Compound containing phosphate ester group, pharmaceutical composition containing the same, preparation method therefor, and use thereof

Abstract

To provide a compound containing a phosphoric ester group which can be used for preventing or treating neurodegenerative diseases.SOLUTION: Provided are a compound represented by formula (I), a pharmaceutical composition containing the same, a preparation method therefor, and a use thereof for treating neurodegenerative diseases. (Ring A is a C6-10 aromatic ring or a 5 - to 14-membered heteroaromatic ring; L1 is a direct bond or - R2 - C1 - 6-alkylene - [R2 is - O -, - NH -, - S -, - S (= O) -, or - S (= O) 2 -]; R1 is halogen or the like) SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to compounds containing a phosphate ester group, pharmaceutical compositions containing same, processes for their preparation, and their use for the treatment of neurodegenerative diseases. [Background technology]

[0002] Alzheimer's disease (commonly known as senile dementia, AD) is a progressive neurodegenerative disease with cognitive and behavioral abnormalities as its primary clinical symptoms. It is the most common form of dementia in the elderly. Alzheimer's disease is primarily characterized by a rapid decline in cognitive ability and memory function. Its main pathological and physiological characteristics are the deposition of beta-amyloid (Aβ) in the brain, which forms senile plaques; hyperphosphorylation of tau protein, which causes neurofibrillary tangles; impaired cerebral glucose metabolism; and neuronal / synaptic loss. The long duration of the disease and the limited ability of patients to care for themselves result in significant psychological and economic burdens for families and society. However, there are currently no drugs available worldwide that can prevent or slow the progression of the disease. Currently, only symptomatic medications are available to treat AD. These can control or improve cognitive and functional symptoms for a certain period of time, but they cannot prevent or prevent the condition from worsening. Summary of the Invention

[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, favorable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and / or fewer side effects), lower tolerance, etc.

[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] [ka] (In the formula, Ring A is C 6-10 an aromatic ring or a 5- to 14-membered heteroaromatic ring, L 1 is a direct bond or -R 2 -C 1-6 alkylene-, R 2 is -O-, -NH-, -S-, -S(=O)-, or -S(=O)2-, R 1 At each occurrence, halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, =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 , -NR3 -C(=O)-NR 3 R 4 , -C 1-6 Alkylene-NR 3 R 4 , -OC 1-6 Alkylene-NR 3 R 4 , and -C 1-6 Alkylene-OC 1-6 alkyl, or when n is greater than 1, two R 1 together with the groups to which they are attached, form C 3-6 Hydrocarbon ring, 3-10 membered heterocycle, C 6-10 Forms an aromatic ring or a 5- to 14-membered heteroaromatic ring, R 3 and R 4 At each occurrence, H and C 1-6 Alkyl, C 3-10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, and C 6-12 aralkyl; The above alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbyl, hydrocarbon ring, heterocyclyl, heterocycle, aryl, aromatic ring, heteroaryl, heteroaromatic ring, and aralkyl may each, at each occurrence, be selected from halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, =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 R6 , -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 Alkylene-NR 5 R 6 , -OC 1-6 Alkylene-NR 5 R 6 and -C 1-6 Alkylene-OC 1-6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl, and aralkyl, which may further include halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, and C 6-12 and optionally substituted with one or more substituents independently selected from the group consisting of aralkyl; R 5 and R 6 At each occurrence, H and C 1-6 Alkyl, C 3-10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, and C 6-12 aralkyl; n is an integer of 0, 1, 2, 3, or 4, However, L 1 is a direct bond, ring A is not a benzene ring.

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

[0007] Another aspect of the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for the prevention or treatment of a neurodegenerative disease, or alleviation of the symptoms of a neurodegenerative disease.

[0008] Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of the present invention, for use in the prevention or treatment of a neurodegenerative disease, or alleviating the symptoms of a neurodegenerative disease.

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

[0010] Another aspect of the present invention provides methods for preparing the compounds of the present invention.

[0011] definitionUnless otherwise defined in the 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 techniques used herein are intended to refer to techniques as commonly understood in the art, including modifications to those techniques or equivalent technique substitutions that would be apparent to those skilled in the art. While the following terms are believed to be readily understood by those skilled in the art, the following definitions are provided to better explain the present invention.

[0012] As used herein, the terms "including," "comprising," "having," "containing," or "relat- ing to," and other variations thereof, are inclusive or open-ended and do not exclude other elements or method steps not recited.

[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, for example, methylene, ethylene, propylene, or butylene.

[0014] As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, alkyl has 1 to 12, e.g., 1 to 6, carbon atoms. For example, as used herein, "C 1-6 The term "alkyl" refers to a straight or branched chain 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 optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogen (in which case the group may be referred to as a "haloalkyl") (e.g., CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). 1-4The term "alkyl" refers to a straight 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 and preferably having 2, 3, 4, 5, or 6 carbon atoms, for example, ethenylene, propylene, or arylene.

[0016] As used herein, the term "alkenyl" refers to a straight or branched chain monovalent hydrocarbyl having a double bond and 2 to 6 carbon atoms ("C 2-6 Alkenyl refers to "alkenyl" (e.g., 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. When the compounds of the present invention contain an alkenylene or alkenyl group, the compounds may exist in the pure E (entgegen) form, the pure Z (zusammen) form, or any mixture thereof.

[0017] As used herein, the term "alkynyl" refers to a monovalent hydrocarbyl containing one or more triple bonds and preferably having 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 within the ring) monocyclic or polycyclic hydrocarbon rings having, for example, 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 the like.

[0019] As used herein, the term "cycloalkyl" refers to 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, fused, or bridged systems, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or bicyclo[5.2.0]nonyl, or decahydronaphthalene)), optionally substituted with one or more (e.g., 1 to 3) suitable substituents. A cycloalkyl has 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 optionally substituted with one or more (e.g., 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl.

[0020] As used herein, the terms "heterocyclyl," "heterocyclylene," and "heterocycle" refer to, for example, a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) cyclic group having 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, the "3-10-membered heterocyclyl(heterocyclylene)" of a "3-10-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 heterocyclylene, heterocyclyl, and heterocycle include oxiranyl (oxiranylene), aziridinyl (aziridinylene), azetidinyl (azetidinylene), oxetanyl (oxetanylene), tetrahydrofuranyl (tetrahydrofuranylene), dioxolinyl (dioxolinylene), pyrrolidinyl (pyrrolidinylene), pyrrolidonyl (pyrrolidonylene), imidazolidinyl (imidazolidinyl), and the like. Examples of heterocyclylenes include, but are not limited to, pyrazolidinyl (pyrazolidinylene), pyrrolinyl (pyrrolinylene), tetrahydropyranyl (tetrahydropyranylene), piperidinyl (piperidinylene), morpholinyl (morpholinylene), dithianyl (dithianylene), thiomorpholinyl (thiomorpholinylene), piperazinyl (piperazinylene), or trithianyl (trithianylene). Such groups also include bicyclic ring systems, including spiro, fused, or bridged systems (e.g., 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc.). Heterocyclylene, heterocyclyl, and heterocycles may be substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0021] As used herein, the terms "aryl(arylene)" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group 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) (a benzene ring) or naphthyl (naphthylene) (a naphthalene ring). The aryl (arylene) or aromatic ring may contain one or more (e.g., 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO, and C). 1-6 It may be substituted with alkyl.

[0022] As used herein, the terms "heteroaryl(arylene)" and "heteroaromatic ring" refer to a monocyclic, bicyclic, or tricyclic aromatic ring system 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 each case, this can be benzo-fused. In particular, "heteroaryl(heteroarylene)" or "heteroaromatic ring" is selected from the group consisting of thienyl(thienylene), furyl(furylene), pyrrolyl(pyrrolylene), oxazolyl(oxazolylene), thiazolyl(thiazolylene), imidazolyl(imidazolylene), pyrazolyl(pyrazolylene), isoxazolyl(isoxazolylene), isothiazolyl(isothiazolylene), oxadiazolyl(oxadiazolylene), triazolyl(triazolylene), thiadiazolyl(thiadiazolylene), etc., and benzo derivatives thereof; or pyridinyl(pyridinylene), pyridazinyl(pyridazinylene), pyrimidinyl(pyrimidinylene), pyrazinyl(pyrazinylene), triazinyl(triazinylene), etc., and benzo derivatives thereof.

[0023] The term "aralkyl" preferably refers to aryl-substituted alkyl, where 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 term "halo" or "halogen" is defined to include F, Cl, Br, or I.

[0025] The term "alkylthio," as used herein, means an alkyl group, as defined above, attached to the parent molecular moiety through 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 may further include 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 a nitrogen atom. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring. In particular, the 3- to 14-membered nitrogen-containing heterocycle is a group having 3 to 14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, and includes, but is not limited to, a 3-membered nitrogen-containing heterocycle (aziridinyl, etc.), a 4-membered nitrogen-containing heterocycle (azetidinyl, etc.), a 5-membered nitrogen-containing heterocycle (pyrrolyl, pyrrolidinyl (pyrrolidinyl ring), pyrrolinyl, pyrrolidonyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl, etc.), a 6-membered nitrogen-containing heterocycle (piperidinyl (piperidinyl ring), morpholinyl, thiomorpholinyl, piperazinyl, etc.), a 7-membered nitrogen-containing heterocycle, etc.

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

[0028] When a substituent is described as being "optionally substituted," the substituent can be either (1) unsubstituted or (2) substituted. When a carbon of a substituent is described as being optionally substituted with one or more of the listed substituents, one or more of the hydrogens on the carbon (if present) can be individually and / or jointly replaced with independently selected substituents. When a nitrogen of a substituent is described as being optionally substituted with one or more of the listed substituents, one or more of the hydrogens on the nitrogen (if present) can each be replaced with an independently selected substituent.

[0029] When substituents are described as being "independently selected" from a group, each substituent is selected independently of the other substituents. Thus, each substituent can be the same or different from the other substituents.

[0030] As used herein, the term "one or more" means, under reasonable conditions, one or more than one (e.g., two, three, four, five, or ten).

[0031] As used herein, unless otherwise specified, the point of attachment of a substituent may be from any suitable position on the substituent.

[0032] When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any of the substitutable ring-forming atoms in that ring.

[0033] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to those of the present invention except that one or more atoms are replaced with an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in compounds of the present invention include isotopes 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 isotopes of fluorine, such as F; 123 I and 125 isotopes of iodine such as I; 13 N and 15 isotopes of nitrogen such as N; 15 O. 17 O, and 18 isotopes of oxygen such as O; 32 Isotopes of phosphorus, such as P; and 35 Certain isotopically labeled compounds of the present invention, for example compounds incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies (e.g., assays). 3 H) and carbon-14 (i.e., 14 C) is particularly useful for this purpose due to its ease of incorporation and ease of detection. 11 C. 18 F, 15 O, and 13 Substitution with positron-emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by processes analogous to those described in the accompanying schemes and / or examples and preparations, by substituting the appropriate isotopically labeled reagent for the previously used non-labeled reagent. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent of crystallization may be isotopically substituted, for example, DO, acetone-d6, or DMSO-d6.

[0034] The term "stereoisomer" refers to an isomer having at least one asymmetric center. Compounds having one or more (e.g., one, two, three, or four) asymmetric centers can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Certain individual molecules may exist as geometric isomers (cis / trans). Similarly, compounds of the present invention may exist as mixtures of two or more structurally distinct forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to 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 encompassed within the scope of the present invention.

[0035] Carbon-carbon bonds in the compounds of the present invention are represented herein by solid lines ( [ka] ), solid wedge ( [ka] ), or a dotted wedge ( [ka] ). The use of a solid line to represent a bond to an asymmetric carbon atom is meant to indicate that all possible stereoisomers at that carbon atom (e.g., a specific enantiomer, a racemic mixture, etc.) are included. The use of a solid or dotted wedge to represent a bond to an asymmetric carbon atom is meant to indicate that the depicted stereoisomer exists. When present in a racemic compound, the solid and dotted wedges are used to define relative stereochemistry rather than absolute stereochemistry. Unless otherwise specified, it is intended that the compounds of the present invention may exist as stereoisomers, including optical isomers such as cis- and trans-isomers, R- and S-enantiomers, diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemates and diastereomeric pairs).

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

[0037] It should also be understood that certain compounds of the present invention can be used for treatment in free form, or, if necessary, in the form of a pharmaceutically acceptable derivative. In the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, a pharmaceutically acceptable salt, ester, solvate, metabolite, or prodrug, which, after administration to a patient in need thereof, can directly or indirectly provide a compound of the present invention or a metabolic product or residue thereof. Thus, the term "compound of the present invention" as used herein is meant to encompass various derivative forms of such compounds.

[0038] Pharmaceutically acceptable salts of the compounds of the present invention include the acid addition and base addition salts thereof.

[0039] Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts, including, but not limited to, aspartate, benzoate, bicarbonate / carbonate, bisulfate / sulfate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodide / iodide, maleate, malonate, methylsulfate, naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, and the like.

[0040] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts, examples of which include aluminium, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium and the like.

[0041] For a discussion of suitable salts, see "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 invention are known to those skilled in the art.

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

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

[0044] Also included within the scope of the present invention are metabolic products of the compounds of the present invention, i.e., substances formed in vivo upon administration of a compound of the present invention. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic degradation, etc. of the administered compound. Accordingly, the present invention includes metabolic products of the compounds of the present invention, including compounds produced by a process comprising contacting a compound of the present invention with a mammal for a period of time sufficient to yield a metabolic product of the compound of the present invention.

[0045] Also within the scope of the present invention are prodrugs of the compounds of the present invention, which are specific derivatives of the compounds of the present invention that may have little or no pharmacological activity themselves but that can be converted, for example, by hydrolytic cleavage, into compounds of the present invention having the desired activity upon administration into or onto the body. Generally, such prodrugs are functional derivatives of compounds that are readily converted in vivo into compounds having the desired therapeutic activity. Further information regarding the use of prodrugs can be found in "Prodrugs 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 EB 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 also encompasses compounds of the present invention having protecting groups. During any of the processes for preparing compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby obtaining chemically protected forms of the compounds of the present invention. This may be achieved using conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973 and T.W. Greene & P. ​​G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 (the contents of which are incorporated herein by reference). Protecting groups may be removed at a convenient subsequent stage using methods known in the art.

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

[0048] compound In some embodiments, 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.

[0049] [ka] (In the formula, Ring A is C 6-10 an aromatic ring or a 5- to 14-membered heteroaromatic ring, L 1 is a direct bond or -R 2 -C 1-6 alkylene-, R 2 is -O-, -NH-, -S-, -S(=O)-, or -S(=O)2-, R 1At each occurrence, halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, =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 Alkylene-NR 3 R 4 , -OC 1-6 Alkylene-NR 3 R 4 , and -C 1-6 Alkylene-OC 1-6 alkyl, or when n is greater than 1, two R 1 together with the groups to which they are attached, form C 3-6 Hydrocarbon ring, 3-10 membered heterocycle, C 6-10 Forms an aromatic ring or a 5- to 14-membered heteroaromatic ring, R 3 and R 4 At each occurrence, H and C 1-6 Alkyl, C3-10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, and C 6-12 aralkyl; The above alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbyl, hydrocarbon ring, heterocyclyl, heterocycle, aryl, aromatic ring, heteroaryl, heteroaromatic ring, and aralkyl may each, at each occurrence, be selected from halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, =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 Alkylene-NR 5 R 6 , -OC 1-6 Alkylene-NR 5 R 6 , and -C 1-6 Alkylene-OC 1-6and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl, and aralkyl, which may further include halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, and C 6-12 and optionally substituted with one or more substituents independently selected from the group consisting of aralkyl; R 5 and R 6 At each occurrence, H and C 1-6 Alkyl, C 3-10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, and C 6-12 aralkyl; n is an integer of 0, 1, 2, 3, or 4, However, L 1 is a direct bond, ring A is not a benzene ring.

[0050] In some embodiments, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein ring A is a benzene ring or a 5- to 6-membered heteroaromatic ring.

[0051] In some embodiments, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein Ring A is a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, or a pyridine ring.

[0052] In some embodiments, the present invention provides a method for producing a compound comprising: 1 is a direct bond or -OC 1-6Provided is a compound of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein:

[0053] In some embodiments, the present invention provides a method for producing a compound comprising: 1 is a direct bond, —O—CH—, or —O—CHCH—, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof.

[0054] In some embodiments, L 1 is a direct bond and n is 0, then ring A is not an unsubstituted furan ring or an unsubstituted thiophene ring.

[0055] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 1 But halogen, C 1-6 C optionally substituted with alkyl or halogen 6-10 Aryl or -C 1-6 Alkylene-OC 1-6 alkyl or two R 1 together with the groups to which they are attached, form C 6-10 It forms an aromatic ring, which is -OR 5 and a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof.

[0056] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 1 is -Cl, methyl, phenyl optionally substituted with F, or -CH2-O-CH3, or two R 1 are taken together with the groups to which they are attached to form a benzene ring, which is optionally further substituted with methoxy, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof.

[0057] In some embodiments, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof.

[0058] where: [ka] but, [ka] is.

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

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

[0061] [ka]

[0062] In some embodiments, the present invention provides the following compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug 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 groups 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 compositions and methods of treatment In some embodiments, pharmaceutical compositions are provided that include a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0068] In some embodiments, there is provided the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the prevention or treatment of a neurodegenerative disease, or alleviation of a symptom of a neurodegenerative disease.

[0069] In some embodiments, there is provided a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of the invention, for use in preventing or treating a neurodegenerative disease or alleviating the symptoms of a neurodegenerative disease.

[0070] In some embodiments, there is provided a method for preventing or treating a neurodegenerative disease or alleviating the symptoms of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of the invention.

[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 cell death, and diseases caused by progressive incontinence, preferably Alzheimer's disease.

[0072] As used herein, the term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a therapeutic is administered which, within the scope of sound medical judgment, is suitable for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, 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, sterile liquids such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.). Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. Pharmaceutical compositions can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. Oral formulations may include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutical carriers are described, for example, in Remington's Pharmaceutical Sciences (1990).

[0074] The pharmaceutical compositions of the present invention can act systemically and / or locally. To this end, they can be administered by a suitable route, such as by injection (intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection (including drip infusion)) or transdermal administration, or they can be administered orally, bucally, nasally, transmucosally, topically, in ophthalmic formulations, or by inhalation.

[0075] For these administration routes, the pharmaceutical composition of the present invention can be administered in a suitable dosage form.

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

[0077] As used herein, the term "effective amount" refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.

[0078] Dosage regimens can be adjusted to provide the optimum desired response. For example, a single push administration can be administered, or several divided administrations can be administered over time, or the dosage can be proportionally reduced or increased as indicated by the urgent need to treat the condition. It should be noted that dosage values ​​vary depending on the type and severity of the condition to be alleviated and can include single or multiple administrations. Furthermore, it is understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition.

[0079] The amount of a compound of the invention administered will depend on the subject, the severity of the disorder or condition being treated, the rate of administration, the nature of the compound, and the discretion of the prescribing physician. Generally, an effective dosage ranges from about 0.0001 to about 50 mg per kg of body weight per day, e.g., about 0.01 to about 10 mg / kg / day, in single or divided doses. For a 70 kg human, an effective dosage would be from about 0.007 mg to about 3500 mg / day, e.g., about 0.7 mg to about 700 mg / day. In some cases, dosage levels below the lower end of the aforementioned range may be more than sufficient, while in other cases, larger doses may be used without causing any adverse side effects, provided that such larger doses are initially divided into several smaller doses administered throughout the 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, suitably 0.1 to 500 mg, preferably 0.5 to 300 mg, more preferably 1 to 150 mg, particularly preferably 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.

[0081] Unless otherwise indicated, the terms "treating" or "treatment," as used herein, mean to reverse, alleviate, inhibit the progression of, or prevent the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0082] As used herein, the term "subject" includes a human or a non-human animal. Exemplary human subjects include a human subject (referred to as a patient) having a disease (such as those described herein) or a normal subject. As used herein, the term "non-human animal" includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (sheep, dogs, cats, cows, pigs, etc.).

[0083] In some embodiments, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents. [Example]

[0084] In order to clarify the objectives and technical solutions of the present invention, the 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 only for illustrating the present invention and should not be construed as limiting the scope of the present invention. If no specific conditions are specified in the examples, they shall be carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or equipment used is not indicated, they are all conventional products available on the market.

[0085] The structure of the compound was determined by nuclear magnetic resonance ( 1The NMR spectra were determined by H NMR or mass spectrometry (MS). NMR was measured using a Bruker AVANCE-500 or Varian-400 MHz NMR. The solvents used were deuterated dimethyl sulfoxide (DMSO-d), deuterated methanol (CD3OD), deuterated water (DO), etc. The internal standard was tetramethylsilane (TMS), and chemical shifts (δ) were expressed in parts per million (ppm).

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

[0087] Preparative HPLC 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 in water.

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

[0090] Example 1: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)2-propylpentanethioate (Compound 1) [ka] Thiamine monophosphate chloride (1a) (83% content, 20 g, 0.04 mol, 1.0 equivalent) was dissolved in water (40 mL) 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 min. The temperature of the system was maintained at 25 °C, and 2-propylpentanoyl chloride (1b) (0.07 mol, 1.75 equivalent) diluted with tetrahydrofuran (20 mL) was added dropwise within 20 min. The mixture was stirred for 10 min, and the pH of the aqueous phase was adjusted to 1.5. The system became turbid, and ethyl acetate (100 mL) was slowly added dropwise. A white solid precipitated, which was filtered, dried, and then dissolved in water (100 mL). The mixture was added NaHCO3 (1.0 equiv.), stirred to generate a few bubbles, concentrated to dryness, added DCM, stirred, dissolved, filtered to remove salts, and the filtrate was concentrated to give the 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-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)2-ethylbutanethioate (Compound 2) [ka] The title compound 2 (white solid) was prepared by the same synthetic route as in Example 1, except that 1b in 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-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)O-phenethylcarbonothioate (Compound 5) [ka] The 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-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)O-benzylcarbonothioate (Compound 6) [ka] The title compound 6 (off-white solid) was prepared by the same synthetic route as in Example 1, except that 1b in 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-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)5-chlorothiophene-2-carbothioate (Compound 7) [ka] The 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-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)5-methoxybenzofuran-2-carbothioate (Compound 8) [ka]

[0096] The 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-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)furan-2-carbothioate (Compound 9) [ka] The 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-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)1H-pyrrole-2-carbothioate (Compound 10) [ka] The 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-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)5-(4-fluorophenyl)thiophene-2-carbothioate (Compound 11) [ka] The 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-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)5-(methoxymethyl)furan-2-carbothioate (Compound 12) [ka] The 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] 1H 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-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)benzofuran-2-carbothioate (Compound 13) [ka] The 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-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)thiophene-2-carbothioate (Compound 14) [ka] The title compound 14 (white solid) was prepared by the same synthetic route as in Example 1, except that 1b in 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-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)furan-3-carbothioate (Compound 15) [ka] The 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-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)pyridine-2-carbothioate (Compound 16) [ka] The 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-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)5-methylfuran-2-carbothioate (Compound 17) [ka] The 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-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)2,5-dimethylfuran-3-carbothioate (Compound 18) [ka] The 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 were purchased from Wako, and the cell culture-related reagents were purchased 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. 4 mM compound stock solutions (prepared by dissolving compounds in DMEM culture medium) were filtered through a 0.22 μm sterile filter and stored at −20°C for subsequent use. At 70% cell density, 40 μL of 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 culture supernatant was collected. A portion of the supernatant was added to the BCA reagent and incubated at room temperature for 30 minutes. The absorbance (i.e., OD) of each well was measured at 570 nm using a microplate reader. The total protein concentration was calculated according to a 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, an HRP (horseradish peroxidase)-conjugated antibody was added and incubated at 4°C for 2 hours. After removing the reagent and washing, TMB color development solution was added, and the plate was incubated at room temperature for 30 minutes. The reaction was then stopped by adding a stop solution. The absorbance (i.e., OD) of each well was measured at 450 nm using a microplate reader. The concentrations of Aβ40 and Aβ42 were calculated according to the standard curves for Aβ40 and Aβ42, respectively. Finally, the concentrations of Aβ40 and Aβ42 were adjusted by the total protein concentration to obtain the final concentrations. The test results are shown in the following table.

[0110] [Table 2]

[0111] *No compound test solution was added to the blank control. According to the above test results, the compounds of the present invention can significantly reduce the levels of Aβ42 and / or Aβ40.

[0112] Experimental Example 2: Acute Toxicity Test 2.1. Test Purpose

[0113] For preliminary evaluation of the safety of the test compounds, the test compounds were administered to mice by gavage, followed by observation of toxic reactions and deaths.

[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 Kunming strain mice weighing 18-20 g 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) A 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 administered the test compound (2000 mg / kg) by oral gavage once daily for a cumulative period of 15 days. After administration, the animals were observed for the following responses: feeding, appearance, behavior, secretions, excretions, symptoms of abnormal animal responses, time of onset, severity, duration, reversibility, and death. Body weights were recorded on the day of administration, 7 days, and 14 days.

[0118] 2.3.Test Results

[0119] [Table 3]

[0120] After administration of the test compound, the animals showed no abnormalities. No significant toxic reactions were observed during continuous observation, indicating that the test compound was safe.

[0121] Experimental Example 3: Water maze behavioral test 3.1. Test Principle Aquatic rodents have a strong motivation to escape from the water environment, and they can escape in the fastest and most direct way. The process of learning to escape from the water environment reflects the animal's learning ability. Spatial positioning according to the surrounding environment and purposeful swimming to a safe location in the water (such as a platform) may reflect the animal's 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 2xTg mice (C57BL / 6 wild-type mice served as blank controls). Mice aged 6-8 months and weighing 20-40 g were purchased from The Jackson Laboratory.

[0124] APP / PS1 mice are a transgenic model of Alzheimer's disease (2xTg-AD) in which the appearance of Aβ deposition precedes pathological changes in tau protein by several months, which can more accurately simulate 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] was prepared according to the method of Example 6 of CN201811435584.X.

[0127] 3) Main equipment

[0128] [Table 4]

[0129] Test Method 1) Drug preparation and administration information 1.1. Preparation of the drug Preparation of 0.7% CMC-Na: 0.7 g of CMC-Na was added to an appropriate amount of water, heated to dissolve, allowed to cool 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.

[0131] Preparation of 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. Dosage Information Experimental mice were randomly divided into groups (9 or 10 mice per group). Mice in each group were orally administered 0.2 mL / 10 g body weight of the compound once daily for 8 weeks.

[0133] [Table 5]

[0134] 2) Test procedure Mice in the blank control group, model group, and test group were orally administered according to the above dosage / specifications for 8 consecutive weeks. Water maze training and testing began during the final week of administration. Water maze training and testing lasted for 6 days, with a 5-day training period and a 1-day test period. Furthermore, during the water maze training and testing period (6 days in total), indoor conditions such as lighting were kept constant, the room was kept quiet, and environmental and personnel interference was eliminated.

[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°C. The platform was placed in a fixed position (target quadrant) 1 cm below the water surface, 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): On each day, before training in the first quadrant, each mouse was placed on the platform for 15 seconds (to enhance the mouse's sense of security on the platform). After that, the mouse was placed from the platform quadrant into the pool (with its head facing the wall of the pool) for a 60-second swim time. 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 failed to find the platform, the time was recorded as 60 seconds. After guiding the mouse to the platform and staying there for 20 seconds, the mouse was removed, marking the end of quadrant training for that mouse.

[0137] After training in the first quadrant, mice were trained in the remaining three quadrants in sequence. There was no need for the mice to be placed on the platform for 15 seconds before training. Training for each mouse in each of the two quadrants was conducted with a 10-15 minute interval. Training was carried out in this manner for five consecutive days.

[0138] 2.3 Test period (Day 6): 24 hours after the last training, the platform was removed and the mouse was dropped into the opposite quadrant (i.e., the farthest position from the platform) of the previous platform. The time the mouse spent in the target quadrant (the quadrant where the platform was previously located), the number of times it crossed the previous platform position (platform crossing count), and the time it first crossed the previous platform position (latency) were recorded and used as indices to evaluate the mouse's spatial learning and memory abilities.

[0139] [Table 6]

[0140] NOTE: Compared with the blank control group, **P<0.01, *P<0.05; compared with the model group, ##P<0.01, #P<0.05. The test results showed that the latency of the animals in the test group administered with the compound of the present application (for example, the latency of the animals in the test group administered with Compound 1 was 22.0±1.5 seconds) was substantially equivalent to the latency of the animals in the blank control group (21.8±3.3 seconds), and was much shorter than the latency of the animals in the test groups 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 application 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 to 4 weeks old and weighing 16 to 18 g.

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

[0145] Preparation of test article: 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.

[0146] 2) Administration information Experimental mice were randomly divided into groups (9 or 10 mice per group). Mice in each group were orally administered with 0.2 mL / 10 g body weight once daily for 3 weeks.

[0147] [Table 7]

[0148] 1.3. Test Procedure The experimental animals were gavaged according to the above doses / specifications for three consecutive weeks. Training began on the last day of administration, and testing was performed 24 hours later.

[0149] 1) Scopolamine-induced acute memory impairment model Experimental animals were gavaged for 3 weeks, and 0.5 hours after the last administration, scopolamine (2 mg / kg) was intraperitoneally injected into mice. The animals were trained using the YLS-3TB platform detector, and memory acquisition function was tested 24 hours later. The latency (the time from the start of counting to the first jump from the platform) and the number of errors (number of electric shocks) were recorded.

[0150] 2) Sodium nitrite-induced hypoxic memory impairment model Experimental animals were gavaged for 3 weeks. One hour after the last administration, the animals were trained using the YLS-3TB platform detector. Immediately after training, sodium nitrite (mice: 120 mg / kg) was injected subcutaneously (in the neck). The platform test was performed 24 hours later. The latency (the time from the start of counting to the first jump off the platform) and the number of errors (number of electric shocks) were recorded.

[0151] 1.4. Behavior detection in the platform test The YLS-3TB jumping platform detector was divided into five compartments by a transparent plate. The bottom of the compartments was covered with a copper grid and a voltage of 50 V was applied. A rubber pad platform measuring 3.5 cm in height and 3.5 cm in diameter was placed in each compartment to serve as a safety area for the mice to avoid electric shock. Experimental mice were trained before the official test: the experimental mice were placed in the small compartment with the platform for 5 minutes to get used to the environment (the five compartments were connected), and then stimulated with a voltage of 50 V and a current of 1.00 mA (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, which creates a memory. The current was applied for 5 minutes, which served as the training process.

[0152] Test: Animals were placed one by one on the platform in the jumping section. The time interval between placing each animal was 5 seconds. After the first animal was placed on the platform, electricity was applied immediately. The duration of electricity application was 6 minutes. After the end of electricity application, the data was printed and the latency period (the time from the start of counting to the first jump off the platform) and the number of errors (the number of electric shocks during the test period) were recorded. Because the time of placing the animals varied, the time difference could be deducted according to the actual time of placing the animals.

[0153] [Table 8]

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

[0155] [Table 9]

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

[0157] Experimental Example 5. Behavioral detection in the dark avoidance test 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 to 4 weeks old and weighing 16 to 18 g.

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

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

[0160] Preparation of test article: 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.

[0161] 2) Administration information Experimental mice were randomly divided into groups (9 or 10 mice per group). Mice in each group were orally administered with 0.2 mL / 10 g body weight once daily for 3 weeks.

[0162] [Table 10]

[0163] 2. Ethanol-induced memory retrieval impairment model Experimental mice were gavaged for 3 weeks. One hour after the last administration, the mice were trained using a YLS-17B dark avoidance tester. The test was performed 24 hours later. A 45% ethanol solution (0.1 mL / 10 g) was gavaged orally 30 minutes before the test. The latency period (the time from the start of counting to the first entry into the dark compartment) and the number of errors (the number of electric shocks) of the animals were recorded.

[0164] The activity box of the automatic dark avoidance tester consists of two compartments (light and dark), with a hole between the two compartments. The bottom of the box is covered with a copper grid, and the animal usually enters the dark compartment. Before the formal test, experimental mice were trained by placing them in the light compartment with their backs facing the entrance of the hole and allowed to acclimate to the environment for 5 minutes. Then, the copper grid in the dark compartment was stimulated with a voltage of 50 V and a current of 1.00 mA (adjustable according to the actual situation) for 2 hours. When the animal received the electric shock, it 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] Test: Mice modeled with ethanol were placed one by one into the light compartment with their backs facing the entrance of the hole, with a 5-second interval between each animal. Electricity was applied immediately after the first animal was placed into the light compartment. The duration of the electric shock test was 6 minutes. After the electric shock test was completed, the data was printed, and the latency period (the time from the start of counting to the first entry into the dark compartment) and the number of errors (the number of electric shocks during the test period) were recorded. Because the time required to place the animals varied, it was necessary to subtract the time difference depending on the actual time the animals were placed. If the mouse did not enter the dark compartment within 5 minutes, the latency period was recorded as 300 seconds.

[0166] Statistical analysis: All data were expressed as mean ± standard deviation and analyzed using SPSS software.

[0167] [Table 11]

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

[0169] Experimental Example 6: Pharmacokinetics test 1.1 Experimental animals and reagents The SD rats used in this study were purchased from Zhejiang Charles River Laboratory Animal Co., Ltd. SPF grade rats of both male and female weighing approximately 250 g were used.

[0170] Carboxymethylcellulose sodium (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] was prepared according to the method described in Example 13 of CN201811435584.X.

[0173] 1.2 Drug preparation 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 article: An appropriate amount of test article was weighed and crushed into a fine powder in a mortar. A specific amount of vehicle was added to an appropriate container, and then the crushed test article was added to the container under magnetic stirring. The mixture was stirred until it was homogeneous in appearance. 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 (six rats per group, half male and half female). Animals in each group were given a single gavage dose of 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 per sample) were collected before drug administration (0 min) and 3, 8, 15, 30 min, 1, 2, 3, 5, 8, 12, 24, and 48 h after drug administration. Blood samples were anticoagulated with EDTA and placed on ice after collection. For blood samples collected at each time point, 150 μL of whole blood was collected, 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 received a single gavage 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-cold water, and absorbed. 50 mg of brain tissue was weighed, added to 0.45 mL of 100 mM dipotassium hydrogen phosphate buffer (pH = 5.0), and homogenized. Blood samples were collected at the same time and anticoagulated with EDTA. After collection, the blood samples were placed on ice. TM was measured by collecting 150 μL of whole blood and adding 150 μL of 5.2% perchloric acid. Four animals were gavaged with saline to measure endogenous TM levels. All samples were frozen and stored in a refrigerator at -80°C.

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

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

[0179] 1.4 Test Results 1.4.1 Plasma Concentrations and Pharmacokinetic Parameters in Rat Absorption Tests A summary of the pharmacokinetic parameters of Compound 1, BTMP, and Comparative Compound 2 after single gavage administration to rats is shown in Table 1.

[0180] [Table 12]

[0181] According to the above test results, at the same drug dose, the TM and TDP exposure levels in the compound 1 administration group were higher than those in the BTMP and comparative compound 2 administration group. 1 / 2 Regarding the compound 1 administration group, 1 / 2 is the t of the BTMP or comparative compound 2 administration group 1 / 2 was significantly higher than

[0182] 1.4.2 Concentration changes in rat brain and whole blood at different times in the brain distribution test Table 2 shows the TM concentrations in the brain and whole blood at different time points after a single gavage administration of Compound 1, BTMP, and Comparative Compound 2 to rats.

[0183] [Table 13]

[0184] According to the above data, the AUC of TM in the brain (calculated by subtracting the concentration at time 0) after gavage 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 group was 1.56-fold that of the BTMP group and 2.08-fold that of the Comparative Compound 2 group.

[0185] In addition to those described herein, various modifications of the present invention will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Each reference, including all patents, applications, journal articles, books, and other disclosures referred to herein, is hereby incorporated by reference in its entirety.

Claims

1. 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. 【Chemistry 1】 (In the formula, Ring A is C ６－１０ an aromatic ring or a 5- to 14-membered heteroaromatic ring; L １ is a direct bond or -R ２ -C １－６ alkylene-, R ２ is -O-, -NH-, -S-, -S(=O)-, or -S(=O) ２ - and R １ At each occurrence, each of the following is selected: halogen, hydroxyl, oxo, amino, cyano, nitro, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C ６－１０ aryl, 5- to 14-membered heteroaryl, C ６－１２ Aralkyl, =N-OR ３ , -C(=NH)NH ２ , -C(=O)R ３ , —OC(═O)R ３ , -C(=O)OR ３ , -OR ３ , -SR ３ , -S(=O)R ３ , -S(=O) ２ R ３ , -S(=O) ２ NR 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 Alkylene -NR ３ R ４ , —O—C １－６ Alkylene -NR ３ R ４ , and -C １－６ Alkylene -O-C １－６ alkyl, or when n is greater than 1, two R １ together with the groups to which they are attached form C ３－６ Hydrocarbon ring, 3- to 10-membered heterocyclic ring, C ６－１０ forming an aromatic ring or a 5- to 14-membered heteroaromatic ring, R ３ and R ４ At each occurrence, H and C １－６ Alkyl, C ３－１０ Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C ６－１０ Aryl, 5- to 14-membered heteroaryl, and C ６－１２ aralkyl; The above alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbyl, hydrocarbon ring, heterocyclyl, heterocycle, aryl, aromatic ring, heteroaryl, heteroaromatic ring, and aralkyl are each independently selected from halogen, hydroxyl, oxo, amino, cyano, nitro, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C ６－１０ aryl, 5- to 14-membered heteroaryl, C ６－１２ Aralkyl, =N-OR ５ , -C(=NH)NH ２ , -C(=O)R ５ , —OC(═O)R ５ , -C(=O)OR ５ , -OR ５ , -SR ５ , -S(=O)R ５ , -S(=O) ２ R ５ , -S(=O) ２ NR 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 Alkylene -NR ５ R ６ , —O—C １－６ Alkylene -NR ５ R ６ , and -C １－６ Alkylene -O-C １－６ and alkyl, wherein the alkyl, alkenyl, alkynyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl, and aralkyl may further be substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, C １－６ Alkyl, C ３－６ Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C ６－１０ Aryl, 5- to 14-membered heteroaryl, and C ６－１２ and optionally substituted with one or more substituents independently selected from the group consisting of aralkyl; R ５ and R ６ At each occurrence, H and C １－６ Alkyl, C ３－１０ Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C ６－１０ Aryl, 5- to 14-membered heteroaryl, and C ６－１２ aralkyl; n is an integer of 0, 1, 2, 3, or 4; However, L １ is a direct bond, ring A is not a benzene ring.

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein ring A is a benzene ring or a 5- to 6-membered heteroaromatic ring.

3. 3. The compound of claim 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein ring A is a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, or a pyridine ring.

4. L １ is a direct bond or —O—C １－６ 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein:

5. L １ is a direct bond, —O—CH ２ - or -O-CH ２ CH ２ 5. The compound of claim 4, wherein: - or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof.

6. R １ But halogen, C １－６ C optionally substituted with alkyl or halogen ６－１０ Aryl or -C １－６ Alkylene -O-C １－６ alkyl or two R １ together with the groups to which they are attached form C ６－１０ An aromatic ring is formed, which is -OR ５ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, optionally further substituted by

7. R １ is —Cl, methyl, phenyl optionally substituted with F, or —CH ２ -O-CH ３ or two R １ are taken together with the groups to which they are attached to form a benzene ring, which is optionally further substituted with methoxy, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof. 【Request Item 8】 【Chemistry 2】 but, 【Transformation 3】 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof.

9. The following compound: or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof: Table 1

10. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

11. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition according to claim 10, in the manufacture of a medicament for the prevention or treatment of a neurodegenerative disease or the alleviation of symptoms of a neurodegenerative disease.

12. 12. The use according to claim 11, 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 cell death, and diseases caused by progressive incontinence, preferably Alzheimer's disease.

13. A process for preparing a compound of formula (I) comprising: A process comprising reacting a compound of formula (I)-a with a compound of formula (I)-b to obtain a compound of formula (I). 【Chemistry 4】 (In the formula, LG is a leaving group, preferably a halogen, most preferably chlorine; The remaining groups are as defined in any one of claims 1 to 9.

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