Novel thienopyrimidinone derivatives

Abstract

The present invention relates to a compound represented by formula (I) TIFF2024510004000063.tif41165 (In the formula, X, R 1 ~R 4 are as defined in the specification and claims. The compounds of formula (I) can be used as medicines.

Description

Technical Field

[0001] The present invention relates to novel organic compounds useful for treatment and / or prevention in mammals, particularly compounds that reduce the protein level of huntingtin (HTT) and are useful for the treatment of Huntington's disease.

[0002] In particular, the present invention relates to formula (I)

Chemical formula

Background Art

[0003] Huntington's disease (HD) is a hereditary autosomal dominant neurodegenerative disease caused by a CAG base repeat expansion in the Huntingtin (HTT) gene. Several evidences have shown that the mutant HTT gene, together with its gene product mHTT protein, contributes to HD pathogenesis through a toxic gain-of-function mechanism.

[0004] The triplet repeat expansion in exon 1 of the HTT gene is translated into a polyglutamine repeat in the HTT protein that is prone to misfolding and aggregation in cells. The exact mechanism by which mutant HTT disrupts cell function is unknown, but several processes involving disruption of RNA translation, toxic RNA species, protein aggregates, RNA translation and stress granules have been implicated.

[0005] At the neural circuit level, HD has been shown to affect deep brain structures such as the striatum, as well as cortical regions, to varying degrees. Seminal plasma mouse gene experiments combined with human imaging studies have pointed to a crucial role in the cortical-striatal connection in the pathogenicity of HD (Wang et al., "Neuronal targets of mutant huntingtin genetic reduction to ameliorate Huntington's disease pathogenesis in mice," Nature Medicine, 20.5(2014):536; Tabrizi et al., "Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24-month observational data," The Lancet Neurology 11.1(2012):42-53).

[0006] Huntington's disease (HD) typically presents at around 30–50 years of age and is characterized by numerous symptoms spanning the motor, cognitive, and emotional domains, ultimately leading to death 10–20 years after the onset of motor symptoms. While CAG repeat length negatively correlates with the age of onset of motor symptoms, this accounts for only 50–70% of the variability in age of onset. To identify genetic modifiers of age of onset in HD, Lee et al. (2019, Onset of Huntington's disease is determined by the length of uninterrupted CAGs, which are not encoded polyglutamines, and modified by DNA maintenance mechanisms. Bioarxiv doi:https: / / doi.org / 10.1101 / 529768) conducted a large-scale genome-wide association study (GWAS) to reveal further genetic modifiers of age of onset.

[0007] Various mouse models have been characterized to model aspects of HD. These include the YAC128 mouse, which expresses a full-length mutant HTT transgene with 128 CAG repeats; the BACHD mouse, which expresses a full-length mutant HTT genome sequence with 97 CAG / CAA repeats; and the R6 / 2 mouse, which expresses exon 1 of a mutant human HTT gene with 110–135 CAG repeats. In addition to these mice expressing human transgenes, there are also a series of mouse models, such as the frequently used Q111 and Q175 knock-in mice, in which elongation repeats are knocked in in relation to the mouse HTT locus.

[0008] There are currently no disease-modifying therapies for Huntington's disease, although several are under development. The underlying disease process behind the symptomatology, characterized by motor, cognitive, and behavioral symptoms, remains unaddressed by the various symptomatic treatments currently approved. Tetrabenazine and tiapride are currently approved for the treatment of motor symptoms, i.e., HD-associated chorea. In addition, anticonvulsants, benzodiazepines, antidepressants, and antipsychotics are also used off-label to treat motor, cognitive, and psychiatric symptoms associated with HD.

[0009] Several therapeutic strategies targeting DNA and RNA have been studied for reducing HTT (E.J. Wild, S. Tabrizi, Lancet Neurol. 2017 16(10):837-847). Reducing HTT is a promising therapeutic approach aimed at slowing disease progression by reaching the root cause of Huntington's disease. HTT reduction is thought to alter the disease when treated in the pre-symptomatic or onset stage, and therefore prevent major neurodegenerative processes in the brain. However, since the age of onset varies considerably across the population (S.J. Tabrizi, R. Ghosh, BR. Leavitt, Neuron, 2019, 102(4), 899), the challenge lies in identifying patients at the correct disease stage.

[0010] Current clinical approaches are primarily based on antisense oligonucleotides (ASOs). A small number of allele-specific reduction strategies, such as SNP (single-nucleotide polymorphism) based ASOs and zinc finger-based gene editing approaches, are also being investigated. While the use of small molecules to reduce HTT expression has been hypothesized, this strategy has not yet been validated and has not proven successful to date.

[0011] Small molecules offer an opportunity to enable HTT reduction in the brain and periphery. Furthermore, small molecule modalities enable access to patient populations that would otherwise be difficult to address with modalities such as ASO or gene therapy. [Overview of the Initiative]

[0012] Therefore, there is a need for new compounds that can lower mHTT.

[0013] The applicant has surprisingly found that the compounds of the present invention are active in reducing mHTT and are therefore useful in the treatment of HD.

[0014] All publications, patent applications, patents, and other references mentioned herein are incorporated in their entirety by reference. Detailed description of the invention

[0015] In this specification, the term “alkyl” means, alone or in combination, a linear or branched alkyl group having 1 to 8 carbon atoms, particularly a linear or branched alkyl group having 1 to 6 carbon atoms, and more specifically a linear or branched alkyl group having 1 to 4 carbon atoms. Examples of linear and branched C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isomer pentyl, isomer hexyl, isomer heptyl, and isomer octyl. Specific examples of “alkyl” are methyl, ethyl, and isopropyl. Methyl is a further specific example of “alkyl” in the compound of formula (I).

[0016] In this specification, the term “alkenyl” means, alone or in combination, a linear or branched alkenyl group having 2 to 8 carbon atoms and further comprising at least one double bond, and more particularly a linear or branched alkenyl group having 2 to 4 carbon atoms and further comprising at least one double bond. Specific examples of “alkenyl” are ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, and tert-butenyl.

[0017] The term "cycloalkyl" alone or in combination refers to a cycloalkyl ring having 3 to 8 carbon atoms, and especially a cycloalkyl ring having 3 to 6 carbon atoms. Examples of cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cycloheptyl and cyclooctyl.

[0018] The term "aryl," alone or in combination, refers to an aromatic monocyclic or bicyclic ring system containing 6 to 10 carbocyclic atoms. Examples of "aryl" include, but are not limited to, phenyl and naphthyl.

[0019] The term "heteroaryl" refers to an aromatic monocyclic or bicyclic ring system having 5 to 12 ring atoms, containing, alone or in combination, one, two, three, or four heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon. Examples of heteroaryls include furanyl, thiophenyl, 1H-pyrazolyl, 1H-imidazolyl, 1H-1,2,3-triazolyl, 4H-1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, 1H-indolyl, 2H-indolyl, 1H-indazolyl, 2H-indazolyl, indolidinyl, and benzofuranyl. Nyl, 1H-benzimidazolyl, 1,3-benzoxazolyl, flo[2,3-b]pyridinyl, flo[2,3-c]pyridinyl, flo[3,2-b]pyridinyl, flo[3,2-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyradinyl, pyrrolo[1,2-b]pyridadinyl, pyrazolo[1, 5-a]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 2H-pyrazolo[4,3-b]pyridinyl, 2H-pyrazolo[4,3-c]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyridadinyl, imidazo[1,2-c Examples include, but are not limited to, pyrimidinyl, imidazo[1,5-a]pyridinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-b]pyridazinyl, benzo[d]oxazolyl, and quinolinyl.

[0020] The terms "alkoxy" or "alkyloxy," alone or in combination, refer to the alkyl-O- group of the formula, in the sense previously given by the term "alkyl." Specific examples of "alkoxy" are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert.-butoxy.

[0021] The term "oxy," either alone or in combination, refers to an -O- group.

[0022] The terms "halogen" or "halo," alone or in combination, mean fluorine, chlorine, bromine, or iodine, particularly fluorine, chlorine, or bromine. A preferred example of a halogen is fluorine. The term "halo," in combination with another group, indicates a substitution of the group with at least one halogen, particularly one to five halogens, particularly one to four halogens, i.e., one, two, three, or four halogens, unless otherwise specified.

[0023] The term "haloalkyl" refers to an alkyl group, either alone or in combination, that is substituted with at least one halogen, particularly substituted with 1 to 5 halogens, and especially substituted with 1 to 3 halogens. Specific examples of "haloalkyl" are fluoromethyl, trifluoromethyl, difluoromethyl, fluoroethyl, fluoropropyl, and fluorobutyl. A specific "haloalkyl" is trifluoromethyl.

[0024] The terms "hydroxyl" and "hydroxy" mean the -OH group, either alone or in combination.

[0025] The term "cyano," either alone or in combination, refers to the -CN group.

[0026] The term "carbonyl," either alone or in combination, refers to a -C(O)- group.

[0027] The term "oxo," either alone or in combination, means an O group.

[0028] The term "amino," either alone or in combination, refers to a primary amino group (-NH2), a secondary amino group (-NH-), or a tertiary amino group (-N-).

[0029] The term "alkylamino" refers to an alkyl group bonded to an -NH- group, either alone or in combination. The term "dialkylamino" refers to two alkyl groups bonded to an -N- atom, either alone or in combination.

[0030] The term "heterocycloalkyl" alone or in combination means a monocyclic or bicyclic saturated or monounsaturated ring system having 3 to 12 ring atoms, comprising 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon. In some specific embodiments, the term "heterocycloalkyl" alone or in combination may mean a monocyclic or bicyclic saturated or monounsaturated ring system having 5 to 10 ring atoms, comprising 1 or 2 nitrogen atoms, with the remaining ring atoms being carbon. Certain "heterocycloalkyl" compounds include piperazinyl, azetidinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3,6-tetrahydropyridine-4-yl, 4,7-diazaspiro[2.5]octan-7-yl, (8aS)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine-2-yl, (8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo [1,2-a]pyrazine-2-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-yl, pyrrolidinyl, 2,8-diazaspiro[4.5]decane-2-yl, 4-piperidyl, and 4-azaspiro[2.5]octan-7-yl. Specific examples of "heterocycloalkyl" are azetidine-3-yl, 4-piperidyl, and 4-azaspiro[2.5]octan-7-yl.

[0031] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a free base or free acid, and is not biologically or otherwise undesirable. Salts are formed using inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. In addition, these salts can be prepared by adding an inorganic base or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, and magnesium. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyamine resins. Compounds of formula (I) can also exist in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of compounds of formula (I) are those formed with trifluoroacetic acid or hydrochloric acid.

[0032] If one of the starting materials or compounds of formula (I) of the present invention contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (e.g., as described in "Protective Groups in Organic Chemistry," 3rd Ed., 1999, Wiley, New York) may be introduced before a key step in which a method well known in the art is applied. Such protecting groups can be removed in later steps of the synthesis using standard methods described in the literature. Examples of protecting groups include tert-butoxycarbonyl (Boc), trityl (Trt), 2,4-dimethoxybenzyl (Dmb), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), carbobenzyloxy (Cbz), and p-methoxybenzyloxycarbonyl (Moz). A specific example of a protecting group is tert-butoxycarbonyl (Boc).

[0033] The compound of formula (I) may contain several chiral centers and may exist in the form of an optically pure enantiomer, a mixture of enantiomers such as a racemate, a mixture of diastereoisomers, a racemate of diastereoisomers, or a mixture of diastereoisomers and racemates.

[0034] The term "chiral carbon atom" refers to a carbon atom having four different substituents. According to the Kahn-Ingold-Prelogue priority rule, a chiral carbon atom can have either an "R" or "S" stereoconfiguration.

[0035] Therefore, the present invention also relates in particular to the following.

[0036] The compound according to the present invention, in which X is a bond, A compound according to the present invention in which X is -O-, R 1 However, R 4The compound according to the invention, which is heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 1 is heterocycloalkyl optionally substituted with one or two substituents independently selected from R 4 The compound according to the invention. <000020​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ 2-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-6-[(3SR,4SR)-3-fluoro-4-piperidyl]-3H-thieno[2,3-d]pyrimidine-4-one, 6-(3,3-difluoro-4-piperidyl)-2-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-3H-thieno[2,3-d]pyrimidine-4-one, 6-(azetidine-3-yloxy)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3H-thieno[2,3-d]pyrimidine-4-one, 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-6-(4-piperidyloxy)-3H-thieno[2,3-d]pyrimidine-4-one, 6-(4-azaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-3H-thieno[2,3-d]pyrimidine-4-one, and 2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-b]pyridazin-6-yl]-6-(4-piperidyl)-3H-thieno[2,3-d]pyrimidine-4-one This relates to compounds selected from, or pharmaceutically acceptable salts thereof.

[0038] The present invention further, 2-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-6-(4-piperidyl)-3H-thieno[2,3-d]pyrimidine-4-one, 2-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-6-[(3SR,4SR)-3-fluoro-4-piperidyl]-3H-thieno[2,3-d]pyrimidine-4-one, 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-6-(4-piperidyloxy)-3H-thieno[2,3-d]pyrimidine-4-one, 6-(4-azaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-3H-thieno[2,3-d]pyrimidine-4-one, and 2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-b]pyridazin-6-yl]-6-(4-piperidyl)-3H-thieno[2,3-d]pyrimidine-4-one This relates to compounds selected from, or pharmaceutically acceptable salts thereof.

[0039] The synthesis of the compound of formula (I) can be achieved, for example, by following the scheme below: X and R 1 ~R 4 Unless otherwise specified, the definitions above apply.

[0040] Scheme 1 [ka]

[0041] The compound of formula (I) can be prepared by deprotecting the intermediate of formula (II) with a protecting group (PG) using methods known in the art, such as using an acid such as trifluoroacetic acid and a solvent such as dichloromethane. The synthesis of the compound of formula (II) is outlined in Scheme 2. General Scheme 1 is further shown below by general procedure C.

[0042] Scheme 2 [ka]

[0043] The compound of formula (II) can be prepared stepwise by methods known in the art, for example, by amide coupling of the carboxamide intermediate of formula (III) and the acid intermediate of formula (IV), and then by thermocyclization of the intermediate of formula (V) with an aqueous solution of an inorganic base such as potassium hydroxide and a solvent such as n-butanol. The acid intermediate of formula (IV) is commercially available or can be prepared by methods known in the art or by the methods described below. The synthesis of the compound of formula (III) is outlined in Scheme 3. General Scheme 2 is further shown below by general procedure B.

[0044] Scheme 3 [ka]

[0045] The carboxamide intermediate of formula (III) can be prepared by methods known in the art, for example, by Gewald-type cyclization of the aldehyde of formula (VI) with cyanoacetamide and sulfur at room temperature up to 80°C, using a base such as triethylamine or morpholine and a solvent such as N,N-dimethylformamide or ethanol. General scheme 3 is further shown below by general procedure A.

[0046] Scheme 4 [ka]

[0047] The acid intermediate of formula (IV) can be commercially available or prepared by methods known in the art, for example, by Pd-catalyzed carbonylation of the intermediate of formula (VII) with a base, such as triethylamine, and a catalyst, such as PdCl2(dppp) with carbon monoxide, in a solvent such as aqueous acetonitrile.

[0048] Therefore, the present invention also relates to a method for preparing a compound according to the present invention, comprising the following steps: (a) Formula (B1) [ka] (In the formula, n is either 0 or 1) The compound is reacted with a suitable base in the presence of a suitable solvent to obtain formula (B2). [ka] The process of obtaining the compound, (b) The compound of formula (B2) (wherein n is 1) is reacted in a suitable solvent in the presence of an acid to obtain formula (I). [ka] (In this method, X and R are used in the formula.) 1 , R 2 , R 3 and R 4 (As defined above, PG is a protecting group.) Steps to obtain the compound This also relates to methods, including at least one of the following.

[0049] A mixture of the crude intermediate of formula (V) in a solvent such as n-butanol or THF and a base such as 2 equivalents of 50% aqueous potassium hydroxide solution is refluxed for 16 to 48 hours. The reaction mixture is partitioned between a solvent such as ethyl acetate and an aqueous sodium bicarbonate solution. Each layer is separated. The aqueous layer is extracted once or twice with an organic solvent. The combined organic layers are washed once with saline solution, dried on anhydrous sodium sulfate, concentrated, and dried. Purification by flash chromatography yields the thienopyrimidinone intermediate of formula (II).

[0050] The reaction in step (a) can be conveniently carried out in a solvent. The solvent may be, for example, THF, n-butanol, or a mixture thereof.

[0051] In the reaction of step (a), the base may be, for example, NaOH or KOH, and especially KOH.

[0052] The favorable conditions for the reaction in step (a) are approximately 40°C to 140°C, particularly approximately 50°C to 130°C, and more specifically approximately 60°C to 120°C.

[0053] The specific conditions for the reaction in step (a) are the use of KOH, n-butanol, or a mixture thereof in THF under reflux for approximately 16 to 48 hours.

[0054] The reaction in step (b) can be conveniently carried out in a solvent. The solvent may be, for example, CH2Cl2 or 1,4-dioxane.

[0055] In the reaction of step (b), the acid may be, for example, 2,2,2-trifluoroacetic acid or HCl, particularly 2,2,2-trifluoroacetic acid.

[0056] In the reaction of step (b), the protecting group may be, for example, Boc, Trt, or Dmb, and in particular Boc.

[0057] The favorable conditions for the reaction in step (b) are approximately 0°C to 100°C, particularly approximately 5°C to 70°C, and more specifically approximately 10°C to 40°C.

[0058] The specific conditions for the reaction in step (b) are the use of 2,2,2-trifluoroacetic acid in dichloromethane at room temperature for about 1 to 72 hours, and especially 1 to 24 hours.

[0059] The present invention also relates to compounds according to the present invention when produced according to the method of the present invention.

[0060] Therefore, the present invention also relates in particular to the following. Compounds according to the present invention for use as therapeutically active substances; A pharmaceutical composition comprising a compound according to the present invention and a therapeutically inactive carrier; Compounds according to the present invention for use in the treatment or prevention of neurodegenerative diseases; Compounds according to the present invention for use in the treatment or prevention of Huntington's disease; Use of the compounds according to the present invention for the treatment or prevention of neurodegenerative diseases, particularly Huntington's disease; Use of compounds according to the present invention for the preparation of medicines for the treatment or prevention of neurodegenerative diseases, particularly Huntington's disease; and A method for treating or preventing neurodegenerative diseases, particularly Huntington's disease, wherein the method comprises administering an effective amount of the compound according to the present invention to a patient in need thereof.

[0061] Specific embodiments of the present invention relate to pharmaceutical compositions comprising a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary substance.

[0062] Specific embodiments of the present invention relate to compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein at least one substituent comprises at least one radioisotope. Specific examples of radioisotopes are: 2 H, 3 H, 13 C, 14 C and 18 It is F.

[0063] Furthermore, the present invention includes, where applicable, all optical isomers of the compound of formula (I), i.e., diastereoisomers, diastereoisomer mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers, and solvated compounds thereof.

[0064] Compounds of formula (I) may contain one or more chiral centers and thus may result in racemates, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers. Depending on the nature of various substituents on the molecule, additional chiral centers may be present. Each of these chiral centers independently produces two optical isomers, and all possible optical isomers and diastereomers as mixtures and pure or partially purified compounds are intended to be included in the present invention. The present invention means that it encompasses all such isomeric forms of these compounds. The independent synthesis of these diastereomers or their chromatographic separation can be achieved as known in the art by appropriate modifications of the methods disclosed herein. Their absolute stereochemistry can, if necessary, be determined by X-ray crystallography of crystalline products or crystalline intermediates derivatized with reagents containing chiral centers of known absolute configuration. If necessary, racemic mixtures of the compounds can be separated to isolate the individual enantiomers. Separation can be carried out by methods known in the art, such as coupling a racemic mixture of compounds enantiomerically with pure compounds to form a diastereoisomer mixture, and then separating the individual diastereomers by standard methods such as fractional recrystallization or chromatography.

[0065] In embodiments providing optically pure enantiomers, an optically pure enantiomer means that the compound contains more than 90% by weight of the desired isomer, more specifically more than 95% by weight of the desired isomer, or more specifically more than 99% by weight of the desired isomer, where the weight percentage is based on the total weight of the isomers of the compound. Chiralally pure or chiralally concentrated compounds can be prepared by chiral selective synthesis or by separation of enantiomers. Separation of enantiomers can be performed on the final product or on a suitable intermediate.

[0066] Furthermore, one embodiment of the present invention is a compound of formula (I) described herein, when produced by any one of the steps described herein.

[0067] Compounds of formula (I) or pharmaceutically acceptable salts thereof can be used as pharmaceuticals (for example, in the form of pharmaceutical formulations). Pharmaceutical formulations of the present invention can be administered orally (for example, in the form of tablets, coated tablets, sugar-coated tablets, hard and soft gelatin capsules, solutions, emulsions, or suspensions), intranasally (for example, in the form of nasal sprays), rectally (for example, in the form of suppositories), or topically (for example, in the form of solutions, ointments, gels, or water-soluble polymer inserts). However, administration can also be carried out parenterally, such as intramuscularly, intravenously, or intraocularly (for example, in the form of sterile injection solutions).

[0068] Compounds of formula (I) or pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert inorganic or organic adjuvants for the manufacture of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injections, or topical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof, etc., can be used as such adjuvants for tablets, gels, and hard gelatin capsules, for example.

[0069] Suitable adjuvants for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

[0070] Suitable adjuvants for the production of solutions and syrups include, for example, water, polyols, sucrose, reverse sugars, and glucose.

[0071] Suitable adjuvants for injection solutions include, for example, water, alcohol, polyol, glycerol, and vegetable oil.

[0072] Suitable adjuvants for suppositories include, for example, natural or hydrogenated oils, waxes, fats, semi-solid or liquid polyols.

[0073] Suitable adjuvants for topical ophthalmic formulations include, for example, cyclodextrin, mannitol, or many other carriers and excipients known in the art.

[0074] Furthermore, pharmaceutical preparations may contain preservatives, solubilizers, viscosity enhancers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts to alter osmotic pressure, buffers, masking agents, or antioxidants. Pharmaceutical preparations may also contain other therapeutically valuable substances.

[0075] Dosages can be varied widely to suit the individual requirements of each specific case. Generally, for oral administration, a daily dose of approximately 0.1 mg to 20 mg per kg of body weight, preferably approximately 0.5 mg to 4 mg per kg of body weight (e.g., approximately 300 mg per person), is preferably divided into 1 to 3 individual doses, which, if appropriate, may consist of equal amounts, for example. For topical administration, the formulation may contain 0.001% to 15% by weight of the drug, and the required dose, which may be between 0.1 and 25 mg, can be administered by a single dose per day or per week, by multiple doses per day (2 to 4 times), or by multiple doses per week. However, where indicated, it will be clear that the upper or lower limits given herein may be exceeded.

[0076] Pharmaceutical composition Compounds of formula (I) or pharmaceutically acceptable salts thereof can be used as therapeutic active substances, for example, in the form of pharmaceutical preparations. Pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules and soft gelatin capsules, solutions, emulsions, or suspensions. However, administration may also be carried out rectally, for example, in the form of suppositories, or parenterally, for example, in the form of injections.

[0077] Compounds of formula (I) or pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert inorganic or organic carriers for the manufacture of pharmaceutical formulations. Lactose, corn starch or its derivatives, talc, and stearic acid or its salts, for example, can be used as carriers for tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. Suitable carriers for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solids, and liquid polyols. However, depending on the properties of the active substance, a carrier is usually not required for soft gelatin capsules. Suitable carrier materials for the manufacture of solutions and syrups include, for example, water, polyols, glycerol, and vegetable oils. Suitable carriers for suppositories include, for example, natural oils or hydrogenated oils, waxes, fats and oils, semi-liquids, or liquid polyols.

[0078] Furthermore, pharmaceutical formulations may contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts, buffers, masking agents, or antioxidants to alter osmotic pressure. They may also contain other substances of further therapeutic value.

[0079] A pharmaceutical product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically inactive carrier is also provided by the present invention, the method for which the preparation comprises forming a herbal drug administration form with a compound of formula (I) and / or a pharmaceutically acceptable salt thereof, and optionally one or more other therapeutically useful substances, together with one or more therapeutically inactive carriers.

[0080] Dosages can vary over a wide range and must be adjusted to the individual requirements of each specific case. For oral administration, adult doses can range from approximately 0.01 mg to approximately 1000 mg per day of the compound of general formula (I) or a corresponding amount of its pharmaceutically acceptable salt. Daily doses may be administered as a single dose or in divided doses, and may exceed the upper limit if indicated.

[0081] The following examples illustrate the present invention without limiting it, but are merely representative examples. For simplicity, the pharmaceutical preparation contains about 1 to 500 mg, particularly 1 to 100 mg, of the compound of formula (I). Examples of compositions according to the present invention are as follows.

[0082] Example A Tablets with the following composition are manufactured by conventional methods: [Table 1]

[0083] Manufacturing procedure 1. Mix ingredients 1, 2, 3, and 4 and granulate with purified water. 2. Dry the granules at 50°C. 3. Pass the granules through an appropriate grinding device. 4. Add ingredient 5, mix for 3 minutes, and compress using a suitable press.

[0084] Example B-1 Manufacture capsules with the following composition: [Table 2]

[0085] Manufacturing procedure 1. Mix ingredients 1, 2, and 3 in a suitable blender for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into appropriate capsules.

[0086] The compound of formula (I), lactose, and corn starch are mixed first in a mixer, and then in a grinder. The mixture is returned to the mixer; talc is added and mixed thoroughly. The mixture is filled into suitable capsules, such as hard gelatin capsules, by machine.

[0087] Example B-2 To manufacture soft gelatin capsules with the following composition: [Table 3] [Table 4]

[0088] Manufacturing procedure The compound of formula (I) is dissolved in the warm melt of the other components, and the mixture is filled into soft gelatin capsules of the appropriate size. The filled soft gelatin capsules are processed according to the usual procedure.

[0089] Example C Prepare suppositories with the following composition: [Table 5]

[0090] Manufacturing procedure The suppository mixture is melted in a glass or steel container, thoroughly mixed, and cooled to 45°C. Then, the finely powdered compound of formula (I) is added and stirred until completely dispersed. The mixture is poured into suppository molds of a suitable size, left to cool, and then the suppositories are removed from the molds and individually wrapped in wax paper or metal foil.

[0091] Example D Prepare an injectable solution with the following composition: [Table 6]

[0092] Manufacturing procedure Dissolve the compound of formula (I) in a mixture of polyethylene glycol 400 and some water for injection. Adjust the pH to 5.0 with acetic acid. Add the remaining water to adjust the volume to 1.0 ml. Filter the solution, fill the vial with an appropriate excess volume, and sterilize.

[0093] Example E Prepare a sachet with the following composition: [Table 7]

[0094] Manufacturing procedure The compound of formula (I) is mixed with lactose, microcrystalline cellulose, and sodium carboxymethylcellulose, and granulated with a mixture of polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and flavoring additives and filled into sachets. [Examples]

[0095] Abbreviation: Boc: tert-butyloxycarbonyl; BuOH: butanol; DCM: dichloromethane; DIBAL-H: diisobutylaluminum hydride; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; dppp: 1,3-bis-(diphenylphosphin)-propane; EC 50 : Maximum effective concentration at half volume; Depositphotos: Ethyl acetate; EtOH: Ethanol; HTRF: Fluorescence with uniform time decomposition; LAH: Lithium aluminum hydride; LCMS: Liquid chromatography-mass spectrometry; MeOH: Methanol; MS: Mass spectrometry; RP-HPLC: Reverse-phase high-performance liquid chromatography; RT: Room temperature; SFC: Supercritical fluid chromatography; TBME: Tert-butyl methyl ether; TFA: Trifluoroacetic acid; THF: Tetrahydrofuran; T3P: Propanephosphonic anhydride.

[0096] The following embodiments are provided to illustrate the present invention. These embodiments are not intended to be construed as limiting the scope of the present invention, but rather as representative examples only.

[0097] Aldehydes of formula VI Aldehyde 1 rac-(3S,4R)-3-fluoro-4-(2-ketoethyl)piperidine-1-carboxylate tert-butyl ester

[0098] a) (4E)-4-(2-ethoxy-2-keto-ethylidene)-3-fluoropiperidine-1-carboxylate tert-butyl ester [ka]

[0099] In a flame-dried 500 mL four-necked flask equipped with a magnetic stirrer bar, dropping funnel, and thermometer, a 60% dispersion of sodium hydride in mineral oil (2.0 g, 46.0 mmol, 1 equivalent) was gradually added to a solution of triethyl phosphonoacetate in tetrahydrofuran (9.8 g, 8.8 mL, 43.7 mmol, 0.950 equivalents) (200 mL), which had been extra-dried at 0–5°C for 25 minutes. The ice bath was removed and the mixture was stirred for 60 minutes. Tert-butyl 3-fluoro-4-keto-piperidine-1-carboxylic acid (10 g, 46.0 mmol, 1 equivalent), dissolved in tetrahydrofuran, was added dropwise over 30 minutes in an extra-dry state (100 mL). The reaction mixture was quenched with saturated NH4Cl solution (160 mL) and then partitioned into water (250 mL) and ethyl acetate (200 mL). The organic layer was separated. The aqueous layer was extracted with 100 ml of ethyl acetate. The combined organic layer was washed with 200 ml of saline solution, dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The title compound (8.51 g, 64%) was obtained as a colorless oil by purification by flash chromatography using heptane / ethyl acetate as the eluent. MS m / e: 188.0 ([M+H-C5H8O2] + ).

[0100] b) (3S,4R)-4-(2-ethoxy-2-keto-ethyl)-3-fluoropiperidine-1-carboxylate tert-butyl ester and (3S,4S)-4-(2-ethoxy-2-keto-ethyl)-3-fluoropiperidine-1-carboxylate tert-butyl ester [ka]

[0101] In a 2 L round-bottom flask, a solution of (4E)-4-(2-ethoxy-2-keto-ethylidene)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (8.51 g, 29.6 mmol, 1 equivalent) in ethyl acetate (567 mL) was degassed by three vacuum / argon cycles. The reaction mixture was then refilled with hydrogen and stirred under a hydrogen atmosphere (1 bar, room temperature) for 1 hour. The catalyst was removed by filtration on a Decalite pad. The filtrate was evaporated under vacuum. Purification by flash chromatography using methyl tert-butyl ether / heptane yielded (3S,4S)-4-(2-ethoxy-2-keto-ethyl)-3-fluoropiperidine-1-carboxylate tert-butyl ester (2.18 g, 25%) as a colorless viscous oil and (3S,4R)-4-(2-ethoxy-2-keto-ethyl)-3-fluoropiperidine-1-carboxylate tert-butyl ester (5.87 g, 69%) as a colorless viscous oil.

[0102] c) (3S,4R)-3-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate tert-butyl ester [ka]

[0103] In a flame-dried 500 mL four-necked flask equipped with a thermometer and dropping funnel, (3S,4R)-4-(2-ethoxy-2-keto-ethyl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (5.87 g, 20.3 mmol, 1 equivalent) was dissolved in tetrahydrofuran and excess dried (298 mL). 1 M lithium aluminum hydride (20.3 mL, 20.3 mmol, 1 equivalent) in THF was added over 30 minutes at 0-5°C. Stirring was continued for 2 hours. The reaction mixture was then quenched by adding water (0.770 mL), 2 M NaOH aqueous solution (0.770 mL), and water (2.31 mL). The ice bath was removed, and the resulting slurry was stirred overnight. A white precipitate formed and was removed by filtration. The filtration cake was washed with THF. When the filtrate was evaporated, the crude title compound (4.72 g, 94%) was obtained as a colorless oil.

[0104] d) (3S,4R)-3-fluoro-4-(2-ketoethyl)piperidine-1-carboxylate tert-butyl ester [ka]

[0105] To a solution of (3S,4R)-3-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (1.83 g, 7.4 mmol, 1 equivalent) in dichloromethane (140 mL), 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one (3.14 g, 7.4 mmol, 1 equivalent) was added. The reaction mixture was stirred at room temperature for 5 hours. TBME was added. The solid was collected by filtration. The filtrate was concentrated under vacuum. The residue was partitioned between ethyl acetate and water. The layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed once with saline solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude gradient compound (2 g) as a white semi-solid, which was used in the next step without further purification.

[0106] Aldehyde 2 (3R,4R)-3-fluoro-4-(2-ketoethyl)piperidine-1-carboxylate tert-butyl ester

[0107] a) (3R,4R)-3-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate tert-butyl ester [ka]

[0108] The title compound was prepared from (3R,4R)-4-(2-ethoxy-2-keto-ethyl)-3-fluoropiperidine-1-carboxylate tert-butyl ester following the procedure used for the synthesis of (3S,4R)-3-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate tert-butyl ester. MS m / e: 192.0 ([M+H-C4H8] + ).

[0109] b) (3R,4R)-3-fluoro-4-(2-ketoethyl)piperidine-1-carboxylate tert-butyl ester [ka]

[0110] To a solution of (3R,4R)-3-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (771 mg, 3.12 mmol, 1 equivalent) in dichloromethane (31 mL), 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one (1.32 g, 3.12 mmol, 1 equivalent) was added at room temperature. The mixture was stirred for 2 hours. The mixture was partitioned between DCM (30 mL) and 1 M Na2CO3 aqueous solution (30 mL). The layers were separated. The aqueous layer was extracted with 50 mL of DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated in diethyl ether (30 mL). The solid was collected by filtration. The filtrate was concentrated under vacuum to obtain the crude title compound (890 mg) as a white solid, which was used in the next step without further purification. MS m / e: 190.1 ([M+H-C4H8] + ).

[0111] Aldehyde 3 3,3-difluoro-4-(2-ketoethyl)piperidine-1-carboxylate tert-butyl ester [ka]

[0112] a) 3,3-difluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate tert-butyl ester

[0113] To a solution of 4-(2-ethoxy-2-keto-ethyl)-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (260 mg, 0.846 mmol, 1 equivalent) in toluene (2 mL), 1 M DIBAL-H in DCM (930 μL, 0.931 mmol, 1.1 equivalents) was added over 10-15 minutes at -78°C. The reaction mixture was stirred for 1.5 hours. 133 μl of water was added at -78°C. The reaction mixture was then quenched by adding water (0.133 mL), 1 M NaOH aqueous solution (0.133 mL), and water (0.399 mL). The ice bath was removed, and the resulting slurry was stirred overnight. A white precipitate formed and was removed by filtration. The filtrate was washed with THF. The filtrate was concentrated under vacuum to obtain a mixture of the aldehyde and the starting material. The mixture was dissolved in toluene (2 mL) and cooled to -78°C. 1 M DIBAL-H (1.70 mL, 1.69 mmol, 2 equivalents) in DCM was slowly added over 10-15 minutes. The reaction mixture was stirred at -30°C for 5 hours. The reaction mixture was then quenched by adding water (0.240 mL), 1 M NaOH aqueous solution (0.240 mL), and water (0.720 mL). The ice bath was removed, and the resulting slurry was stirred overnight. A white precipitate formed and was removed by filtration. The filtration cake was washed with THF. The title compound (127 mg, 56.58%) was obtained as a colorless oil by purification by flash chromatography using n-heptane / ethyl acetate as the eluent. MS m / e: 210.1([M+H] + ).

[0114] b) 3,3-difluoro-4-(2-ketoethyl)piperidine-1-carboxylate tert-butyl ester [ka]

[0115] To a solution of DMSO (90 mg, 82 uL, 1.15 mmol, 2.4 equivalents) in dichloromethane (1.5 mL), oxalyl chloride (73 mg, 50 uL, 0.574 mmol, 1.2 equivalents) was added at -78°C. The mixture was stirred at -50°C for 30 minutes. The reaction mixture was cooled to -78°C. A solution of 3,3-difluoro-4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (127 mg, 0.479 mmol, 1 equivalent) in dichloromethane (1 mL) was slowly added. Stirring was continued for 1 hour. Triethylamine (242 mg, 334 uL, 2.39 mmol, 5 equivalents) was added. After 15 minutes, the ice bath was removed and the reaction mixture was warmed to room temperature. After 2 hours, the reaction mixture was partitioned between ethyl acetate and water. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed once with water / ammonium chloride and once with saline solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude title compound (132 mg) as a colorless oil, which was used in the next step without further purification. MS m / e: 164.0 ([M+H-C5H8O2] + ).

[0116] Aldehyde 4 7-(2-ketoethyl)-4-azaspiro[2.5]octane-4-carboxylate tert-butyl ester

[0117] a) tert-butyl(7E)-7-(2-ethoxy-2-oxo-ethylidene)-4-azaspiro[2.5]octane-4-carboxylate [ka]

[0118] A solution of tetrahydrofuran (2 mL) containing triethylphosphonoacetate (896 mg, 800 uL, 4.0 mmol, 0.900 equivalents) was added dropwise at 0°C to a solution of tetrahydrofuran (2 mL) containing a NaH dispersion (194 mg, 4.44 mmol, 1 equivalent). The reaction mixture was warmed to room temperature and stirred for 15 minutes. The reaction mixture was cooled to 0°C, and a solution of 7-keto-4-azaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (1 g, 4.44 mmol, 1 equivalent) in tetrahydrofuran (2 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between ethyl acetate and 1 M NaOH aqueous solution. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed once with saline solution, dried over sodium sulfate, filtered, and concentrated under vacuum. The title compound (883 mg, 66%) was obtained as a colorless oil with a purity of 98% by purification using flash chromatography with heptane / ethyl acetate as the eluent. MS m / e: 196.1([M+H-C5H8O2] + ).

[0119] b) 7-(2-ethoxy-2-keto-ethyl)-4-azaspiro[2.5]octane-4-carboxylate tert-butyl ester [ka]

[0120] (7E)-7-(2-ethoxy-2-keto-ethylidene)-4-azaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (883 mg, 2.93 mmol, 1 equivalent) was dissolved in ethyl acetate (10 mL). The atmosphere was changed to argon (3 × vacuum / argon). Palladium supported on activated carbon (17 mg, 0.164 mmol, 0.056 equivalents) was added. The atmosphere was changed to hydrogen (3 × vacuum / hydrogen). The reaction mixture was stirred overnight at room temperature. The catalyst was removed by filtration through a Sartorius filter, and the mixture was concentrated under vacuum. The title compound (846 mg, 97.1%) was obtained as a colorless oil by purification by flash chromatography using heptane / ethyl acetate as the eluent. MS m / e: 198.2 ([M+H-C5H8O2] + ).

[0121] c) 7-(2-hydroxyethyl)-4-azaspiro[2.5]octane-4-carboxylate tert-butyl ester [ka]

[0122] To a solution of 7-(2-ethoxy-2-keto-ethyl)-4-azaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (846 mg, 2.85 mmol, 1 equivalent) in tetrahydrofuran (20 mL), 1 M LAH in THF (2.9 mL, 2.9 mmol, 1.01 equivalent) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was then quenched by adding water (0.15 mL), 4N NaOH (0.15 mL), and water (0.45 mL). The solid was collected by filtration. The filtrate was concentrated under vacuum. The reaction mixture was partitioned between ethyl acetate and water, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed once with saline solution, dried on anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude title compound (730 mg, 100%) as a pale yellow oil, which was used in the next step without further purification. MS m / e: 156.1([M+H-C5H8O2]+ ).

[0123] d) 7-(2-ketoethyl)-4-azaspiro[2.5]octane-4-carboxylate tert-butyl ester [ka]

[0124] 7-(2-hydroxyethyl)-4-azaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (730 mg, 2.86 mmol, 1 equivalent) was dissolved in dichloromethane (55 mL) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one (1.21 g, 2.86 mmol, 1 equivalent) was added. The reaction mixture was stirred at room temperature for 3 hours. TBME was added. The solid was collected by filtration. The filtrate was concentrated under vacuum. The residue was partitioned between ethyl acetate and water. The layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed once with saline solution, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was triturated in ethyl acetate. The solid was collected by filtration. The filtrate was concentrated under vacuum to obtain the crude title compound as a white semi-solid. MS m / e:154.1([M+H-C5H8O2] + ).

[0125] Carboxamide of formula III General Procedure A: A mixture of the aldehyde of formula (VI) (1 equivalent), cyanoacetamide (1 equivalent), triethylamine (1 equivalent), and sulfur (1 equivalent) in N,N-dimethylformamide is stirred at room temperature for 16 to 48 hours. The reaction mixture is partitioned between a solvent such as ethyl acetate and water. Each layer is separated. The aqueous layer is extracted once or twice with an organic solvent. The combined organic layers are washed once with saline solution, dried on anhydrous sodium sulfate, concentrated, and dried. Purification by flash chromatography yields the carboxamide of formula (III).

[0126] Carboxamide 1 4-(5-amino-4-carbamoyl-2-thienyl)piperidine-1-carboxylate tert-butyl ester [ka]

[0127] According to general procedure A, the title compound was obtained from 4-(2-ketoethyl)piperidine-1-carboxylate tert-butyl ester as a brown oil with a purity of 93% in 98% yield by LC-MS. MS m / e: 270.1([M+H] + )

[0128] Carboxamide 2 (3S,4S)-4-(5-amino-4-carbamoyl-2-thienyl)-3-fluoropiperidine-1-carboxylate tert-butyl ester [ka]

[0129] According to general procedure A, the title compound was obtained from (3S,4R)-3-fluoro-4-(2-ketoethyl)piperidine-1-carboxylate tert-butyl ester by LC-MS as an off-white solid with a purity of 97%, in a yield of 17%. MS m / e: 342.3([M+H] + )

[0130] Carboxamide 3 4-(5-amino-4-carbamoyl-2-thienyl)-3,3-difluoropiperidine-1-carboxylate tert-butyl ester [ka]

[0131] According to general procedure A, the title compound was obtained from 3,3-difluoro-4-(2-ketoethyl)piperidine-1-carboxylate tert-butyl ester by LC-MS as an orange solid with 99% purity in 63% yield. MS m / e: 360.3 ([MH] - )

[0132] Carboxamide 4 7-(5-amino-4-carbamoyl-2-thienyl)-4-azaspiro[2.5]octane-4-carboxylate tert-butyl ester [ka]

[0133] The title compound was obtained from 7-(2-ketoethyl)-4-azaspiro[2.5]octane-4-carboxylate tert-butyl ester by LC-MS in 37% yield and 98% purity according to general procedure A. MS m / e: 350.2 ([MH] - )

[0134] Carboxamide 5 3-[(5-amino-4-carbamoyl-2-thienyl)oxy]azetidine-1-carboxylate tert-butyl ester [ka]

[0135] According to general procedure A, the title compound was obtained from 3-(2-ketoethoxy)azetidine-1-carboxylate tert-butyl ester by LC-MS as a brown oil with a purity of 95% in 16% yield. MS m / e: 312.2 ([MH] - )

[0136] Carboxamide 6 4-[(5-amino-4-carbamoyl-2-thienyl)oxy]piperidine-1-carboxylate tert-butyl ester [ka]

[0137] According to general procedure A, the title compound was obtained from 4-(2-ketoethoxy)piperidine-1-carboxylate tert-butyl ester as a brown oil with a purity of 95% in 23% yield by LC-MS. MS m / e: 340.3 ([MH] - )

[0138] Carboxamide 7 7-(5-amino-4-carbamoyl-2-thienyl)-4-azaspiro[2.5]octane-4-carboxylate tert-butyl ester [ka]

[0139] The title compound was obtained from 7-(2-ketoethyl)-4-azaspiro[2.5]octane-4-carboxylate tert-butyl ester by LC-MS in 37% yield and purity of 98% according to general procedure A. MS m / e: 350.2 ([MH] - )

[0140] Carboxamide 8 (3R,4S)-4-(5-amino-4-carbamoyl-2-thienyl)-3-fluoropiperidine-1-carboxylate tert-butyl ester [ka]

[0141] According to general procedure A, the title compound was obtained from (3R,4R)-3-fluoro-4-(2-ketoethyl)piperidine-1-carboxylate tert-butyl ester by LC-MS as a light brown solid with a purity of 94%, in a yield of 39%. MS m / e: 342 ([MH] - )

[0142] Carboxamide 9 (+)-(3S,4S)-4-(5-amino-4-carbamoyl-2-thienyl)-3-fluoropiperidine-1-carboxylate tert-butyl ester (enantiomer a) [ka] and Carboxamide 10 (-)-(3R,4R)-4-(5-amino-4-carbamoyl-2-thienyl)-3-fluoropiperidine-1-carboxylate tert-butyl ester (enantiomer b) [ka]

[0143] Two presumably assigned enantiomers were obtained from racemic (3S,4S)-4-(5-amino-4-carbamoyl-2-thienyl)-3-fluoropiperidine-1-carboxylate tert-butyl ester by chiral SFC separation using a chiral Daicel IG column, 5 μm, 250 × 30 mm, with 35% MeOH as the cosolvent.

[0144] (+)-(3S,4S)-4-(5-amino-4-carbamoyl-2-thienyl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester enantiomer a was obtained as a brown solid in 35% yield. MS m / e: 342.3 ([MH] - ),[α]D=+72.542(c=0.182g / 100ml,MeOH,20℃).

[0145] (-)-(3R,4R)-4-(5-amino-4-carbamoyl-2-thienyl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester enantiomer b was obtained as a brown solid in 39% yield. MS m / e: 342.2 ([MH] - ),[α]D=-86.017(c=0.182g / 100ml,MeOH,20℃).

[0146] Carboxamide 11 (+)-(7S)-7-(5-amino-4-carbamoyl-2-thienyl)-4-azaspiro[2.5]octane-4-carboxylate tert-butyl ester (enantiomer a) [ka] and Carboxamide 12 (-)-(7R)-7-(5-amino-4-carbamoyl-2-thienyl)-4-azaspiro[2.5]octane-4-carboxylate tert-butyl ester (enantiomer b) [ka]

[0147] Two presumably assigned enantiomers were obtained from racemic 7-(5-amino-4-carbamoyl-2-thienyl)-4-azaspiro[2.5]octane-4-carboxylate tert-butyl ester by chiral SFC separation using a chiral CHIRALCEL OJ-H column, 5 μm, 250 × 20 mm, with 15% MeOH as a cosolvent.

[0148] (+)-(7S)-7-(5-amino-4-carbamoyl-2-thienyl)-4-azaspiro[2.5]octane-4-carboxylic acid tert-butyl ester enantiomer a was obtained as brown oil in 48% yield. MS m / e: 350.2 ([MH] - ),[α]D=+27.439(c=0.252g / 100ml,MeOH,20℃).

[0149] (-)-(7R)-7-(5-amino-4-carbamoyl-2-thienyl)-4-azaspiro[2.5]octane-4-carboxylic acid tert-butyl ester enantiomer a was obtained as a brown solid in 49% yield. MS m / e: 350.2 ([MH] - ),[α]D=-21.999(c=0.280g / 100ml,MeOH,20℃).

[0150] Acid intermediate of formula IV Acid 1 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylic acid [ka]

[0151] A mixture of 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine (10.0 g, 56.06 mmol) in acetonitrile (80 ml) and water (20 ml) was purged with argon. PdCl2 (dppp) (0.325 g, 0.551 mmol, 0.01 equivalent) and triethylamine (15.4 ml, 110.12 mmol, 2.0 equivalent) were added. The mixture was carbonylated at 90°C for 72 hours under a 60 bar carbon monoxide atmosphere. The solid was removed by filtration, and the 20 ml portion of acetonitrile was washed twice. The filtrate was evaporated. The crude product was dissolved in dichloromethane (100 ml). After adding 4 M hydrogen chloride (13.8 ml, 55.08 mmol) in 1,4-dioxane, the mixture was stirred for 3 hours. The precipitate was collected by filtration, washed twice with 20 ml of EtOH, and dried in vacuum to obtain the title compound as an off-white solid (9.46 g, 75%). MS m / e: 192.1([M+H] + )

[0152] Acid 2 2-methyl-8-(trifluoromethyl)imidazo[1,2-b]pyridazine-6-carboxylic acid

[0153] a) 6-chloro-2-methyl-8-(trifluoromethyl)imidazo[1,2-b]pyridazine [ka]

[0154] In a 10 mL round-bottom flask equipped with a magnetic stirrer bar, reflux condenser, and N2 inlet bubbler, [6-chloro-4-(trifluoromethyl)pyridazin-3-yl]amine (94 mg, 0.476 mmol) and pyridinium p-toluenesulfonate (11.9 mg, 0.048 mmol) were combined with isopropanol (2 mL). 1-bromo-2,2-dimethoxypropane (105 mg, 77 μL, 0.571 mmol, 1.2 equivalents) was added, and the colorless solution was stirred at 75°C for 24 hours. The resulting dark brown reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with saturated aqueous NaHCO3 (10 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under vacuum. Purification by column chromatography yielded the title compound (46 mg, 34%) as a pale yellow solid. MS m / e:236.1([M+H] + )

[0155] b) 2-methyl-8-(trifluoromethyl)imidazo[1,2-b]pyridazine-6-carboxylic acid [ka]

[0156] Similar to the preparation of 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylic acid, the title compound was obtained from 6-chloro-2-methyl-8-(trifluoromethyl)imidazo[1,2-b]pyridazine in 56% yield as a light brown solid. MS m / e: 246.1([M+H] + )

[0157] Thienopyrimidinone intermediate of formula II General Procedure B: To a mixture of the carboxamide intermediate of formula (III) (1 equivalent) and the acid intermediate of formula (IV) (1.05-1.2 equivalents) in pyridine (0.3 M), add an amide coupling reagent, such as n-propylphosphonic anhydride (T3P) (1.2 equivalents), and stir at room temperature for 2-16 hours. The reaction mixture is partitioned between a solvent such as ethyl acetate and an aqueous sodium bicarbonate solution. Separate each layer. Extract the aqueous layer with one or two organic solvents. Wash the combined organic layers once with saline solution, dry on anhydrous sodium sulfate, concentrate, and dry. Reflux a mixture of the crude intermediate of formula (V) in a solvent such as n-butanol or THF with a base such as 50% aqueous potassium hydroxide solution (2 equivalents) for 16-48 hours. Partition the reaction mixture between a solvent such as ethyl acetate and an aqueous sodium bicarbonate solution. Separate each layer. Extract the aqueous layer with one or two organic solvents. The combined organic layers are washed once with saline solution, dried on anhydrous sodium sulfate, concentrated, and dried. Purification by flash chromatography yields the thienopyrimidinone intermediate of formula (II).

[0158] Thienopyrimidinone 1 4-[2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-keto-3H-thieno[2,3-d]pyrimidine-6-yl]piperidine-1-carboxylate tert-butyl ester [ka]

[0159] Following general procedure B, the title compound was obtained from 4-(5-amino-4-carbamoyl-2-thienyl)piperidine-1-carboxylic acid tert-butyl ester and 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylic acid as an off-white solid with a purity of 97% by LC-MS. MS m / e: 481.3([M+H] + )

[0160] Thienopyrimidinone 2 (3SR,4SR)-4-[2-(2,8-Dimethylimidazo[1,2-b]pyridazin-6-yl)-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl]-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester

Chem.

[0161] According to General Procedure B, the title compound was obtained as a pale yellow solid with a purity of 94% by LCMS from (3SR,4SR)-4-(5-amino-4-carbamoyl-2-thienyl)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester and 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylic acid. MS m / e: 499.3 ([M+H] + )

[0162] Thienopyrimidinone 3 4-[2-(2,8-Dimethylimidazo[1,2-b]pyridazin-6-yl)-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl]-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester

Chem.

[0163] The title compound was obtained as a pale yellow solid with a purity of 94% by LCMS from 4-(5-amino-4-carbamoyl-2-thienyl)-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester and 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylic acid according to General Procedure B. MS m / e: 535.2 ([M+H] + )

[0164] Thienopyrimidinone 4 3-[[2-(2,8-Dimethylimidazo[1,2-b]pyridazin-6-yl)-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl]oxy]azetidine-1-carboxylic acid tert-butyl ester [Chemical formula]

[0165] The title compound was obtained as an off-white solid with a purity of 99% by LCMS from 3-[(5-amino-4-carbamoyl-2-thienyl)oxy]azetidine-1-carboxylic acid tert-butyl ester and 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylic acid according to General Procedure B. MS m / e: 469.2 ([M+H] + )[[ID=·12]]

[0166] Thienopyrimidinone 5 tert-Butyl 4-[[2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl]oxy]piperidine-1-carboxylate [Chemical formula]

[0167] The title compound was obtained as a yellow solid with a purity of 94% by LCMS from tert-butyl 4-[(5-amino-4-carbamoyl-2-thienyl)oxy]piperidine-1-carboxylate and 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylic acid according to General Procedure B. MS m / e: 497.2 ([M+H] + )

[0168] Thienopyrimidinone 6[[ID=·34]] tert-Butyl 7-[2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl]-4-azaspiro[2.5]octane-4-carboxylate [Chemical formula] <00M931> The title compound was obtained from 7-(5-amino-4-carbamoyl-2-thienyl)-4-azaspiro[2.5]octane-4-carboxylic acid tert-butyl ester and 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylic acid by LC-MS according to general procedure B as a pale yellow solid with a purity of 83%. MS m / e: 507.3([M+H] + )

[0170] Thienopyrimidinone 7 4-[4-keto-2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-b]pyridazin-6-yl]-3H-thieno[2,3-d]pyrimidine-6-yl]piperidine-1-carboxylate tert-butyl ester [ka]

[0171] Following general procedure B, the title compound was obtained from 4-(5-amino-4-carbamoyl-2-thienyl)piperidine-1-carboxylic acid tert-butyl ester and 2-methyl-8-(trifluoromethyl)imidazo[1,2-b]pyridazine-6-carboxylic acid as a yellow solid with a purity of 98% by LC-MS. MS m / e: 553.2([M+H] + )

[0172] Exemplary compounds of formula (I) General Procedure C: A solution of the N-BOC thienopyrimidinone derivative of general formula (II) (1 equivalent) and 2,2,2-trifluoroacetic acid (10-100 equivalents) in dichloromethane is stirred at room temperature for 1-24 hours. Once deprotection is complete, the reaction mixture is concentrated under vacuum. The free base can be obtained by partitioning the TFA salt between a base such as a 1 M aqueous sodium bicarbonate solution or a 1 M aqueous sodium carbonate solution and an organic solvent, such as ethyl acetate or dichloromethane. The layers are separated, and the aqueous layer is extracted twice with organic solvents. The combined organic layers are dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The compound of formula (I) can be obtained by purification by RP-HPLC, flash chromatography, or by trituration from a suitable solvent such as ethyl acetate, ethanol, or methanol.

[0173] Example 1 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-6-(4-piperidyl)-3H-thieno[2,3-d]pyrimidine-4-one hydrogen chloride [ka]

[0174] A suspension of 4-[2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-keto-3H-thieno[2,3-d]pyrimidine-6-yl]piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.105 mmol, 1 equivalent) in methanol (1 mL) was mixed with 4 M aqueous HCl (324 mg, 270 μL, 1.08 mmol, 10.24 equivalents). The reaction mixture was stirred at room temperature for 3 days. The solid was recovered by filtration, washed with ethyl acetate, and dried under vacuum to obtain the title compound (28.9 mg, 65%) as a pale yellow solid. MS m / e: 381.3 ([M+H] + )

[0175] Example 2 2-(2,8-Dimethylimidazo[1,2-b]pyridazin-6-yl)-6-[(3SR,4SR)-3-fluoro-4-piperidyl]-3H-thieno[2,3-d]pyrimidin-4-one

Chem.

[0176] According to General Procedure C, the title compound was obtained as a pale yellow solid with a purity of 97% by LCMS from (3SR,4SR)-4-[2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl]-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester. MS m / e: 397.3 ([M+H] + )

[0177] Example 3 6-(3,3-Difluoro-4-piperidyl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3H-thieno[2,3-d]pyrimidin-4-one

Chem.

[0178] The title compound was obtained as a white solid with a purity of 99% by LCMS from 4-[2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl]-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester according to General Procedure C. MS m / e: 417.2 ([M+H] + )

[0179] Example 4 6-(Azetidin-3-yloxy)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3H-thieno[2,3-d]pyrimidin-4-one

Chem.

[0180] Following general procedure C, the title compound was obtained from 3-[[2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-keto-3H-thieno[2,3-d]pyrimidine-6-yl]oxy]azetidine-1-carboxylic acid tert-butyl ester as a pale yellow solid with a purity of 98% by LC-MS. MS m / e: 369.1([M+H] + )

[0181] Example 5 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-6-(4-piperidyloxy)-3H-thieno[2,3-d]pyrimidine-4-one [ka]

[0182] Following general procedure C, the title compound was obtained from 4-[[2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-keto-3H-thieno[2,3-d]pyrimidine-6-yl]oxy]piperidine-1-carboxylate tert-butyl ester as a yellow solid with a purity of 96% by LC-MS. MS m / e: 397.2([M+H] + )

[0183] Example 6 6-(4-azaspiro[2,5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-3H-thieno[2,3-d]pyrimidine-4-one [ka]

[0184] The title compound was obtained from 7-[2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-keto-3H-thieno[2,3-d]pyrimidine-6-yl]-4-azaspiro[2.5]octane-4-carboxylic acid tert-butyl ester by LC-MS according to general procedure C as an off-white solid with a purity of 96%. MS m / e: 407.2([M+H] + )

[0185] Example 7 2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-b]pyridazin-6-yl]-6-(4-piperidyl)-3H-thieno[2,3-d]pyrimidine-4-one [ka]

[0186] Following general procedure C, the title compound was obtained from 4-[4-keto-2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-b]pyridazin-6-yl]-3H-thieno[2,3-d]pyrimidine-6-yl]piperidine-1-carboxylate tert-butyl ester as a yellow solid with a purity of 98% by LC-MS. MS m / e: 435.2([M+H] + )

[0187] Example 8 Uniform time-resolved fluorescence for HTT reduction The HTRF assay was adapted to cells derived from the GENEAe1020-A cell line (https: / / hpscreg.eu / cell-line / GENEAe020-A), as described by Weiss et al. (Analytical Biochemistry Volume 395, Issue 1, 1 December 2009, Pages 8-15 and Analytical Biochemistry Volume 410, 2011, Pages 304-306).

[0188] We tested compounds on the effect of mutant HTT levels in Huntington's patient human cells (GENEAe020-A cell line) using homogeneous time-resolved fluorescence (HTRF) against mutant HTT protein (mHTT). The GENEAe020-A cell line was induced by Genea Biocells from human blastocysts of HD donors. After assessing viability, cells were seeded in 384-well collagen-coated plates in growth medium. Once cells adhered, the medium was removed, and the test compounds dissolved in DMSO were diluted in buffer and added to the adherent cells. Controls included cell-free experiments, DMSO without the compounds, and Hsp90 inhibitor controls. Cells were incubated with the compounds and controls for 48 hours. Subsequently, the cells were lysed and transferred to assay plates containing an HTRF-labeled monoclonal antibody developed by Paul Patterson that recognizes a specific region of the HTT protein (Ko et al., Brain Research Bulletin, Volume 56, Numbers 3 and 4, 2001, Pages 319-329). The terbium-labeled "donor" antibody (2B7) binds to the N-terminus of the HTT protein, while the Alexa488-labeled "acceptor" antibody (MW1) is specific to the polyglutamine region of the protein. Binding of the acceptor-labeled antibody is more efficient for the extended polyglutamine repeats of the mutant HTT protein, which translate to a signal boost that allows for specific measurement of mutant HTT protein levels. The HTRF donor and HTRF acceptor detection reagents are incubated with cell lysates, and the ratio between the signals of the two fluorophores indicates the relative amount of mHTT.

[0189] The results of this assay are shown in Table 1. Table 1 shows the EC values ​​for the decrease in mHTT obtained for specific examples of the present invention as measured by the HTRF assay. 50 The values ​​are provided (the data shown below is the average from three iterations). [Table 8]

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, X is a bond or -O-, R １ is azetidine-3-yl, 4-piperidyl, or 4-azaspiro[2.5]octan-7-yl, R ４ Optionally substituted with one or two substituents independently selected from, R ２ is alkyl or haloalkyl, R ３ It is an alkyl, R ４ (These are halogens, alkyls, heterocycloalkyls, heterocycloalkylalkyls, alkylheterocycloalkyls, haloheterocycloalkyls, cycloalkyls, cycloalkylalkyls, alkylcycloalkyls, halocycloalkyls, cycloalkylaminos, aryls, arylalkyls, alkylaryls, haloaryls, cyanos, hydroxys, oxos, haloalkyls, alkylcarbonyls, alkoxys, haloalkoxys, alkoxyalkyls, alkoxycarbonyls, aminos, alkylaminos, dialkylaminos, aminoalkyls, alkylaminoalkyls, dialkylaminoalkyls, aminoalkylaminos, alkoxyalkylaminos, alkylcarbonylaminos, alkoxycarbonylaminos, hydroxyalkyls, hydroxyalkoxyalkyls, or hydroxyalkylaminos.) Compounds thereof, or pharmaceutically acceptable salts thereof.

2. R １ However, it is 4-piperidyl or 4-azaspiro[2.5]octan-7-yl, R １ However, R ４ The compound according to claim 1, which is optionally substituted with one or two substituents independently selected from the above.

3. R ２ The compound according to claim 1 or 2, wherein R is methyl or trifluoromethyl.

4. R ３ The compound according to any one of claims 1 to 3, wherein the compound is methyl.

5. R ４ The compound according to any one of claims 1 to 4, wherein the compound is a halogen.

6. R ４ The compound according to any one of claims 1 to 5, wherein it is fluoro.

7. The compound according to any one of claims 1 to 6, wherein X is a bond.

8. 2-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-6-(4-piperidyl)-3H-thieno[2,3-d]pyrimidine-4-one, 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-6-[(3SR,4SR)-3-fluoro-4-piperidyl]-3H-thieno[2,3-d]pyrimidine-4-one, 6-(3,3-difluoro-4-piperidyl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3H-thieno[2,3-d]pyrimidine-4-one, 6-(azetidine-3-yloxy)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3H-thieno[2,3-d]pyrimidine-4-one, 2-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-6-(4-piperidyloxy)-3H-thieno[2,3-d]pyrimidine-4-one, 6-(4-azaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-3H-thieno[2,3-d]pyrimidine-4-one, and 2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-b]pyridazin-6-yl]-6-(4-piperidyl)-3H-thieno[2,3-d]pyrimidine-4-one A compound according to any one of claims 1 to 7, selected from, or a pharmaceutically acceptable salt thereof.

9. 2-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-6-(4-piperidyl)-3H-thieno[2,3-d]pyrimidine-4-one, 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-6-[(3SR,4SR)-3-fluoro-4-piperidyl]-3H-thieno[2,3-d]pyrimidine-4-one, 2-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-6-(4-piperidyloxy)-3H-thieno[2,3-d]pyrimidine-4-one, 6-(4-azaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-3H-thieno[2,3-d]pyrimidine-4-one, and 2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-b]pyridazin-6-yl]-6-(4-piperidyl)-3H-thieno[2,3-d]pyrimidine-4-one A compound according to any one of claims 1 to 8, selected from, or a pharmaceutically acceptable salt thereof.

10. A method for preparing the compound according to any one of claims 1 to 9, comprising the following steps: (a) Formula (B1) 【Chemistry 2】 (In the formula, n is either 0 or 1) The compound is reacted with a suitable base in the presence of a suitable solvent to produce formula (B2). 【Transformation 3】 The process of obtaining the compound, (b) The compound of formula (B2) (wherein n is 1) is reacted in a suitable solvent in the presence of an acid to obtain formula (I) 【Chemistry 4】 (In the formula, X, R １ , R ２ , R ３ and R ４ (is defined in any one of claims 1 to 9, where PG is a protecting group.) Steps to obtain the compound A method that includes at least one of the following.

11. A compound according to any one of claims 1 to 9 for use as a therapeutically active substance.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a therapeutically inactive carrier.

13. The compound according to any one of claims 1 to 9 for use in the treatment or prevention of neurodegenerative diseases.

14. The pharmaceutical composition according to claim 12 for the treatment or prevention of neurodegenerative diseases.

15. Use of the compound according to any one of claims 1 to 9 for the preparation of a pharmaceutical for the treatment or prevention of neurodegenerative diseases.

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