Novel forms of pyrido[1,2-a]pyrimidin-4-one derivatives, their formulations and their manufacturing process

Abstract

To provide a solid form and a pharmaceutical composition of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one useful as pharmaceutically active compounds.SOLUTION: There is provided a solid form of a compound of formula (I) or a salt thereof, wherein the solid form is crystalline polymorphic Form A. There is also provided a pharmaceutical composition comprising the compound or pharmaceutically acceptable salts thereof, wherein the composition is an oral aqueous solution or a dry powder suitable for constitution of an oral aqueous solution.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a compound represented by formula (I) [ka] The present invention relates to crystalline forms of the compound 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, processes for their preparation, compositions thereof and their use as pharma- ceutical active compounds. [Brief description of the drawings]

[0002] [Figure 1] FIG. 1 shows the X-ray powder diffraction pattern of the 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one crystal form, also known as Form A. [Diagram 2] FIG. 2 shows the Raman spectrum of the 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one crystal form, also known as Form A. [Diagram 3] FIG. 3 shows the IR spectrum of the 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one crystal form, also known as Form A. [Figure 4] FIG. 4 shows the X-ray powder diffraction pattern of the 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one crystalline form, also known as Form D. [Diagram 5]FIG. 5 shows the Raman spectrum of the 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one crystal form, also known as Form D. [Figure 6] FIG. 6 shows the IR spectrum of the 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one crystal form, also known as Form D. [Figure 7] FIG. 7 shows the X-ray powder diffraction pattern of the 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one crystal form, also known as Form B. [Figure 8] Figure 8 shows the X-ray powder diffraction pattern of the 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one crystal form, also known as Form C. The broad signal at 5-6° 2-theta is due to the Kapton foil. [Figure 9] Figure 9 shows the X-ray powder diffraction pattern of the 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one crystal form, also known as Form E. The broad signal at 5-6° 2-theta is due to the Kapton foil. [Figure 10] Figure 10 shows the X-ray powder diffraction pattern of the 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one crystal form, also known as Form F. The broad signal at 5-6° 2-theta is due to the Kapton foil. [Figure 11]FIG. 11 shows the X-ray powder diffraction pattern of the 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one crystal form, also known as Form G. [Figure 12] FIG. 12 shows the X-ray powder diffraction pattern of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one hydrochloride. [Figure 13] FIG. 13 shows the X-ray powder diffraction pattern of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one tartrate. [Figure 14] FIG. 14 shows the X-ray powder diffraction pattern of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one citrate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0003] The present invention relates to a compound represented by formula (I) [ka] This invention relates to the crystalline polymorph Form A and the crystalline hydrate Form D of the compound.

[0004] Crystalline polymorph Form A of the compound of formula (I) is a thermodynamically stable polymorph.

[0005] Crystalline hydrate Form D of the compound of formula (I) is a crystalline form obtained under high water activity conditions.

[0006] In another aspect, the present invention also relates to a composition or medicine containing the crystalline polymorph A. Its use is also described. Such a novel polymorph has advantageous properties in terms of ease of manufacture (formulation), and has dosage form stability, which improves storage and / or makes packaging easier.

[0007] In particular, type A has improved chemical stability compared to type D.

[0008] In particular, Form A has improved processability in terms of its filtration compared to Form D. This improvement allows for faster isolation of the compound of interest and saves on solvents that can have a significant environmental impact.

[0009] In one embodiment, the crystalline polymorph Form A of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, is characterized by an X-ray powder diffraction pattern that includes characteristic peaks at one or more of about 11.4 degrees 2-theta, about 12.7 degrees 2-theta, about 15.9 degrees 2-theta, about 24.0 degrees 2-theta, or about 25.6 degrees 2-theta. In one embodiment, Form A includes two or more, three or more, four or more, or all five of these characteristic peaks. For example, Form A may include a combination of characteristic X-ray powder diffraction pattern peaks at about 8.3 degrees 2-theta, about 11.4 degrees 2-theta, about 12.7 degrees 2-theta, about 13.0 degrees 2-theta, about 15.1 degrees 2-theta, about 15.9 degrees 2-theta, about 17.0 degrees 2-theta, about 19.7 degrees 2-theta, about 22.4 degrees 2-theta, about 24.0 degrees 2-theta, about 25.6 degrees 2-theta, and / or about 26.8 degrees 2-theta. In another example, there may be three characteristic peaks at about 12.7 degrees 2-theta, about 24.0 degrees 2-theta, and about 25.6 degrees 2-theta, which may be further combined with a fourth peak. In some cases, all five peaks may be present. For example, the crystalline polymorph Form A of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, is characterized by an X-ray powder diffraction pattern that includes characteristic peaks at one or more of 11.4±0.2 degrees two-theta, 12.7±0.2 degrees two-theta, 15.9±0.2 degrees two-theta, 24.0±0.2 degrees two-theta, or 25.6±0.2 degrees two-theta. In one embodiment, Form A includes two or more, three or more, four or more, or all five of these peaks.For example, Form A may include a combination of characteristic X-ray powder diffraction pattern peaks at 8.3±0.2 degrees 2-theta and 11.4±0.2 degrees 2-theta, 12.7±0.2 degrees 2-theta, 13.0±0.2 degrees 2-theta, 15.1±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 17.0±0.2 degrees 2-theta, 19.7±0.2 degrees 2-theta, 22.4±0.2 and 24.0±0.2 degrees 2-theta, or 25.6±0.2 degrees 2-theta and 26.8±0.2 degrees 2-theta. In another example, there may be three characteristic peaks at 12.7±0.2 degrees 2-theta, 24.0±0.2 degrees 2-theta, and 25.6±0.2 degrees 2-theta, which may be further combined with a fourth peak. Optionally, all five peaks may be present. In a further embodiment, Form A comprises an XRPD peak at a diffraction angle of about 8.3 degrees 2-theta (±0.2) and at least one, specifically two, more specifically three, even more specifically four, even more specifically five, and most specifically six additional XRPD peaks at 11.4 degrees 2-theta (±0.2), 15.1 degrees 2-theta (±0.2), 15.9 degrees 2-theta (±0.2), 17.0 degrees 2-theta (±0.2), 24.0 degrees 2-theta (±0.2), or 25.6 degrees 2-theta (±0.2). In another embodiment, Form A comprises XRPD peaks at diffraction angles of about 11.4 degrees 2-theta (±0.2), 15.1 degrees 2-theta (±0.2), and 25.6 degrees 2-theta (±0.2). In another embodiment, Form A comprises XRPD peaks at diffraction angles of about 15.1 degrees 2-theta (±0.2), 17.0 degrees 2-theta (±0.2), and 25.6 degrees 2-theta (±0.2). In another embodiment, Form A comprises XRPD peaks at diffraction angles of about 15.1 degrees 2-theta (±0.2), 24.0 degrees 2-theta (±0.2), and 25.6 degrees 2-theta (±0.2).In a more particular embodiment, Form A comprises an XRPD peak at a diffraction angle of about 8.3 degrees 2-theta (±0.2) and at least one, specifically two, more specifically three, even more specifically four, even more specifically five, and most specifically six additional XRPD peaks at 11.4 degrees 2-theta (±0.2), 15.1 degrees 2-theta (±0.2), 15.9 degrees 2-theta (±0.2), 17.0 degrees 2-theta (±0.2), 24.0 degrees 2-theta (±0.2), or 25.6 degrees 2-theta (±0.2).

[0010] Certain embodiments of the present invention relate to the crystalline polymorph Form A of the compound of formula I described herein, characterized by the X-ray powder diffraction pattern depicted in FIG.

[0011] A particular embodiment of the present invention relates to crystalline Form A of the compound of formula I described herein, characterized by the infrared spectrum depicted in FIG.

[0012] A particular embodiment of the present invention relates to crystalline Form A of the compound of formula I described herein, characterized by the Raman spectrum shown in FIG.

[0013] In another embodiment, the crystalline polymorph Form A of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, has a melting point greater than 298° C., specifically between 298° C. and 302° C., more specifically between 299° C. and 301° C., as measured by DSC using a heating rate of 10 K / min and nitrogen flow. In one embodiment, the crystalline polymorph form A of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, is anhydrous, i.e., does not contain bound water in the crystal lattice, and is non-hygroscopic to slightly hygroscopic (water absorption less than 2% according to the European Pharmacopoeia). In another embodiment, the crystalline polymorph form A of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, is substantially free of water and other solvents (in particular ethanol<5000 ppm; H2O<0.5% by weight).

[0014] In one embodiment, the crystalline polymorph Form A of the compound of formula (I) prepared herein, 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, is at least 90% pure, specifically at least 95% pure, more specifically at least 97% pure, even more specifically at least 99% pure, even more specifically at least 99.5% pure, and most specifically at least 99.7% pure. By "pure" it is meant that it is free of contaminants, including, for example, solvents, organic impurities, or inorganic impurities.

[0015] In one embodiment, the compound of formula (I), crystalline hydrate Form D of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, is characterized by an X-ray powder diffraction pattern including characteristic peaks at one or more of about 8.4 degrees 2theta, about 12.8 degrees 2theta, about 13.9 degrees 2theta, about 19.9 degrees 2theta, about 20.8 degrees 2theta, about 22.0 degrees 2theta, about 22.6 degrees 2theta, about 23.5 degrees 2theta, about 24.4 degrees 2theta, about 25.3 degrees 2theta, about 26.1 degrees 2theta, and about 27.2 degrees 2theta. In one embodiment, Form D includes two or more, three or more, four or more, or all five of these characteristic peaks. For example, Form D may include a combination of characteristic peaks in an X-ray powder diffraction pattern selected from 8.4 degrees 2-theta, about 12.8 degrees 2-theta, about 13.9 degrees 2-theta, about 19.9 degrees 2-theta, about 20.8 degrees 2-theta, about 22.0 degrees 2-theta, about 22.6 degrees 2-theta, about 23.5 degrees 2-theta, about 24.4 degrees 2-theta, about 25.3 degrees 2-theta, about 26.1 degrees 2-theta, or about 27.2 degrees 2-theta. In another example, there may be three characteristic peaks at 8.4±0.2 degrees 2-theta, 23.5±0.2 degrees 2-theta, 24.4±0.2 degrees 2-theta, 25.3±0.2 degrees 2-theta, or 27.2±0.2 degrees 2-theta, plus a fourth peak in combination. Optionally, all five peaks may be present. For example, the crystalline hydrate Form D of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, is characterized by an X-ray powder diffraction pattern that includes characteristic peaks at one or more of 8.4±0.2 degrees 2-theta, 23.5±0.2 degrees 2-theta, 24.4±0.2 degrees 2-theta, 25.3±0.2 degrees 2-theta, or 27.2±0.2 degrees 2-theta. In one embodiment, Form D includes two or more, three or more, four or more, or all five of these peaks.For example, Form D may include a combination of characteristic X-ray powder diffraction patterns at 8.4±0.2 degrees 2-theta, 12.8±0.2 degrees 2-theta, 13.9±0.2 degrees 2-theta, 19.9±0.2 degrees 2-theta, 20.8±0.2 degrees 2-theta, 22.0±0.2 degrees 2-theta, 22.6±0.2 degrees 2-theta, 23.5±0.2 degrees 2-theta, 24.4±0.2 degrees 2-theta, 25.3±0.2 degrees 2-theta, or 26.1±0.2 degrees 2-theta, and 27.2±0.2 degrees 2-theta. In another example, there may be three characteristic peaks at 23.5±0.2 degrees 2-theta, 24.4±0.2 degrees 2-theta, and 25.3±0.2 degrees 2-theta, which may be further combined with a fourth peak. Optionally, all five peaks may be present.

[0016] A particular embodiment of the present invention relates to crystalline hydrate Form D of the compound of formula I described herein, characterized by the X-ray powder diffraction pattern shown in FIG.

[0017] A particular embodiment of the present invention relates to crystalline Form D of the compound of Formula I described herein, characterized by the infrared spectrum depicted in FIG.

[0018] A particular embodiment of the present invention relates to crystalline Form D of the compound of formula (I) described herein, characterized by the Raman spectrum shown in FIG.

[0019] In another embodiment, the crystalline hydrate form D of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, exhibits an endotherm between about 80° C. and 120° C. in a standard differential scanning calorimetry (DSC) run at a heating rate of 10 K / min, indicating the loss of water of hydration. The crystalline hydrate form D of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, is a trihydrate.

[0020] In one embodiment, the crystalline hydrate form D of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, is at least 90% pure, at least 95% pure, at least 97% pure, about 98% pure. In a further embodiment, the crystalline form D of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, contains up to 1% of a solvent, in particular ethanol and 1-propanol.

[0021] The present application relates to a compound of formula (I) [ka] A process for preparing a compound of the formula Formula (II) [ka] With a strong acid, particularly HCl. The process disclosed herein, wherein HCl is generated in situ in the presence of 1-propanol and acetyl chloride.

[0022] In particular, the preparation of the compound of formula (I) is carried out in a solvent such as alcohol, aqueous alcohol, ethyl acetate, 1-propyl acetate, toluene, acetonitrile, THF or dichloromethane. More preferably, the preparation of the compound of formula (I) is carried out in the presence of 1-propanol and toluene.

[0023] Further, the present application discloses the process described herein, wherein 3 to 15 equivalents, more particularly 4 to 8 equivalents, and most particularly 5 equivalents of strong acid relative to the compound of formula (II) are used, particularly wherein the strong acid is HCl.

[0024] In particular, the present application discloses the above process for the preparation of a compound of formula (I), wherein the reaction is carried out at a temperature between 20°C and 100°C, specifically between 60°C and 80°C, more specifically at 75°C.

[0025] 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one is a valuable pharmaceutical compound as described in WO 2015173181. Similarly, it can be prepared according to WO 201573181.

[0026] Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen, unless otherwise indicated.

[0027] The present application also discloses further forms of lidiplam which have been identified as follows: a) Form B as a metastable polymorph b) Form C as a monohydrate c) Form E as a trihydrate d) F-type as a hydrate e) Form G as a metastable polymorph.

[0028] The present application also discloses salts of lidipram such as the hydrochloride, tartrate and citrate salts of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. Unless otherwise stated, the following terms used in the specification and claims have the meanings indicated below.

[0029] "About" or "approximately" refers to a range value within 5% greater or less than the stated reference value. More specifically, "about" or "approximately" refers to ±0.2°C 2 theta or ±0.5°C.

[0030] "Ambient conditions" refers to conditions experienced in a standard laboratory, e.g., atmospheric pressure, air, ambient temperature between 18°C ​​and 28°C, and humidity between 30% rH and 80% rH.

[0031] "Compound of formula (I)" means [ka] Also known as 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one or 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4H-pyrido[1,2a]pyrimidin-4-one. The compound of formula (I) is also known as lidipram, RG7916 or RO7034067. In this specification, the names or references of the compound of formula (I) can be used interchangeably.

[0032] As used herein, "Form A" refers to the crystalline anhydrous polymorph Form A of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one.

[0033] As used herein, "Form D" refers to crystalline hydrate Form D of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. Form D contains 3 molar equivalents of water. Form D is a trihydrate.

[0034] "(C1-C8) alkyl" refers to a branched or straight hydrocarbon chain, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl, pentyl, hexyl, heptyl or octyl. "(C1-C3) alkyl" refers to methyl, ethyl, n-propyl or isopropyl.

[0035] "Alcohol" refers to benzyl alcohol, aminoethanol, or a (C1-8) alkyl, as defined above, substituted with one or two hydroxy groups, more specifically substituted with one hydroxy group (more specifically (C1-C 3) Alcohol refers to an alcohol (alkyl). Examples of alcohol include, but are not limited to, methanol, ethanol, isopropanol, 1-propanol, propylene glycol, 1-butanol, 2-butanol, t-butanol, benzyl alcohol, 2-aminoethanol, and octanol. Specifically, alcohol refers to methanol, ethanol, 1-propanol, or benzyl alcohol, most specifically 1-propanol.

[0036] "Ambient conditions" refers to conditions experienced in a standard laboratory, e.g., atmospheric pressure, air, ambient temperature between 18°C ​​and 28°C, and humidity between 30% rH and 80% rH.

[0037] "Base" refers to a compound that deprotonates another compound when reacted with it. Bases suitable for use according to the present disclosure include, but are not limited to, for example, organic bases and basic alkali metal salts. In particular, organic bases include nitrogen-containing heterocycles and tertiary amines. Examples of nitrogen-containing heterocycles include pyridine, imidazole, and benzimidazole. In some embodiments, tertiary amines include triethylamine, N-methylmorpholine, and diisopropylethylamine. In some embodiments, basic alkali metal salts include, for example, sodium carbonate (Na2CO3), potassium carbonate (K2CO3), sodium bicarbonate (NaHCO3), sodium hydroxide (NaOH), sodium and potassium alkoxides (including, but not limited to, sodium and potassium t-butoxide, 1-propoxide, 2-propoxide, ethoxide, methoxide, etc.), sodium amide (NaNH2), potassium amide (KNH2), etc.

[0038] "Crystallization" and "recrystallization" can be used interchangeably and refer to a process in which a compound dissolved or suspended in a solvent system results in a stable polymorph or crystalline form of the particular compound. For example, the crystallization step can be carried out by forming crystals using a solvent and an anti-solvent.

[0039] The terms "halo," "halogen," and "halide," which may be used interchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.

[0040] "Strong acid" refers to an acid that completely dissociates in an aqueous solution with a pH of 2 or less. Strong acids include, but are not limited to, sulfuric acid (H2SO4), hydrohalic acids (i.e., HX'' where X'' is I, Br, Cl, or F), nitric acid (HNO3), phosphoric acid (H3PO4), and combinations thereof. Specifically, the strong acid is a hydrohalic acid where X is Br or Cl. Most specifically, the strong acid is HCl.

[0041] "Nickel catalyst" refers to a catalyst that includes nickel or nickel oxide or a mixture thereof. An example of a nickel catalyst is Raney nickel catalyst (Ra-Ni).

[0042] The term "optional" or "optionally" means that the subsequently described event or circumstance may occur, but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur.

[0043] "Palladium catalyst" refers to a reagent that is a source of palladium 0 (Pd(0)). Suitable sources of Pd(0) include palladium bis(dibenzylideneacetone) (Pd(dba)2), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), palladium acetate (Pd(OAc)2), palladium chloride (PdCl2), tetrakis(triphenyl-phosphino)palladium (Pd(PPh3)4), 1,2 bis(diphenylphosphino)ethanepalladium (Pd( dppe)2), 1,3-bis(diphenylphosphino)-propane palladium (Pd(dppp)2), dichloro-1,3-bis(diphenylphosphino)-propane palladium (PdCl2(dppp)), 1,4-bis(diphenylphosphino)butane palladium, 1,1-bis(diphenylphosphine)-ferrocenedichloropalladium (PdCl2(dppf)), palladium on carbon, Pd(OH)2 on carbon , tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), bis(acetonitrile)-palladium(II) dichloride (PdCl2(CH3CN)2), cyclopentadienylallylpalladium, allylpalladium(II) chloride dimer (Pd(allyl)Cl)2), (2-butenyl)chloropalladium dimer, (2-methylallyl)palladium(II) chloride dimer, palladium(1-phenyl) Examples of suitable palladium catalysts include, but are not limited to, di-μ-chlorobis[2′-(amino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II), di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II) or dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium (Pd(XantPhos)Cl2). Specifically, the palladium catalyst is Pd(OAc) 2、 Pd(PPh3)4, Pd(PPh3)2Cl2, Pd2(dba)3, (Pd(XantPhos)Cl2) or PdCl2(dppf). More specifically, the palladium catalyst is Pd(OAc)2, Pd2(dba)3, (Pd(XantPhos)Cl2) or PdCl2(dppf).

[0044] "XRPD" refers to the analytical method of X-ray powder diffraction. The reproducibility of the angle values ​​is within 2 theta ± 0.2°. The term "about" given in combination with the angle values ​​indicates a reproducibility within 2 theta ± 0.2°. The relative XRPD peak intensities depend on many factors, such as structure factors, temperature factors, crystallinity, polarization factors, multiplicity, and Lorentz factors. The relative intensities can vary considerably from measurement to measurement due to preferred orientation effects. According to USP941 (United States Pharmacopeia, 37th Edition, General Chapter 941), the relative intensities between two samples of the same material can vary considerably due to "preferred orientation" effects. Anisotropic materials that adopt preferred orientations result in anisotropic distributions of properties such as elastic modulus, strength, ductility, toughness, electrical conductivity, and thermal expansion, as described, for example, in Kocks UF et al. (Texture and Anisotropy: Preferred Orientations in Polycrystals and Their Effects on Material Properties, Cambridge University Press, 2000). In Raman spectroscopy as well as XRPD, preferred orientation induces changes in the intensity distribution. The preferred orientation effect is especially pronounced for crystalline APIs with relatively large particle sizes.

[0045] "Diagrammatic peaks" refer to the presence of X-ray powder diffraction peaks that conclusively identify 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one as the reference crystalline form (Form A or Form D). Typically, X-ray powder diffraction analysis is performed at ambient conditions in transmission geometry using a STOE STADI P diffractometer (CuKα1 radiation, primary monochromator, silicon strip detector, angular range 3-42 degrees 2-theta, total measurement time of approximately 30 minutes). Samples (approximately 10-50 mg) are prepared between thin polymer membranes and the material is analyzed without further processing (e.g., grinding or sieving).

[0046] "Polymorphs" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions that form the crystal. Generally, references throughout this specification are to polymorphs of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one.

[0047] The term "solvate" as used herein refers to a molecular complex comprising a compound of formula (I) and one or more solvent molecules (eg, ethanol) in either stoichiometric or non-stoichiometric amounts.

[0048] "Hydrate," as used herein, refers to a solvate that comprises a compound of formula (I) and a stoichiometric or non-stoichiometric amount of water.

[0049] The terms "pharmaceutically acceptable excipient", "pharmaceutically acceptable carrier" and "therapeutically inactive excipient" may be used interchangeably and refer to any pharma- ceutically acceptable ingredient in a pharmaceutical composition that has no therapeutic activity and is non-toxic to a subject to which it is administered, such as a disintegrant, binder, filler, solvent, buffer, isotonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent or lubricant used in formulating a pharmaceutical product.

[0050] "Transition metal hydrogenation catalyst" refers to a transition metal hydrogenation catalyst that operates in a different phase than the substrate. In particular, the transition metal hydrogenation catalyst is in the solid phase. In particular, the reactants are in the liquid phase while the transition metal hydrogenation catalyst is in the solid phase. Transition metal hydrogenation catalysts include fibrous metals (i.e., Pd, Pt, Rh, Au, Ni, Co, Ru, Ir, V, Fe), especially precious metals such as Pd, Pt, Rh or Au, that form one or more stable ions with incompletely filled d-orbitals. In these catalysts, the transition metal is especially "supported", meaning that the catalyst is dispersed on a second material that enhances its effectiveness. The "support" can simply be a surface on which the metal is spread to increase the surface area. Supports are porous materials with high surface areas, most commonly alumina or various types of carbon. Further examples of supports include, but are not limited to, silicon dioxide, titanium dioxide, calcium carbonate, barium sulfate, diatomaceous earth and clay. The metal itself can also act as a support if no other support is present. More specifically, the term "transition metal hydrogenation catalyst" includes, but is not limited to, Raney catalysts (e.g., Ra-Ni, Ra-Co,) Pd / C, Pd(OH)2 / C, Au / TiO2, Rh / C, Ru / Al2O3, Ir / CaCO3, Pt-V / C or Pt / C, especially Pt-V / C.

[0051] A "tertiary amine" is an amine of the formula R a N(R b )R c (In the formula, R a , R b and R c are independently selected from (C1-C6) alkyl or phenyl). Representative examples include, but are not limited to, triethylamine, tributylamine, diethyl-methylamine, dimethyl-ethylamine, di-isopropylethylamine, N,N-dimethylaniline and methylethylbutylamine. Preferably, the tertiary amine is selected from triethylamine or di-isopropylethylamine. The most preferred tertiary amine is triethylamine.

[0052] The terms "treating," "contacting," or "reacting," which are used interchangeably, refer to the addition, combining, or mixing of two or more chemicals (usually referred to as reagents or reactants), more specifically, under appropriate conditions to produce the indicated and / or desired product. It is understood that the reaction that produces the indicated and / or desired product does not necessarily result directly from the combination of the two reagents initially added, i.e., there may be one or more intermediates that are produced in the mixture that ultimately results in the formation of the indicated and / or desired product.

[0053] The term "active pharmaceutical ingredient" (or "API") refers to a compound or molecule in a pharmaceutical composition that has a specific biological activity.

[0054] The terms "pharmaceutical composition" and "pharmaceutical formulation" (or "formulation") are used interchangeably and refer to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient and pharma- ceutical acceptable excipients, for administration to a mammal, e.g., a human, in need of treatment.

[0055] The term "pharmaceutical acceptable" refers to the properties of a material useful in preparing pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and that are acceptable for veterinary and human pharmaceutical use.

[0056] The terms "pharmaceutically acceptable excipient", "pharmaceutically acceptable carrier" and "therapeutically inactive excipient" may be used interchangeably and refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition that has no therapeutic activity and is non-toxic to a subject to which it is administered, such as a disintegrant, binder, filler, solvent, buffer, isotonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent or lubricant used in formulating a pharmaceutical product.

[0057] The term "individual" or "subject" refers to a mammal. Mammals include, but are not limited to, domestic animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human.

[0058] The term "therapeutically effective amount" refers to an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The therapeutically effective amount will vary depending on the compound, the condition being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0059] The term "treating" or "treatment" of a medical condition includes inhibiting the medical condition, i.e., arresting the medical condition or its occurrence, or relieving the medical condition, i.e., causing a temporary or permanent regression of the medical condition or its clinical symptoms.

[0060] The term "Spinal Muscular Atrophy" (or SMA) refers to a disease caused by inactivating mutations or deletions of both SMN1 genes on chromosomes, resulting in loss of SMN1 gene function. Symptoms of SMA include muscle weakness, poor muscle tone, weak cry, weak cough, lameness or tendency to float, difficulty in aspirating or swallowing, difficulty breathing, accumulation of secretions in the lungs or throat, calluses with sweaty hands, flickering / shaking tongue, head frequently tilted to one side even when lying down, legs that tend to be weaker than arms, legs frequently adopting a "frog leg" position, difficulty feeding, increased susceptibility to respiratory tract infections, bowel / bladder weakness, lower than normal weight, inability to sit unsupported, inability to walk, inability to crawl, and hypotonia, anorexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells.

[0061] The term "treating spinal muscular atrophy (SMA)" or "treatment of spinal muscular atrophy (SMA)" includes one or more of the following effects: (i) reducing or reversing the severity of SMA; (ii) delaying the onset of SMA; (iii) inhibiting the progression of SMA; (iv) reducing the need for hospitalization in a subject; (v) reducing the length of hospitalization in a subject; (vi) extending survival in a subject; (vii) improving the quality of life in a subject; (viii) reducing the number of symptoms associated with SMA; (ix) reducing or reversing the severity of one or more symptoms associated with SMA; (x) reducing the duration of symptoms associated with SMA; (xi) preventing the recurrence of symptoms associated with SMA; (xii) inhibiting the onset or onset of SMA; and / or (xiii) inhibiting the progression of symptoms associated with SMA.

[0062] More specifically, the term "treating SMA" refers to one or more of the following beneficial effects: (i) reducing muscle weakness; (ii) increasing muscle strength; (iii) reducing muscle atrophy; (iv) reducing loss of motor function; (v) increasing motor neurons; (vii) reducing loss of motor neurons; (viii) protecting SMN-deficient motor neurons from degeneration; (ix) increasing motor function; (x) increasing pulmonary function; and / or (xi) reducing loss of pulmonary function.

[0063] More specifically, the term "treating SMA" refers to the functional ability or retention of the functional ability of a human infant or human toddler to sit unassisted, or of a human infant, human toddler, human child, or human adult to stand unassisted, walk unassisted, run unassisted, breathe unassisted, turn in sleep unassisted, or swallow unassisted.

[0064] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical composition, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0065] The term "buffer" or "buffer system" refers to a pharma- ceutically acceptable excipient or mixture of excipients that stabilizes the pH of a pharmaceutical formulation. Suitable buffers are well known in the art and can be found in the literature. Particular pharma-ceutically acceptable buffers include citrate, malate, maleate or tartrate buffers, most particularly tartrate buffers. Particular buffer systems of the present invention include a combination of an organic acid and a selected salt thereof, such as tribasic sodium citrate and citric acid, malic acid and sodium malate, sodium potassium tartrate and tartaric acid, or disodium tartrate and tartaric acid, specifically sodium potassium tartrate and tartaric acid. Alternatively, an organic acid, specifically tartaric acid, may be used alone as an "acidifier", instead of a combination of an acid and a corresponding salt. Regardless of the buffer used, the pH can be adjusted with acids or bases known in the art, such as hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid and citric acid, sodium hydroxide and potassium hydroxide. A particular acidifier is tartaric acid.

[0066] The term "antioxidant" refers to a pharma- ceutically acceptable excipient that prevents oxidation of an active pharmaceutical ingredient. Antioxidants include ascorbic acid, glutathione, cysteine, methionine, vitamin ETPGS, EDTA.

[0067] The term "surfactant" refers to a pharma- ceutically acceptable excipient used to protect a protein composition from mechanical stresses such as agitation and shear. Examples of pharma-ceutically acceptable surfactants include poloxamers, polysorbates, polyoxyethylene alkyl ethers (BRIJ®), alkylphenyl polyoxyethylene ethers (TRITON®-X) or sodium dodecyl sulfate (SDS).

[0068] The term "poloxamer" refers to a non-ionic triblock copolymer composed of a central hydrophobic chain of poly(propylene oxide) (PPO) flanked by two hydrophilic chains of poly(ethylene oxide) (PEO), where each PPO or PEO chain may be of different molecular weight. Poloxamers are also known by the trade name Pluronics. A specific poloxamer is Poloxamer 188, which is a poloxamer with a molecular mass of the PPO chain of 1800 g / mol and a PEO content of 80% by weight.

[0069] The term "polysorbate" typically refers to oleic acid esters of sorbitol and its anhydrides copolymerized with ethylene oxide. Particular polysorbates are polysorbate 20 (poly(ethylene oxide)(20) sorbitan monolaurate, TWEEN® 20) or polysorbate 80 (poly(ethylene oxide)(80) sorbitan monolaurate, TWEEN® 80).

[0070] The "hydrophilic-lipophilic balance" (HLB) value refers to the degree of hydrophilicity of a nonionic surfactant. The HLB value is determined by the ratio of the molecular mass of the hydrophilic portion of the surfactant molecule to its total molecular mass, as described by Griffin WC, Journal of the Society of Cosmetic Chemists (1949) 1:311. The term "hydrophilic" refers to the ability of a molecule or a portion of a molecule to interact with polar solvents, particularly water, or other polar moieties driven by hydrogen bonding, dipole-ion interactions, and / or dipole-dipole interactions.

[0071] The terms "lipophilic" and "hydrophobic" can be used interchangeably and refer to the tendency of a molecule or part of a molecule to dissolve in non-polar environments such as fats, oils, and non-polar solvents, driven by London dispersion forces.

[0072] The term "mg / ml" in accordance with the pharmaceutical compositions of the present invention means the amount of either the compound of formula (I) or an individual excipient in the formulation in milligrams per volume of solvent, specifically when the solvent is water, most specifically purified water in the constituted solution in milliliters.

[0073] The present application relates to a compound of formula (II) [ka] A process for preparing a compound of the formula Formula (III) [ka] where X is an alkyl or aryl sulfonate (e.g., 3-, CH3SO3-, phenylSO3), a fluorinated alkyl or aryl sulfonate (e.g., CF3SO3, nonaflate), or a halide (such as Cl, Br, or I) Formula (III'), (III a ') or (III b '), in particular of formula (III') [ka] in the presence of a palladium or nickel catalyst, particularly in the presence of a palladium catalyst.

[0074] More specifically, the present application relates to a compound of formula (II): [ka] A process for preparing a compound of the formula Formula (III a ) [ka] Compound Formula (III') [ka] in the presence of a palladium or nickel catalyst, particularly in the presence of a palladium catalyst further comprising a base (particularly, the base is Na2CO3, K2CO3, Cs2CO3, KOAc or KOtBu, more particularly, the base is K2CO3).

[0075] The present application relates to a compound of formula (II) [ka] A process for preparing a compound of the formula a) reacting a compound of formula (III″) with [ka] and bis(pinacolato)diboron to give a compound of formula (III') [ka] obtaining a compound of formula (I), b) Formula (III) [ka] Compound (wherein X is an alkyl or aryl sulfonic acid (e.g., pTolSO3-, CH3SO3-, phenyl-SO3-), a fluorinated alkyl or aryl sulfonate (e.g., CF3SO3, nonaflate), or a halide (such as Cl, Br, or I), formula (III'), (III a ') or (III b '), In particular, the formula (III') [ka] in the presence of a palladium or nickel catalyst, in particular in the presence of a palladium catalyst, to obtain a compound of formula (II) A process is disclosed that includes:

[0076] The present application relates to a compound of formula (II) [ka] A process for preparing a compound of the formula a) reacting a compound of formula (III″) with [ka] reacting with bis(pinacolato)diboron to obtain a compound of formula (III'); [ka] b) Formula (III a ) compound, [ka] Formula (III') [ka] in the presence of a palladium or nickel catalyst, in particular in the presence of a palladium catalyst, to obtain a compound of formula (II), a ) with a compound of formula (III'), (III a ') or (III b '), in particular a compound of formula (III'), in the presence of a palladium or nickel catalyst, in particular a palladium catalyst as defined herein, in the presence of a base, in particular the base being Na2CO3, K2CO3, Cs2CO3, KOAc or KOtBu, more particularly the base being K2CO3. A process is disclosed that includes:

[0077] The present application relates to a compound represented by formula (III) [ka] A process for preparing wherein X is an alkyl or aryl sulfonic acid (e.g., pTolSO3-, CH3SO3-, phenyl-SO3-), a fluorinated alkyl or aryl sulfonic acid (e.g., CF3SO3-, nonaflate), or a halide (such as Cl, Br, or I), the compound of formula (IV) can be reacted with [ka] with tosyl chloride when X is pTol-SO3-, with methanesulfonyl chloride when X is CH3SO3-, with triflyl chloride when X is CF3SO3-, or with phenylsulfonyl chloride when X is phenyl-SO3-, and in the presence of a base (particularly, the base is an organic base or a basic alkali metal salt, more particularly, the base is a nitrogen-containing heterocycle, a tertiary amine or a basic alkali metal salt, and most particularly, the base is a tertiary amine); - POCl3 if X is Cl; - POBr3 if X is Br; or - If X is I 、A process is disclosed that involves reacting with Ph3PI2 or POCl3 followed by NaI or CuI.

[0078] The present application relates to a compound of formula (III a A process for preparing a compound of formula (I), comprising the steps of: [ka] The compound of formula (IV) [ka] Disclosed is a process comprising reacting tosyl chloride in the presence of a base, particularly where the base is an organic base or a basic alkali metal salt, more particularly where the base is a nitrogen-containing heterocycle, a tertiary amine or a basic alkali metal salt, most particularly where the base is a tertiary amine.

[0079] The present application relates to a compound of formula (IV) [ka] A process for preparing a compound of the formula The compound of formula (V) [ka] A process is disclosed that includes reacting with di-tert-butyl malonate.

[0080] The present application relates to a compound of formula (IV) [ka] A process for preparing a compound of the formula a) reacting a compound of formula (VI) [ka] reducing to a compound of formula (V), [ka] b) reacting the compound of formula (V) with di-tert-butyl malonate to obtain the compound of formula (IV) A process is disclosed that includes:

[0081] The present application relates to a compound of formula (IV) [ka] A process for preparing a compound of the formula Compound of formula (VI) [ka] a) reacting with a transition metal hydrogenation catalyst to obtain a compound of formula (V); [ka] b) reacting the compound of formula (V) with di-tert-butyl malonate to obtain the compound of formula (IV) A process is disclosed that includes:

[0082] In particular, the process for the preparation of a compound of formula (IV) comprising reacting a compound of formula (V) with di-tert-butyl malonate is carried out in the presence of xylene, dichlorobenzene, toluene or anisole, in particular in the presence of anisole.

[0083] More specifically, the preparation of compounds of formula (IV) wherein the transition metal hydrogenation catalyst is a Raney catalyst (e.g. Ra-Ni, Ra-Co,) Pd / C, Pd(OH)2 / C, Au / TiO2, Rh / C, Ru / Al2O3, Ir / CaCO3, Pt-V / C or Pt / C or combinations thereof, in particular Pt-V / C, more specifically Pt 1% and V 2% on activated carbon.

[0084] The present application relates to a compound of formula (VI) [ka] 2. The preparation of a compound of formula (I), Formula (VII) [ka] Compound Formula (VIII) [ka] or a salt thereof (particularly the oxalate salt), (more specifically the salt of the compound of formula (III) is tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate oxalate).

[0085] In particular, a process for the preparation of a compound of formula (VI), comprising reacting a compound of formula (VII) with a compound of formula (VIII) in the presence of lithium chloride, dimethylsulfoxide and a base such as tetramethylguanidine, triethylamine, diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), specifically tetramethylguanidine.

[0086] In a further embodiment, the present application discloses the preparation of compounds of formula (V) according to Scheme 1.

[0087] Scheme 1: [ka]

[0088] In particular, compounds of formula (IX) may be used in the preparation of catalysts such as Pd(PPh3)4, PdCl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf), CH2Cl2, PdCl2(dppp), PdCl2(CH3CN), cyclopentadienylallylpalladium, allylpalladium(II) chloride dimer (Pd(allyl)Cl)2, (2-butenyl)chloropalladium dimer, (2-methylallyl)palladium(II) chloride dimer, palladium(1-phenylallyl) chloride dimer, di-μ-chlorobis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl ... The compound of formula (X) can be prepared by reacting a compound of formula (X) with a compound of formula (VIII) in the presence of dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium (such as, but not limited to, Pd(xantphos)Cl), in particular in the presence of dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium, and in the presence of a base (such as, for example, Na2CO3, K2CO3, Cs2CO3, KOtBu, NaOtBu((CH3)3CONa) or KOAc; in particular KOtBu), in particular in the presence of 2-methyltetrahydrofuran, THF or dioxane, more particularly in the presence of 2-methyltetrahydrofuran.

[0089] Compound (V) is Pd(PPh3)4, PdCl 2、Pd(OAc)2, Pd2(dba)3, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf).CH2Cl2, PdCl2(dppp), PdCl2(CH3CN), cyclopentadienylallylpalladium, allylpalladium(II) chloride dimer, (Pd(allyl)Cl)2, (2-butenyl)chloropalladium dimer, (2-methylallyl)palladium(II) chloride dimer, palladium(1-phenylallyl) chloride dimer, di-μ-chlorobis[2'-(amino-N)[1 The compound (IX) can be prepared by reacting compound (IX) with ammonia (NH3) in the presence of a catalyst such as di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II), particularly in the presence of Pd2(dba)3, and in the presence of a base (e.g. Na2CO3, K2CO3, Cs2CO3, KOtBu, NaOtBu((CH3)3CONa) or KOAc; particularly KOtBu) and t-BuBrettPhos.

[0090] Preferably, this step is carried out in dioxane.

[0091] Compounds of formula (V) may also be prepared according to Scheme 2. Scheme 2: [ka]

[0092] In particular, compounds of formula (V) can be prepared by the reaction of the aryl palladium(II) chloride dimer (Pd(allyl)Cl), in the presence of a catalyst (e.g. Pd(PPh3)4, Pd(OAc)2, Pd2(dba)3, PdCl2, PdCl2(dppf), PdCl2(dppf).CH2Cl2, PdCl2(dppp), allylpalladium(II) chloride dimer (Pd(allyl)Cl)2, (2-butenyl)chloropalladium dimer, (2-methylallyl)palladium(II) chloride dimer, palladium(1-phenylallyl) chloride dimer, di-μ-chlorobis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II)), in particular allylpalladium(II) chloride dimer (Pd(allyl)Cl). )Cl)2 or palladium(1-phenylallyl)chloride dimer; and in the presence of a ligand (e.g., 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (DavePhos) or 2-di-tert-butylphosphino-2'-(N,N-dimethylamino)biphenyl (tBuDavePhos), in particular: tBuDavePhos) and a base (e.g., Na2CO3, K2CO3, Cs2CO3, KOtBu, NaOtBu((CH3)3CONa), KOAc or lithium-bis(trimethylsilyl)amide; in particular lithium-bis(trimethylsilyl)amide, in particular tetrahydrofuran), by reacting a compound of formula (X) with a compound of formula (VIII).

[0093] The present invention is carried out in the presence of an organic solvent, such as an ethereal solvent (e.g., tetrahydrofuran, diisopropyl ether, t-butyl methyl ether, cyclopentyl-methyl-ether or dibutyl ether), a chlorinated solvent (e.g., dichloromethane, chloroform) or an aromatic solvent (e.g., anisole, toluene or t-butyl-benzene). In particular, the solvent used in the preparation of the compound of formula (I) according to embodiment 1 is toluene.

[0094] The reaction is especially carried out under an inert gas atmosphere, more especially under argon or nitrogen.

[0095] The present application discloses a process for the preparation of the compound of formula (III″) according to Scheme 3.

[0096] Scheme 3: [ka]

[0097] In particular, depending on the application, the compound of formula (XII) is prepared by reacting the compound of formula (XIII) with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), N-bromo-succinimide or bromine, optionally with sodium acetate or sodium bicarbonate, in the presence of a solvent such as an alcohol (e.g., methanol or ethanol). Further, compounds of formula (XI) can be prepared by reacting compounds of formula (XII) with methylmagnesium chloride or bromide, methylboronic acid, methylborate, dimethylzinc or methyllithium, optionally in the presence of zinc chloride, or in the presence of a catalyst (e.g., Pd(PPh3)4, PdCl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf).CH2Cl2, PdCl2(dppp), cyclopentadienylallylpalladium, allylpalladium(II) chloride dimer (Pd(allyl)Cl) in methyltetrahydrofuran or THF. 2(2-butenyl)chloropalladium dimer, (2-methylallyl)palladium(II) chloride dimer, palladium(1-phenylallyl)chloride dimer, di-μ-chlorobis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium (Pd(XantPhos)Cl2)), in particular in the presence of Pd(PPh3)4), are prepared by reacting with dimethylzinc in the presence of 2(2-butenyl)chloropalladium dimer, (2-methylallyl)palladium(II) chloride dimer, (2-methylallyl)palladium(II) chloride dimer, di-μ-chlorobis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium (Pd(XantPhos)Cl2)), in particular in the presence of Pd(PPh3)4). Compounds of formula (III'') are prepared by reacting chloroacteon with compounds of formula (XI) in the presence of a tertiary amine and sodium bromide.

[0098] Alternatively, compounds of formula (III'') can be prepared according to the process described in WO2015173181.

[0099] Furthermore, the present application relates to a compound of formula (III) according to Scheme 4. a ') or (III b A process for preparing the compound of formula (I) is disclosed.

[0100] Scheme 4: [ka]

[0101] A particular embodiment of the present invention also relates to a pharmaceutical composition comprising a compound of formula (I) obtained as described herein and at least one pharma- ceutically acceptable excipient.

[0102] A further particular embodiment of the present invention also relates to a compound of formula (I) obtained by the process described herein for use as a therapeutically active substance.

[0103] A-type manufacturing process: Form A of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one can be obtained by dissolving 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one in dioxane at elevated temperatures (e.g., above 22° C.), in particular at 80° C. Upon cooling, 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one crystallized spontaneously as Form A.

[0104] Alternatively, Form A can be obtained by prolonged equilibration of solid 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one in an organic solvent or mixtures thereof. In particular, 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one can be suspended in ethanol, methyl ethyl ketone, ethyl acetate or dioxane at ambient or elevated temperatures (e.g., 22-65° C.) for 2-3 weeks to provide 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one as Form A.

[0105] To obtain Form A, 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one is dissolved in water as the corresponding hydrochloride salt with hydrochloric acid. This solution is slowly added to an ethanolic solution of sodium hydroxide (a molar excess of sodium hydroxide relative to the hydrochloric acid added) at elevated temperature (e.g., above 22°C), particularly at 60-70°C, more particularly at 60°C. Spontaneous crystallization By , saturated solutions and suspensions containing crystalline solids of Form A but The suspension is cooled, filtered, washed to remove sodium chloride, and dried under vacuum at elevated temperature (e.g., above 22° C., especially 60° C.). To control solid Form A, the final conditions in the suspension need to be controlled by controlling the maximum water concentration and minimum temperature.

[0106] Alternatively, with the application of crystals of Form A used as seed crystals, further Form A can be obtained during crystallization. 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one can be dissolved in water as the corresponding hydrochloride salt with hydrochloric acid. A portion of this solution is added to an ethanolic solution of sodium hydroxide (a molar excess of sodium hydroxide relative to the hydrochloric acid added) at elevated temperatures (20-70°C, specifically 60°C) to obtain a 20% yield of Form A. In addition To the solution thus produced, crystals of Form A are added (either as dry crystals or suspended in an organic solvent, e.g. ethanol). A suspension is formed. The remaining hydrochloride solution is added slowly at elevated temperature. The suspension is cooled, filtered, washed to remove sodium chloride, and dried at elevated temperature (e.g. above 22°C, especially 60°C) under reduced pressure. To control the solid Form A, the final conditions in the suspension need to be controlled by controlling the maximum water concentration and the minimum temperature (e.g. no more than 12% water by weight in ethanol above 40°C).

[0107] Preparation process of D type: Form D can be obtained by prolonged equilibration of solid 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one in water or an organic solvent containing water. 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one can be suspended in water or a mixture of organic solvents and water, in particular an ethanol / water mixture. In particular, by equilibrating the mixture in water or ethanol / water (20 / 80 v / v) at 65° C. for 2-3 weeks, 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one can be obtained as the D-form. In particular, by equilibrating the mixture in water or ethanol / water (20 / 80-50 / 50-80 / 20) at 22° C. for 2-3 weeks, 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one can be obtained as the D-form.

[0108] A particular embodiment of the present invention relates to crystalline Form A of the compound of formula I described herein, characterized by the X-ray powder diffraction pattern shown in FIG.

[0109] A particular embodiment of the present invention relates to crystalline Form A of the compound of formula I described herein, characterized by the Raman spectrum shown in FIG.

[0110] A particular embodiment of the present invention relates to crystalline Form A of the compound of formula I described herein, characterized by the infrared spectrum depicted in FIG.

[0111] Starting materials and reagents that do not have a synthetic route thereto expressly disclosed herein are generally available from commercial sources or are readily prepared using methods well known to those of ordinary skill in the art.

[0112] 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one was found to crystallize in various crystal structures as a pure compound (polymorphs). Of these, Form A is the thermodynamically stable polymorph, especially between 5°C and 65°C.

[0113] In another embodiment, 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one was found to crystallize in various crystal structures as a hydrous compound. With sufficiently high water activity, Form D is the stable hydrated form.

[0114] In another embodiment, the present invention provides crystalline Form A or D of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one.

[0115] In certain embodiments, the present invention provides polymorphic Form A of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, characterized by an X-ray powder diffraction pattern (XRPD) with peaks at diffraction angles 2-theta of about 12.7°, 15.9°, 24.0°, and 25.6° (±0.2°).

[0116] In certain embodiments, Form A is characterized by an XRPD diffraction pattern comprising the XRPD peaks at diffraction angles 2 theta shown in Table 2.

[0117] In certain embodiments, Form A is characterized by the XRPD in FIG.

[0118] Table 1 shows the relevant crystal structure data for Form A.

[0119] Lattice constants, unit cell volumes and density calculations are based on ambient temperature data.

[0120] [Table 1]

[0121] [Table 2]

[0122] In a particular embodiment, the present invention provides a method for determining the wavelength of a magnetic field having a wavelength of 848 (±2) cm -1 , 885(±2)cm -1 , 939(±2)cm -1 , or 1218(±2)cm -1 Specifically, the peak at one of the positions is 848 (± 2) cm -1 , 885(±2)cm -1 , 939(±2)cm -1 , or 1218(±2)cm -1 More specifically, at least two peaks at 848 (± 2) cm -1 , 885(±2)cm -1 , 939(±2)cm -1 , or 1218(±2)cm -1 At least three peaks at positions 848 (± 2) cm -1 , 885(±2)cm -1 , 939(±2)cm -1 , and 1218(±2)cm -1 The present invention provides a polymorphic Form A of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, characterized by an infrared (IR) spectrum including four peaks at positions

[0123] In a further embodiment, Form A is characterized by an IR spectrum comprising IR peaks at the positions indicated in Table 3.

[0124] [Table 3]

[0125] According to the invention described herein, ATR FTIR spectra were recorded without sample preparation using a Thermo Nicolet iS5 FTIR spectrometer equipped with an iD5ATR accessory and a DTGS detector. The spectral range was 4000 cm -1 ~650cm -1 and the resolution is 2cm -1 and at least 50 simultaneous additional scans were collected. Happ-Genzel apodization was applied.

[0126] In a particular embodiment, the present invention provides a method for determining the degree of freedom of movement of a fiber having a fiber length of 213(±2) cm -1 , 257(±2)cm -1 , 1061(±2)cm -1 , or 1570(±2)cm -1 Specifically, the peak is at least one peak at one of the positions at 213 (± 2) cm -1 , 257(±2)cm -1 , 1061(±2)cm -1 , or 1570(±2)cm -1 More specifically, at least two peaks at 213(±2) cm -1 , 257(±2)cm -1 , 1061(±2)cm -1 , or 1570(±2)cm -1 and more specifically, at least two peaks at 213(±2) cm -1 , 257(±2)cm -1 , 1061(±2)cm -1 , or 1570(±2)cm -1 At least three peaks at positions 213(±2) cm -1 , 257(±2)cm -1 , 1061(±2)cm -1 , or 1570(±2)cm -1The present invention provides a polymorphic form A of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, characterized by a Raman spectrum containing four peaks at positions

[0127] In a further embodiment, Form A is characterized by a Raman spectrum comprising Raman peaks at the positions indicated in Table 4.

[0128] [Table 4]

[0129] In accordance with the invention described herein, FT-Raman spectra were obtained using a Bruker MultiRam FT-Raman spectrometer equipped with a NdYAG 1064 nm laser and a liquid nitrogen cooled germanium detector from 4000 to 50 cm. -1 The laser power at the sample was approximately 200 mW and the focal length was 2 cm -1 A resolution of 1024 or 2048 scans were added simultaneously. The apodization used was Blackman-Harris 4-term.

[0130] In certain embodiments, the present invention provides a hydrate Form D of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, characterized by an XRPD with peaks at diffraction angles at about 8.4 (±0.2) degrees two-theta, 23.5 (±0.2) degrees two-theta, 24.4 (±0.2) degrees two-theta, and 25.3 (±0.2) degrees two-theta.

[0131] In certain embodiments, Form D is characterized by an XRPD diffraction pattern comprising the XRPD peaks at diffraction angles 2-theta shown in Table 5.

[0132] In certain embodiments, Form D is characterized by the XRPD diffraction pattern of FIG.

[0133] [Table 5]

[0134] In a specific embodiment, the present invention provides a method for detecting a magnetic field of 800(±2) cm -1 , 1212(±2)cm -1 , 1349(±2)cm -1 , or 1577(±2)cm -1 Specifically, the peak at one of the positions is 800 (± 2) cm -1 , 1212(±2)cm -1 , 1349(±2)cm -1 , or 1577(±2)cm -1 More specifically, at least two peaks at positions 800 (± 2) cm -1 , 1212(±2)cm -1 , 1349(±2)cm -1 , or 1577(±2)cm -1 and more specifically, at least two peaks at positions 800 (± 2) cm -1 , 1212(±2)cm -1 , 1349(±2)cm -1 , or 1577(±2)cm -1 At least three peaks at positions 800 (± 2) cm -1 , 1212(±2)cm -1 , 1349(±2)cm -1 , or 1577(±2)cm -1 The present invention provides a hydrate form D of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, characterized by an infrared (IR) spectrum containing four peaks at positions

[0135] In a further embodiment, Form D is characterized by an IR spectrum comprising IR peaks at the positions indicated in Table 6.

[0136] [Table 6]

[0137] In a specific embodiment, the present invention provides a method for measuring the temperature of a semiconductor laser using a 452 (± 2 cm -1 ), 870 (± 2 cm -1 ), 1311 (±2cm -1 ), or 1578 (±2 cm -1 ) position, specifically, at least one peak at one of 452 (± 2 cm -1 ), 870 (± 2 cm -1 ), 1311 (±2cm -1 ) or 1578 (±2 cm -1 ), more specifically, at least two peaks at 452 (± 2 cm -1 ), 870 (± 2 cm -1 ), 1311 (±2cm -1 ) or 1578 (±2 cm -1 ) and more specifically, at least two peaks at 452 (± 2 cm -1 ), 870 (± 2 cm -1 ), 1311 (±2cm -1 ) or 1578 (±2 cm -1 ), most specifically, at least three peaks at 452 (± 2 cm -1 ), 870 (± 2 cm -1 ), 1311 (±2cm -1 ), or 1578 (±2 cm -1 ) of hydrated form D of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, characterized by a Raman spectrum containing four peaks at positions

[0138] In a further embodiment, Form D is characterized by a Raman spectrum comprising Raman peaks at the positions indicated in Table 7.

[0139] [Table 7]

[0140] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), particularly 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one or a pharma- ceutically acceptable salt thereof, and more particularly Form A of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, wherein the composition is an oral solution or a dry powder suitable for constituting an oral solution in water.

[0141] The compounds of formula (I) can be formulated as an oral aqueous solution by dissolving the drug substance in a buffer system, such as a citrate buffer system, a malate buffer system, a maleate buffer system or a tartrate buffer system, most particularly a tartrate buffer system, at a pH below pH 4, particularly below pH 3.8, more particularly below pH 3.6, and most particularly between pH 3.0 and pH 3.2, to provide a sufficiently high drug concentration.

[0142] A low pH has been found to improve the preservative effectiveness of the formulation, thereby helping to minimize the concentration of the compounds of the invention described herein, this refers to the formulation once reconstituted in an aqueous solution.

[0143] The long-term stability of the formulation of the compound of formula (I) can be achieved by preparing a dry powder to constitute an oral solution or by granulation.A buffer system can be incorporated into the dry formulation by selecting an organic acid and its salt, such as tribasic sodium citrate and citric acid, disodium malate and malic acid, sodium potassium tartrate and tartaric acid, or disodium tartrate and tartaric acid, specifically sodium potassium tartrate and tartaric acid, as fine powder.Alternatively, an organic acid, specifically tartaric acid, can be used alone as an acidifier, instead of the combination of the acid and the corresponding salt.

[0144] Powders or granules containing the compound of formula (I) may contain diluents such as sorbitol, isomalt, or specifically mannitol, and combinations thereof, which ensure rapid dissolution of the powder blend when forming an oral solution. Upon introduction of fillers, the powder blend may be granulated by dry compression to improve flowability and ensure robust uniformity.

[0145] The components for constituting the solvent system of the compound of formula (I) can be formulated as separate preparations. The constituted solvent can be used to dissolve the compound of formula (I) in the bottle at the beginning of the period of use of the oral solution.

[0146] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof in powder form for constituting an oral solution.

[0147] In a particular embodiment of the present invention, the pharmaceutical composition comprising the compound of formula (I) or a pharma- ceutically acceptable salt thereof is packaged in a multi-dose bottle with an adaptor for use with an oral dispenser. It has been found that such a multi-dose bottle with an adaptor for use with an oral dispenser provides increased dosing flexibility, for example, by allowing the dosage to be adjusted according to body weight, and provides safe and convenient dosing.

[0148] In a particular embodiment of the present invention, the pharmaceutical composition comprising the compound of formula (I) or a pharma- ceutically acceptable salt thereof is prepared by dry granulation by roller compaction and then filled into a bottle. Such processing has been found to be beneficial (especially for water-soluble fillers) to prevent segregation.

[0149] Certain embodiments of the present invention relate to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, which is an oral aqueous solution or a dry powder suitable for constitution into an oral aqueous solution.

[0150] Certain embodiments of the present invention relate to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, which is an aerosol-free oral solution or a dry powder suitable for making up an oral aqueous solution.

[0151] In certain embodiments of the invention, a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof is not an aerosol.

[0152] In certain embodiments of the invention, the pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof does not include an isotonicity agent, for example a salt such as sodium chloride.

[0153] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, in the form of an oral solution, or a dry powder suitable for constituting an oral solution having a pH of less than pH 4, particularly less than pH 3.8, more particularly less than pH 3.6, and most particularly between pH 3.0 and pH 3.2.

[0154] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and a citrate, malate, maleate or tartrate buffer system, particularly a malate or tartrate buffer system, most particularly a tartrate buffer system; or alternatively, the corresponding acid of the buffer system alone as an acidifying agent, particularly tartaric acid, which is an oral aqueous solution or a dry powder suitable for constituting an oral aqueous solution.

[0155] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the pharmaceutical composition is an oral aqueous solution.

[0156] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, the pharmaceutical composition being an oral aqueous solution in a buffer system at a pH of less than pH 4, particularly less than pH 3.8, more particularly less than pH 3.6, and most particularly between pH 3.0 and pH 3.2.

[0157] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the pharmaceutical composition is an oral aqueous solution, comprising a citrate, malate, maleate or tartrate buffer system, particularly a malate or tartrate buffer system, most particularly a tartrate buffer system; or alternatively, the corresponding acid of the buffer system alone as an acidifying agent, particularly tartaric acid.

[0158] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the pharmaceutical composition is a dry powder suitable for constitution into an oral aqueous solution.

[0159] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, said composition being a dry powder comprising a buffer system suitable for constitution of an oral aqueous solution, at a buffer system having a pH of less than pH 4, particularly less than pH 3.8, more particularly less than pH 3.6, and most particularly between pH 3.0 and pH 3.2.

[0160] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, in a citrate, malate, maleate or tartrate buffer system, in particular a malate or tartrate buffer system, most in particular a tartrate buffer system; or alternatively, the corresponding acid of the buffer system alone as an acidifying agent, in particular tartaric acid, which is a dry powder suitable for constitution of an oral aqueous solution.

[0161] In one embodiment of the present invention, the pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof optionally further comprises an extragranular filler such as lactose, starch, hydrolyzed starch, maltodextrin, microcrystalline cellulose, mannitol, sorbitol, sucrose, dextrose, basic xylitol or combinations thereof.

[0162] In a particular embodiment of the invention, the extragranular filler is sorbitol, isomalt, mannitol, or a combination thereof, particularly mannitol, more particularly crystalline mannitol, most particularly crystalline mannitol with an average diameter of 160 μm (Pearlitol® 160C).

[0163] Upon introduction of a diluent, the powder blend can be granulated by dry compression to improve flowability and ensure robust uniformity.

[0164] In one embodiment of the present invention, the pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof optionally further comprises a diluent such as lactose, starch, hydrolyzed starch, maltodextrin, microcrystalline cellulose, mannitol, isomalt (E953, (2ξ)-6-O-α-D-glucopyranosyl-D-arabino-hexitol), sorbitol, sucrose, dextrose, xylitol basic or combinations thereof.

[0165] In one embodiment of the present invention, the pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof optionally further comprises a diluent such as lactose, starch, hydrolyzed starch, microcrystalline cellulose, mannitol, sorbitol, sucrose, dextrose, basic xylitol or combinations thereof.

[0166] In a particular embodiment of the invention, the diluent is mannitol, specifically D-mannitol suitable for direct compression, such as Parteck® M100.

[0167] In a particular embodiment of the invention, the diluent is a mixture of mannitol and isomalt, specifically D-mannitol and (2ξ)-6-O-α-D-glucopyranosyl-D-arabino-hexitol.

[0168] Isomalt as a second diluent has been found by the present inventors to improve granulation properties.

[0169] Constituted oral solutions of a compound of formula (I) in a buffer solution can provide a shelf life of greater than two weeks through the use of preservatives, stabilizers and antioxidants such as vitamin A, vitamin C, vitamin E, vitamin ETPGS, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sodium benzoate, sorbic acid, potassium sorbate, disodium edetate, butylhydroxyltoluene, riboflavin, ascorbic acid, or combinations thereof.

[0170] Constituted oral solutions of a compound of formula (I) in a buffered solution can provide a shelf life of greater than two weeks through the use of preservatives, stabilizers and antioxidants such as Vitamin E TPGS, edetate disodium, butyl hydroxyl toluene, riboflavin, ascorbic acid, or combinations thereof.

[0171] In one embodiment of the present invention, the pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof optionally further comprises a preservative, antioxidant and / or stabilizer, such as Vitamin E TPGS (D-alpha tocopheryl polyethylene glycol 1000 succinate), disodium ethylenediaminetetraacetate (disodium edetate, Na2EDTA), butyl hydroxyl toluene, riboflavin, ascorbic acid, or combinations thereof. It has been found that preservatives, antioxidants and / or stabilizers can be beneficial in extending the time of use in multi-dose containers or improving drug stability in solution over a period of time during use.

[0172] In a particular embodiment of the invention, the preservative is potassium sorbate, sorbic acid or sodium benzoate (E211), in particular sodium benzoate.

[0173] In a particular embodiment of the invention, the antioxidant is ascorbic acid ((5R)-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxyfuran-2(5H)-one).

[0174] In a particular embodiment of the invention, the stabilizer is disodium ethylenediaminetetraacetic acid (disodium edetate, Na2EDTA).

[0175] In one embodiment of the present invention, the pharmaceutical composition comprising the compound of formula (I) or its pharma- ceutically acceptable salt may further comprise a lubricant.It has been found that lubricants can be used as processing aids for roller compaction.In addition, lubricants can be used for water-soluble components such as PEG to ensure acceptable appearance.

[0176] In a particular embodiment of the invention, the lubricant is poly(ethylene glycol), specifically having a number average molar mass M n The molecular weight of the polymer is 6,000 (PEG6000).

[0177] In one embodiment of the present invention, the pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof optionally further comprises sweeteners and / or flavors to improve palatability.

[0178] In particular embodiments of the present invention, the flavor is strawberry flavor or vanilla flavor.

[0179] In a particular embodiment of the invention, the sweetener is sucralose (1,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl-4-chloro-4-deoxy-α-D-galactopyranoside, E955) or sodium saccharin.

[0180] In a particular embodiment of the invention, the compound of formula (I) is 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one.

[0181] In certain embodiments of the invention, the pharmaceutical composition comprises: a compound of formula (I) or a pharma- ceutically acceptable salt thereof; and - a buffer system selected from citrate, malate, maleate, or tartrate, particularly malate or tartrate, most particularly tartrate; or alternatively comprising the corresponding acid of the buffer system alone as the acidifying agent, particularly tartaric acid.

[0182] In certain embodiments of the invention, the pharmaceutical composition comprises: - a compound of formula (I) or a pharma- ceutically acceptable salt thereof; a buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as the acidifying agent, specifically tartaric acid; and - A diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol.

[0183] In certain embodiments of the invention, the pharmaceutical composition comprises: a compound of formula (I) or a pharma- ceutically acceptable salt thereof; and - A diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol.

[0184] In certain embodiments of the invention, the pharmaceutical composition comprises: - a compound of formula (I) or a pharma- ceutically acceptable salt thereof; a buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as the acidifying agent, specifically tartaric acid; Antioxidants, specifically ascorbic acid; and • Contains stabilizers, specifically edetate disodium.

[0185] In certain embodiments of the invention, the pharmaceutical composition comprises: - a compound of formula (I) or a pharma- ceutically acceptable salt thereof; a buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as the acidifying agent, specifically tartaric acid; • a diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; Antioxidants, specifically ascorbic acid; and • Contains stabilizers, specifically edetate disodium.

[0186] In certain embodiments of the invention, the pharmaceutical composition comprises: - a compound of formula (I) or a pharma- ceutically acceptable salt thereof; a buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as the acidifying agent, specifically tartaric acid; • a diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; ● Antioxidants, specifically ascorbic acid; • Stabilizers, specifically edetate disodium; and ● Contains lubricants, specifically PEG6000.

[0187] In certain embodiments of the invention, the pharmaceutical composition comprises: - a compound of formula (I) or a pharma- ceutically acceptable salt thereof; a buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as the acidifying agent, specifically tartaric acid; • a diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; ● Antioxidants, specifically ascorbic acid; • Stabilizers, specifically edetate disodium; and ● Contains lubricants, specifically PEG6000.

[0188] In certain embodiments of the invention, the pharmaceutical composition comprises: - a compound of formula (I) in form A or D, in particular in form A; a buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as the acidifying agent, specifically tartaric acid; • a diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; ● Antioxidants, specifically ascorbic acid; • Stabilizers, specifically edetate disodium; ● Lubricants, specifically PEG 6000; optionally a sweetener, particularly sucralose or sodium saccharin, most particularly sucralose; and - Optionally containing flavouring, specifically strawberry flavouring or vanilla flavouring.

[0189] In certain embodiments of the invention, the pharmaceutical composition comprises: - a compound of formula (I) in form A or D, in particular in form A; a buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as the acidifying agent, specifically tartaric acid; • a diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; ● Antioxidants, specifically ascorbic acid; • Stabilizers, specifically edetate disodium; ● Lubricants, specifically PEG 6000; • A preservative selected from sorbic acid or sodium benzoate; optionally a sweetener, particularly sucralose or sodium saccharin, most particularly sucralose; and - Optionally including flavouring, specifically strawberry flavouring or vanilla flavouring.

[0190] In certain embodiments of the invention, the pharmaceutical composition comprises: - a compound of formula (I) in form A or D, in particular in form A; a buffer system, specifically selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate, or alternatively, alone, the corresponding acid of the buffer system as the acidifying agent, specifically tartaric acid; • a diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; ● Antioxidants, specifically ascorbic acid; • Stabilizers, specifically edetate disodium; ● Lubricants, specifically PEG 6000; • A preservative selected from potassium sorbate or sodium benzoate; optionally a sweetener, particularly sucralose or sodium saccharin, most particularly sucralose; and - Optionally including flavouring, specifically strawberry flavouring or vanilla flavouring.

[0191] In certain embodiments of the invention, the pharmaceutical composition comprises: ● 1-10% by weight of a compound of formula (I) as form A or D, in particular form A; ● 2-15% by weight, in particular 4-6% by weight, of a buffer system, in particular a buffer system selected from citrate, malate, maleate or tartrate, more in particular malate or tartrate, most in particular tartrate; or alternatively alone, the corresponding acid of the buffer system as acidifying agent, in particular tartaric acid; • 40-90% by weight of a diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; ● 0.5-4% by weight of an antioxidant, specifically ascorbic acid; • 0.2-2% by weight of a stabilizer, specifically disodium edetate; ● 0.5-2% by weight of a lubricant, specifically PEG 6000; ● 1-8% by weight, in particular 1-4% by weight, of a preservative selected from potassium sorbate or sodium benzoate; ● 0-3% by weight of a sweetener, specifically sucralose or sodium saccharin, most specifically sucralose; and ● 0 to 20% by weight of a flavoring, specifically strawberry flavoring or vanilla flavoring; The total amount of ingredients does not exceed 100% by weight.

[0192] In certain embodiments of the invention, the pharmaceutical composition comprises: ● 1-10% by weight of a compound of formula (I) as form A or D, in particular form A; ● 2-15% by weight of a buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as the acidifying agent, specifically tartaric acid; • 40-80% by weight of a diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; ● 0.5-4% by weight of an antioxidant, specifically ascorbic acid; • 0.2-2% by weight of a stabilizer, specifically disodium edetate; ● 0.5-2% by weight of a lubricant, specifically PEG 6000; ● 0-3% by weight of a sweetener, specifically sucralose or sodium saccharin, most specifically sucralose; and ● Contains 0 to 20% by weight of flavoring, specifically strawberry flavoring or vanilla flavoring; The total amount of ingredients does not exceed 100% by weight.

[0193] In certain embodiments of the invention, the pharmaceutical composition comprises: ● 1-10% by weight of a compound of formula (I) as form A or D, in particular form A; ● 2-15% by weight, in particular 4-6% by weight, of a buffer system, in particular a buffer system selected from citrate, malate, maleate or tartrate, more in particular malate or tartrate, most in particular tartrate; or alternatively alone, the corresponding acid of the buffer system as acidifying agent, in particular tartaric acid; • 40-80% by weight of a diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; ● 0.5-4% by weight of an antioxidant, specifically ascorbic acid; • 0.2-2% by weight of a stabilizer, specifically disodium edetate; ● 0.5-2% by weight of a lubricant, specifically PEG 6000; ● 1-8% by weight, in particular 1-4% by weight, of a preservative selected from potassium sorbate or sodium benzoate; ● 0-3% by weight of a sweetener, specifically sucralose or sodium saccharin, most specifically sucralose; and ● 0-20% by weight of flavoring, specifically strawberry flavoring or vanilla flavoring; The total amount of ingredients does not exceed 100% by weight.

[0194] In certain embodiments of the invention, the pharmaceutical composition comprises: ● 1-10% by weight of a compound of formula (I) as form A or D, in particular form A; ● 2-15% by weight, in particular 4-6% by weight, of a buffer system, in particular a buffer system selected from citrate, malate, maleate or tartrate, more in particular malate or tartrate, most in particular tartrate; or alternatively alone, the corresponding acid of the buffer system as acidifying agent, in particular tartaric acid; • 40-80% by weight of a diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; ● 0.5-4% by weight of an antioxidant, specifically ascorbic acid; • 0.2-2% by weight of a stabilizer, specifically disodium edetate; ● 0.5-2% by weight of a lubricant, specifically PEG 6000; ● 1-8% by weight, in particular 1-4% by weight, of a preservative chosen from sorbic acid or sodium benzoate; ● 0-3% by weight of a sweetener, specifically sucralose or sodium saccharin, most specifically sucralose; and ● 0-20% by weight of flavoring, specifically strawberry flavoring or vanilla flavoring; The total amount of ingredients does not exceed 100% by weight.

[0195] In a particular embodiment of the invention, the pharmaceutical composition after constitution in water (80 ml) as a solvent comprises: - 0.25 to 2.5 mg / ml, in particular 0.25 to 0.5 mg / ml, of Form A of the compound of formula (I); ● 0.5-3.8 mg / ml, in particular 0.9-1.4 mg / ml of a buffer system, in particular a buffer system selected from citrate, malate, maleate or tartrate, more in particular malate or tartrate, most in particular tartrate; or alternatively alone the corresponding acid of the buffer system as the acidifying agent, in particular tartaric acid; • 10.0-22.5 mg / ml, especially 18.0-22.0 mg / ml of a diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; • 0.1-1.0 mg / ml, especially 0.15-0.5 mg / ml, of an antioxidant, specifically ascorbic acid; • 0.05-1.0 mg / ml, especially 0.05-0.5 mg / ml, of a stabilizer, specifically edetate disodium; • 0.1-0.5mg / ml, especially 0.2-0.3mg / ml of lubricant, specifically PEG6000; • 0.3-1.0 mg / ml, in particular 0.3-0.5 mg / ml, of a preservative selected from sorbic acid or sodium benzoate; ● 0.0 to 0.75 mg / ml, particularly 0.1 to 0.4 mg / ml of a sweetener, particularly sucralose or sodium saccharin, most particularly sucralose; and - 0.0-5.0 mg / ml, particularly 1.0-2.1 mg / ml of flavouring, specifically strawberry flavouring or vanilla flavouring.

[0196] In certain embodiments of the invention, the pharmaceutical composition comprises: ● 1-5% by weight of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one as form A or D, especially form A; • 2-8% by weight tartrate buffer system; • 60-75% by weight of mannitol as a first diluent and 8-10% by weight of isomalt as a second diluent; ● 0.5-1.5% by weight ascorbic acid as an antioxidant; • 0.25-0.75% by weight of disodium edetate as a stabilizer; ● 0.5-2 wt% PEG 6000 as a lubricant; 0.5 to 1% by weight of sucralose as a sweetener; and ● Contains 5-10% by weight of strawberry flavoring; The total amount of ingredients does not exceed 100% by weight.

[0197] In certain embodiments of the invention, the pharmaceutical composition comprises: ● 1-5% by weight of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one as form A or D, especially form A; • 2-8% by weight, especially 4-6% by weight, of a tartrate buffer system; • 60-75% by weight of mannitol as a first diluent and 10-15% by weight of isomalt as a second diluent; ● 0.5-1.5% by weight ascorbic acid as an antioxidant; • 0.25-0.75% by weight of disodium edetate as a stabilizer; ● 0.5-2 wt% PEG 6000 as a lubricant; • 1-8% by weight, especially 1-4% by weight, of sodium benzoate as a preservative; 0.5 to 1% by weight of sucralose as a sweetener; and ● Contains 5-10% by weight of strawberry flavoring; The total amount of ingredients does not exceed 100% by weight.

[0198] In a particular embodiment of the invention, the pharmaceutical composition after constitution in water (80 ml) as a solvent comprises: ● 0.25 to 1.25 mg / ml, especially 0.25 to 0.5 mg / ml of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one as form A or D, especially form A; • Tartrate buffer system of 0.5-2.0 mg / ml, especially 0.9-1.4 mg / ml; • 15.0-18.75mg / ml mannitol as the first diluent and 2.0-3.75mg / ml isomalt as the second diluent; ● 0.18-0.53mg / ml ascorbic acid as an antioxidant; • 0.05-0.15mg / ml disodium edetate as a stabilizer; • PEG 6000 at 0.1-0.5mg / ml, especially 0.2-0.3mg / ml, as a lubricant; • Sodium benzoate at 0.3-0.8mg / ml as a preservative; ● 0.13 to 0.25 mg / ml sucralose as a sweetener; and ● Contains 1.25-2.5mg / ml strawberry flavoring.

[0199] In certain embodiments of the invention, the pharmaceutical composition comprises: • 1-5% by weight of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one as Form A; • 2-8% by weight, especially 4-6% by weight, of tartaric acid; • 60-75% by weight mannitol and 8-10% by weight isomalt; ● 0.5-1.5% by weight ascorbic acid; • 0.25-0.75% by weight of disodium edetate; ● 0.5-2 wt% PEG 6000 as a lubricant; • 1-8% by weight, in particular 1-4% by weight, of sodium benzoate; 0.5 to 1% by weight of sucralose; and ● Contains 5-10% by weight of strawberry flavoring; The total amount of ingredients does not exceed 100% by weight.

[0200] In a particular embodiment of the invention, the pharmaceutical composition after constitution in water (80 ml) as a solvent comprises: • 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one as form A at 0.25-1.25 mg / ml, especially 0.25-0.5 mg / ml; • Tartaric acid at 0.5-2.0 mg / ml, especially 0.9-1.4 mg / ml; ● 15.0-18.75mg / ml mannitol and 2.0-3.75mg / ml isomalt; ● 0.18-0.53mg / ml ascorbic acid; • 0.05-0.15mg / ml disodium edetate; ● PEG6000 at 0.1-0.5mg / ml, especially 0.2-0.3mg / ml; ● Sodium benzoate at 0.3-0.8mg / ml; ● 0.13 to 0.25 mg / ml of sucralose; and ● Contains 1.25-2.5mg / ml strawberry flavoring.

[0201] Another embodiment of the invention is a kit for preparing a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, comprising: - a powder blend comprising a compound of formula (I) in form A or form D, in particular in form A; and ● Water as a constituent solvent The present invention relates to a kit comprising: Another embodiment of the invention is a kit for preparing a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, comprising: a powder blend comprising Form A of a compound of formula (I), and ● Specifically, water as a solvent to make 80ml The present invention relates to a kit comprising:

[0202] Another embodiment of the invention is a kit for preparing a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, comprising: a pharmaceutical composition as described herein comprising a compound of formula (I) as Form A; and Specifically, water as a solvent to be composed of 80 ml of purified water The present invention relates to a kit comprising:

[0203] Another embodiment of the invention is a kit for preparing a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, comprising: - compounds of formula (I) in form A or D, in particular in form A; ● Powder blends as a vehicle for construction; and Possibly water as a solvent for the composition The present invention relates to a kit comprising:

[0204] Another embodiment of the invention is a kit for preparing a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, comprising: the compound of formula (I) as Form A, ● Powder blends as a vehicle for construction; and Optionally, water as a solvent for the composition, in particular 80 ml of purified water The present invention relates to a kit comprising:

[0205] Another embodiment is a powder blend as a suitable medium for the constitution of the compound of formula (I) as Form A or D, particularly Form A, as described herein, a buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as the acidifying agent, specifically tartaric acid; and A diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol The present invention relates to a powder blend comprising:

[0206] Another embodiment is a powder blend as a vehicle suitable for the constitution of a compound of formula (I) or a pharma- ceutically acceptable salt thereof as described herein, comprising: a buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as the acidifying agent, specifically tartaric acid; • A diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; ● Antioxidants, specifically ascorbic acid; • Stabilizers, specifically edetate disodium; and ● Lubricants, specifically PEG6000 The present invention relates to a powder blend comprising:

[0207] Another embodiment is a powder blend as a suitable medium for the constitution of the compound of formula (I) as Form A or D, particularly Form A, as described herein, a buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as the acidifying agent, specifically tartaric acid; • A diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; ● Antioxidants, specifically ascorbic acid; • Stabilizers, specifically edetate disodium; ● Lubricants, specifically PEG 6000; optionally a sweetener, particularly sucralose or sodium saccharin, most particularly sucralose; and Optionally, flavoring, specifically strawberry or vanilla flavoring The present invention relates to a powder blend comprising:

[0208] Another embodiment is a powder blend as a suitable medium for the constitution of the compound of formula (I) as Form A or D, particularly Form A, as described herein, ● 3-15% by weight of a buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as the acidifying agent, specifically tartaric acid; • 40-80% by weight of a diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; ● 1-4% by weight of an antioxidant, specifically ascorbic acid; • 0.2-2% by weight of a stabilizer, specifically disodium edetate; ● 0.5-2% by weight of a lubricant, specifically PEG 6000; ● 0-3% by weight of a sweetener, specifically sucralose or sodium saccharin, most specifically sucralose; and ● 0-20% by weight of flavoring, specifically strawberry flavoring or vanilla flavoring; It concerns powder blends, the total amount of components not exceeding 100% by weight.

[0209] Another embodiment is a powder blend as a suitable medium for the constitution of the compound of formula (I) as Form A or D, particularly Form A, as described herein, ● 3-15% by weight of a buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as the acidifying agent, specifically tartaric acid; • 40-90% by weight, in particular 40-80% by weight, of a diluent, in particular mannitol, or a mixture of mannitol and isomalt, more in particular mannitol; ● 1-4% by weight of an antioxidant, specifically ascorbic acid; • 0.2-2% by weight of a stabilizer, specifically disodium edetate; ● 0.5-2% by weight of a lubricant, specifically PEG 6000; • 1-8% by weight, especially 1-4% by weight, of a preservative, specifically sodium benzoate; ● 0-3% by weight of a sweetener, specifically sucralose or sodium saccharin, most specifically sucralose; and ● 0-20% by weight of flavoring, specifically strawberry flavoring or vanilla flavoring; It concerns powder blends, the total amount of components not exceeding 100% by weight.

[0210] Another embodiment is a powder blend as a suitable medium for the constitution of the compound of formula (I) as Form A or D, particularly Form A, as described herein, ● 3-7% by weight tartaric acid; • 60-75% by weight of mannitol as a first diluent and 10-15% by weight of isomalt as a second diluent; ● 0.5-1.0% by weight ascorbic acid as an antioxidant; • 0.3-0.7% by weight of disodium edetate as a stabilizer; ● 0.5-2 wt% PEG 6000 as a lubricant; 0.6 to 1.0% by weight of sucralose as a sweetener; and ● Contains 5-10% by weight of strawberry flavoring; It concerns powder blends, the total amount of components not exceeding 100% by weight.

[0211] Another embodiment is a powder blend as a suitable medium for the constitution of the compound of formula (I) of Form A or Form D, particularly Form A, as described herein, • 3-7% by weight, especially 4-6% by weight, of tartaric acid; • 60-75% by weight of mannitol as a first diluent and 10-15% by weight of isomalt as a second diluent; ● 0.5-1.0% by weight ascorbic acid as an antioxidant; • 0.3-0.7% by weight of disodium edetate as a stabilizer; ● 0.5-2 wt% PEG 6000 as a lubricant; • 1-8% by weight of sodium benzoate as a preservative, especially 1-4% by weight of sodium benzoate as a preservative; 0.6 to 1.0% by weight of sucralose as a sweetener; and ● Contains 5-10% by weight of strawberry flavoring; A powder blend in which the total amount of ingredients does not exceed 100% by weight.

[0212] Another embodiment is a powder blend as a suitable medium for the constitution of the compound of formula (I) of Form A or Form D, particularly Form A, as described herein, • 3-7% by weight, especially 4-6% by weight, of tartaric acid; • 60-75% by weight mannitol and 10-15% by weight isomalt; ● 0.5-1.0% by weight ascorbic acid; • 0.3-0.7% by weight of disodium edetate; ● 0.5-2 wt% PEG6000; ● 1-8% by weight of sodium benzoate, in particular 1-4% by weight of sodium benzoate; 0.6 to 1.0% by weight of sucralose; and ● Contains 5-10% by weight of strawberry flavoring; A powder blend in which the total amount of ingredients does not exceed 100% by weight.

[0213] Another embodiment is a powder blend as a medium suitable for constitution of the compound of formula (I) as Form A described herein, after constitution in water (80 ml) as a solvent: The pharmaceutical composition after constitution in water (80 ml) as the solvent is • 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one as form A at 0.25-1.25 mg / ml, especially 0.25-0.5 mg / ml; • Tartaric acid at 0.5-2.0 mg / ml, especially 0.9-1.4 mg / ml; ● 15.0-18.75mg / ml mannitol and 2.0-3.75mg / ml isomalt; ● 0.18-0.53mg / ml ascorbic acid; • 0.05-0.15mg / ml disodium edetate; ● PEG6000 at 0.1-0.5mg / ml, especially 0.2-0.3mg / ml; ● Sodium benzoate at 0.3-0.8mg / ml; ● 0.13 to 0.25 mg / ml of sucralose; and ● 1.25~2.5mg / ml strawberry flavoring The present invention relates to a powder blend comprising:

[0214] The compounds of formula (I) have been found to have beneficial pharmacological properties and promote the incorporation of exon 7 of SMN1 and / or SMN2 into mRNA transcribed from the SMN1 and / or SMN2 genes, thereby increasing expression of the SMN protein in a human subject in need thereof.

[0215] The compounds of the present invention can be used alone or in combination with other drugs to treat, prevent, delay progression and / or ameliorate diseases caused by inactivating mutations or deletions in the SMN1 gene and / or associated with loss or deficiency of SMN1 gene function, including, but not limited to, spinal muscular atrophy (SMA).

[0216] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I), in particular form A as defined above, and one or more pharma- ceutically acceptable excipients, for the treatment, prevention, delay of progression and / or amelioration of diseases caused by inactivating mutations or deletions in the SMN1 gene and / or diseases associated with loss or deficiency of SMN1 gene function, in particular the treatment, prevention, delay of progression and / or amelioration of SMA.

[0217] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I), in particular of type A, as defined above, for use as a therapeutically active substance, in particular for the treatment, prevention, slowing down and / or amelioration of diseases caused by inactivating mutations or deletions in the SMN1 gene and / or diseases associated with loss or deficiency of SMN1 gene function, in particular for the treatment, prevention, slowing down and / or amelioration of spinal muscular atrophy (SMA).

[0218] A particular embodiment of the invention relates to a pharmaceutical composition comprising a compound of formula (I), in particular form A as defined above, for use in the treatment, prevention, delay of progression and / or remission of diseases caused by inactivating mutations or deletions in the SMN1 gene and / or diseases associated with loss or defective SMN1 gene function, in particular for use in the treatment, prevention, delay of progression and / or remission of spinal muscular atrophy (SMA).

[0219] A particular embodiment of the present invention relates to a method for the treatment, prevention, slowing of progression and / or amelioration of diseases caused by inactivating mutations or deletions in the SMN1 gene and / or diseases associated with loss or deficiency of SMN1 gene function, in particular for the treatment, prevention, slowing of progression and / or amelioration of spinal muscular atrophy (SMA), which method comprises administering to a subject a pharmaceutical composition comprising a compound of formula (I), in particular of type A, as defined above.

[0220] A particular embodiment of the invention relates to the use of a pharmaceutical composition comprising a compound of formula (i), in particular of type A, as defined above, for the treatment, prevention, slowing of progression and / or amelioration of diseases caused by inactivating mutations or deletions in the SMN1 gene and / or diseases associated with loss or deficiency of SMN1 gene function, in particular for the treatment, prevention, slowing of progression and / or amelioration of spinal muscular atrophy (SMA).

[0221] A particular embodiment of the invention relates to the use of a pharmaceutical composition comprising a compound of formula (i), particularly of type A, for the preparation of a medicament for the treatment, prevention, slowing of progression and / or amelioration of diseases caused by inactivating mutations or deletions in the SMN1 gene and / or diseases associated with loss or deficiency of SMN1 gene function, in particular for the treatment, prevention, slowing of progression and / or amelioration of spinal muscular atrophy (SMA). Such a medicament comprises a compound of formula (I), particularly of type A, as defined above.

[0222] In general, the nomenclature used in this application is based on AUTONOM™ 2000, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. The chemical structures depicted herein were generated using MDLISIS™ version 2.5SP2. Any open valence appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.

[0223] The following examples are provided for illustrative purposes and are not intended to limit the scope of the present invention.

[0224] The following abbreviations and definitions are used in this application: br (broad); BuLi (butyl lithium); CDCl3 (deuterated chloroform); d (doublet); eq; (equivalent); g (gram); GC (gas chromatography); h (hour); HCl (hydrochloric acid); H2O (water); HPLC (high performance liquid chromatography); ISP (isotopic spin content); KOH (potassium hydroxide); L (liter); LDA (lithium diisopropylamide); LCMS (liquid chromatography-mass spectrometry); M (molar); m (multiplet); MS (mass spectrometry). ;mL (milliliter);NaOH (sodium hydroxide);NMR (nuclear magnetic resonance);Pd(dba)3 (tris(dibenzylideneacetone)dipalladium(0));Pd(xantphos)Cl2 (dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene]palladium(II));s (singlet);sec (sec);t (triplet);t-BuBrettPhos (2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl);THF (tetrahydrofuran);

[0225] Example 17-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (unseeded form A) 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (5.81 g, 13.71 mmol) was dissolved in water (28 g) and aqueous hydrochloric acid (37%, 2.61 g, 26.49 mmol) at 30-33 °C. The hydrochloride solution was added to a solution of NaOH (1.15 g, 28.75 mmol) in ethanol (220 g) at 60 °C within 100 min, resulting in spontaneous crystallization. The apparatus of the hydrochloride solution was rinsed with water (1.2 g) and added to the suspension. The suspension was cooled to 40 °C and stirred overnight. The precipitate was filtered, washed three times with a mixture of water / ethanol 88:12 (16.5 g) followed by ethanol (16.5 g) and dried under high vacuum at 60° C. for 21 h to give Form A of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (4.95 g, 90.0%).

[0226] Example 27-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (Form A) 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (5.81 g, 13.71 mmol) was dissolved in water (28 g) and aqueous hydrochloric acid (37%, 2.57 g, 26.08 mmol) at 30-33 °C. The first portion of the hydrochloride solution (3.64 g) was added to a solution of NaOH (1.12 g, 28.00 mmol) in ethanol (220 g) at 60 °C. Seeding was performed by adding a suspension of Form A crystals (0.055 g, 0.01 mmol) in ethanol (1.7 g). The remaining portion of the hydrochloride solution was added to the NaOH solution at 60 °C within 87 min. The hydrochloride solution apparatus was rinsed with water (1.2 g) and added to the suspension. The mixture was cooled to 40° C. and stirred overnight. The precipitate was filtered, washed four times with a mixture of water / ethanol 88:12 (16.5 g) followed by ethanol (16.5 g) and dried under high vacuum at 60° C. for 21 hours to give Form A of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (5.06 g, 91.1%).

[0227] Example 3 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (D-form) Form A of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (0.5 g, 1.23 mmol) was suspended in a mixture of ethanol / water (4:1 wt / wt) (2.1 g). The solution was stirred at 35° C. for 4 days. The solid was isolated and dried under reduced pressure (30° C. for 4 h, 200 mbar, or 40° C. for 2 h, 100 mbar) to give Form D of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one.

[0228] Example 4 Oral solution containing 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one can be formulated as an oral aqueous solution by dissolving the drug substance in a buffer system, e.g., citrate buffer, malate buffer, maleate buffer or tartrate buffer, more specifically malate buffer or tartrate buffer, most specifically tartrate buffer, at a pH below pH 4, specifically pH 3.0 to pH 3.2, to provide a sufficiently high drug concentration.

[0229] Long-term stability of the formulation of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one can be obtained by preparing a dry powder or granules for constituting an oral solution. A buffer system can be incorporated into the dry formulation by selecting an organic acid and its salt as fine powder, such as tribasic sodium citrate dihydrate and anhydrous citric acid, sodium malate and malic acid, or preferably sodium potassium tartrate and tartaric acid.

[0230] Powders or granules containing 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one may contain extragranular fillers such as sorbitol, isomalt, or mannitol, and combinations thereof, which ensure that the powder blend dissolves quickly during the constitution of the oral solution. Upon introduction of the diluent, the powder blend may be granulated by dry compression to improve flowability and ensure robust uniformity.

[0231] The components for making up the solvent system of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, more specifically Form A, may be formulated as separate formulations.

[0232] The constituted solvent can be used to dissolve 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, more specifically Form A, in the bottle at the beginning of the oral solution use period.

[0233] Constitutional oral solutions of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, more specifically Form A, in a buffer solution can provide a shelf life of greater than two weeks by using stabilizers and antioxidants such as Vitamin E TPGS, edetate disodium, butylhydroxytoluene, riboflavin, or preferably ascorbic acid, and combinations thereof.

[0234] Table 8 shows several oral solutions that provide stability in solution for greater than two weeks.

[0235] [Table 8]

[0236] Example 5 Powder blend as a vehicle for forming an oral solution of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one Table 9 shows a granulation blend for the composition of a suitable solvent to dissolve 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one and obtain a stable oral solution at pH 3.4 for more than two weeks. The blend contains polyethylene glycol 6000 as a water-soluble lubricant, sodium benzoate as a preservative, sucralose as a sweetener, and strawberry flavoring to improve taste, specifically for use in pediatric patients.

[0237] The compositions in Table 9 show constituent solvents suitable for dissolving 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (20 mg and 60 mg, respectively) together with 79 ml of water.

[0238] [Table 9]

[0239] Example 6 Powder blend containing 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one for forming an oral solution

[0240] Table 10 shows oral solutions containing 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, which are composed by using the composed vehicle solution obtained in Example 4 to dissolve the active compound. The vehicle is suitable for forming an oral solution with a stable pH of 3.4 for more than two weeks. The composition in Table 9 shows oral solutions containing 1 mg / ml, 3 mg / ml of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, together with 79 ml of water.

[0241] [Table 10]

[0242] Example 7 Powder blend of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one to constitute an oral solution Table 11 shows powder blends containing 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one that can be used to constitute an oral solution together with 90 ml of water. The compositions in Table 10 may also be constituted from a solvent prepared from a vehicle powder blend (as in Example 4) and then the API dissolved.

[0243] [Table 11]

[0244] Example 8 Powder blend of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one to constitute an oral solution Table 12 shows powder blends containing 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one that can be used to make up an oral solution with water to obtain an 80 ml solution. The compositions in Table 11 may also be made up of a solvent prepared from a vehicle powder blend (as in Example 5) and then the API is dissolved.

[0245] [Table 12]

[0246] Example 9 Powder blend of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one to constitute an oral solution Table 13 shows the powder blend of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one used to make up the oral solution with water to obtain 80 mL of solution. The compositions in Table 12 may also be made up of a solvent prepared from the vehicle powder blend (as in Example 4) and then the API dissolved.

[0247] [Table 13]

Claims

1. Formula (I) 【Chemistry 1】 A method for producing a crystal of Form A of the compound of the present invention, comprising dissolving 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one in dioxane at a high temperature of more than 22° C., and then cooling to obtain 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one 2. A method of making a crystalline form comprising: crystallizing a crystalline form of propylene glycol as Form A crystals, wherein the Form A crystals are characterized by an XRPD diffraction pattern comprising an XRPD peak at a diffraction angle of 8.3 degrees two-theta (±0.2) and at least one additional XRPD peak at 11.4 degrees two-theta (±0.2), 15.1 degrees two-theta (±0.2), 15.9 degrees two-theta (±0.2), 17.0 degrees two-theta (±0.2), 24.0 degrees two-theta (±0.2), or 25.6 degrees two-theta (±0.2).

2. A method for producing type A crystals as described in claim 1, wherein the high temperature is 80°C.

3. Formula (I) 【Chemistry 1】 A method for producing a type A crystal of the compound of the present invention, comprising suspending solid 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one in ethanol, methyl ethyl ketone, ethyl acetate or dioxane at a temperature of 22 to 65° C. for 2 to 3 weeks to obtain 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one 1. A method of making do[1,2-a]pyrimidin-4-one as crystalline Form A, wherein the crystalline Form A is characterized by an XRPD diffraction pattern comprising an XRPD peak at a diffraction angle of 8.3 degrees two-theta (±0.2) and at least one additional XRPD peak at 11.4 degrees two-theta (±0.2), 15.1 degrees two-theta (±0.2), 15.9 degrees two-theta (±0.2), 17.0 degrees two-theta (±0.2), 24.0 degrees two-theta (±0.2), or 25.6 degrees two-theta (±0.2).

4. Formula (I) 【Chemistry 1】 A method for preparing Form A crystals of the hydrochloride salt of the compound of formula (I) comprises dissolving 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one in water with hydrochloric acid, adding the solution to a molar excess of sodium hydroxide in ethanol relative to the added hydrochloric acid at an elevated temperature above 22° C., allowing crystallization to form a saturated solution and a suspension containing crystalline solids of Form A crystals, and then cooling the suspension, filtering and washing the suspension.

3. A method of producing crystalline Form A comprising: washing to remove sodium chloride and drying under reduced pressure at an elevated temperature above 22° C., wherein the Form A crystals are characterized by an XRPD diffraction pattern comprising an XRPD peak at a diffraction angle of 8.3 degrees 2-theta (±0.2) and at least one additional XRPD peak at 11.4 degrees 2-theta (±0.2), 15.1 degrees 2-theta (±0.2), 15.9 degrees 2-theta (±0.2), 17.0 degrees 2-theta (±0.2), 24.0 degrees 2-theta (±0.2), or 25.6 degrees 2-theta (±0.2).

5. A method for producing type A crystals as described in claim 4, which comprises adding an aqueous solution of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one using hydrochloric acid at a high temperature of 60 to 70°C.

6. Formula (I) 【Chemistry 1】 A method for preparing a crystal of type A of the hydrochloride salt of the compound of formula (I) comprises dissolving 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one in water using hydrochloric acid, adding a portion of this solution to an ethanolic solution of sodium hydroxide in molar excess relative to the added hydrochloric acid at an elevated temperature of 20-70° C., adding the crystal of type A to the solution thus formed to form a suspension, adding the remaining hydrochloride solution at an elevated temperature of 20-70° C., and then dissolving the suspension. cooling, filtering, washing to remove sodium chloride, and drying under reduced pressure at an elevated temperature above 22° C., wherein the Form A crystals are characterized by an XRPD diffraction pattern comprising an XRPD peak at a diffraction angle of 8.3 degrees two-theta (±0.2) and at least one additional XRPD peak at 11.4 degrees two-theta (±0.2), 15.1 degrees two-theta (±0.2), 15.9 degrees two-theta (±0.2), 17.0 degrees two-theta (±0.2), 24.0 degrees two-theta (±0.2), or 25.6 degrees two-theta (±0.2).

7. A method for producing type A crystals as described in claim 6, comprising adding an aqueous solution of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one using hydrochloric acid at a high temperature of 60°C.

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