellose 5 cP and macrogol 3350 are combined with purified water in bulk to result in a homogeneous coating suspension which is sprayed onto the tablets in a suitable coating device, e.g., perforated drum coater.

[0309] The hypromellose 5 cP used in said coating was purchased from Nutrition & Biosciences as Methocel E5 Premium LV : BHC 243008 FOREIGN FILING 2025 08 https: / / www.answercenter.iff.com / products / methocel-specialty-lv-hpmc .

[0310] For information, cP is the abbreviation for centipoise, (which are old units which are still commonly used), the new units being mPas (milliPascalseconds (SI unit equivalent)).

[0311] The Macrogol 3350 used in said coating was purchased from Dow Chemical Company as Polyethylene Glycol 3350 : https: / / www.dow.com / en-us / pdp.carbowax-sentry-polyethylene-glycol-3350-usp-powder-inhibited- macrogol-3350-ph-eur.446418z.html#overview .

[0312] BHC 243008 FOREIGN FILING 2025 08

[0313] Flow diagram of the manufacturing process of compound (A) coated tablet 10 mg by roller compaction with twin screw granulator (Formulation C)

[0314] Ingredients Manufacture BHC 243008 FOREIGN FILING 2025 08

[0315] Flow diagram of the manufacturing process of compound (A) coated tablet 10 mg by roller compaction with twin screw granulator (Formulation C)

[0316] Ingredients Manufacture

[0317] BHC 243008 FOREIGN FILING

[0318] 2025 08

[0319] The following flow diagram illustrates the processing of the pre-blend with sieving only:

[0320] Flow diagram of the manufacturing process of compound (A) coated tablet 10 mg by roller compaction without twin screw granulator (Formulation D)

[0321] Ingredients Manufacture

[0322] | mixing BHC 243008 FOREIGN FILING 2025 08

[0323] Flow diagram of the manufacturing process of compound (A) coated tablet 10 mg by roller compaction without twin screw granulator (Formulation D)

[0324] Ingredients Manufacture

[0325] BHC 243008 FOREIGN FILING

[0326] 202508

[0327] EXAMPLE 4: DISSOLUTION TESTS PERFORMED ON UNCOATED TABLETS COMPRISING COMPOUND (A)

[0328] Dissolution examples

[0329] Examples with good dissolution:

[0330] Example A: compound (A) without agglomerates processed using rough sieving (e.g. 0.8 mm)

[0331] Example B: fine sieving (e.g. 0.3 mm)

[0332] Example C: sieving combined with twin screw processing : this is the final process for the manufacture of the pharmaceutical composition of the present invention, which final process is implemented as a batch operation for mixing, sieving, mixing and as a continuous operation for the following unit operations on the GEA ConsiGma line.

[0333] Example D: twin screw processing only (can be performed using different scales or different screw configurations)

[0334] Examples of bad dissolution:

[0335] Example E: compound (A) containing agglomerates combined with rough sieving (0.8 mm). Such process has strong compound (A) batch dependance, process is not robust with regard to the to compound (A) batches (presence of agglomerates) -agglomerates seen in the compound (A) and also in the final tablets which have bad dissolution.

[0336] Example F: no deagglomeration by sieving or twin screw granulator processing.

[0337] BHC 243008 FOREIGN FILING

[0338] 2025 08

[0339] Comparison of rough sieving combined with twin screw processing with rough sieve only for the same compound (A) batches

[0340] Processing of the compound (A) Batch 1 and compound (A) Batch 2 using sieving of the pre-blend with 0.8 mm or 1.0 mm mesh size and processing on a continuous manufacturing line that includes twin screw granulator for transport resulted in good dissolution (Example Cl, Example C2) compared to sieving with 0.8 mm and no twin screw and processed with batch process, resulted in slow dissolution (Example El, Example E2).

[0341] BHC 243008 FOREIGN FILING 2025 08

[0342] Comparison of dissolution for compound (A) containing agglomerates sieved by fine sieving (0.3 mm)

[0343] (Bl) and rough sieving (0.8 mm) (E3) and for compound (A) without sieving (Example Fl).

[0344] Preprocessing of the compound (A) - either compound (A) alone or with excipients (e.g. in pre-blend containing compound (A)) with a small sieve (0.3) make complete dissolution

[0345] Disadvantage: slow thoughput of the pre-blend using fine sieve (1 kg / h Frewitt or Hand sieve)

[0346] BHC 243008 FOREIGN FILING 202508

[0347] Comparison of compound (A) batches containing agglomerates (E4 compound (A) Batch 2) and without agglomerates (Al compound (A) Batch 2). Both same processing rough sieving (0.8 mm) result in a very variable dissolution. Additionally, the compound (A) was evaluated using air jet sieve (Alpine Jet Sieve) using a sieve mesh size of 63 pm. Approximately 3 g of compound (A) is put on the sieve and then exposed to underpressure of 15 mbar for 2 minutes and 25 mbar for 2 minutes afterwards. Finally, the remaining amount of material was weighted and expressed as fraction remaining. Example of experiments where same compound (A) batch (Batch 4) and the same processing by rough sieving with 0.8 mm was used as before (Example Al) and slower dissolution (Example E5) was observed. BHC 243008 FOREIGN FILING 2025 08

[0348] BHC 243008 FOREIGN FILING 2025 08

[0349] 1 EXAMPLE 5: Analytical methods

[0350] 5.1 Dissolution

[0351] Dissolution of compound (A) in phosphate buffer pH 6.8 with 0.5 % of sodium lauryl sulfate using paddle apparatus ( USPXXI 11 Paddle Method II apparatus 2) with paddle speed of 50 rpm at 37°C.

[0352] 5.2 Assay and degradation

[0353] The Assay and Degradation analytics is performed via Ultra high-performance liquid chromatography using a BEH C18 column (length 100 mm, internal diameter 3 mm, particle size 1.7 pm) with UV detection at 250 nm. The following eluents are used in the following composition:

[0354] Eluent A: 5 mM ammonium acetate buffer at pH 5

[0355] Eluent B: Acetonitrile

[0356] The sample concentration is 0.35 mg / mL (solvent: eluent A / B 50:50 (v / v)), the column temperature is

[0357] 40 °C and the flow rate is 1.0 mL / min.

[0358] COMMERCIAL UTILITY

[0359] The pharmaceutical compositions according to the invention as described herein and as defined by the claims herein may have useful pharmacological properties and may be employed for the prevention and treatment of disorders in humans and animals. The pharmaceutical compositions according to the invention as described herein and as defined by the claims herein may open up a further treatment alternatives and may therefore be an enrichment of pharmacy.

[0360] In accordance with a third aspect, the present invention, as described herein and as defined in the claims herein, relates to pharmaceutical compositions 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, 16 to 18, 20, 34, or 37, or a coated pharmaceutical composition according to any one of claims 22 to 29, 32 to 33, 35 to 36, or 38 to 39, for use in the treatment or prevention of a disease, which is a cancer selected from leukaemia, myelodysplastic syndrome, malignant lymphoma, a head and neck tumour, BHC 243008 FOREIGN FILING

[0361] 2025 08 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.

[0362] In accordance with a fourth aspect, the present invention, as described herein and as defined in the claims herein, relates to pharmaceutical combinations comprising a pharmaceutical composition 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, 16 to 18, 20, 34, or 37, or a coated pharmaceutical composition according to any one of claims 22 to 29, 32 to 33, 35 to 36, or 38 to 39, and one or more second active ingredients selected from a chemotherapeutic anti-cancer agent and a target-specific anti-cancer agent.

[0363] In accordance with a fifth aspect, the present invention, as described herein and as defined in the claims herein, relates to methods 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 pharmaceutical composition 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, 16 to 18, 20, 34, or 37, or a coated pharmaceutical composition according to any one of claims 22 to 29, 32 to 33, 35 to 36, or 38 to 39.

[0364] In accordance with a sixth aspect, the present invention, as described herein and as defined in the claims herein, relates to pharmaceutical compositions 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, 16 to 18, 20, 34, or 37, or a coated pharmaceutical composition according to any one of claims 22 to 29, 32 to 33, 35 to 36, or 38 to 39„ for use in the treatment and / or prophylaxis of a disease according to claim 40, or the pharmaceutical combination for use in the treatment and / or prophylaxis of a disease according to claim 41, or the method of treatment according to claim 42, wherein said treatment is preceded by, made concomitantly with, or followed by, the administration of an anti-diarrhoeal medicine, such as loperamide, for example. BHC 243008 FOREIGN FILING

[0365] 2025 08

[0366] The pharmaceutical compositions according to the invention as described herein and as defined by the claims herein 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, 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.

[0367] The pharmaceutical compositions according to the invention as described herein and as defined by the claims herein may be used in the treatment and / or prophylaxis of hyperproliferative disorders or disorders responsive to induction of cell death, i.e., apoptosis.

[0368] 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. BHC 243008 FOREIGN FILING

[0369] 2025 08

[0370] 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.

[0371] 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 pharmaceutical compositions according to the invention as described herein and as defined by the claims herein.

[0372] 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 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 pharmaceutical compositions according to the invention as described herein and as defined by the claims herein.

[0373] The pharmaceutical compositions according to the invention as described herein and as defined by the claims herein 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 pharmaceutical compositions according to the invention as described herein and as defined by the claims herein 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, BHC 243008 FOREIGN FILING

[0374] 2025 08 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, 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, BHC 243008 FOREIGN FILING

[0375] 2025 08 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 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.

[0376] Combination Therapies

[0377] The pharmaceutical compositions according to the invention as described herein and as defined by the claims herein 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. BHC 243008 FOREIGN FILING 2025 08

[0378] 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.

[0379] 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.

[0380] Pharmaceutical compositions:

[0381] It is possible for the pharmaceutical compositions according to the invention as described herein and as defined by the claims herein to have systemic and / or local activity. For this purpose, it can be administered in a suitable manner via the oral route.

[0382] For oral administration, it is possible to formulate the crystalline Hydrate 1 Modification A compound of formula (A) 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.

[0383] The pharmaceutical compositions according to the invention as described herein and as defined by the claims herein may contain further pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia,

[0384] • fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel*), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos*)),

[0385] • solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chainlength triglycerides fatty oils, liquid polyethylene glycols, paraffins),

[0386] • 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 example, BHC 243008 FOREIGN FILING

[0387] 2025 08

[0388] Tween’), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®),

[0389] • buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),

[0390] • isotonicity agents (for example glucose, sodium chloride),

[0391] • adsorbents (for example highly-disperse silicas),

[0392] • viscosity-increasing agents, gel formers, thickeners and / or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine),

[0393] • disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose- sodium (such as, for example, AcDiSol®)),

[0394] • flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)),

[0395] • coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)),

[0396] • capsule materials (for example gelatine, hydroxypropylmethylcellulose),

[0397] • synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),

[0398] • plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),

[0399] • penetration enhancers, BHC 243008 FOREIGN FILING 2025 08

[0400] • stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate),

[0401] • preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

[0402] • colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide),

[0403] • flavourings, sweeteners, flavour- and / or odour-masking agents.

[0404] Dosage of the pharmaceutical compositions of the present invention:

[0405] 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.

[0406] 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. BHC 243008 FOREIGN FILING

[0407] 2025 08

[0408] 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.

[0409] 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.

Claims

1. BHC 243008 FOREIGN FILING2025 08CLAIMS1. A pharmaceutical composition comprising: a) 0.1 to 30%, by weight of the total composition, 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):(A), wherein the content of water is greater than 0% (w / w) of the total weight of said compound of formula (A); b) 30 to 80%, particularly 35 to 70%, by weight of the total composition, of a bulking agent (or "filler / binder"), such as microcrystalline cellulose; c) 30 to 80%, particularly 35 to 70%, by weight of the total composition, of a filler, such as lactose monohydrate; d) 0.1 to 20%, by weight of the total composition, of a disintegrant, such as cross-linked polyvinylpyrrolidone, such as crospovidone, or croscarmellose sodium; e) 0 to 5%, by weight of the total composition, of a binder, such as hypromellose, such as hypromellose 3 cP for example; f) 0.1 to 5%, by weight of the total composition, of a lubricant, such as magnesium stearate; and g) 0 to 1%, by weight of the total composition, of a glidant, such as anhydrous colloidal silica.

2. The pharmaceutical composition according to claim 1, comprising:BHC 243008 FOREIGN FILING2025 08 a) 5 to 30%, particularly 20 to 30%, more particularly 10 to 25%, even more particularly 10 to 15%, by weight of the total composition, 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):wherein the content of water is greater than 0% and less than or equal to 4% of the total weight of said compound of formula (A).

3. The pharmaceutical composition according to claim 1 or 2, comprising: b) 30 to 45%, particularly 35 to 45%, more particularly 40 to 45%, by weight of the total composition, of a bulking agent (or "f il ler / binder").

4. The pharmaceutical composition according to claim 3, wherein said bulking agent (or "filler / binder") is microcrystalline cellulose.

5. The pharmaceutical composition according to any one of claims 1 to 4, comprising: c) 30 to 45%, particularly 35 to 45%, more particularly 40 to 45%, by weight of the total composition, of a filler.

6. The pharmaceutical composition according to claim 5, wherein said filler is lactose monohydrate.

7. The pharmaceutical composition according to any one of claims 1 to 6, comprising: d) 0.1 to 20%, particularly 1 to 10%, more particularly 2 to 6%, by weight of the total composition, of a disintegrant.

8. The pharmaceutical composition according to claim 7, wherein said disintegrant is cross-linked polyvinylpyrrolidone, such as crospovidone.

9. The pharmaceutical composition according to any one of claims 1 to 8, comprising: e) 0 to 5%, by weight of the total composition, of a binder.BHC 243008 FOREIGN FILING2025 0810. The pharmaceutical composition according to claim 9, wherein said binder is hydroxypropylmethylcellulose.

11. The pharmaceutical composition according to any one of claims 1 to 10, comprising: f) 0.1 to 5%, particularly 0.2 to 3%, more particularly 0.5 to 2.5%, by weight of the total composition, of a lubricant.

12. The pharmaceutical composition according to claim 11, wherein said lubricant is magnesium stearate.

13. The pharmaceutical composition according to any one of claims 1 to 12, comprising: g) 0 to 1%, by weight of the total composition, of a glidant.

14. The pharmaceutical composition according to claim 13, wherein said glidant is anhydrous colloidal silica.

15. A method of preparing the pharmaceutical composition according to any one of claims 1 to 14, which comprises the following Steps:Step A : blending a mixture of: i) micronized, optionally sieved, 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) of the total weight of said compound of formula (A), optionally wherein the content of water is greater than 0% and less than or equal to 4% of the total weight of said compound of formula (A); ii) a bulking agent (or "filler / binder"), as defined in any one of claims 1 to 14, such as microcrystalline cellulose;BHC 243008 FOREIGN FILING2025 08 iii) a disintegrant, as defined in any one of claims 1 to 14, such as cross-linked polyvinylpyrrolidone, such as crospovidone; and iv) a filler, as defined in any one of claims 1 to 14, such as lactose monohydrate; thereby producing a blended mixture;Step B : sieving the thus-produced blended mixture from Step A, thereby producing a sieved, blended mixture;Step C : blending the thus-produced sieved, blended mixture from Step B with excipients, such as in pre-blend containing compound (A)) with a small sieve, such as with a 0.5 mm, particularly 0.3 mm, sieve, thereby producing a pre-blend;Step D : dry processing the thus-produced pre-blend from Step C in a twin screw granulator, thereby producing a final pre-blend;Step E : dry granulating the final pre-blend from Step D by roller compaction, thereby producing dry granules;Step F : post-blending the thus-produced dry granules from Step E with a sieved lubricant, such as magnesium stearate, thereby producing a ready-to-press blend.

16. The pharmaceutical composition according to any one of claims 1 to 14, which is prepared by a method according to claim 15.

17. The pharmaceutical composition according to claim 16, which is obtainable by dry granulating by roller compaction.

18. The pharmaceutical composition according to any one of claims 1 to 14, 16 or 17, which is in the form of a tablet.

19. The method according to claim 15, comprising the following additional step:Step G : tableting the thus-produced ready-to-press blend, thereby producing a pharmaceutical composition in the form of a tablet with a complete dissolution.

20. The pharmaceutical composition according to claim 18, which is prepared by a method according to claim 19.BHC 243008 FOREIGN FILING2025 0821. The pharmaceutical composition according to claim 20, containing said compound of formula (A) which is contaminated with less than 1.50 %, particularly 1.10 %, more particularly 1.01%, by weight of the total pharmaceutical composition, of degradation products.

22. The pharmaceutical composition according to claim 18 or 20, which is a coated pharmaceutical composition in the form of a tablet coated with a coating.

23. The coated pharmaceutical composition according to claim 22, wherein said coating is 0.5 to 10%, by weight of said coated pharmaceutical composition.

24. The coated pharmaceutical composition according to claim 22 or 23, wherein said coating comprises: h) 0.5 to 10%, by weight of said coated pharmaceutical composition, of a film-forming agent, such as hydroxypropylmethylcellulose, such as Hypromellose 5 cP, or polyethylene glycol, such as polyethylene glycol 3350, such as macrogol 3350; and i) 0.5 to 10%, by weight of the coated pharmaceutical composition, of a colourant / pigment a colourant / pigment, such as ferric oxide red.

25. The coated pharmaceutical composition according to any one of claims 22 to 24, wherein said coating comprises: h) 0.5 to 10%, particularly 0.5 to 4.5%, more particularly 1.5 to 4.5%, by weight of said coated pharmaceutical composition, of a film-forming agent.

26. The coated pharmaceutical composition according to claim 25, wherein said film-forming agent is hydroxypropylmethylcellulose, such as Hypromellose 5 cP.

27. The coated pharmaceutical composition according to claim 25, wherein said film-forming agent is polyethylene glycol, such as polyethylene glycol 3350, such as macrogol 3350.

28. The coated pharmaceutical composition according to any one of claims 22 to 27, wherein said coating comprises: i) 0.01 to 6.0%, particularly 0.05 to 3.0%, more particularly 0.1 to 2.0%, by weight of the coated pharmaceutical composition, of a colourant / pigment.

29. The coated pharmaceutical composition according to claim 28, wherein said colourant / pigment is ferric oxide red.

30. The method according to claim 19, comprising the following additional step:BHC 243008 FOREIGN FILING2025 08Step H : coating the thus-produced uncoated tablets with a coating suspension comprising mixture of: v) a pigment, such as ferric oxide red; vi) a film-forming agent, such as a mixture of hydroxypropylmethylcellulose, such as Hypromellose 5 cP, and polyethylene glycol 3350, such as macrogol 3350; and vii) purified water in bulk; thereby producing coated tablets.

31. The method according to any one of claims 15, 19 and 30, which is performed in an operation selected from the group consisting of:- a batch operation,- a fully integrated continuous manufacturing operation, and- a combination of a batch operation and a fully integrated continuous manufacturing operation.

32. The coated pharmaceutical composition according to any one of claims 22 to 29, which is prepared by a method according to claim 30 or 31.

33. The coated pharmaceutical composition according to claim 32, which contains 10 mg of said compound (A).

34. The pharmaceutical composition according to any one of claims 1 to 14, 16 to 18, or 20, comprising: a) 10 to 15%, by weight of the total composition, 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):wherein the content of water is greater than 0% (w / w) of the total weight of said compound of formula (A), optionally wherein the content of water is greater than 0% and less than or equal to 4% of the total weight of said compound of formula (A);BHC 243008 FOREIGN FILING2025 08 b) 40 to 45%, by weight of the total composition, of a bulking agent (or "filler / binder"); c) 40 to 45%, by weight of the total composition, of a filler; d) 2 to 6%, by weight of the total composition, of a disintegrant; e) 0 to 5%, by weight of the total composition, of a binder; f) 0.5 to 2.5%, by weight of the total composition, of a lubricant; and g) 0 to 1%, by weight of the total composition, of a glidant.

35. The pharmaceutical composition according to claim 34, further comprising: a coating, said coating being 0.5 to 10%, by weight of said coated pharmaceutical composition.

36. The pharmaceutical composition according to claim 35, said coating comprising: h) 1.5 to 4.5%, by weight of said coated pharmaceutical composition, of a film-forming agent; and i) 0.1 to 2.0%, by weight of said coated pharmaceutical composition, of a colourant / pigment.

37. The pharmaceutical composition according to any one of claims 1 to 14, 16 to 18, or 20, or 36, comprising: a) 10 to 15%, by weight of the total composition, 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):wherein the content of water is greater than 0% (w / w) of the total weight of said compound of formula (A), optionally wherein the content of water is greater than 0% and less than or equal to 4% of the total weight of said compound of formula (A); b) 40 to 45%, by weight of the total composition, of microcrystalline cellulose;BHC 243008 FOREIGN FILING2025 08 c) 40 to 45%, by weight of the total composition, of lactose monohydrate; d) 2 to 6%, by weight of the total composition, of crospovidone; e) 0 to 5%, by weight of the total composition, of hydroxypropylmethylcellulose; f) 0.5 to 2.5%, by weight of the total composition, of magnesium stearate; and g) 0 to 1%, by weight of the total composition, of anhydrous colloidal silica.

38. The pharmaceutical composition according to claim 37, further comprising: a coating, said coating being 0.5 to 10%, by weight of said coated pharmaceutical composition.

39. The pharmaceutical composition according to claim 36, said coating comprising: h) 1.5 to 4.5%, by weight of the coated pharmaceutical composition, of hydroxypropylmethylcellulose, such as Hypromellose 5 cP, and polyethylene glycol 3350, such as macrogol 3350; and i) 0.1 to 2.0%, by weight of the coated pharmaceutical composition, of ferric oxide red.

40. A pharmaceutical composition 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, 16 to 18, 20, 34, or 37, or a coated pharmaceutical composition according to any one of claims 22 to 29, 32 to 33, 35 to 36, or 38 to 39, for use in 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.

41. A pharmaceutical combination comprising a pharmaceutical composition 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, 16 to 18, 20, 34, or 37, or a coated pharmaceutical composition according to any one of claims 22 to 29, 32 to 33, 35 to 36, or 38 to 39, and one or more second active ingredients selected from a chemotherapeutic anti-cancer agent and a target-specific anti-cancer agent.

42. 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,BHC 243008 FOREIGN FILING2025 08 and a sarcoma, comprising administering to said mammal in need thereof a therapeutically effective amount of the pharmaceutical composition 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, 16 to 18, 20, 34, or 37, or a coated pharmaceutical composition according to any one of claims 22 to 29, 32 to33, 35 to 36, or 38 to 39.

43. The pharmaceutical composition 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, 16 to 18, 20, 34, or 37, or a coated pharmaceutical composition according to any one of claims 22 to 29, 32 to33, 35 to 36, or 38 to 39„ for use in the treatment and / or prophylaxis of a disease according to claim 40, or the pharmaceutical combination for use in the treatment and / or prophylaxis of a disease according to claim 41, or the method of treatment according to claim 42, wherein said treatment is preceded by, made concomitantly with, or followed by, the administration of an anti-diarrhoeal medicine, such as loperamide, for example.

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