PROCESS FOR THE PREPARATION OF 7-(4,7-DIAZAESPIRO[2,5]OCTAN-7-YL)-2-(2,8-DIMETHYLIMIDAZO[1,2-B]PYRIDAZIN-6-YL)PYRIDO[1,2-A]PYRIMIDIN-4-ONE, AND COMPOUNDS USEFUL AS INTERMEDIATES IN SAID PROCESS

Abstract

This application relates to a process for the preparation of 7-(4,7-diazaespiro[2,5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one derivatives useful as pharmaceutically active compounds.

Description

Case P34332 Process for the preparation of 7-(4,7-diazaespiro[2,51octan-7-yl)-2(2,8-dimethylimidazo[1,2-b1pyridazin-6-yl)pyrido[1,2-a1pyrimidin-4-one, and compounds useful as intermediates in said process The present invention relates to a process for the preparation of 7-(4,7diazaespiro[2,51octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b1pyridazin-6-yl)pyrido[1,2a1pyrimidin-4-one] useful as pharmaceutically active compounds. In a first aspect, the present invention provides a process for the preparation of a compound of formula (I) or the HCl salt thereof: which involves reacting a compound of formula (II): with a strong acid, in particular HCl. The process according to the first aspect, in which the HCl salt is prepared in situ in the presence of 1-propanol and acetyl chloride. 2548390 of 62 In particular, the preparation of the compound of formula (I) is carried out in a solvent, such as an alcohol, an aqueous alcohol, ethyl acetate, 1-propylacetate, 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. In one particular embodiment, the present invention provides a process as described herein, wherein 3 to 15 equivalents, more particularly 4 to 8 equivalents, most particularly 5 equivalents of strong acid are used, particularly wherein the strong acid is HCl, with respect to the compound of formula (II). In another embodiment, the present invention provides a process as described above for the preparation of the compound of formula (I), wherein the reaction is carried out at a temperature between 20 °C and 100 °C, particularly between 60 °C and 80 °C, more particularly at 75 °C. The compound of formula (I) 7-(4,7-diazaespiro[2,5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one is a valuable pharmaceutical compound as described in document WO2015173181. Unless otherwise stated, the following terms used in the descriptive memorandum and claims have the meanings given below: “Alkyl (C1-C8)” refers to a branched or linear hydrocarbon chain, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl, pentyl, hexyl, heptyl, or octyl. “Alkyl (C1-C3)” refers to methyl, ethyl, n-propyl, or isopropyl. “Alcohol” refers to benzyl alcohol, aminoethanol, or a (C1-C3) alkyl group (more particularly a C1-C3 alkyl group) as defined above, substituted with one or two hydroxyl groups, more particularly substituted with one hydroxyl group. Examples of alcohols 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. In particular, “alcohol” refers to methanol, ethanol, 1-propanol, or benzyl alcohol, most particularly to 1-propanol. 2548390 of 62 “Ambient conditions” refers to conditions such as those experienced in a conventional laboratory, for example atmospheric pressure, air, ambient temperature between 18 °C and 28 °C, humidity between 30 %RH and 80 %RH. “Base” refers to a chemical compound that deprotonates another compound when reacted with it. Suitable bases for use in accordance with this disclosure include, but are not limited to, organic bases and basic alkali metal salts. In particular, an organic base includes tertiary amines and nitrogen-containing heterocycles. 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 alkoxide including, but not limited to, t-butoxide, 1-propoxide, 2-propoxide, ethoxide, methoxide of sodium and potassium, and the like, sodium amide (NaNH2), potassium amide (KNH2), and the like. “Crystallization” and “recrystallization” can be used interchangeably; they refer to a process in which a chemical compound dissolved or suspended in a solvent system leads to a polymorph or stable crystalline form of that particular chemical compound. For example, crystallization steps can be carried out by forming a crystal with a solvent and an antisolvent. The terms “halo”, halogen and halide, which can be used interchangeably, refer to a chlorine, bromine or iodine substituent. “Strong acid” refers to an acid that completely dissociates in an aqueous solution with a pH < 2. Strong acids include, but are not limited to: sulfuric acid (H₂SO₄), hydroxychlorohydric acids (i.e., HX₂ where X₂ is I, Br, Cl, or F), nitric acid (HNO₃), phosphoric acid (H₃PO₄), and combinations thereof. In particular, the strong acid is a hydroxychlorohydric acid where X₂ is Br or Cl. More specifically, the strong acid is HCl. 2548390 of 62 “Nickel catalyst” refers to catalysts comprising nickel or nickel oxides or mixtures thereof. An example of a nickel catalyst is Raney nickel catalyst (Ra-Ni). The term “optional” or “optionally” denotes that an event or circumstance described below may happen but does not necessarily, and that the description includes cases where the event or circumstance does happen and cases where it does not. “Palladium catalyst” refers to a reagent that is a source of zero palladium (Pd(0)). Suitable sources of Pd(0) include, but are not limited to, palladium bis(dibenzylideneacetone) (Pd(dba)2), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), palladium acetate (Pd(OAc)2), palladium chloride (PdCh), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), 1,2 bis(diphenylphosphino)ethane palladium (Pd(dppe)2), 1,3bis(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)ferrocene dichloropalladium (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), cyclopentadienyl allyl palladium, allyl palladium(II) chloride dimer (Pd(allyl)Cl)2), (2-butenyl)chloropalladium dimer, (2-methylallyl) palladium(II) chloride dimer,dimer of paladium chloride(1-phenylalyl), di^-chlorobis[2'-(amino-N) [1,1'biphenyl]-2-yl-C ]dipaladium(II), di^-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipaladium(n) or dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xantheno]paladium (Pd(XantPhos)Ch). In particular, the palatal catalyst refers to Pd(OAc)2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd2(dba)3, (Pd(XantPhos)Cl2) or PdCl2(dppf)). More specifically, the palate catalyst is Pd(OAc)2, Pd2(dba)3, (Pd(XantPhos)Cl2) or PdCl2(dppf)., The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable vehicle”, and “therapeutically inert excipient” may be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition that has no therapeutic activity and is not toxic to the subject to whom it is administered, such as disintegrants, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, vehicles, diluents, or lubricants used in the formulation of pharmaceutical products. 2548390 of 62 “Transition metal hydrogenation catalyst” refers to a transition metal hydrogenation catalyst that operates in a different phase than the substrate. Specifically, the transition metal hydrogenation catalyst is in the solid phase. In particular, although the transition metal hydrogenation catalyst is in the solid phase, the reactants are in the liquid phase. The transition metal hydrogenation catalyst contains a transition metal, which forms one or more stable ions with incompletely charged d orbitals (i.e., Pd, Pt, Rh, Au, Ni, Co, Ru, Ir, V, Fe), particularly a noble metal such as Pd, Pt, Rh, or Au. In these catalysts, the transition metal is specifically “supported,” meaning that the catalyst is dispersed in a second material that enhances its efficiency.The “support” can simply be a surface on which the metal is spread to increase the surface area. Supports are porous materials with a high surface area, most commonly alumina or various types of carbon. Additional 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 act as a support if no other support is present. More specifically, the term “transition metal hydrogenation catalyst” includes, but is not limited to, a Raney catalyst (e.g., RaNi, Ra-Co), Pd / C, Pd(OH)2 / C, Au / TiO2, Rh / C, Ru / AhO3, Ir / CaCO3, Pt-V / C, or Pt / C, particularly Pt-V / C. “Tertiary amine” refers to an amine of formula RaN(Rb)Rc in which Ra, Rb, and Rc are independently selected from either alkyl (Ci-Co) or phenyl. Representative examples include, but are not limited to, triethylamine, tributylamine, diethylmethylamine, dimethylethylamine, diisopropylethylamine, N,N-dimethylaniline, and methylethylbutylamine. Preferably, the tertiary amine is selected from either triethylamine or diisopropylethylamine. The most preferred tertiary amine is triethylamine. The terms “treat,” “communicate,” and “react,” used interchangeably, refer to adding, combining, or mixing two chemical substances (commonly called reagents or reactants), particularly under suitable conditions, to produce the indicated and / or desired product. It should be noted that the reaction that produces the indicated and / or desired product may not necessarily be the result of the combination. 2548390 of 62 of two or more reagents that were initially added; that is, there may be one or more intermediates that are produced in the mixture that ultimately leads to the formation of the indicated and / or desired product. In another aspect (aspect 2), the present invention provides a process for the preparation of a compound of formula (II) which involves reacting a compound of formula (III) wherein X is an alkyl or aryl sulfonate (such as pTolSO3-, CH3SO3-, phenyl-SO3-), 10 fluorinated alkyl or aryl sulfonates (such as CF3SO3-, nonaphthalate) or a halide (such as Cl, Br or I), with a compound of formula (III'), (IIIa') or (IIIb'), in particular with a compound of formula (III') 2548390 of 62 in the presence of a palladium catalyst or nickel catalyst, in particular, in the presence of a palladium catalyst. In a particular embodiment of aspect 2, the present invention provides a process for the preparation of a compound of formula (II) which involves reacting a compound of formula (III) wherein X is an alkyl or aryl sulfonate (such as pTolSO3-, CH3SO3-, phenyl-SO3-), fluorinated alkyl or aryl sulfonates (such as CF3SO3-, nonaphthalate), with a compound of formula (III') 2548390 of 62 (III') in the presence of a palladium catalyst or nickel catalyst, in particular, in the presence of a palladium catalyst. In a more particular embodiment of aspect 2, the present invention provides a process for the preparation of a compound of formula (II) which involves reacting a compound of formula (IIIa) with a compound of formula (III') 2548390 of 62 in the presence of a palladium catalyst or nickel catalyst, in particular, in the presence of a palladium catalyst. In particular, the process as described herein (i.e., aspect 2) further comprising a base, in particular wherein the base is Na2CO3, K2CO3, Cs2CO3, KOAc or KOtBu, more particularly wherein the base is K2CO3. In another aspect (aspect 3), the present invention provides a process for the preparation of a compound of formula (II) which includes a) react a compound of formula (III”) 2548390 of 62 (III) with bis(pinacolato)diboron to obtain a compound of formula (III'): b) react a compound of formula (III) wherein X is an alkyl or aryl sulfonate (such as pTolSO3-, CH3SO3-, phenyl-SO3-), fluorinated alkyl or aryl sulfonates (such as CF3SO3-, nonaphthalate) or a halide (such as Cl, Br or I) with a compound of formula (III')), (IIIa') or (IIIb'), in particular with a compound of formula (III'), (IIIb') 2548390 of 62 in the presence of a palladium catalyst or nickel catalyst, in particular in the presence of a palladium catalyst, to obtain a compound of formula (II). In a particular embodiment of aspect 3, the present invention provides a process for the preparation of a compound of formula (II) which includes a) react a compound of formula (III”) with bis(pinacolato)diboron to obtain a compound of formula (III'): b) react a compound of formula (III) 2548390 of 62 wherein X is an alkyl or aryl sulfonate (such as pTolSÜ3-, CH3SO3-, phenyl-SÜ3-), fluorinated alkyl or aryl sulfonates (such as CF3SO3-, nonaphthalate) with a compound of formula (III') in the presence of a palladium catalyst or nickel catalyst, in particular in the presence of a palladium catalyst, to obtain a compound of formula (II). In a more particular embodiment of aspect 3, the present invention provides a process for the preparation of a compound of formula (II) which includes a) react a compound of formula (III”) 2548390 of 62 (III) with bis(pinacolato)diboron to obtain a compound of formula (III'): b) react a compound of formula (IIIa) in the presence of a palladium catalyst or nickel catalyst, in particular in the presence of a palladium catalyst, to obtain a compound of formula (II). 2548390 of 62 In particular, the invention provides a process as described above, wherein the reaction of the compound of formulas (III) or (IIIa) with a compound of formulas (III'), (IIIa') or (IIIb'), in particular with a compound of formula (III') in the presence of a palladium catalyst or a nickel catalyst, in particular in the presence of a palladium catalyst as defined herein, is carried out in the presence of a base, in particular wherein the base is Na2CO3, K2CO3, Cs2CO3, KOAc or KOtBu, more particularly wherein the base is K2CO3. In one particular embodiment, the present invention provides the processes described in this document in which the intermediates formed in steps a) and b) are not isolated. In another aspect (aspect 4), the present invention provides a process for the preparation of a compound of formula (III) (III) wherein X is an alkyl or aryl sulfonate (such as pTolSO3-, CH3SO3-, phenyl-SO3-), fluorinated alkyl or aryl sulfonates (such as CF3SO3-, nonaphthalate) or a halide (such as Cl, Br or I), comprising reacting a compound of formula (IV) (IV) 2548390 of 62 - with tosyl chloride when X is pTol-SÜ3-, methanesulfonyl chloride when X is CH3SÜ3-, trifyl chloride when X is CF3SÜ3- or phenylsulfonyl chloride when X is phenyl-SÜ3-, and in the presence of a base, in particular where the base is an organic base or basic alkali metal salts, more particularly where the base is a nitrogen-containing heterocycle, a tertiary amine or basic alkali metal salts, most particularly where the base is a tertiary amine; - with PÜCl3 when X is Cl; - with PÜBr3 when X is Br; or - with, Ph3Pl2 or PÜCl3, followed by Nal or Cul, when X is I. In a particular embodiment of aspect 4, the present invention provides a process for the preparation of a compound of formula (III) wherein X is an alkyl or aryl sulfonate (such as pTolSÜ3-, CH3SÜ3-, phenyl-SÜ3-), fluorinated alkyl or aryl sulfonates (such as CF3SÜ3-, nonaphthalate), comprising reacting a compound of formula (IV) 2548390 of 62 with tosyl chloride, methanesulfonyl chloride, phenylsulfonyl chloride or triflyl chloride respectively and in the presence of a base, in particular wherein the base is an organic base or basic alkali metal salts, more particularly wherein the base is a nitrogen-containing heterocycle, a tertiary amine or basic alkali metal salts, more particularly wherein the base is a tertiary amine. In a more particular embodiment of aspect 4, the present invention provides a process for the preparation of a compound of formula (IIIa) which involves reacting a compound of formula (IV) with tosyl chloride and in the presence of a base, in particular where the base is an organic base or basic alkali metal salts, more particularly where the base is a nitrogen-containing heterocycle, a tertiary amine or basic alkali metal salts, more particularly where the base is a tertiary amine. In another aspect (aspect 5), the present invention provides a process for the preparation of a compound of formula (IV) 2548390 of 62 which involves reacting a compound of formula (V) In another aspect (aspect 6), the present invention provides a process for the preparation of a compound of formula (IV) which includes: a) reduction of a compound of formula (VI) 2548390 of 62 to give a compound of formula (V) b) reacting a compound of formula (V) with di-tert-butyl malonate to obtain a compound of formula (IV). In a more particular embodiment (aspect 7), the present invention provides a process for the preparation of a compound of formula (IV) which includes: a) react a compound of formula (VI) 2548390 of 62 with a transition metal hydrogenation catalyst to obtain a compound of formula (V) b) reacting a compound of formula (V) with di-tert-butyl malonate to obtain a compound of formula (IV). In particular, the process for the preparation (i.e., aspects 5 to 7) 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. More particularly, the preparation of the compound 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 / AhO3, Ir / CaCO3, Pt-V / C or Pt / C or combinations thereof, particularly Pt-V / C, more particularly 1% Pt and 2% V on activated carbon. In one particular embodiment, the present invention provides the processes described herein wherein the intermediates formed in steps a) and b) are not isolated. 2548390 of 62 In another embodiment (aspect 8) the present application discloses the preparation of a compound of formula (VI) which involves reacting a compound of formula (VII) with a compound of formula (VIII) (VIII) or a salt thereof (in particular the oxalate salt), more particularly wherein the salt of the compound of formula (VIII) is the oxalate salt of tert-butyl 4,7-diazaespiro[2,5]octane-4-carboxylate. In particular, the process for preparing a compound of formula (VI) comprising reacting a compound of formula (VII) with a compound of formula 2548390 of 62 (VIII), in the presence of lithium chloride, dimethyl sulfoxide and a base, such as tetramethylguanidine, triethylamine, diisopropylethylamine or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), most particularly with tetramethylguanidine. In a further embodiment, the present application discloses the preparation of a compound of formula (V) according to scheme 1. Scheme 1: (VIII) (X) (IX) V In particular, the compound of formula (IX) can be prepared by reacting a compound of formula (X) with a compound of formula (VIII), in the presence of a catalyst (such as, but not limited to, Pd(PPh3)4, PdCl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf).CH2Cl2, PdCl2(dppp), PdCl2(CH3CN), cyclopentadienyl allyl palladium, allyl palladium(II) chloride dimer, (Pd(allyl)Cl)2, (2-butenyl)chloropalladium dimer, (2-methylallyl) palladium(II) chloride dimer, chloride dimer of 2548390 of 62 palladium(l-phenylalyl), di^-chlorobis[2'-(amino- N) [1,1'-biphenyl]-2-yl-C] dipalladium(II), di-μchlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II), dichloro[9,9-dimethyl-4,5bis(diphenylphosphino)xanthene]palladium (Pd(XantPhos)Ch), [Pd(allyl)(tBuBrettPhos)]OTf, [Pd(crotyl)(tBuBrettPhos)]OTf, [Pd(cinnamil)(tBuBrettPhos)]OTf in particular in the presence of dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium); and a base (such as Na2CO3, K2CO3, Cs2CO3, KOtBu, NaOtBu ((Cft^CONa) or KOAc; in particular KOtBu), in particular 2-methyltetrahydrofuran, THF or dioxane, more particularly 2-methyltetrahydrofuran. Compound (V) can be prepared by reacting compound (IX) with ammonia (NH3) in the presence of a catalyst, such as Pd(PPh3)4, PdCl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf).CH2Cl2, PdCl2(dppp), PdCl2(CH3CN), cyclopentadienyl allyl palladium, allyl palladium(II) chloride dimer (Pd(allyl)Cl)2, (2-butenyl)chloropalladium dimer, (2-methylallyl) palladium(II) chloride dimer, palladium(1-phenylallyl) chloride dimer, di^-chlorobis[2'-(amino-N)[1,1'biphenyl]-2-yl-C]dipalladium(II), di^-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II), in particular in the presence of Pd2(dba)3, a base (such as Na2CO3, K2CO3, Cs2CO3, KOtBu, NaOtBu ((Cft^CONa) or KOAc; in particular KOtBu) and t-Bu Brett Phos. Preferably, this step is carried out in dioxane. The catalyst [Pd(allyl)(tBuBrettPhos)]OTf, [Pd(crotyl)(tBuBrettPhos)]OTf and [Pd(cinnamyl)(tBuBrettPhos)]OTf can be prepared according to compounds 8A, 8B and 8C respectively on page 6804 of AJ DeAngelis, J. Org. Chem, 80, 6794-6813. The compound of formula (V) can also be prepared according to scheme 2. Scheme 2: (VIII) 2548390 of 62 In particular, the compound of formula (V) can be prepared by reacting a compound of formula (X) with a compound of formula (VIII), in the presence of a catalyst (such as Pd(PPh3)4, Pd(OAc)2, Pd2(dba)3, PdCl2, PdCh(dppf), PdCl2(dppf).CH2Cl2, PdCl2(dppp), allyl palladium(II) chloride dimer (Pd(allyl)Cl)2, (2-butenyl)chloropalladium dimer 5, (2-methylallyl) palladium(n) chloride dimer, palladium(1-phenylallyl) chloride dimer, di^-chlorobis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), di-μchlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II), in particular in the presence of allyl palladium(II) chloride dimer (Pd(allyl)Cl)2 or palladium(1-phenylallyl) chloride dimer; and a ligand (such as 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (DavePhos) or 2-di-tere-butylphosphino-2'-(N,N-dimethylamino)biphenyl (tBuDavePhos), in particular: tBuDavePhos) and a base (such as Na2CO3, K2CO3, Cs2CO3, KOtBu, NaOtBu ((CH3)3CONa), KOAc or lithium bis(trimethylsilyl)amide; in particular lithium bis(trimethylsilyl)amide), in particular tetrahydrofuran. In another embodiment, the present invention provides a compound of formula (II): In another embodiment, the present invention provides a compound of formula (III): 2548390 of 62 wherein X is an alkyl or aryl sulfonate (such as pTolSÜ3-, CH3SO3-, phenyl-SÜ3-), fluorinated alkyl or aryl sulfonates (such as CF3SO3-, nonaphthalate), or a halide (such as Cl, Br or I). In another embodiment, the present invention provides a compound of formula (III): wherein X is an alkyl or aryl sulfonate (such as pTolSO3-, CH3SO3-, phenyl-SO3-), fluorinated alkyl or aryl sulfonates (such as CF3SO3-, nonaflate). In another embodiment, the present invention provides a compound of formula (IIIa): In another embodiment, the present invention provides a compound of formula (IV): The present invention takes place in the presence of an organic solvent, such as an ether as a solvent (for example tetrahydrofuran, diisopropyl ether, t-butylmethyl ether, 2548390 of 62 cyclopentyl methyl ether or dibutyl ether), chlorinated solvents (for example, dichloromethane, chloroform) or aromatic solvent (for example, anisole, toluene or t-butylbenzene). In particular, the solvent to be used for the preparation of a compound of formula (I) according to aspect 1 is toluene. The reactions are carried out in particular in an inert gas atmosphere, more specifically in an argon or nitrogen atmosphere. In a further embodiment, the present invention provides a process for the preparation of 7-(4,7-diazaespiro[2,5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one comprising the formation of a compound of formula (I) 10 obtained by any of the processes and conditions mentioned above. In another embodiment (aspect 9), the present invention provides a process for the preparation of a compound of formula (I) or the HCl salt thereof: which includes: a) react a compound of formula (III) 2548390 of 62 wherein X is an alkyl or aryl sulfonate (such as pTolSÜ3-, CF3SO3-, phenyl-SÜ3-), fluorinated alkyl or aryl sulfonates (such as CH3SO3-, nonaphthalate), or a halide (such as Cl, Br or I), with a compound of formula (III'), (IIIa') or (IIIb'), in particular with a compound of formula (III') presence of a palladium catalyst or nickel catalyst, in particular in the presence of a palladium catalyst, optionally in the presence of a base, as previously described, to obtain a compound of formula (II): b) react said compound of formula (II) with a strong acid as previously described. In a particular embodiment of aspect 9, the present invention provides a process for the preparation of a compound of formula (I) or the HCl salt thereof: 2548390 of 62 which includes: a) react a compound of formula (III) wherein X is an alkyl or aryl sulfonate (such as pTolSO3-, CH3SO3-, phenyl-SO3-), fluorinated alkyl or aryl sulfonates (such as CF3SO3-, nonaphthalate), with a compound of formula (III') in the presence of a palladium catalyst or nickel catalyst, in particular in the presence of a palladium catalyst, optionally in the presence of a base, as previously described, to obtain a compound of formula (II): 2548390 of 62 b) react said compound of formula (II) with a strong acid as previously described. In a more particular embodiment of aspect 9, the present invention provides a process for the preparation of a compound of formula (I) or the HCl salt thereof: which includes: a) react a compound of formula (IIIa) 2548390 of 62 in the presence of a palladium catalyst or nickel catalyst, in particular in the presence of a palladium catalyst, optionally in the presence of a base, as previously described, to obtain a compound of formula (II): b) react said compound of formula (II) with a strong acid as previously described. 2548390 of 62 In another embodiment (aspect 10), the present invention provides a process for the preparation of a compound of formula (I) or the HCl salt thereof: which includes: a) react a compound of formula (IV) - with tosyl chloride when X is pTol-SO3-, methanesulfonyl chloride when X is CH3SO3-, trifyl chloride when X is CF3SO3- or phenylsulfonyl chloride when X is phenyl-SO3-, and in the presence of a base, in particular where the base is an organic base or basic alkali metal salts, more particularly where the base is a nitrogen-containing heterocycle, a tertiary amine or basic alkali metal salts, most particularly where the base is a tertiary amine; - with POCl3 when X is Cl; - with POBr3 when X is Br; or - with, Ph3PI2 or POCl3, followed by NaI or CuI, when X is I. as previously described, to obtain a compound of formula (III): 2548390 of 62 wherein X is an alkyl or aryl sulfonate (such as pTolSÜ3-, CH3SO3-, phenyl-SÜ3-), fluorinated alkyl or aryl sulfonates (such as CF3SO3-, nonaphthalate) or a halide (such as Cl, Br or I), b) reacting said compound of formula (III), (IIIa') or (IIIb'), in particular with a compound of formula (III'), more particularly with a compound of formula (III') (III') (Illa') (IIIb') in the presence of a palladium catalyst or nickel catalyst, in particular in the presence of a palladium catalyst, optionally in the presence of a base, to obtain a compound of formula (II): as previously described; 2548390 of 62 c) reacting said compound of formula (II) with a strong acid as previously described. In a particular embodiment of aspect 10, the present invention provides a process for the preparation of a compound of formula (I) or the HCl salt thereof: which includes: a) react a compound of formula (IV) - when X is pTol-SO3-,CH3SO3-, CF3SO3- or phenyl-SO3- with tosyl chloride, methanesulfonyl chloride, trifyl chloride or phenylsulfonyl chloride respectively and in the presence of a base, in particular wherein the base is an organic base or basic alkali metal salts, more particularly wherein the base is a nitrogen-containing heterocycle, a tertiary amine or basic alkali metal salts, most particularly wherein the base is a tertiary amine; as previously described, to obtain a compound of formula (III): 2548390 of 62 wherein X is an alkyl or aryl sulfonate (such as pTolSÜ3-, CH3SO3-, phenyl-SÜ3-), fluorinated alkyl or aryl sulfonates (such as CF3SO3-, nonaphthalate), b) reacting said compound of formula (III) with a compound of formula (III') in the presence of a palladium catalyst or nickel catalyst, in particular in the presence of a palladium catalyst, optionally in the presence of a base, to obtain a compound of formula (II): as previously described; 2548390 of 62 c) reacting said compound of formula (II) with a strong acid as previously described. In a more particular embodiment of aspect 10, the present invention provides a process for the preparation of a compound of formula (I) or the HCl salt thereof: which includes: a) react a compound of formula (IV) with tosyl chloride and in the presence of a base, in particular wherein the base is an organic base or basic alkali metal salts, more particularly wherein the base is a nitrogen-containing heterocycle, a tertiary amine or basic alkali metal salts, most particularly wherein the base is a tertiary amine, as previously described, to obtain a compound of formula (IIIa) 2548390 of 62 b) reacting said compound of formula (IIIa) with a compound of formula (III') in the presence of a palladium catalyst or nickel catalyst, in particular in the presence of a palladium catalyst, optionally in the presence of a base, to obtain a compound of formula (II): as previously described; 2548390 of 62 c) reacting said compound of formula (II) with a strong acid as previously described. In another embodiment (aspect 11), the present invention provides a process for the preparation of a compound of formula (I) or the HCl salt thereof: which includes: with di-tert-butyl malonate to obtain a compound of formula (IV) b) react said compound of formula (IV) 2548390 of 62 - with tosyl chloride when X is pTol-SÜ3-, methanesulfonyl chloride when X is CH3SÜ3-, trifyl chloride when X is CF3SÜ3- or phenylsulfonyl chloride when X is phenyl-SÜ3-, and in the presence of a base, in particular where the base is an organic base or basic alkali metal salts, more particularly where the base is a nitrogen-containing heterocycle, a tertiary amine or basic alkali metal salts, most particularly where the base is a tertiary amine; - with PÜCl3 when X is Cl; - with PÜBr3 when X is Br; or - with, Ph3Pl2 or PÜCl3, followed by Nal or Cul, when X is I. as previously described, to obtain a compound of formula (III) wherein X is an alkyl or aryl sulfonate (such as pTolSÜ3-, CH3SÜ3-, phenyl-SÜ3-), fluorinated alkyl or aryl sulfonates (such as CF3SÜ3-, nonaphthalate) or a halide (such as Cl, Br or I); c) reacting said compound of formula (III) with a compound of formula (III'), (IIIa') or (IIIb'), in particular with a compound of formula (III'), more particularly with a compound of formula (III') 2548390 of 62 (IIb') presence of a palladium catalyst or nickel catalyst, in particular in the presence of a palladium catalyst, optionally in the presence of a base, to obtain a compound of formula (II): as previously described; d) react said compound of formula (II) with a strong acid as previously described. In a particular embodiment of aspect 11, the present invention provides a process for the preparation of a compound of formula (I) or the HCl salt thereof: 2548390 of 62 comprising: a) react a compound of formula (V) with di-tert-butyl malonate to obtain a compound of formula (IV) b) reacting said compound of formula (IV) where X is pTol-SO3-, CH3SO3-, CF3SO3- or phenyl-SO3-, with tosyl chloride, methanesulfonyl chloride, trifyl chloride or phenylsulfonyl chloride respectively and in the presence of a base, in particular wherein the base is an organic base or basic alkali metal salts, more particularly wherein the base is a nitrogen-containing heterocycle, a tertiary amine or basic alkali metal salts, most particularly wherein the base is a tertiary amine as previously described, to obtain a compound of formula (III) 2548390 of 62 wherein X is an alkyl or aryl sulfonate (such as pTolSÜ3-, CH3SO3-, phenyl-SÜ3-), fluorinated alkyl or aryl sulfonates (such as CF3SO3-, nonaflate); c) reacting said compound of formula (III) with a compound of formula (III') in the presence of a palladium catalyst or nickel catalyst, in particular in the presence of a palladium catalyst, optionally in the presence of a base, to obtain a compound of formula (II): as previously described; d) react said compound of formula (II) with a strong acid as previously described. In a more particular embodiment of aspect 11, the present invention provides a process for the preparation of a compound of formula (I) or the HCl salt thereof: 2548390 of 62 which includes: with di-tert-butyl malonate to obtain a compound of formula (IV) b) reacting said compound of formula (IV) with tosyl chloride and in the presence of a tertiary amine, as previously described, to obtain a compound of formula (IIIa) 2548390 of 62 c) reacting said compound of formula (IIIa) with a compound of formula (III') in the presence of a palladium catalyst or nickel catalyst, in particular in the presence of a palladium catalyst, optionally in the presence of a base, to obtain a compound of formula (II): as previously described; d) react said compound of formula (II) with a strong acid as previously described. 2548390 of 62 In another embodiment (aspect 12), the present invention provides a process for the preparation of a compound of formula (III”) according to scheme 3: Scheme 3: (XII) In particular according to the invention, a compound of formula (XII) is prepared by reacting a compound of formula (XIII) with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), N-bromo-succinimide or bromine, optionally with sodium acetate or sodium bicarbonate and in the presence of a solvent, such as alcohols (e.g. methanol or ethanol). Additionally, a compound of (XI) is prepared by reacting a compound of formula (XII) with methylmagnesium chloride or bromide, methylboronic acid, methyl borate, dimethylzinc or methyllithium, optionally in the presence of zinc chloride or with dimethylzinc in methyltetrahydrofuran or THF, in the presence of a catalyst (such as Pd(PPh3)4, PdCl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)2Cl2, PdCk(dppf), PdCl2(dppf).CH2Cl2, PdCl2(dppp), cyclopentadienyl allyl palladium, allyl palladium(II) chloride dimer (Pd(allyl)Cl)2, (2-butenyl)chloropalladium dimer, (2-methylallyl) palladium(II) chloride dimer, palladium(1-phenylalyl) chloride dimer, di^-chlorobis[2'-(amino- N) [1,1'-biphenyl]-2-yl-C ]dipalladium(II), di^-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(n), dichloro[9,9-dimethyl-4,5bis(diphenylphosphino)xanthene]palladium (Pd(XantPhos)Cl2), in particular in the presence of Pd(PPh3)4). A compound of formula (III”) is prepared by reacting chloroacteone with a compound of formula (XI) in the presence of tertiary amine and sodium bromide. Alternatively, the compound of formula (III”) can be prepared according to the process described in document WO2015173181. The present application further discloses a process for the preparation of a compound of formula (IIIa') or (IIIb') according to scheme 4. Scheme 4: 2548390 of 62 A particular embodiment of the invention also relates to a pharmaceutical composition comprising the compound of formula (I) obtained according to what is described herein and at least one pharmaceutically acceptable excipient. A further particular embodiment of the invention also relates to a compound of formula (I) obtained by the process as described herein for use as therapeutically active substances. The starting materials and reagents, whose synthetic routes are not explicitly disclosed in this document, are generally available from commercial sources 10 or are easily prepared using methods well known to the expert in the field. In general, the nomenclature used in this Application is based on AUTONOM™2000, the Beilstein Institute's computerized system for generating systematic IUPAC nomenclature. The chemical structures shown herein were prepared using MDL ISIS™ version 2.5 SP2. Any open valency appearing on a carbon, oxygen, or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. The following examples are provided for the purpose of further illustration and are not intended to limit the scope of the claimed invention. 2548390 of 62 In this application, the following abbreviations and definitions are used: a (width); BuLi (butyllithium); CDCl3 (deuterated chloroform); d (doblet); equiv. (equivalent); g (gram); GC (gas chromatography); h (hour); HCl (hydrochloric acid); H2O (water); HPLC (high-performance liquid chromatography); ISP (isotopic spin population); KOH (potassium hydroxide); l (liter); LDA (lithium diisopropylamide); CLEM (liquid chromatography-mass spectrometry); M (molar); m (multiplet); MS (mass spectroscopy); ml (milliliter); NaOH (sodium hydroxide); NMR (nuclear magnetic resonance); Pd(dba)3 (tris(dibenzylideneacetone)dipalladium(O)); Pd(Xantphos)Cl2 (Dichloro[9,9-dimethyl4,5-bis(diphenylphosphino)-xanthene]palladium(II)); s (singlet); sec (second); t (triplet); t-Bu Brett Phos (2-(Di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl); THF (tetrahydrofuran); Example 1: 7-(6-Chloro-3-pyridyl)-4,7-diazaespiro[2,5]octane-4-carboxylate tert-butyl 5-Bromo-2-chloropyridine (85.0 g, 442 mmol), tert-butyl 4,7-diazaespiro[2,5]octane-4-carboxylate (102 g, 442 mmol), and Me-THF (722 g) were loaded into a reaction vessel. After stirring for 10 minutes, most of the solids dissolved, and [Pd(Xantphos)Cl2] (3.34 g) was added, followed after 5 minutes by a solution of sodium tert-butanolate (56.3 g, 574 mmol) in Me-THF (173 g). The reaction mixture was stirred at 70 °C for 1.25 hours, cooled to room temperature, and water (595 g) and 1-propyl acetate (378 g) were added. After vigorous stirring, the phases were separated. The organic phase was washed with a second portion of water (425 g) and with a mixture of water (425 g) and brine (25 mL). The organic phase was treated with activated carbon (6.8 g), filtered, and concentrated under reduced pressure to yield a brown oil, which was dissolved in tert-amyl methyl ether (347 g) under reflux. The solution was then slowly cooled to room temperature.After stirring for 18 hours at room temperature, n-heptane (205 g) was added and the suspension was further cooled to -10 °C. The precipitate was removed. 2548390 of 62 filtration and was dried under high vacuum to provide 7-(6-chloro-3-pyridyl)-4,7diazaespiro[2,5]octane-4-tert-butyl carboxylate (110.9 g, 77.5%) in the form of a beige solid. 1H NMR (CDCl3, 600 MHz): 7.95 (d, 1H); 7.18 - 7.14 (m, 1H); 7.13 - 7.09 (m, 1H); 3.79 3.63 (m, 2H); 3.24 - 3.12 (m, 2H); 2.96 (s, 2H); 1.47 (s, 9H); 1.11 - 1.04 (m, 2H); 0.90 0.79 (m, 2H); CLEM: 324.15, 326.15 (M+H+) Example 2: 7-(6-Amino-3-pyridyl)-4,7-diazaespiro[2,5]octane-4-carboxylate of tert-butyl An autoclave equipped with a riser pipe was charged with ammonia (78.7 g, 15 equiv.; 10 equiv. is sufficient) at -70 °C. Another autoclave was charged with tert-butyl 7-(6-chloro-3-pyridyl)4,7-diazaespiro[2,5]octane-4-carboxylate (100 g, 309 mmol), sodium tert-butanolate (32.6 g, 340 mmol), and dioxane (800 mL). After 10 minutes of stirring at room temperature in an Ar atmosphere, a solution of Pd2(dba)3 (1.41 g, 1.54 mmol) and tBuBrettPhos (1.50 g, 3.09 mmol) in dioxane (180 mL) was added. After this, the connected ammonia vessel was warmed in a warm water bath and the connecting valve was opened. The autoclave was heated to 30 °C and the reaction mixture was stirred for 5 hours at this temperature. The ammonia vessel was then closed and disconnected. Excess ammonia was removed by washing the autoclave with argon.The reaction solution was poured into a separatory funnel, the autoclave was washed with ethyl acetate (300 mL), and water (100 mL) and these two portions of solvent were added to the separatory funnel. The two-phase mixture was further diluted with ethyl acetate (900 mL) and water (1000 mL). After vigorous stirring, the phases separated. The organic phase was washed with a mixture of water (500 mL) and brine (10 mL). The combined aqueous phases were extracted twice with ethyl acetate (500 mL). The combined organic phases were treated with activated carbon (3.70 g, 309 mmol), filtered, and the filtrate was concentrated under reduced pressure to yield a thick, brownish oil. This oil was dissolved in 1-propyl acetate. 2548390 of 62 (160 ml) at 45-50 °C and n-heptane (940 ml) was added dropwise over 1.5 hours. The suspension was slowly cooled to -5 °C, stirred for 4 hours at -5 °C and filtered. The precipitate was washed with cold n-heptane and dried under high vacuum at 50 °C to give tert-butyl 7-(6-amino-3-pyridyl)4,7-diazaespiro[2,5]octane-4-carboxylate (81.4 g, 86.5%) as a beige solid. 1H NMR (CDCl3, 600 MHz): 7.71 (d, 1H); 7.12 (dd, 1H); 6.47 (d, 1H); 4.18 (sa, 2H); 3.74 - 3.58 (m, 2H); 3.09 - 2.94 (m, 2H); 2.81 (s, 2H); 1.52 - 1.39 (m, 9H); 1.17 - 0.98 (m, 2H); 0.92 - 0.75 (m, 2H); CLEM: 305.20 (M+H+) Example 3: 7-(6-Amino-3-pyridyl)-4,7-diazaespiro[2,5]octane-4-carboxylate of tert-butyl An autoclave was charged with 7-(6-chloro-3-pyridyl)-4,7-diazaespiro[2,5]octane-4-carboxylate (339 mg, 1 mmol), sodium tert-butanolate (109 mg, 1.1 mmol), and dioxane (5 mL). After 5 minutes of stirring at room temperature in an argon atmosphere, [Pd(allyl)(tBuBrettPhos)]OTf (4 mg, 5 gmol) was added. The autoclave was then closed and connected to an ammonia tank. The valve was opened, and ammonia (230 mg, 13.5 mmol) was introduced into the autoclave. The valve was closed, and the autoclave was disconnected. The autoclave was heated to 30 °C, and the reaction mixture was stirred for 4 hours at this temperature. The autoclave was then opened and the excess ammonia was removed by washing the autoclave with argon. The reaction solution was transferred to a flask and dried under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / ethyl acetate to dichloromethane / methanol).After evaporation of the solvents, 7(6-amino-3-pyridyl)-4,7-diazaespiro[2,5]octane-4-carboxylate tert-butyl (283 mg, 93%) was isolated in the form of a brown oil containing 4% dichloromethane and 3% ethyl acetate. Example 4: 7-(6-Nitro-3-pyridyl)-4,7-diazaespiro[2,5]octane-4-carboxylate of tert-butyl 2548390 of 62 4,7-diazaespiro[2,5]octane-4-carboxylate tert-butyl oxalate (2.46 kg, 8.13 mol), 5-bromo-2-nitropyridine (1.50 kg, 7.39 mol), and dimethyl sulfoxide (7.80 L) were loaded into a reaction vessel preheated to 35 °C. With stirring and maintaining the temperature below 40 °C, lithium chloride (1.25 kg, 25.6 mol) was added in portions, followed by tetramethylguanidine (2.98 kg, 25.9 mol). Dimethyl sulfoxide (450 mL) was used to rinse the feed line. The reaction mixture was stirred at 79 °C for 8 hours, cooled to 70 °C, and water (2.48 L) was added over 2 hours. After stirring at 70 °C for 1 hour, the precipitate was removed by filtration and washed three times with water (4.5 L). The precipitate was dissolved in ethyl acetate (15 L) and water (7.5 L) at reflux temperature. The phases were separated at 60 °C, and n-heptane (7.5 L) was added to the organic layer at 60 °C for 30 minutes.The solution was cooled to 0 °C in 2 hours and further stirred at 0 °C for 1 hour. The precipitate was removed by filtration, washed twice with a mixture of ethyl acetate (750 ml) / n-heptane (375 ml) and dried under reduced pressure to give 1.89 kg (76.4%) of tert-butyl 7-(6-nitro-3-pyridyl)-4,7-diazaespiro[2,5]octane-4-carboxylate as a yellow to light brown solid. 1H NMR (CDCl3, 600 MHz): 8.16 (d, 1H); 8.07 (d, 1H); 7.15 (dd, 1H); 3.80 - 3.72 (m, 2H); 3.49 - 3.41 (m, 2H); 3.23 (s, 2H); 1.48 (s, 9H); 1.16 - 1.08 (m, 2H); 0.92 - 0.85 (m, 2H); CLEM: 335.17 (M+H+) Example 5: 7-(2-Hydroxy-4-oxo-pyrido[1,2-a]pyrimidin-7-yl)-4,7-diazaespiro[2,5]octane-4-carboxylate of tert-butyl 2548390 of 62 7-(6-Amino-3-pyridyl)-4,7-diazaespiro[2,5]octane-4-carboxylate tert-butyl (80.0 g, 263 mmol) was dissolved in anisole (800 ml) and di-tert-butyl malonate (71.1 g, 315 mmol) was added. The solution was stirred for 3.5 hours at 145 °C, then cooled to room temperature. The precipitate was removed by filtration, washed with toluene (in portions, 320 ml total) and dried under high vacuum at 50 °C to provide tert-butyl 7-(2-hydroxy-4-oxo-pyrido[1,2a]pyrimidin-7-yl)-4,7-diazaespiro[2,5]octane-4-carboxylate (65.6 g, 67%) in the form of a light pink powder. 1H NMR (CDCl3, 600 MHz): 8.46 (d, 1H); 7.74 (dd, 1H); 7.52 (d, 1H); 5.37 (s, 2H); 3.83 10 3.69 (m, 2H); 3.23 (t, 2H); 3.01 (s, 2H); 1.48 (s, 9H); 1.17 - 1.03 (m, 2H); 0.95 - 0.75 (m, 2H); CLEM: 373.19 (M+H+) Example 6: 7-(2-Hydroxy-4-oxo-pyrido[1,2-a]pyrimidin-7-yl)-4,7-diazaespiro[2,5]octane-4-carboxylate of tert-butyl 7-(6-nitro-3-pyridyl)-4,7-diazaespiro[2,5]octane-4-carboxylate tert-butyl (950 g, 2.84 mol), 1% Pt, 2% V on activated carbon (95.1 g, 2 mmol), and ethyl acetate (9.5 L) were loaded into an autoclave pressurized with hydrogen gas to 0.3 MPa (3 bar). The reaction mixture was stirred at room temperature for 6 hours. Excess hydrogen was vented. The reaction mixture was filtered, and the catalyst was washed three times with ethyl acetate (0.95 L). The filtrate was concentrated under reduced pressure, and the solvent was changed to anisole (added in two portions of 2.85 L and 5.18 L) by distillation. tert-butyl dimalonate (921.7 g, 4.26 mol) was added and the loading line was rinsed with anisole (618 ml) and the mixture of The reaction of batch 2548390 of 62 was stirred at 125–135 °C for 8 hours. It may be necessary to remove the tert-butanol byproduct by distillation to reach this temperature. The progress of the reaction was monitored, for example, by HPLC. If the reaction stalled, the temperature was increased to 135–145 °C and its progress was checked after 1 hour. When the reaction was complete, the batch was cooled to room temperature and stirred at room temperature for 4 hours. The precipitate was removed by filtration, washed with toluene (3.55 l) and dried under vacuum at 60 °C to provide tert-butyl 7-(2-hydroxy-4-oxo-pyrido[1,2-a]pyrimidin-7-yl)-4,7diazaespiro[2,5]octane-4-carboxylate (861.0 g, 81.4%) as a yellow to light brown solid. Example 7: 7-[4-Oxo-2-(p-tolylsulfonyloxy)pyrido[1,2-a]pyrimidin-7-yl]-4,7diazaespiro[2,5]octane-4-carboxylate tert-butyl S N N O. .N EITHER EITHER A reactor was charged with tert-butyl 7-(2-hydroxy-4-oxo-pyrido[1,2-a]pyrimidin-7-yl)-4,7-diazaespiro[2,5]octane-4-carboxylate (920 g, 2.47 mol) and then triethylamine (325 g, 3.21 mol), followed by tosyl chloride (527.1 g, 2.77 mol) and dichloromethane (4.6 L). The reaction mixture was stirred at 20–25 °C for at least three hours. After the reaction was complete, the organic solution was washed with a prepared solution of HCl (32%, 247.8 mL) and water (4.6 L), followed by a prepared solution of sodium hydroxide (432.3 mL from a 30% stock solution) and water (3.9 L), in that order. Finally, the organic phase was washed with water (4.8 L) and then almost completely removed by distillation of dichloromethane at reduced pressure at 50-55 °C. Ethyl acetate (920 mL) was added and the mixture was distilled twice at this temperature at reduced pressure, and then ethyl acetate (4.8 L) was added and the suspension was cooled to 20-25 °C for two hours.n-Heptane (944.4 ml) was added and the mixture was cooled to 0-5 °C and then stirred for a further 3 hours. The precipitate was removed by filtration, washed with a prepared solution of ethyl acetate (772.8 ml) and n-heptane (147.2 ml). 2548390 of 62 then twice with n-heptane (2.6 l). The solid was vacuum dried at 45-50 °C to give 1122.6 g (86.3%) of 7-[4-oxo-2-(p-tolylsulfonyloxy)pyrido[1,2-a]pyrimidin-7yl]-4,7-diazaespiro[2,5]octane-4-carboxylate tert-butyl in the form of yellow crystals. 1HNMR (CDCE, 600 MHz): 8.32 (d, 1H); 8.00 - 7.89 (m, 2H); 7.66 (dd, 1H); 7.50 (d, 1H); 7.36 (d, 2H); 6.04 (s, 1H); 3.80 - 3.68 (m, 2H); 3.23 (t, 2H); 3.01 (s, 2H); 1.48 (s, 9H); 1.15 - 1.04 (m, 2H); 0.92 - 0.82 (m, 2H); CLEM: 527.20 (M+H+) Example 8: 2,8-Dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2b]pyridazine 6-Chloro-2,8-dimethylimidazo[1,2-b]pyridazine (40.0 g, 220 mmol), bispinacol diborane (69.9 g, 275 mmol), and potassium acetate (43.2 g, 440 mmol) were suspended in acetonitrile (440 mL). The suspension was heated under reflux and stirred for 30 minutes under reflux, after which a suspension of PdCl₂(dppf) (4.03 g, 5.51 mmol) and dppf (610 mg, 1.1 mmol) in 40 mL of acetonitrile was added. The vessel was rinsed with 20 mL of acetonitrile, which was also added to the reaction mixture. The orange suspension was further stirred under reflux, whereupon acetonitrile (50 mL) was removed by distillation. After 4 hours, the reaction mixture was removed by filtration, and the filter was washed with several portions of acetonitrile (150 mL total). The filtrate was diluted to a volume of 700 mL. The 314 mmolar solution of 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2b]pyridazine in acetonitrile was used as such in the next step. Example 9: 2,8-Dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2b]pyridazine 2548390 of 62 6-Chloro-2,8-dimethylimidazo[1,2-b]pyridazine (29.0 g, 22.8 mmol), bispinacol diborane (44.6 g, 25.1 mmol), and potassium acetate (31.3 g, 45.6 mmol) were suspended in 1-propyl acetate (365 mL). The suspension was heated to 80 °C, and a solution of tricyclohexylphosphine (448 mg, 0.23 mmol) and Pd(OAc)₂ (179 mg, 0.11 mmol) in 1-propyl acetate (37 mL) was added over 20 minutes. After 2.5 hours of further stirring at 80 °C, the suspension was cooled to 40 °C and filtered at this temperature. The precipitate was washed with 1-propyl acetate (200 mL). The filtrate corresponds to 516.4 g of an 8.5% solution of 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine in acetate of 1-propyl. Example 10: Isolation of 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)imidazo[1,2-b]pyridazine In another experiment, the above solution was cooled to 0-5 °C for 3 hours. The precipitate was removed by filtration, washed with cold 1-propyl acetate, and dried under high vacuum at 60 °C to give 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (24.0 g, 55%) as a colorless solid. 1H NMR (CDCl3, 600 MHz, ) δ ppm 7.86 (d, J=0.7 Hz, 1 H), 7.20 (d, J=1.0 Hz, 1 H), 2.63 (d, J=1.0 Hz, 3 H), 2.51 (d, J=0.7 Hz, 3 H), 1.33 - 1.49 (m, 12 H) 2548390 of 62 Example 11: (Step 6) 7-[2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-oxo-pyrido[1,2a]pyrimidin-7-yl]-4,7-diazaespiro[2,5]octane-4-carboxylate tert-butyl 7-[4-oxo-2-(p-tolylsulfonyloxy)pyrido[1,2-a]pyrimidin-7-yl]-4,7-diazaespiro[2,5]octane-4-carboxylate tert-butyl (25 g, 47.5 mmol), 2,8-dimethyl-6-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (314 mM in acetonitrile, 191 ml, 59.8 mmol), PdCh(dppf) (868 mg, 1.19 mmol) and 4.07 M aqueous potassium carbonate (17.1 ml, 69.8 mmol) were loaded into a reaction vessel. The reaction mixture was stirred under reflux for 3 hours, cooled overnight at room temperature, and filtered. The precipitate was washed with several portions of acetonitrile (146 mL total), then resuspended in methyl-THF (750 mL) and methanol (75 mL). 5% aqueous sodium bicarbonate (250 mL) was added, and the mixture was stirred vigorously at 35 °C. The phases separated, and the organic phase was washed again with 5% aqueous sodium bicarbonate (250 mL).The organic phase was treated with activated carbon for 1 hour at room temperature, filtered, and the filtrate was concentrated under reduced pressure at 60 °C to a volume of 225 mL. This was heated under reflux, then cooled to room temperature, stirred at room temperature for 16 hours, then cooled to 0 °C and stirred at 0 °C for 3 hours. The precipitate was removed by filtration, washed with n-heptane (60 mL), and dried under high vacuum at 55 °C to provide tert-butyl 7-[2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-oxo-pyrido[1,2-a]pyrimidin-7-yl]-4,7-diazaespiro[2,5]octane-4-carboxylate (20.13 g, 84.5%) as a yellow solid. This solid was recrystallized as follows: 15 g of the previous solid were dissolved under reflux in toluene (135 mL) and ethanol (15 mL). The solution was slowly cooled to room temperature, stirred for 16 hours at room temperature, then cooled to 0 °C and stirred at 0 °C for 4 hours. The precipitate was removed by filtration and washed with 2548390 of 62 cold toluene and dried under high vacuum at 55 °C to provide 7-[2-(2,8-dimethylimidazo[1,2b]pyridazin-6-yl)-4-oxo-pyrido[1,2-a]pyrimidin-7-yl]-4,7-diazaespiro[2,5]octane-4-carboxylate tert-butyl (11.92 g, 79.5%) in the form of a yellow-green solid. 1H NMR (CDCl3, 600 MHz): 8.44 (d, 1H); 7.93 (d, 1H); 7.96 - 7.89 (m, 1H); 7.80 (d, 1H); 7.76 - 7.72 (m, 1H); 7.70 - 7.63 (m, 1H); 7.38 (s, 1H); 3.85 - 3.69 (m, 2H); 3.28 (t, 2H); 3.07 (s, 2H); 2.74 (d, 3H); 2.55 (s, 3H); 1.49 (s, 9H); 1.16 - 1.09 (m, 2H); 0.93 - 0.86 (m, 2H); CLEM: 502.26 (M+H+) Example 12: 7-[2-(2,8-Dimethylimidazo[1,2-b]pyridazin-6-yl)-4-oxo-pyrido[1,2-a]pyrimidin-7-yl]-4,7-diazaespiro[2,5]octane-4-carboxylate tert-butyl 6-Chloro-2,8-dimethylimidazo[1,2-b]pyridazine (4.14 g, 22.8 mmol), bispinacol diborane (6.37 g, 25.1 mmol), and potassium acetate (4.47 g, 45.6 mmol) were suspended in 1-propyl acetate (59 mL). The suspension was heated to 80 °C, and a solution of tricyclohexylphosphine (63.9 mg, 0.23 mmol) and Pd(OAc)₂ (25.6 mg, 0.11 mmol) in 1-propyl acetate (6 mL) was added over 20 minutes. After 2.5 hours of further stirring at 80 °C, the suspension was cooled to 40 °C and filtered at this temperature. The precipitate was washed with 1-propyl acetate (32 mL). The filtrate corresponds to 74.6 g of an 8.5% solution of 2,8dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine in 1-propyl acetate. A pressure vessel was charged with 7-[4-oxo-2-(p-tolylsulfonyloxy)pyrido[1,2-a]pyrimidin-7yl]-4,7-diazaespiro[2,5]octane-4-carboxylate tert-butyl (10.0 g, 19.0 mmol), tricyclohexylphosphine (58.6 mg, 0.21 mmol), Pd(OAc)2 (21.3 mg, 0.10 mmol), and 1-propyl acetate (42 mL), and a solution of potassium carbonate (5.25 g, 38.0 mmol) in water (19.0 mL) was added. The suspension was heated to 70 °C, and the 2,8-dimethyl-6-(4,4,5,554 2548390 of 62 tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine in 1-propyl acetate was added over 30 minutes. The mixture was stirred for 2 hours at 70–75 °C. The suspension was cooled to 40 °C, and water (10 mL) was added. The suspension was allowed to mature for 30 minutes. The crude product was removed by filtration and rinsed with 1-propyl acetate (41 mL). The crude product was collected in toluene (100 mL), a 5% aqueous solution of NaHCl (30 mL), and 1-propanol (20.0 mL). The mixture was heated to 60–65 °C, the phases separated, and the organic phase was washed with two additional portions of water (30.0 mL). The organic phase was filtered through activated carbon, and the filter was washed with toluene (60.0 mL). The filtrate was concentrated under reduced pressure to a volume of approximately 120 mL, heated under reflux, and 1-propanol (0.8 mL) was added to obtain a solution. The solution was cooled to 0–5 °C over 4–6 hours and stirred at 0–5 °C for 1 hour.The precipitate was removed by filtration, washed with toluene (30 ml) and dried under reduced pressure at 70-80 °C to provide 7-[2-(2,8-dimethylimidazo[1,2-b]pyridazin-6yl)-4-oxo-pyrido[1,2-a]pyrimidin-7-yl]-4,7-diazaespiro[2,5]octane-4-carboxylate tert-butyl (7.7 g, 80.8%) in the form of a yellowish solid. Example 13: Dihydrochloride salt of 7-(4,7-diazaspiro[2,5]octan-7-yl)-2-(2,8dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one To prepare an HCl solution in 1-propyl acetate / 1-propanol, acetyl chloride (15.8 g, 199 mmol) was slowly added to a mixture of 1-propyl acetate (60 ml) and 1-propanol (30 ml) at 0 °C, and stirring continued for a further 2 hours at room temperature. 7-[2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-oxo-pyrido[1,2-a]pyrimidin-7-yl]-4,7-diazaespiro[2,5]octane-4-carboxylate of tert-butyl (20 g, 39.9 mmol) was suspended in 55 acetate 2548390 of 62 1-propyl acetate (60 mL) and 1-propanol (30 mL) were added to the HCl solution in 1-propyl acetate and 1-propanol at room temperature. The reaction mixture was heated to 70 °C for 3 hours and stirred for 16 hours at this temperature, then cooled to 20 °C. The precipitate was removed by filtration, washed with 1-propyl acetate (50 mL) in several portions, and dried under vacuum at 55 °C to give 7-(4,7diazaspiro[2,5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2a]pyrimidin-4-one hydrochloride salt (18.8 g, 99%) in the form of yellow crystals. 1H NMR (CDCl3, 600 MHz): 8.34 (s, 1H); 8.22 (s, 1H); 8.05 (s, 1H); 8.01 (dd, 1H); 7.80 (d, 1H); 7.16 (s, 1H); 3.71 - 3.67 (m, 2H); 3.64 - 3.59 (m, 2H); 3.52 (s, 2H); 2.69 (s, 3H); 2.54 (s, 3H); 1.23- 1.20 (m, 2H); 1.14 - 1.08 (m, 2H); CLEM: 402.20 (M+H+) Example 14: 7-(4,7-diazaespiro[2,5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-oneA suspension of 7-[2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-oxo-pyrido[1,2a]pyrimidin-7-yl]-4,7-diazaespiro[2,5]octane-4-carboxylate tert-butyl (25 g, 50 mmol) in 1-propyl acetate (375 ml) was mixed with a solution of HCl in 1-propanol (prepared by slowly adding acetyl chloride (18.0 ml) to 1-propanol (37.6 ml) at 5 °C and stirring for 1 hour at room temperature). The stirred suspension was heated to 75 °C for 10 hours and stirred for a further 5 hours at 75 °C. Water (160.0 ml) was added, and the phases were separated at 75 °C. 32% aqueous sodium hydroxide (27.8 ml) was added to the aqueous phase. The resulting suspension was cooled to room temperature in 5 hours and stirred for one hour at room temperature.The precipitate was removed by filtration, washed with water (100.0 ml) and dried under reduced pressure at 50 °C for 18 hours to provide 7-(4,7diazaespiro[2,5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2a]pyrimidin-4-one (19.7 g, 98.3%) in the form of yellow crystals. 2548390 of 62 1H NMR (CDCI3, 600 MHz): 8.45 (d, 1H); 7.92 (d, 1H); 7.80 (s, 1H); 7.75 - 7.71 (m, 1H); 7.71 - 7.67 (m, 1H); 7.37 (s, 1H); 3.31 - 3.24 (m, 2H); 3.22 - 3.16 (m, 2H); 3.09 (s, 2H); 2.73 (s, 3H); 2.55 (s, 3H); 0.82- 0.76 (m, 2H); 0.71 - 0.63 (m, 2H); CLEM: 402.20 (M+H+) Example 15: 7-(4,7-diazaespiro[2,5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one A suspension of 7-[2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-oxo-pyrido[1,2a]pyrimidin-7-yl]-4,7-diazaespiro[2,5]octane-4-carboxylate tert-butyl (13.5 g, 26.9 mmol) in toluene (237.0 g) was stirred at 75 °C and a 21.9% HCl solution in 1-propanol (21.4 g, 134.5 mmol) was added over 2.5 hours. The reaction mixture was further stirred at 75 °C until conversion was complete. The reaction mixture was cooled to 20–25 °C. Water (70 g) was added. The two-phase mixture was stirred for a further 10 minutes at 20–25 °C and the phases separated. The organic phase was extracted twice with water (17 g) and the combined aqueous phases were added to a mixture of 28% aqueous sodium hydroxide (15.0 g) and water (45.0 g). The resulting suspension was cooled to 20 °C.The precipitate was removed by filtration, washed three times with water (25 g) and dried under reduced pressure at 60 °C to provide 7(4,7-diazaespiro[2,5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2a]pyrimidin-4-one (9.5 g, 95.1%) in the form of yellow crystals. Example 16: 4-Bromo-6-chloro-pyridazin-3-amine 3-Amino-6-chloropyridazine (20 g, 154 mmol), sodium bicarbonate (25.9 g, 309 mmol), and methanol (158 g) were loaded into a reaction vessel and cooled to 0–10 °C. 2548390 of 62 bromine dropwise (34.5 g, 216 mmol) and the reaction mixture was stirred for 3 days at room temperature. 10% aqueous sodium sulfate was added. The suspension was removed by filtration. The filtrate was washed twice with ethyl acetate (300 mL). The combined organic layers were dried and evaporated. A suspension of the residue in methanol (50 mL) was heated under reflux, water (120 mL) was added, and the suspension was stirred for 16 hours at room temperature. The precipitate was removed by filtration and dried. The residue was suspended in n-heptane (50 mL), stirred for 2 hours at room temperature, removed by filtration, and dried to give 4-bromo-6-chloro-pyridazin-3-amine (14.5 g, 46.2%) as a light brown solid. 1H NMR (CDCl3, 600 MHz): 7.55 (s, 1H); 5.83-4.89 (m, 2H); CLEM: 209.93 (M+H+) Example 17: 4-Bromo-6-chloro-pyridazin-3-amine Br NH2 3-Amino-6-chloropyridazine (50 g, 360 mmol), acetic acid (5.8 g, 96.5 mmol), sodium acetate (28.7 g, 289.5 mmol), and methanol (395 g) were loaded into a reaction vessel and heated to 25–35 °C. Dibromodimethylhydantoin (66.0 g, 231.6 mmol) was added in several portions, and the reaction mixture was stirred for 3 hours at 30 °C. Completion was checked by IPC, and if the conversion was incomplete, dibromodimethylhydantoin (5.5 g) was added. At the end of the reaction, 38% aqueous sodium sulfate (77.2 mmol NaHSO₄) was slowly added. The suspension was concentrated under reduced pressure and water (500 g) was slowly added at 45 °C, then 30% aqueous sodium hydroxide (31.5 g, 231.6 mmol NaOH) was added at 20 °C to adjust the pH to 7-8. The precipitate was removed by filtration, washed with water and dried under reduced pressure to give 4-bromo-6-chloro-pyridazin-3-amine (50.2 g, 62.5%) as a gray solid. Example 18: 6-chloro-4-methylpyridazin-3-amine 2548390 of 62 4-Bromo-6-chloro-pyridazin-3-amine (3.0 g, 14.4 mmol) and tetrakis(triphenylphosphine) palladium (1666 mg, 144 μmol) were suspended in THF (13.2 g), and a zinc chloride solution in Me-THF (2.0 M, 9 mL, 18 mmol) was added. The reaction mixture was cooled to -5 °C, and methyllithium in dietoxymethane (3.1 M, 11.6 mL, 36 mmol) was added. The reaction mixture was stirred at 45 °C for 4 hours. Sodium sulfate decahydrate (11.7 g, 36 mmol) was added at room temperature, the mixture was stirred for 1.5 hours at 60 °C, diluted with water (100 mL), and after 30 minutes the precipitate was removed by filtration. The precipitate was dissolved in 2M aqueous HCl (100 mL) and ethyl acetate (140 mL). The two-phase system was filtered, the phases separated, and the pH of the aqueous layer was adjusted to 7 with 32% aqueous NaOH (18 mL). The precipitate was filtered and dried. The resulting solid was digested twice in methanol (20 mL) at room temperature.The two filtrates were combined, evaporated, and dried under high vacuum to provide 6-chloro-4-methyl-pyridazin-3-amine (1.2 g, 58.1%) in the form of a red solid. 1H NMR (CDCl3, 600 MHz): 7.09 (d, 1H); 4.90 (sa, 2H), 2.17 (d, 3H) Example 19: 6-chloro-4-methyl-pyridazin-3-amine 4-Bromo-6-chloro-pyridazin-3-amine (30.02 g, 143 mmol) and THF (180 mL) were loaded into a reaction vessel. Methylmagnesium chloride (22% in THF, 50.0 mL, 1.03 equiv.) was added at 20 °C for 60 minutes, followed by zinc chloride in Me-THF (25%, 37 mL, 0.50 equiv.) and palladium tetrakis(triphenylphosphine) (1.66 g, 1 mol%). The reaction mixture was heated to 50 °C, and methylmagnesium chloride (22% in THF, 81 mL, 1.7 equiv.) was slowly added. The reaction mixture was stirred at 50 °C until conversion was complete, then at 10 °C for 14.5 hours and poured into a mixture of water (90 g), 33% aqueous HCl 2548390 of 62 (52.5 g) and toluene (150 ml) maintained at 20-30 °C. The aqueous phase was separated and the organic phase was extracted with a 33% aqueous HCl solution (2.0 g) and water (45 g). The aqueous layers were combined and washed twice with toluene (30 ml) and the pH was adjusted by adding a 25% aqueous ammonia solution. When a pH of 2.4 was reached, seed crystals were added, the mixture was further stirred for 15 minutes, and then the pH was adjusted to 4.0. The suspension was stirred at 20 °C for 2 hours, the precipitate was removed by filtration, and washed three times with water (20 ml) to provide crude 6-chloro-4-methyl-pyridazin-3-amine (29 g) in the form of a brown solid. 29 g of crude product were transferred to a reaction vessel and methanol (20 mL) was added. The mixture was refluxed for 30 minutes and 12 g of water were added. The solution was cooled to 0 °C and stirred for 2 hours at this temperature. The precipitate was removed by filtration, washed three times with water, and dried under reduced pressure at 40 °C to give purified 6-chloro-4-methylpyridazin-3-amine (13.8 g, 66%) as a light brown solid. Alternative purification: Fifty grams of crude 6-chloro-4-methylpyridazin-3-amine were dissolved in 250 mL of methanol, and 4.0 g of activated carbon and 2.5 g of diatomaceous earth were added. The suspension was stirred at 45 °C for 1 hour, cooled to 30 °C, and 2.1 g of potassium hydrogen phosphate were added. The suspension was stirred at 30 °C for a further 90 minutes, filtered, and the precipitate was washed with 100 mL of methanol. The filtrate was concentrated to a residual volume of 175 mL, and 120 mL of water was added. The resulting suspension was heated under reflux, yielding a solution that was cooled to 20 °C. The precipitate was removed by filtration, washed with water (90 ml) and dried under reduced pressure to provide pure 6-chloro-4-methylpyridazin-3-amine (38 g, 76%) in the form of a light yellow solid. Example 20: 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine 2548390 of 62 6-Chloro-4-methylpyridazin-3-amine (70.95 kg, 494.2 mol), sodium bromide (35 kg, 345.9 mol), isopropyl acetate (611 kg), isopropanol (28 kg), and water (35 kg) were loaded into a reaction vessel. The reaction mixture was stirred at 80–85 °C for 8 hours. Isopropyl acetate (310 kg) and water (420 kg) were added. 30% aqueous NaOH was added at 45–55 °C, and the system was stirred for 2 hours. The phases were separated at 25–35 °C. The organic layer was washed with water (370 kg), filtered over diatomaceous earth (7 kg), and the filter was washed with isopropyl acetate (35 kg). The organic phase was extracted with two portions of 5.4% aqueous sulfuric acid (910 kg followed by 579 kg). The combined aqueous phases were basified with 30% aqueous NaOH (158 kg). The suspension was stirred for 2 hours at 15–25 °C. The precipitate was isolated by centrifugation in three portions, each washed with water (31 kg).The wet solid was dissolved in isopropyl acetate (980 kg) at 25–35 °C, and the solution was washed three times with water (210 kg). The organic phase was treated with activated carbon for 12 hours at 45–50 °C, concentrated to approximately 300 kg, and heated to 70–80 °C to obtain a clear solution. This solution was cooled to 50–60 °C, stirred at this temperature for 1 hour, n-heptane (378 kg) was added, and stirring continued for another 1 hour. The mixture was then cooled to -10 to -5 °C and stirred for a further 3 hours. The precipitate was isolated by centrifugation, washed with n-heptane (33 kg) and dried under reduced pressure at 30-50 °C for 15 hours to provide 67.4 kg (76%) of 6-chloro-2,8-dimethylimidazo[1,220 b]pyridazine in the form of a whitish solid. 1H NMR (CDCl3, 600 MHz): 7.67 (s, 1H); 6.86 (s, 1H); 2.65 (s, 3H), 2.50 (s, 3H) 2548390 of 62 G. BREUER - 30525624826 Digitally signed by PORTALTRAMITES - INPI Date: 2023.12.04 14:20:17 -03:00 Reason: Digitally Signed by the INPI Location: Buenos Aires, Argentina 2548390

Claims

1. A process for the preparation of a compound of formula (I) or the HCl salt thereof: FORMULA 1, characterized in that it consists of reacting a compound of formula (II): FORMULA 2 with a strong acid, in particular HCl. 14 Claims follow