Compounds containing phosphate ester groups, pharmaceutical compositions containing the same, methods for preparing the same, and uses thereof.

Abstract

The present invention relates to compounds of formula (I), pharmaceutical compositions containing them, processes for their preparation and their use for the treatment of neurodegenerative diseases. [Formula 1] JPEG2024519938000050.jpg5175

Description

[Technical Field]

[0001] The present invention relates to a compound containing a phosphate ester group, a pharmaceutical composition containing the same, a method for preparing the same, and its use for the treatment of neurodegenerative diseases. [Background technology]

[0002] Alzheimer's disease (commonly known as senile dementia, or AD) is a progressive neurodegenerative disease characterized by cognitive and behavioral abnormalities as its primary clinical symptoms, and is the most common form of dementia in older adults. Alzheimer's disease is primarily characterized by a decline in cognitive abilities and a rapid decline in memory function. The main pathological and physiological features are the deposition of β-amyloid (Aβ) in the brain, which forms senile plaques; hyperphosphorylation of tau protein, which causes neurofibrillary tangles; impaired cerebral glucose metabolism; and loss of neurons / synapses. The disease is long-lasting and, due to the patient's low self-care capacity, places a serious mental and economic burden on families and society. However, there are currently no drugs available worldwide that can prevent or slow the progression of the disease. Currently available treatments for AD are only symptomatic treatments, which can control or improve cognitive and functional symptoms for a certain period, but cannot stop or prevent the deterioration of the condition. [Overview of the project]

[0003] The present invention provides compounds containing a phosphate ester group that can be used for the prevention or treatment of neurodegenerative diseases. Furthermore, the compounds of the present invention also have superior properties, including better physicochemical properties (e.g., solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, suitable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and / or fewer side effects), and lower tolerance.

[0004] One aspect of the present invention provides a compound having the structure of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof.

[0005]

Chemical formula

[0006] Another aspect of the present invention provides a pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0007] Another aspect of the present invention provides the use of the compounds of the present invention, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds, or prodrugs thereof, or pharmaceutical compositions of the present invention, in the manufacture of agents for the prevention or treatment of neurodegenerative diseases or for the alleviation of symptoms of neurodegenerative diseases.

[0008] Another aspect of the present invention provides compounds of the present invention, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds, or prodrugs thereof, or pharmaceutical compositions of the present invention, for use in the prevention or treatment of neurodegenerative diseases, or in the alleviation of symptoms of neurodegenerative diseases.

[0009] Another aspect of the present invention provides a method for the prevention or treatment of neurodegenerative diseases, or for the alleviation of symptoms of neurodegenerative diseases, comprising administering an effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof, or a pharmaceutical composition of the present invention, to a subject in need thereof.

[0010] Another aspect of the present invention provides a method for preparing the compounds of the present invention. Detailed description of the invention

[0011] definition Unless otherwise defined in context, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. References to technologies used herein are intended to refer to technologies commonly understood in the art, including variations on those technologies or substitutions of equivalent technologies that would be obvious to those skilled in the art. The following terms are expected to be readily understood by those skilled in the art, but the following definitions are provided for the better explanation of the invention.

[0012] The terms “including,” “consisting of,” “possessing,” “containing,” and “related to,” as used herein, and other variations thereof, are inclusive or open-ended and do not exclude other elements or methods or processes not described herein.

[0013] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbyl, preferably a saturated divalent hydrocarbyl having 1, 2, 3, 4, 5, or 6 carbon atoms, such as methylene, ethylene, propylene, or butylene.

[0014] As used herein, the term "alkyl" is defined as a straight-chain or branched-chain saturated aliphatic hydrocarbon. In some embodiments, alkyl has 1 to 12 carbon atoms, for example, 1 to 6 carbon atoms. For example, as used herein, "C 1-6 The term "alkyl" refers to a linear or branched group having 1 to 6 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl), which may be substituted with one or more (e.g., 1 to 3) preferred substituents such as halogens (in this case, the group may be called a "haloalkyl") (e.g., CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, or -CH2CH2CF3). 1-4The term "alkyl" refers to a linear or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0015] As used herein, the term "alkenylene" refers to a divalent hydrocarbyl containing one or more double bonds, preferably having 2, 3, 4, 5, or 6 carbon atoms, such as ethenylene, propylene, or allylene.

[0016] As used herein, the term "alkenyl" refers to a monovalent hydrocarbyl ("C") in a straight or branched chain having a double bond and 2 to 6 carbon atoms. 2-6 This refers to alkenyls. Examples of alkenyls include vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. If the compounds of the present invention contain alkenylene or alkenyl groups, the compounds may exist in a pure E (entgegen) form, a pure Z (zusammen) form, or any mixture thereof.

[0017] As used herein, the term "alkynyl" refers to a monovalent hydrocarbyl having one or more triple bonds, preferably 2, 3, 4, 5, or 6 carbon atoms, such as ethynyl or propynyl.

[0018] As used herein, the terms “cyclic hydrocarbylene,” “cyclic hydrocarbyl,” and “hydrocarbon ring” refer to saturated (i.e., “cycloalkylene” and “cycloalkyl”) or unsaturated (i.e., having one or more double and / or triple bonds in the ring) monocyclic or polycyclic hydrocarbon rings having 3 to 10 (preferably 3 to 8 and more preferably 3 to 6) ring carbon atoms, including, but not limited to, cyclopropyl(cyclopropylene)(ring), cyclobutyl(cyclobutylene), cyclopentyl(cyclopentylene)(ring), cyclohexyl(cyclohexylene)(ring), cycloheptyl(cycloheptylene)(ring), cyclooctyl(cyclooctylene)(ring), cyclononyl(cyclononylene)(ring), cyclohexenyl(cyclohexenylene)(ring), and others.

[0019] As used herein, the term "cycloalkyl" means a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl, or bicyclic including spiro, condensed, or crosslinked systems (e.g., bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or bicyclo[5.2.0]nonyl, or decahydronaphthalene)) which may be substituted with one or more (e.g., 1 to 3) preferred substituents. Cycloalkyls have 3 to 15 carbon atoms. For example, "C 3-6 The term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring having 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which may be substituted with one or more (e.g., 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0020] As used herein, the terms “heterocyclyl,” “heterocyclylene,” and “heterocycle” refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double and / or triple bonds in the ring) cyclic group having, for example, 3 to 10 (preferably 3 to 8 and more preferably 3 to 6) ring atoms, wherein at least one ring atom is a heteroatom selected from the group consisting of N, O, and S, and the remaining ring atoms are C. For example, “3 to 10 membered heterocyclyl (heterocyclylene)” in “3 to 10 membered heterocycle” refers to a saturated or partially unsaturated heterocyclyl (heterocyclylene) or heterocycle having 2 to 9 (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from the group consisting of N, O, and S. Examples of heterocyclylenes, heterocyclyls, and heterocycles include oxyranil (oxyranylene), azilidinil (azilidinylene), azetidinil (azetidinylene), oxetanil (oxetanylene), tetrahydrofuranil (tetrahydrofuranylene), dioxolinil (dioxolinylene), pyrrolidinil (pyrrolidinylene), pyrrolidonyl (pyrrolidonylene), and imidazolidinil (imidazo). Examples of such groups include, but are not limited to, lysinylene, pyrazolidinyl (pyrazolidinylene), pyrrolinyl (pyrrolinylene), tetrahydropyranyl (tetrahydropyranylene), piperidinyl (piperidinylene), morpholinyl (morpholinylene), dithianyl (dithianylene), thiomorpholinyl (thiomorpholinylene), piperazinyl (piperazinylene), or trithianyl (trithianylene). The group also includes bicyclic systems including spiro, condensed, or crosslinked systems (e.g., 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane). Heterocyclylenes, heterocyclyls, and heterocycles may be substituted with one or more (e.g., 1, 2, 3, or 4) preferred substituents.

[0021] As used herein, the terms “aryl (arylene)” and “aromatic ring” refer to all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated π-electron system. For example, as used herein, “C 6-10 "Aryl (Arylene)" and "C 6-10 The term "aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl(phenylene)(benzene ring) or naphthyl(naphthylene)(naphthalene ring). Aryl(arylene) or aromatic rings have one or more (e.g., 1 to 3) suitable substituents (e.g., halogens, -OH, -CN, -NO2, and C). 1-6 It may be substituted with alkyl groups, etc.

[0022] As used herein, the terms "heteroaryl (heteroarylene)" and "heteroaromatic ring" refer to monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and containing at least one heteroatom (such as O, N, or S), which may be the same or different. Furthermore, in any case, these can be benzo-condensed. In particular, "heteroaryl (heteroarylene)" or "heteroaromatic ring" is selected from the group consisting of thienyl (thienylene), furyl (furylene), pyrrolyl (pyrolylene), oxazolyl (oxazolylene), thiazolyl (thiazolylen), imidazolyl (imidazolylene), pyrazolyl (pyrazolylen), isoxazolyl (isoxazolylene), isothiazolyl (isothiazolylen), oxadiazolyl (oxadiazolylen), triazolyl (triazolylene), thiadiazolyl (thiadiazolylen), etc., and their benzo derivatives; or pyridinyl (pyridinylene), pyridadinyl (pyridadinylene), pyrimidinyl (pyrimidinylene), pyrazinyl (pyradinylene), triazinyl (triazinylene), etc., and their benzo derivatives.

[0023] The term "aralkyl" preferably means an aryl-substituted alkyl group (aryl and alkyl are as defined herein). Typically, the aryl group may have 6 to 14 carbon atoms, and the alkyl group may have 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0024] As used herein, the terms "halo" or "halogen" are defined as containing F, Cl, Br, or I.

[0025] As used herein, the term "alkylthio" means the alkyl group defined above, bonded to the parent molecule via a sulfur atom. 1-6 Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.

[0026] As used herein, the term “nitrogen-containing heterocycle” refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least one nitrogen atom in the ring, and which may further contain one or more (e.g., 1, 2, 3, or 4) ring members selected from the group consisting of N, O, C=O, S, S=O, and S(=O)2. The nitrogen-containing heterocycle is connected to the rest of the molecule via the nitrogen atom. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring. In particular, 3- to 14-membered nitrogen-containing heterocycles are groups having 3 to 14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) within the ring, and include, but are not limited to, 3-membered nitrogen-containing heterocycles (such as azilidinyl), 4-membered nitrogen-containing heterocycles (such as azetidinyl), 5-membered nitrogen-containing heterocycles (such as pyrrolyl, pyrrolidinyl (pyrrolidinyl ring), pyrrolinyl, pyrrolidonyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), 6-membered nitrogen-containing heterocycles (such as piperidinyl (piperidinyl ring), morpholinyl, thiomorpholinyl, piperazinyl), and 7-membered nitrogen-containing heterocycles.

[0027] The term "substitution" means that one or more hydrogen atoms (e.g., 1, 2, 3, or 4) on a specified atom are replaced by a group selected from the indicated group (provided that the substitution does not exceed the normal valence of the specified atom under existing circumstances and that the substitution results in a stable compound). Combinations of substituents and / or variables are permitted only if such combinations result in a stable compound.

[0028] If a substituent is described as "may be substituted," then that substituent may be either (1) unsubstituted or (2) substituted. If a substituent's carbon may be substituted with one or more of the listed substituents, then one or more of the hydrogen atoms on the carbon (if any) may be replaced separately and / or together with independently selected substituents. If a substituent's nitrogen may be substituted with one or more of the listed substituents, then one or more of the hydrogen atoms on the nitrogen (if any) may each be replaced with independently selected substituents.

[0029] When a substituent is described as being "independently selected" from a group, each substituent is selected independently of the others. Therefore, each substituent may be identical or different from the others.

[0030] As used herein, the term "one or more" means, under reasonable conditions, one or two or more (e.g., 2, 3, 4, 5, or 10).

[0031] When used herein, unless otherwise specified, the bonding point of a substituent may be any preferred position on the substituent.

[0032] If it is shown that a bond to a substituent intersects with a bond connecting two atoms in the ring, then such a substituent may be bonded to any of the substituteable ring-forming atoms in that ring.

[0033] The present invention also includes all pharmaceutically acceptable isotope-labeled compounds, which are identical to those of the present invention except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the atomic mass or mass number that is dominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include the isotope of hydrogen (deuterium (D), 2 H), tritium (T, 3 H) etc); 11 C, 13 C, and 14Isotopes of carbon, such as C; 36 Chlorine such as Cl; 18 Fluorine isotopes such as F; 123 I and 125 Iodine isotopes such as I; 13 N and 15 Isotopes of nitrogen, such as N; 15 O, 17 O, and 18 Oxygen isotopes such as O; 32 Phosphorus isotopes such as P; and 35 Examples of sulfur isotopes include, but are not limited to, S. Specific isotope-labeled compounds of the present invention, such as compounds incorporating radioactive isotopes, are useful for studying the tissue distribution of drugs and / or substrates (e.g., assays). Radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) is particularly useful for this purpose because it is easy to implement and easy to detect. 11 C, 18 F, 15 O, and 13 Substitution with positron-emitting isotopes such as 1N may be useful in positron emission tomography (PET) studies to investigate substrate acceptor occupancy. The isotope-labeled compounds of the present invention can generally be prepared by a process similar to that described in the attached scheme and / or examples and preparation examples, by using a suitable isotope-labeling reagent instead of a previously used unlabeled reagent. Examples of pharmaceutically acceptable solvates according to the present invention include solvates in which the crystallization solvent may be substituted with an isotope, such as D2O, acetone-d6, or DMSO-d6.

[0034] The term "stereoisomer" refers to an isomer having at least one chiral center. Compounds having one or more chiral centers (e.g., 1, 2, 3, or 4) can give rise to racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers. Certain individual molecules may exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention may exist as mixtures of two or more structurally different forms in a rapidly equilibrium state (generally called tautomers). Typical examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. It should be understood that all such isomers and mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%) are all included within the scope of the present invention.

[0035] The carbon-carbon bonds of the compounds of the present invention are shown by solid lines herein. [ka] ), solid wedge shape ( [ka] ), or a dotted wedge shape ( [ka] ) can be represented using ). Using a solid line to represent a bond to a chiral carbon atom means that all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.) are included. Using a solid or dotted wedge to represent a bond to a chiral carbon atom means that the indicated stereoisomer is present. When present in a racemic compound, solid and dotted wedge shapes are used to define relative stereochemistry rather than absolute stereochemistry. Unless otherwise noted, the compounds of the present invention are intended to exist as stereoisomers including optical isomers such as cis and trans isomers, R enantiomers and S enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit two or more isomers and consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0036] The present invention includes all possible crystalline forms or polymorphs of the compound of the present invention, either as a single polymorph or as a mixture of two or more polymorphs in any ratio.

[0037] Furthermore, it should be understood that certain compounds of the present invention may be used for therapeutic purposes in their free form or, as necessary, in the form of pharmaceutically acceptable derivatives. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that can directly or indirectly provide the compound of the present invention or its metabolites or residues after administration to a patient in need. Accordingly, "compounds of the present invention" as used herein means encompassing various derivative forms of such compounds.

[0038] Examples of pharmaceutically acceptable salts of the compound of the present invention include its acid addition salts and base addition salts.

[0039] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Specific examples include aspartates, benzoates, bicarbonates / carbonates, bisulfates / sulfates, fumarates, gluceptates, glucons, glucurons, hexafluorophosphates, hydrobroms / bromides, hydroiodides / iodides, maleates, malons, methylsulfates, naphthylates, nicotinates, nitrates, orotates, oxalates, and palmitates.

[0040] Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Specific examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, and potassium.

[0041] For considerations regarding suitable salts, please refer to “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0042] As used herein, the term "ester" refers to compounds derived from the various formulas of this application, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acids or alcohols). The compounds of the present invention themselves may be esters.

[0043] The compounds of the present invention can exist as solvates (preferably hydrates), and for example, the compounds of the present invention contain a polar solvent, particularly water, methanol, or ethanol, as structural elements in the crystal lattice of the compound. The amount of the polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.

[0044] The scope of the present invention also includes metabolites of the compounds of the present invention, i.e., substances formed in vivo by administration of the compounds of the present invention. Such products may arise, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic degradation, etc. of the administered compound. Accordingly, the present invention encompasses metabolites of the compounds of the present invention, including compounds produced by methods comprising contacting the compounds of the present invention with a mammal for a period of time sufficient to yield metabolites of the compounds of the present invention.

[0045] Furthermore, prodrugs of the compounds of the present invention also fall within the scope of the present invention, which are specific derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity, but can be converted into the compounds of the present invention having the desired activity, for example, by hydrolytic cleavage, when administered intracellularly or onto the body. In general, such prodrugs are functional derivatives of compounds that are readily converted in vivo into compounds having the desired therapeutic activity. Further information on the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems”, Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987 (edited by E.B. Roche, American Pharmaceutical Association). Prodrugs according to the present invention can be produced, for example, by replacing appropriate functional groups present in the compounds of the present invention with specific molecules known to those skilled in the art as “promolecules,” as described, for example, in “Design of Prodrugs” by H. Bundgaard (Elsevier, 1985).

[0046] The present invention further encompasses compounds of the present invention having protecting groups. During any of the processes for preparing the compounds of the present invention, it may be necessary and / or desirable to protect a sensitive or reactive group on any of the molecules involved, thereby obtaining a chemically protected form of the compounds of the present invention. This may be achieved by conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973 and TW Greene & P. ​​G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 (the contents of which are incorporated herein by reference). The protecting group may be removed in a convenient subsequent step using methods known in the art.

[0047] As used herein, the term “about” refers to a range of ±10%, preferably ±5%, and more preferably ±2% of a given value.

[0048] compound In some embodiments, the present invention provides compounds having the structure of formula (I), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds, or prodrugs thereof.

[0049] [ka] (In the formula, Ring A is C 6-10 It is an aromatic ring or a 5-14 member heteroaromatic ring. L 1 However, direct bonding or -R 2 -C 1-6 It is alkylene-, R 2 However, these are -O-, -NH-, -S-, -S(=O)-, or -S(=O)2-, R 1However, at each generation, halogen, hydroxyl, oxo, amino, cyano, nitro, and C are produced respectively. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 member heteroaryl, C 6-12 Aralquil, =N-OR 3 -C(=NH)NH2, -C(=O)R 3 -OC(=O)R 3 , -C(=O)OR 3 , -OR 3 , -SR 3 -S(=O)R 3 -S(=O)2R 3 -S(=O)2NR 3 R 4 , -NR 3 R 4 -C(=O)NR 3 R 4 , -NR 3 -C(=O)R 4 , -NR 3 -C(=O)OR 4 , -NR 3 -S(=O)2-R 4 , -NR 3 -C(=O)-NR 3 R 4 , -C 1-6 Alkilen-NR 3 R 4 ,-OC 1-6 Alkilen-NR 3 R 4 , and -C 1-6 Alkylene-OC 1-6 Either independently selected from the group consisting of alkyls, or if n is greater than 1, two R 1 However, together with the group to which they are bonded, C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 It forms an aromatic ring, or a 5-14 member complex aromatic ring. R 3 and R 4 However, at each occurrence, H and C 1-6 Alkyl, C3-10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6-10 Aryls, 5-14 member heteroaryls, and C 6-12 Selected independently from the group consisting of Aralquil, The above alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbyl, hydrocarbon ring, heterocyclyl, heterocyclic, heterocyclic, aryl, aromatic ring, heteroaryl, heteroaromatic ring, and aralkyl are each generated as halogen, hydroxyl, oxo, amino, cyano, nitro, and C, respectively. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 member heteroaryl, C 6-12 Aralquil, =N-OR 5 -C(=NH)NH2, -C(=O)R 5 -OC(=O)R 5 , -C(=O)OR 5 , -OR 5 , -SR 5 -S(=O)R 5 -S(=O)2R 5 -S(=O)2NR 5 R 6 , -NR 5 R 6 -C(=O)NR 5 R 6 , -NR 5 -C(=O)R 6 , -NR 5 -C(=O)OR 6 , -NR 5 -S(=O)2-R 6 , -NR 5 -C(=O)-NR 5 R 6 , -C 1-6 Alkilen-NR 5 R 6 ,-OC 1-6 Alkilen-NR 5 R 6 , and -C 1-6 Alkylene-OC 1-6The alkyl, alkenyl, alkynyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl, and aralkyl groups may be substituted with one or more substituents independently selected from the group consisting of alkyl groups, and the alkyl, alkenyl, alkynyl, cyclic hydrocarbyl, heterocyclyl, heteroaryl, and aralkyl groups may be further substituted with halogen, hydroxyl, oxo, amino, cyano, nitro, and C 1-6 Alkyl, C 3-6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6-10 Aryls, 5-14 member heteroaryls, and C 6-12 It may be substituted with one or more substituents independently selected from the group consisting of aralkyls. R 5 and R 6 However, at each occurrence, H and C 1-6 Alkyl, C 3-10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6-10 Aryls, 5-14 member heteroaryls, and C 6-12 Selected independently from the group consisting of Aralquil, n is an integer of 0, 1, 2, 3, or 4, However, L 1 If the bond is direct, then ring A is not a benzene ring.

[0050] In some embodiments, the present invention provides compounds of formula (I) in which ring A is a benzene ring or a 5-6 membered heteroaromatic ring, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds, or prodrugs thereof.

[0051] In some embodiments, the present invention provides compounds of formula (I) in which ring A is a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, or a pyridine ring, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds, or prodrugs thereof.

[0052] In some embodiments, the present invention is L 1 Direct bonding or -OC 1-6The present invention provides a compound of formula (I) that is alkylene-, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

[0053] In some embodiments, the present invention is L 1 The present invention provides compounds of formula (I) in which the group is directly bonded, -O-CH2-, or -O-CH2CH2-, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds, or prodrugs thereof.

[0054] In some embodiments, L 1 If the bond is direct and n is 0, then ring A is neither an unsubstituted furan ring nor an unsubstituted thiophene ring.

[0055] In some embodiments, the present invention is R 1 However, halogen, C 1-6 C may be substituted with alkyl or halogen compounds. 6-10 Aryl, or -C 1-6 Alkylene-OC 1-6 Alkyl or two R 1 However, together with the group to which they are bonded, C 6-10 It forms an aromatic ring, which is -OR 5 The present invention provides compounds of formula (I), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds, or prodrugs thereof, which may be further substituted.

[0056] In some embodiments, the present invention is R 1 However, it may be phenyl substituted with -Cl, methyl, or F, or -CH2-O-CH3, or two R 1 The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof, wherein these groups together form a benzene ring, which may be further substituted with methoxy.

[0057] In some embodiments, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds, or prodrugs thereof.

[0058] Here, [ka] but, [ka] That is the case.

[0059] Compounds obtained by any combination of the various embodiments are included in the present invention.

[0060] In some embodiments, the compound of formula (I) is not the following compound.

[0061] [ka]

[0062] In some embodiments, the present invention provides the following compounds, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds, or prodrugs thereof.

[0063] [Table 1A] [Table 1B] [Table 1C] [Table 1D]

[0064] Preparation method In some embodiments, the present invention provides a method for preparing a compound of formula (I), comprising reacting a compound of formula (I)-a with a compound of formula (I)-b to obtain a compound of formula (I).

[0065] [ka] (In the formula, LG is a leaving group, preferably a halogen, most preferably chlorine. The remaining bases are as defined above.

[0066] This reaction is preferably carried out in the presence of a base, such as an inorganic base (e.g., sodium hydroxide) or an organic base. Preferably, the compound of formula (I)-a is first mixed with the base, and then the compound of formula (I)-b is added to the resulting mixture. The reaction solvent is preferably water, dichloromethane, tetrahydrofuran, or a mixture thereof (e.g., a mixture of water and tetrahydrofuran). The reaction temperature is preferably 0 to 50°C, for example, 25°C.

[0067] Pharmaceutical composition and therapeutic method In some embodiments, the present invention provides a pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0068] In some embodiments, the use of the compounds of the present invention, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds, or prodrugs thereof, or pharmaceutical compositions of the present invention, in the manufacture of agents for the prevention or treatment of neurodegenerative diseases or for the alleviation of symptoms of neurodegenerative diseases is provided.

[0069] In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds, or prodrugs thereof, or pharmaceutical compositions of the present invention, for use in the prevention or treatment of neurodegenerative diseases or in the alleviation of symptoms of neurodegenerative diseases.

[0070] In some embodiments, the present invention provides a method for the prevention or treatment of neurodegenerative diseases, or for the alleviation of symptoms of neurodegenerative diseases, comprising administering an effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof, or a pharmaceutical composition of the present invention, to a subject in need thereof.

[0071] In some embodiments, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Creutzfeldt-Jakob disease, Huntington's disease, multiple sclerosis, Guillain-Barré syndrome, Parkinson's disease, Lou Gehrig's disease, paralytic dementia caused by gradual neuronal death, and diseases caused by progressive incontinence, preferably Alzheimer's disease.

[0072] In this invention, the term "pharmaceutically acceptable carrier" refers to a diluent, auxiliary substance, excipient, or vehicle with which a therapeutic agent is administered, and which, within reasonable medical judgment, is suitable for contact with human and animal tissues without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, and is commensurate with a reasonable benefit / risk ratio.

[0073] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, water and sterile liquids such as oils (peanut oil, soybean oil, mineral oil, sesame oil, etc.) of petroleum, animal, plant, or synthetic origin. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Saline solution, as well as aqueous dextrose and aqueous glycerol solutions, can also be used as liquid carriers, particularly for injection solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, and ethanol. The pharmaceutical composition may also contain small amounts of wetting agents or emulsifiers, or pH buffers, if desired. Oral formulations may include standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. Examples of suitable drug carriers are described, for example, in Remington's Pharmaceutical Sciences (1990).

[0074] The pharmaceutical composition of the present invention can act systemically and / or locally. For this purpose, the composition can be administered by appropriate routes such as injection (intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection (including intravenous infusion)) or transdermal administration, or by oral, buccal, nasal, transmucosal, or topical administration, or by administration as an ophthalmic preparation, or by inhalation.

[0075] With regard to these routes of administration, the pharmaceutical compositions of the present invention can be administered in a suitable dosage form.

[0076] Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injections, elixirs, and syrups.

[0077] As used herein, the term “effective dose” refers to the amount of compound administered that reduces, to some extent, one or more of the symptoms of the disorder being treated.

[0078] The administration regimen can be adjusted to provide the optimal desired response. For example, it may be administered as a single push dose, in several divided doses over time, or proportionally reduced or increased as indicated by the urgent need to treat the condition. It should be noted that the dose value will vary depending on the type and severity of the condition being alleviated and may include single or multiple doses. Furthermore, it should be understood that for any particular subject, a specific medication plan should be adjusted over time in accordance with the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0079] The amount of the compound of the present invention administered will depend on the subject being treated, the severity of the disorder or condition, the administration rate, the properties of the compound, and the discretion of the prescribing physician. Generally, the effective dose is in the range of about 0.0001 to about 50 mg per kg of body weight per day, for example, about 0.01 to about 10 mg / kg / day, in single or divided doses. For a person weighing 70 kg, the effective dose would be about 0.007 mg to about 3500 mg / day, for example, about 0.7 mg to about 700 mg / day. In some cases, a dose level below the lower limit of the aforementioned range may be more than sufficient, but in other cases, even larger doses may be used without causing any adverse side effects, provided that they are initially administered in several smaller doses over the course of a day.

[0080] The content or dosage of the compound of the present invention in the pharmaceutical composition is about 0.01 mg to about 1000 mg, preferably 0.1 to 500 mg, more preferably 0.5 to 300 mg, more preferably 1 to 150 mg, and particularly preferably 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.

[0081] Unless otherwise indicated, as used herein, “to treat” or “to cure” means to reverse, alleviate, inhibit the progression of, or prevent one or more symptoms of the disorder or condition to which such term applies.

[0082] As used herein, the term “subject” includes human or non-human animals. Exemplary human subjects include human subjects with a disease (such as those described herein) (referred to as patients) or healthy subjects. As used herein, the term “non-human animals” includes all vertebrates, including non-mammals (e.g., birds, amphibians, reptiles) and mammals such as non-human primates, livestock and / or domesticated animals (sheep, dogs, cats, cattle, pigs, etc.).

[0083] In some embodiments, the pharmaceutical composition of the present invention may further include one or more additional therapeutic or prophylactic agents. [Examples]

[0084] To further clarify the object and technical solutions of the present invention, embodiments of the present invention will be described in detail with reference to the following examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be construed as limiting the scope of the present invention. Unless otherwise specified in the examples, they shall be carried out according to conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified by the manufacturer, the reagents or equipment used are all conventional products available on the market.

[0085] The structure of the compound is nuclear magnetic resonance ( 1The chemical composition was determined by 1H NMR or mass spectrometry (MS). NMR was measured using a Bruker AVANCE-500 or Varian-400 MHz NMR spectrum analyzer. Solvents used included deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated water (D2O). Tetramethylsilane (TMS) was used as the internal standard, and the chemical shift (δ) was expressed in parts per million (ppm).

[0086] The MS measuring instrument was an Agilent (ESI) mass spectrometer (manufacturer: Agilent, model: Agilent 6110).

[0087] Preparative high-performance liquid chromatography separation method:

[0088] Instrument model: Elite P3500; Chromatography column: Welch Ultimate XB-C18 (30 × 250 mm, 10 μm); Chromatography column temperature: 25°C; Flow rate: 42 mL / min; Detection wavelength: 254 nm; Elution gradient: (0 min: 10% A, 90% B; 25 min: 90% A, 10% B; 35 min: 90% A, 10% B; 38 min: 10% A, 90% B; 40 min: 10% A, 90% B); Mobile phase: A: Methanol, B: 0.05% formic acid aqueous solution.

[0089] The compounds synthesized in the following examples are represented by molecular formulas, and their names were generated by ChemBioDraw software.

[0090] Example 1: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)2-propylpentanethioate (Compound 1) [ka] Thiamine monophosphate chloride (1a) (83% content, 20g, 0.04 mol, 1.0 equivalent) was dissolved in water (40mL) and stirred. Sodium hydroxide solution (30%) was added dropwise to adjust the pH to 10.5-11.0, and the mixture was stirred for 30 minutes. The system temperature was maintained at 25°C, and 2-propylpentanoyl chloride (1b) (0.07 mol, 1.75 equivalent) diluted with tetrahydrofuran (20mL) was added dropwise within 20 minutes. The mixture was stirred for 10 minutes, and the pH of the aqueous phase was adjusted to 1.5. The system became turbid, and ethyl acetate (100mL) was slowly added dropwise. A white solid precipitated, which was filtered, dried, and dissolved in water (100mL). NaHCO3 (1.0 equivalent) was added to the mixture, stirred to generate a few bubbles, concentrated to dryness, DCM was added, stirred, dissolved, filtered to remove salts, and the filtrate was concentrated to obtain title compound 1 (white solid). MS m / z(ESI):489[M+1] 1 H NMR (400MHz, DMSO-d6): δ7.90(s,1H),7.74(s,1H),4.42(s,2H),3.74-3.76(m,2H),2.58(s,2H),2.42-2.43( m,1H),2.38(s,3H),2.10(s,3H),1.41-1.44(m,2H),1.30-1.35(m,2H),1.28-1.33(m,4H),0.80-0.83(t,6H).

[0091] Example 2: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)2-ethylbutanethioate (Compound 2) [ka] Title compound 2 (white solid) was prepared by the same synthetic route as in Example 1, except that 1b of Example 1 was replaced with 2-ethylbutanoyl chloride. MS m / z(ESI):461[M+1] 1H NMR(400MHz,DMSO-d6)δ9.18(br,1H),8.19(s,1H),8.15(br,1H),7.84(s,1H),4.48(s,2H),3.89( q,2H),2.63(t,2H),2.48(s,3H),2.34-2.27(m,1H),2.14(s,3H),1.51-1.37(m,4H),0.80(t,6H).

[0092] Example 5: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)O-phenethylcarbonothioate (Compound 5) [ka] Title compound 5 (off-white solid) was prepared by the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with phenethyl chloroformate. MS m / z (ESI): 511.1 [M+1] 1 H NMR(500MHz,DMSO-d6)δ7.84(s,2H),7.29-7.21(m,5H),6.73(s,2H),4.25(m,4H),3.65(m,4H),2.87(t,2H),2.25(s,3H),2.07(s,3H).

[0093] Example 6: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)O-benzylcarbonothioate (Compound 6) [ka] Title compound 6 (off-white solid) was prepared by the same synthetic route as in Example 1, except that 1b of Example 1 was replaced with benzyl chloroformate. MS m / z(ESI):497.1[M+1] 1H NMR(500MHz,DMSO-d6)δ7.84(m,2H),7.37(m,5H),6.75(s,2H),5.04(m,2H),4.37(m,2H),3.37(m,2H)2.59(m,2H),2.26(s,3H),2.08(s,3H).

[0094] Example 7: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)5-chlorothiophene-2-carbothioate (compound 7) [ka] Title compound 7 (white solid) was prepared by the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 5-chlorothiophene-2-carbonyl chloride. MS m / z(ESI):507[M+1] 1 H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.92(s,1H),7.61(d,1H),7.31(d,1H),4.49(s,2H),3.86(t,2H),2.70(t,2H),2.33(s,3H),2.20(s,3H).

[0095] Example 8: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)5-methoxybenzofuran-2-carbothioate (Compound 8) [ka]

[0096] Title compound 8 (off-white solid) was prepared by the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 5-methoxybenzofuran-2-carbonyl chloride. MS m / z(ESI):537[M+1] 1H NMR(500MHz,DMSO-d6)δ7.95(s,2H),7.63(s,2H),7.28(s,1H),7.18(s,1H),4 .47(s,2H),3.86(q,2H),3.82(s,3H),2.71(t,2H),2.28(s,3H),2.20(s,3H).

[0097] Example 9: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)furan-2-carbothioate (Compound 9) [ka] Title compound 9 (off-white solid) was prepared by the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with furan-2-carbonyl chloride. MS m / z (ESI): 456.9 [M+1] 1 H NMR(500MHz,DMSO-d6)δ8.02(s,1H),7.85(s,1H),7.83(s,1H),7.27(d,1H),6 .75(t,1H),4.45(s,2H),3.85(q,2H),2.70(t,2H),2.30(s,3H),2.17(s,3H).

[0098] Example 10: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)1H-pyrrole-2-carbothioate (Compound 10) [ka] Title compound 10 (off-white solid) was prepared by the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 1H-pyrrole-2-carbonyl chloride. MS m / z(ESI):456.0[M+1] 1H NMR(500MHz,DMSO-d6)δ12.12(s,1H),7.88(s,1H),7.86(s,1H),7.14(s,1H),6.77(d ,1H),6.20(m,1H),4.45(s,2H),3.85(q,2H),2.70(t,2H),2.36(s,3H),2.15(s,3H).

[0099] Example 11: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)5-(4-fluorophenyl)thiophene-2-carbothioate (compound 11) [ka] Title compound 11 (off-white solid) was prepared by the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 5-(4-fluorophenyl)thiophene-2-carbonyl chloride. MS m / z(ESI):567[M+1] 1 H NMR(500MHz,DMSO-d6)δ7.92(s,2H),7.84(dd,2H),7.70(d,1H),7.62(d,1H),7 .35(dd,2H),4.48(s,2H),3.88(q,2H),2.72(t,2H),2.31(s,3H),2.19(s,3H).

[0100] Example 12: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)5-(methoxymethyl)furan-2-carbothioate (compound 12) [ka] Title compound 12 (off-white solid) was prepared by the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 5-(methoxymethyl)furan-2-carbonyl chloride. MS m / z (ESI): 501.5 [M+1] 1 H NMR(500MHz,DMSO-d6)δ7.88(s,2H),7.40(s,2H),7.24(s,1H),6.69(s,1H),4 .44(s,4H),3.86(q,2H),3.30(s,3H),2.72(t,2H),2.32(s,3H),2.16(s,3H).

[0101] Example 13: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)benzofuran-2-carbothioate (Compound 13) [ka] Title compound 13 (white solid) was prepared by the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with benzofuran-2-carbonyl chloride. MS m / z(ESI):507[M+1] 1 H NMR(500MHz,DMSO-d6)δ7.98(d,2H),7.83(d,1H),7.73(s,2H),7.58(t,1H),7 .40(t,1H),4.49(s,2H),3.89(d,2H),2.72(s,2H),2.29(s,3H),2.21(s,3H).

[0102] Example 14: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)thiophene-2-carbothioate (compound 14) [ka] Title compound 14 (white solid) was prepared by the same synthetic route as in Example 1, except that 1b of Example 1 was replaced with thiophene-2-carbonyl chloride. MS m / z(ESI):473[M+1] 1H NMR(500MHz,DMSO-d6)δ8.08(d,1H),7.92(s,1H),7.90(s,1H),7.71(d,1H),7 .24(t,1H),4.47(s,2H),3.85(q,2H),2.70(t,2H),2.31(s,3H),2.18(s,3H).

[0103] Example 15: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)furan-3-carbothioate (Compound 15) [ka] Title compound 15 (off-white solid) was prepared by the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with furan-3-carbonyl chloride. MS m / z (ESI): 457 [M+1] 1 H NMR(500MHz,DMSO-d6)δ8.39(s,1H),7.96(s,1H),7.88(s,1H),7.86(s,1H),6 .68(d,1H),4.49(s,2H),3.86(q,2H),2.69(t,2H),2.34(s,3H),2.17(s,3H).

[0104] Example 16: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)pyridine-2-carbocioate (Compound 16) [ka] Title compound 16 (off-white solid) was prepared by the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 2-pyridylcarbonyl chloride. MS m / z (ESI): 468.1 [M+1] 1H NMR(500MHz,DMSO-d6)δ8.67(d,1H),8.03(t,1H),7.90(s,2H),7.78(d,1H),7.73(t ,1H),7.28(s,2H),4.43(s,2H),3.86(q,2H),2.70(t,2H),2.25(s,3H),2.16(s,3H).

[0105] Example 17: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)5-methylfuran-2-carbothioate (Compound 17) [ka] Title compound 17 (off-white solid) was prepared by the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 5-methylfuran-2-carbonyl chloride. MS m / z(ESI):471[M+1] 1 H NMR(500MHz,DMSO-d6)δ7.86(s,2H),7.19(d,1H),7.40(d,1H),4.44(s,2H),3.86(q,2H),2.67(t,2H),2.37(s,3H),2.32(s,3H),2.15(s,3H).

[0106] Example 18: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)2,5-dimethylfuran-3-carbothioate (compound 18) [ka] Title compound 18 (off-white solid) was prepared by the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 2,5-dimethylfuran-3-carbonyl chloride. MS m / z (ESI): 485 [M+1] 1H NMR(500MHz,DMSO-d6)δ7.94(s,1H),7.84(s,1H),6.17(s,1H),4.47(s,2H),3.8 3-3.79(m,2H),2.67(s,2H),2.41(s,3H),2.35(s,3H),2.22(s,3H),2.17(s,3H).

[0107] Biological assays Experimental Example 1 The BCA protein assay kit was purchased from Beyotime, the Aβ40 and Aβ42 detection kits from Wako, and the cell culture-related reagents from Gibco.

[0108] HEK293APP / sw overexpressing cells were cultured in 48-well plates in DMEM medium containing 10% FBS, 100 μg / mL G418 (Geneticin), and 1× penicillin-streptomycin. A 4 mM compound stock solution (prepared by dissolving the compound in DMEM culture medium) was filtered through a 0.22 μm sterile filter and stored at -20°C for subsequent use. At a cell density of 70%, 40 μL of the compound test solution was added to each well to reach a final concentration of 400 μM, and the plates were incubated for 24 hours.

[0109] The supernatant of the culture medium was collected. BCA reagent was added to a portion of the supernatant and incubated at room temperature for 30 minutes. The absorbance (i.e., OD value) of each well was measured at 570 nm using a microplate reader. The total protein concentration was calculated according to the protein standard curve. Meanwhile, the remaining portion of the supernatant (100 μL) was added to a coated 96-well plate and incubated overnight at 4°C. After removing the solution and washing the reagent, HRP (horseradish peroxidase) labeled antibody was added and incubated at 4°C for 2 hours. After removing the reagent and washing, TMB chromogenic solution was added, and the plate was incubated at room temperature for 30 minutes. Then, the reaction was stopped by adding stop solution. The absorbance (i.e., OD value) of each well was measured at 450 nm using a microplate reader. The concentrations of Aβ40 and Aβ42 were calculated according to the Aβ40 and Aβ42 standard curves, respectively. Finally, the concentrations of Aβ40 and Aβ42 were adjusted according to the total protein concentration to obtain the final concentrations. The test results are shown in the following table.

[0110] [Table 2]

[0111] *The compound test solution was not added to the blank control. According to the above test results, the compound of the present invention can significantly reduce the levels of Aβ42 and / or Aβ40.

[0112] Experimental Example 2. Acute Toxicity Test 2.1. Test Objectives

[0113] To conduct a preliminary safety assessment of the test compound, toxic reactions and deaths were observed after force-administering the test compound to mice.

[0114] 2.2. Test Method

[0115] 2.2.1. Test Materials CMC-Na (carboxymethylcellulose sodium) was purchased from Shanghai Sinopharm Chemical Reagent Co., Ltd.

[0116] The test animals were 18-20g Kunming strain mice provided by Beijing Keao Xieli Feed Co., Ltd.

[0117] 2.2.2. Test Procedure 1) Preparation of 0.7% CMC-Na: 0.7 g of CMC-Na was added to distilled water to prepare a 0.7 g / 100 mL solution. 2) The test compound was added to 0.7% CMC-Na to prepare a 100 mg / mL suspension. 3) Each test group consisted of 10 male mice. Each mouse was orally administered the test compound (2000 mg / kg) once daily for a cumulative period of 15 days. After administration, the following responses of the animals were observed: diet, appearance, behavior, secretions, excretions, symptoms of abnormal animal responses, onset time, severity, duration, reversibility, and death. Body weight was recorded on the day of administration, and on days 7 and 14.

[0118] 2.3. Test Results

[0119] [Table 3]

[0120] The animals showed no abnormalities after administration of the test compound. No serious toxic reactions were observed during continuous observation, indicating that the test compound is safe.

[0121] Experiment Example 3: Water Maze Behavior Test 3.1. Test Principle Aquatic rodents have a strong motivation to escape their aquatic environment and can escape in the fastest and most direct way possible. The process of learning to escape from the aquatic environment reflects the animals' learning ability. Spatial positioning in relation to the surrounding environment and intentionally swimming to a safe place in the water (such as a platform) may reflect the animals' spatial learning and memory abilities.

[0122] 3.2. Test Method

[0123] 3.2.1. Test Materials 1) Test animals The test animals were APP / PS1 2×Tg mice (with C57BL / 6 wild-type mice as a blank control). Mice aged 6-8 months and weighing 20-40g were purchased from Jackson Laboratory.

[0124] The APP / PS1 mouse is a ditransgenic Alzheimer's disease (2×Tg-AD) model mouse in which Aβ deposition appears several months earlier than pathological changes in tau protein, allowing for a more accurate simulation of the clinical process and pathological changes of Alzheimer's disease.

[0125] 2) Main reagents CMC-Na (sodium carboxymethylcellulose), purchased from Shanghai Sinopharm Chemical Reagent Co., Ltd. Positive control: BTMP (benfotiamine), prepared by Shanghai Raising Pharmaceutical Co., Ltd.

[0126] Comparative compound 1: [ka] This was prepared according to the method of Example 6 in CN201811435584.X.

[0127] 3) Main equipment

[0128]

Table 4

[0129] 3.2.2. Test Method 1) Information on Preparation and Administration of Drugs 1.1. Preparation of Drugs Preparation of 0.7% CMC-Na: An appropriate amount of water was added to 0.7 g of CMC-Na, heated and dissolved, cooled to room temperature, diluted to 100 mL, and stored at 4°C.

[0130] Preparation of BTMP: 100 mg of BTMP was added to 10 mL of 0.7% CMC-Na to prepare a 10 mg / mL suspension for use.

[0131] Preparation of the test compound and Comparative Compound 1: 100 mg of the test compound was weighed and added to 10 mL of 0.7% CMC-Na to prepare a 10 mg / mL suspension for use.

[0132] 1.2. Administration Information The experimental mice were randomly grouped (9 or 10 mice per group). The mice in each group were force-fed orally once a day at a dosage of 0.2 mL / 10 g body weight for 8 weeks.

[0133]

Table 5

[0134] 2) Test Procedure The mice in the blank control group, model group, and test group were orally administered according to the above dosage / specification for 8 consecutive weeks. The training and test of the water maze were started in the final week of administration. The training and test of the water maze were continued for 6 days, with the training period being 5 days and the test period being 1 day. Furthermore, during the training and test period of the water maze (a total of 6 days), the indoor conditions such as lighting were kept constant, the room was kept quiet, and interference from the environment and personnel was excluded.

[0135] 2.1. Preparation before the test: An appropriate amount of water was placed in the water maze pool while maintaining the water temperature at 22±3℃. The platform was placed in a fixed position 1 cm below the water surface (target quadrant), and titanium dioxide was added until the water turned white and the platform was no longer clearly visible.

[0136] 2.2. Training Period (Days 1-5): Each day, before the first quadrant training, each mouse was placed on the platform for 15 seconds (to increase the mouse's sense of security on the platform). Then, the mouse was placed from the quadrant where the platform was located into the pool (with its head facing the pool wall), and the swimming time was set to 60 seconds. If the mouse found the platform within 60 seconds and stayed there for 5 seconds, it was considered to have successfully found the platform. If the mouse did not find the platform, the time was recorded as 60 seconds. The mouse was then guided to the platform and kept there for 20 seconds before being removed, ending the quadrant training for that mouse.

[0137] After training in the first quadrant, the mice were trained sequentially in the remaining three quadrants. It was not necessary to place the mice on the platform for 15 seconds before training. Training for each mouse in every two quadrants was conducted at 10-15 minute intervals. This training was carried out continuously for five days.

[0138] 2.3. Test Period (Day 6): 24 hours after the last training session, the platform was removed, and the mice were dropped to the opposite quadrant from where the platform had previously been placed (i.e., the position furthest from the platform). The time the mice spent in the target quadrant (the quadrant where the platform had previously been placed), the number of times they crossed the previously placed platform location (number of platform crossings), and the time it took for them to cross the previously placed platform location for the first time (latency) were recorded and used as indicators to evaluate the mice's spatial learning and memory abilities.

[0139] [Table 6]

[0140] Note: Compared to the blank control group, **P<0.01, *P<0.05; compared to the model group, ##P<0.01, #P<0.05. According to the test results, the incubation period of animals in the test group administered with the compound of the present invention (for example, the incubation period of animals in the test group administered with compound 1 was 22.0 ± 1.5 seconds) was substantially equivalent to that of animals in the blank control group (21.8 ± 3.3 seconds), and was significantly shorter than that of animals in the test group administered with BTMP or comparative compound 1 (27.3 ± 1.6 seconds and 27.0 ± 1.3 seconds, respectively). This effect achieved by the compound of the present invention is unexpected.

[0141] Experimental Example 4. Jumping Platform Test 1.1. Test animals and reagents The mice used in this study were purchased from Xipuer-BIKAI Laboratory Animal Co., Ltd. and were SPF-grade ICR mice, 3-4 weeks old and weighing 16-18g.

[0142] Scopolamine hydrobromide trihydrate was purchased from Aladdin (product number: S107418, purity: 98%).

[0143] Sodium nitrite (NaNO2) was purchased from Sinopharm Chemical Reagent Co., Ltd. (Product number: 10020018, Specification: Analytical grade).

[0144] 1.2. Information on drug preparation and administration 1) Preparation of drugs Preparation of 0.7% CMC-Na: 0.7 g of CMC-Na was weighed, an appropriate amount of purified water was added, it was heated to dissolve, allowed to cool to room temperature, diluted to 100 mL, and stored at 4°C.

[0145] Preparation of test sample: 100 mg of the test compound was weighed and added to 10 mL of 0.7% CMC-Na to prepare a 10 mg / mL suspension, which was then used.

[0146] 2) Administration information The experimental mice were randomly grouped (9 or 10 mice per group). The mice in each group were force-fed orally once a day at a dose of 0.2 mL / 10 g body weight for 3 weeks.

[0147]

Table 7

[0148] / 1.3. Test procedure The experimental animals were force-fed continuously for 3 weeks according to the above dosage / specification. Training was started on the last day of administration, and the test was conducted 24 hours later.

[0149] 1) Scopolamine-induced acute memory impairment model The experimental animals were force-fed for 3 weeks, and 0.5 hours after the last dose, scopolamine (mouse: 2mg / kg) was injected intraperitoneally. The animals were trained using a YLS-3TB jumping stand detector, and the memory acquisition function was tested 24 hours later. The latency period (the time from the start of counting to the first time jumping off the stand) and the number of errors (the number of electric shocks) were recorded.

[0150] 2) Sodium nitrite-induced hypoxic memory impairment model The experimental animals were force-fed for 3 weeks. One hour after the last dose, the animals were trained using a YLS-3TB jumping stand detector. Immediately after training, sodium nitrite (mouse: 120mg / kg) was injected subcutaneously (into the neck). The jumping stand test was conducted 24 hours later. The latency period (the time from the start of counting to the first time jumping off the stand) and the number of errors (the number of electric shocks) were recorded.

[0151] 1.4. Behavioral detection in the jumping stand test The YLS-3TB jumping platform detector was divided into five sections by a transparent plate. The bottom of each section was covered with a copper grid, and a voltage of 50V was applied. A rubber pad platform measuring 3.5cm in height and 3.5cm in diameter was placed in each section to serve as a safety area to prevent the mouse from receiving an electric shock. Training of experimental mice before formal testing: To acclimate the experimental mice to the environment, they were placed in small sections with platforms for 5 minutes (the five sections were connected), and then stimulated with a voltage of 50V and a current of 1.00mA (at this point all experimental mice were on the grid). Mice have a habit of jumping from high places. When they jump, they receive a shock, and a memory is generated. Applying the current for 5 minutes served as a training process.

[0152] Test: Animals were placed one at a time on a platform in the jumping area. There was a 5-second interval between placing each animal. Immediately after placing the first animal on the platform, electricity was applied. The electricity was applied for 6 minutes. After the electricity was applied, the data was printed and the latency period (time from the start of counting to the first jump off the platform) and the number of errors (number of electric shocks during the test period) were recorded. Since the time between placing the animals varied, the time difference could be subtracted according to the actual time the animals were placed.

[0153] [Table 8]

[0154] Note: Compared to the blank control group, **P<0.01, *P<0.05; compared to the AD model group, ##P<0.01, #P<0.05.

[0155] [Table 9]

[0156] Note: Compared to the blank control group, **P<0.01, *P<0.05; compared to the AD model group, ##P<0.01, #P<0.05.

[0157] Experimental Example 5. Behavior Detection in Darkness Avoidance Tests 1. Test materials 1.1. Test animals and reagents The mice used in this study were purchased from Xipuer-BIKAI Laboratory Animal Co., Ltd. and were SPF-grade ICR mice, 3-4 weeks old and weighing 16-18g.

[0158] Anhydrous ethanol: Shanghai Titan Technology Co., Ltd.; Product number: G73537B; Purity: ≥99.7%.

[0159] 1.2. Preparation and Information of Drugs 1) Preparation of drugs Preparation of 0.7% CMC-Na: 0.7 g of CMC-Na was weighed, an appropriate amount of purified water was added, it was heated to dissolve, allowed to cool to room temperature, diluted to 100 mL, and stored at 4°C.

[0160] Preparation of test sample: 100 mg of the test compound was weighed and added to 10 mL of 0.7% CMC-Na to prepare a 10 mg / mL suspension, which was then used.

[0161] 2) Administration Information Experimental mice were randomly divided into groups (9 or 10 mice per group). Each group of mice was orally administered 0.2 mL / 10 g body weight once daily for 3 weeks.

[0162] [Table 10]

[0163] 2. A model of memory recall impairment induced by ethanol. Experimental mice were force-administered for three weeks. One hour after the last dose, the mice were trained using a YLS-17B dark-avoidance test machine. The test was performed 24 hours later. A 45% ethanol solution (0.1 mL / 10 g) was force-administered orally 30 minutes before the test. The incubation period (time from the start of counting to the first entry into the dark area) and the number of errors (number of electric shocks) were recorded.

[0164] The activity box of the automatic dark-avoidance testing machine consists of two compartments (light and dark), with a hole between them. The box is covered with a copper grid at the bottom, and animals normally enter the dark compartment. Before the formal test, laboratory mice were trained to acclimate to the environment for 5 minutes by being placed in the light compartment with their backs facing the entrance of the hole. Then, the copper grid in the dark compartment was stimulated by applying a voltage of 50V and a current of 1.00mA (adjustable according to the actual situation) for 2 hours. When the animals received the electric shock, they either entered the light compartment or moved back and forth between the two compartments. The current was applied continuously for 5 minutes, which served as the training process.

[0165] Experiment: Mice modeled with ethanol were placed one by one into a light-filled compartment with their backs facing the entrance of a hole, with a 5-second interval between each animal. Electricity was applied immediately after the first animal was placed in the light-filled compartment. The electrical stimulation lasted for 6 minutes. After the electrical stimulation ended, data was printed and the incubation period (time from the start of counting until the first entry into the dark compartment) and the number of errors (number of electric shocks during the experiment) were recorded. Due to the varying times the animals were placed, it was necessary to subtract the time difference according to the actual time the animals were placed. If a mouse did not enter the dark compartment within 5 minutes, the incubation period was recorded as 300 seconds.

[0166] Statistical analysis: All data were expressed as mean ± standard deviation, and SPSS software was used for the analysis.

[0167] [Table 11]

[0168] Note: Compared to the blank group, **P<0.01, *P<0.05; compared to the AD model group, ##P<0.01, #P<0.05.

[0169] Experimental Example 6. Pharmacokinetic Study 1.1 Experimental Animals and Reagents The SD rats used in this study were purchased from Zhejiang Charles Rive Laboratory Animal Co., Ltd. Both male and female SPF grade rats weighing approximately 250g were used.

[0170] Sodium carboxymethylcellulose (CMC-Na) was obtained from Sinopharm Chemical Reagent Co., Ltd. (product number: 20160704).

[0171] BTMP is prepared by Shanghai Raising Pharmaceutical Co., Ltd.

[0172] Comparative compound 2: [ka] This was prepared according to the method described in Example 13 of CN201811435584.X.

[0173] 1.2 Preparation of drugs Preparation of 0.7% CMC-Na: 7 g of CMC-Na was accurately weighed and placed in a 1 L beaker. A magnetic stirrer was placed in the beaker, and then 1 L of purified water was added. The mixture was stirred until a clear solution was obtained.

[0174] Preparation of test specimen: An appropriate amount of test specimen was weighed and ground into a fine powder in a mortar. A specific amount of vehicle was added to a suitable container, and then the ground test specimen was added to the container under magnetic stirring. The mixture was stirred until the appearance was uniform. The remaining vehicle was gradually added, followed by magnetic stirring for at least 20 minutes to prepare a solution with a concentration of 15.353 mM.

[0175] 1.3 Test Procedure (1) Absorption test SD rats were divided into three groups (6 rats per group, half male and half female). Each group of animals was administered a single dose of either compound 1 (75 mg / kg free base, 15.353 mM), BTMP (71.6 mg / kg, 15.353 mM), or comparative compound 2 (75 mg / kg free base, 15.353 mM). Blood samples (approximately 200 μL / sample) were collected before drug administration (0 minutes) and at 3, 8, 15, 30 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours, and 48 hours after drug administration. The blood was treated with EDTA for anticoagulation and placed on ice after collection. For each blood sample collected at each time point, 150 μL of whole blood was taken, and 150 μL of 5.2% perchloric acid was added to measure TM (thiamine) and TDP (thiamine diphosphate) (TM and TDP were in vivo metabolites of compound 1, BTMP, and comparative compound 2). All samples were frozen and stored in a refrigerator at -80°C.

[0176] (2) Brain distribution test Male SD rats were divided into three groups (16 rats per group) (four animals were sacrificed at four time points). Each group of animals was administered a single forced dose of either compound 1 (75 mg / kg free base, 15.353 mM), BTMP (71.6 mg / kg, 15.353 mM), or comparative compound 2 (75 mg / kg free base, 15.353 mM). The animals were sacrificed 5 minutes, 1 hour, 3 hours, and 9 hours after administration. Immediately after sacrifice, the brains were removed, rinsed with ice water, and allowed to absorb moisture. 50 mg of brain tissue was weighed and added to 0.45 mL of 100 mM dipotassium hydrogen phosphate buffer (pH=5.0) and homogenized. Blood samples were collected simultaneously and treated with EDTA for anticoagulation. After collection, the blood samples were placed on ice. 150 μL of whole blood was collected, and TM was measured after adding 150 μL of 5.2% perchlorate. Four other animals were force-fed with physiological saline to measure endogenous TM concentration. All samples were frozen and stored in a -80°C refrigerator.

[0177] (3) Sample assay The concentrations of TM and TDP in the sample were measured by HPLC-FLD.

[0178] (4) Data processing The pharmacokinetic parameters of TM and TDP in the blood of rats after administration were calculated using a non-compartment model of DAS software. TM concentrations in brain tissue were measured in rats after drug administration, and the mean and standard deviation were calculated. The area under the drug-time curve (AUC) was calculated using the trapezoidal rule.

[0179] 1.4 Test Results 1.4.1 Plasma concentration and pharmacokinetic parameters in rats in absorption studies Table 1 shows a summary of the pharmacokinetic parameters of compound 1, BTMP, and comparative compound 2 after a single forced administration to rats.

[0180] [Table 12]

[0181] According to the above test results, at the same drug dose, TM and TDP exposure levels were higher in the compound 1 administration group than in the BTMP and comparative compound 2 administration groups. Furthermore, TDP t 1 / 2 Regarding the t of the compound 1 dose group, 1 / 2 This refers to the t of the BTMP or comparative compound 2 dose group. 1 / 2 It was significantly higher compared to [another factor].

[0182] 1.4.2 Changes in concentration in rat brain and whole blood at different time points in the brain distribution study Table 2 shows the TM concentrations in the brain and whole blood of rats at different time points after a single forced administration of compound 1, BTMP, and comparative compound 2.

[0183] [Table 13]

[0184] According to the data above, the AUC (calculated by subtracting the concentration at 0 hours) of TM in the brain after force-administration of compound 1, BTMP, and comparative compound 2 to rats was 1156.6 ng·h / g, 739.9 ng·h / g, and 555.9 ng·h / g, respectively. The AUC of TM in the compound 1 administration group was 1.56 times that of the BTMP administration group and 2.08 times that of the comparative compound 2 administration group.

[0185] In addition to the modifications described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are intended to be included in the appended claims. All references herein, including patents, applications, journal articles, books, and other disclosures, are incorporated herein by reference in their entirety.

Claims

1. (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)5-chlorothiophene-2-carbothioate, (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)5-methoxybenzofuran-2-carbothioate, (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)benzofuran-2-carbothioate, or its pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, or isotope-labeled compounds.

2. A pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotope-labeled compound thereof, and one or more pharmaceutically acceptable carriers.

3. Use of the compound described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotope-labeled compound thereof, or the pharmaceutical composition described in claim 2, in the manufacture of a drug for the prevention or treatment of neurodegenerative diseases, or for the alleviation of symptoms of neurodegenerative diseases.

4. The use according to claim 3, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Creutzfeldt-Jakob disease, Huntington's disease, multiple sclerosis, Guillain-Barré syndrome, Parkinson's disease, Lou Gehrig's disease, paralytic dementia caused by gradual neuronal death, and diseases caused by progressive incontinence.

5. The use according to claim 4, wherein the neurodegenerative disease is Alzheimer's disease.

6. A method for preparing (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)5-chlorothiophene-2-carbothioate, The method is represented by the following formula. 【Chemistry 1】

7. A method for preparing (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)5-methoxybenzofuran-2-carbothioate, The method is represented by the following formula. 【Chemistry 2】

8. A method for preparing (Z)-S-(2-(N-((4-amino-2-methylpyrimidine-5-yl)methyl)formamide)-5-(phosphonooxy)pento-2-en-3-yl)benzofuran-2-carbothioate, The method is represented by the following formula. 【Transformation 3】

Images