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

Abstract

The present invention relates to a compound of formula (I), a pharmaceutical composition containing the compound, a preparation method thereof and use thereof for treating neurodegenerative diseases.

Description

Technical Field

[0001] The present invention relates to a compound containing a phosphate group, a pharmaceutical composition containing the compound, a preparation method thereof and use thereof for treating neurodegenerative diseases. Background Art

[0002] Alzheimer's disease (commonly known as senile dementia, Alzheimer's disease, AD) is a progressive neurodegenerative disease with cognitive and behavioral disorders as the main clinical manifestations. It is the most common type of senile dementia, mainly manifested by impaired recognition ability and rapid decline of memory function. The main pathophysiological characteristics are the deposition of β-amyloid protein (β-amyloid, Aβ) in the brain to form senile plaques, hyperphosphorylation of tau protein to form neurofibrillary tangles, impaired brain glucose metabolism and loss of neurons / synapses. Due to the long course of the disease and the poor self-care ability of patients, it brings serious mental and economic burdens to families and society. However, there are currently no drugs that can prevent or delay the progression of the disease worldwide. The drugs currently sold on the market for the treatment of AD are only symptomatic drugs, which can only control or improve cognitive and functional symptoms for a period of time, and cannot prevent or delay the deterioration of the disease. Summary of the Invention

[0003] The present invention provides compounds containing phosphate groups that can be used to prevent or treat neurodegenerative diseases. In addition, the compounds of the present invention also have more excellent properties such as better physicochemical properties (such as solubility, physical and / or chemical stability), improved pharmacokinetic properties (such as improved bioavailability, suitable half-life and duration of action), improved safety (lower toxicity (such as reduced cardiotoxicity) and / or fewer side effects), and less prone to drug resistance.

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

[0005]

[0006] in:

[0007] Ring A is C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring;

[0008] L 1 Direct key or -R 2 -C 1-6 Alkylene-;

[0009] R 2is -O-, -NH-, -S-, -S(=O)- or -S(=O)2-;

[0010] R 1 Each occurrence is independently selected from halogen, hydroxy, oxo, amino, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, 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 connected, they form C 3-6 Hydrocarbon ring, 3-10 membered heterocycle, C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring;

[0011] R 3 and R 4 Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl;

[0012] The above alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, hydrocarbon ring, heterocyclic radical, heterocyclic ring, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl groups are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, amino, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, 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 1-6 Alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl further optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl;

[0013] R 5 and R 6 Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 aralkyl; and

[0014] n is an integer of 0, 1, 2, 3 or 4;

[0015] The condition is that when L 1 When it is a direct bond, ring A is not a benzene ring.

[0016] Another aspect of the present invention provides a pharmaceutical composition 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.

[0017] 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, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating a neurodegenerative disease or alleviating the symptoms of a neurodegenerative disease.

[0018] Another aspect of the present invention provides a 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, for use in preventing or treating a neurodegenerative disease or alleviating the symptoms of a neurodegenerative disease.

[0019] Another aspect of the present invention provides a method for preventing or treating a neurodegenerative disease or alleviating the symptoms of a neurodegenerative disease, which comprises 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, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention.

[0020] Another aspect of the present invention provides a process for preparing the compound of the present invention. DETAILED DESCRIPTION

[0021] definition

[0022] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0023] The terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0024] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0025] As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6, carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogen (in which case the group is referred to as "haloalkyl") (e.g., CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl or -CH2CH2CF3, etc.). The term "C 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0026] As used herein, the term "alkenylene" denotes a divalent hydrocarbon radical containing one or more double bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as vinylene, propenylene or allylene.

[0027] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon radical containing one double bond and having 2 to 6 carbon atoms ("C 2-6 The alkenyl group is, for example, 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.

[0028] When the compounds of the present invention contain an alkenylene or alkenyl group, the compounds may be present in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof.

[0029] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.

[0030] As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including but not limited to (cyclo)propyl, (cyclo)butyl, (cyclo)pentyl, (cyclo)hexyl, (cyclo)heptyl, (cyclo)octyl, (cyclo)nonyl, (cyclo)hexenyl, and the like.

[0031] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including spirocyclic, 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, decalinyl, etc.), which is optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-6 "Cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl.

[0032] 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 within the ring) cyclic group having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C. For example, a "3-10 membered heterocyclyl" is a saturated or partially unsaturated heterocyclyl having 2-9 (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 N, O and S. Examples of heterocyclylene and heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl. The group also encompasses bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc.). The heterocyclylene and heterocyclyl groups may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.

[0033] As used herein, the terms "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, the term "C 6-10 (E)aryl" and "C 6-10 The term "aromatic ring" means an aromatic group containing 6 to 10 carbon atoms, such as (ene)phenyl (phenyl ring) or (ene)naphthyl (naphthalene ring). The (ene)aryl group and the aromatic ring are optionally substituted by one or more (such as one to three) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.) substituted.

[0034] As used herein, the terms "heteroaryl(ene)" 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, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being for example oxygen, nitrogen or sulfur) and, in each case, may additionally be benzo-fused. In particular, “heteroaryl” or “heteroaromatic ring” is selected from thiophenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof.

[0035] The term "aralkyl" preferably refers to an alkyl group substituted with an aryl group, wherein the aryl group and the alkyl group 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.

[0036] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0037] The term "alkylthio" as used herein, means an alkyl group, as defined above, appended 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.

[0038] 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, which may optionally further contain one or more (e.g., one, two, three or four) ring members selected from N, O, C=O, S, S=O and S(=O); the nitrogen-containing heterocycle is linked to the rest of the molecule via the 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 3-14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to a three-membered nitrogen-containing heterocycle (such as aziridine), a four-membered nitrogen-containing heterocycle (such as azetidinyl), a five-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidine ring), pyrrolinyl, pyrrolidonyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), a six-membered nitrogen-containing heterocycle (such as piperidinyl (piperidine ring), morpholinyl, thiomorpholinyl, piperazinyl), a seven-membered nitrogen-containing heterocycle, etc.

[0039] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context 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.

[0040] If a substituent is described as being "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0041] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0042] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0043] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0044] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0045] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, 2 H), tritium (T, 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g.13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13 N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0046] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0047] In this article, solid lines can be used Solid wedge or virtual wedge The carbon-carbon bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomers exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0048] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0049] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0050] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0051] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate / carbonate, bisulfate / sulfate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodide / iodide, maleate, malonate, methylsulfate, naphthoate (naphthylate), nicotinate, nitrate, orotate, oxalate, palmitate and other similar salts.

[0052] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium and other similar salts.

[0053] Suitable salts are reviewed in "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.

[0054] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acid or alcohol). The compounds of the present invention themselves may also be esters.

[0055] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0056] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, and the like of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0057] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are easily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). The prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0058] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the 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 forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P.GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0059] As used herein, the term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0060] Compound

[0061] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein the compound has the structure of Formula (I):

[0062]

[0063] in:

[0064] Ring A is C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring;

[0065] L 1 Direct key or -R 2 -C 1-6 Alkylene-;

[0066] R 2 is -O-, -NH-, -S-, -S(=O)- or -S(=O)2-;

[0067] R 1 Each occurrence is independently selected from halogen, hydroxy, oxo, amino, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, 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 、-C1-6 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 connected, they form C 3-6 Hydrocarbon ring, 3-10 membered heterocycle, C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring;

[0068] R 3 and R 4 Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl;

[0069] The above alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, hydrocarbon ring, heterocyclic radical, heterocyclic ring, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl groups are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, amino, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, 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-R6 、-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 Alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl further optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl;

[0070] R 5 and R 6 Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 aralkyl; and

[0071] n is an integer of 0, 1, 2, 3 or 4;

[0072] The condition is that when L 1 When it is a direct bond, ring A is not a benzene ring.

[0073] 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 5-6 membered heteroaromatic ring.

[0074] 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.

[0075] 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 L 1 For direct key or -OC 1-6Alkylene-.

[0076] 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 L 1 It is a direct bond, -O-CH2- or -O-CH2CH2-.

[0077] In some embodiments, when L 1 When it is a direct bond and n is 0, ring A is not an unsubstituted furan ring or an unsubstituted thiophene ring.

[0078] 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 R 1 Halogen, C 1-6 Alkyl, optionally substituted by halogen C 6-10 Aryl or -C 1-6 Alkylene-OC 1-6 Alkyl; or two R 1 Together with the groups to which they are connected, they form C 6-10 aromatic ring, which is optionally further substituted with -OR 5 replace.

[0079] 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 R 1 is -Cl, methyl, phenyl optionally substituted by F, or -CH2-O-CH3; or two R 1 Together with the groups to which they are attached, they form a benzene ring, which is optionally further substituted by a methoxy group.

[0080] 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 for

[0081] The present invention encompasses compounds resulting from any combination of the various embodiments.

[0082] In some embodiments, the compound of formula (I) is not:

[0083]

[0084] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein the compound is:

[0085]

[0086]

[0087]

[0088] Preparation method

[0089] In some embodiments, the present invention provides a method for preparing a compound of formula (I):

[0090]

[0091] in:

[0092] LG is a leaving group, preferably a halogen, most preferably chlorine;

[0093] The remaining groups are as defined above;

[0094] The method comprises reacting a compound of formula (I)-a with a compound of formula (I)-b to obtain a compound of formula (I).

[0095] The reaction is preferably carried out in the presence of a base (e.g., 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 0-50° C., for example, 25° C.

[0096] Pharmaceutical compositions and methods of treatment

[0097] In some embodiments, 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.

[0098] In some embodiments, the present invention provides use of a 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 in the preparation of a medicament for preventing or treating a neurodegenerative disease or alleviating the symptoms of a neurodegenerative disease.

[0099] In some embodiments, 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 preventing or treating a neurodegenerative disease or alleviating the symptoms of a neurodegenerative disease.

[0100] In some embodiments, the present invention provides a method for preventing or treating a neurodegenerative disease or alleviating a symptom 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.

[0101] In some embodiments, the neurodegenerative disease is selected from Alzheimer's disease, Creutzfeldt-Jakob disease, Huntington's disease, multiple sclerosis, Guillain-Barré syndrome, Parkinson's disease, Loewenstein's disease, paralytic dementias and progressive disorders caused by gradual nerve cell death; preferably Alzheimer's disease.

[0102] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0103] 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, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous glucose and glycerol solutions can also be used as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, and the like. The composition may also contain a small amount of a wetting agent, emulsifier, or pH buffer, as needed. Oral formulations may contain standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0104] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by suitable routes, for example, by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

[0105] For these administration routes, the pharmaceutical composition of the present invention can be administered in suitable dosage forms.

[0106] 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, injectable solutions, elixirs, and syrups.

[0107] As used herein, the term "effective amount" refers to that amount of a compound which, when administered, will relieve to some extent one or more of the symptoms of the condition being treated.

[0108] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0109] The amount of the compound of the present invention administered will depend on the severity of the individual, disease or the patient's condition, the speed of administration, the disposal of the compound and the judgment of the prescribing physician for treatment. Generally speaking, effective dose is about 0.0001 to about 50mg per kg body weight per day, for example, about 0.01 to about 10mg / kg / day (single or divided administration). For 70kg people, this will add up to about 0.007mg / day to about 3500mg / day, for example, about 0.7mg / day to about 700mg / day. In some cases, it can be enough to be not higher than the dosage level of the lower limit of the aforementioned range, and in other cases, it is still possible to adopt a larger dose in the case of not causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

[0110] The content or dosage of the compound of the present invention in the pharmaceutical composition can be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, for example 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.

[0111] As used herein, unless otherwise indicated, the terms "treat," ...

[0112] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0113] In another embodiment, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.

[0114] Example

[0115] In order to make the purpose and technical scheme of the present invention clearer, the embodiments of the present invention are described in detail below in conjunction with embodiment.But those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.Unindicated specific conditions in the examples are all carried out according to the conditions of normal conditions or manufacturer's recommendations.Reagents used or instruments not indicated by manufacturer are all conventional products that can be purchased on the market.

[0116] The structures of the compounds were determined by nuclear magnetic resonance (1 Chemical shifts (δ) are determined by H NMR or mass spectrometry (MS). NMR measurements are performed using a Bruker AVANCE-500 NMR spectrometer or a Varian-400 MHz NMR spectrometer. The solvents used are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated water (D2O), etc. The internal standard is tetramethylsilane (TMS). Chemical shifts (δ) are given in parts per million (ppm).

[0117] The MS measurement instrument was an Agilent (ESI) mass spectrometer (manufacturer: Agilent, model: Agilent 6110).

[0118] Preparative HPLC separation method:

[0119] Instrument model: Elite P3500, chromatographic column: Welch Ultimate XB-C18 (30×250 mm, 10 μm); 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.

[0120] The compounds synthesized in the following examples are based on the compounds represented by the molecular formulas, and the compound names were generated by ChemBioDraw software.

[0121] Example 1: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)2-propylthiopentanoate (Compound 1)

[0122]

[0123] Dissolve phosphothiamine (1a) (83% content, 20 g, 0.04 mol, 1.0 eq.) in water (40 mL) and stir until clear. Add sodium hydroxide solution (30%) dropwise to adjust the pH to 10.5-11.0, and stir for 30 minutes. Maintain the system temperature at 25°C. Add 2-propylpentanoyl chloride (1b) (0.07 mol, 1.75 eq.) diluted in tetrahydrofuran (20 mL) dropwise over 20 minutes and stir for 10 minutes. Adjust the aqueous phase to pH 1.5. The system becomes turbid, and slowly add ethyl acetate (100 mL). A white solid precipitates, which is filtered, dried, and dissolved in water (100 mL). Add NaHCO3 (1.0 eq.). A small amount of bubbles may form during stirring. Concentrate the water to dryness, add DCM, and stir to dissolve. Filter to remove salts, and concentrate the filtrate to obtain the title compound 1 (white solid).

[0124] MS m / z(ESI):489[M+1]

[0125] 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).

[0126] Example 2: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)2-ethylthiobutyrate (Compound 2)

[0127]

[0128] The title compound 2 (white solid) was prepared by following the same synthetic route as in Example 1, except that 1b in Example 1 was replaced by 2-ethylbutyryl chloride.

[0129] MS m / z(ESI):461[M+1]

[0130] 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).

[0131] Example 5: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)O-phenethylthiocarbonate (Compound 5)

[0132]

[0133] 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 by phenethyl chloroformate.

[0134] MS m / z(ESI):511.1[M+1]

[0135] 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).

[0136] 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)

[0137]

[0138] 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 by benzyl chloroformate.

[0139] MS m / z(ESI):497.1[M+1]

[0140] 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).

[0141] 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)

[0142]

[0143] 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 by 5-chlorothiophene-2-carbonyl chloride.

[0144] MS m / z(ESI):507[M+1]

[0145] 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).

[0146] 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)

[0147]

[0148] 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 by 5-methoxybenzofuran-2-carbonyl chloride.

[0149] MS m / z(ESI):537[M+1]

[0150] 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).

[0151] 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)

[0152]

[0153] 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 by furan-2-carbonyl chloride.

[0154] MS m / z(ESI):456.9[M+1]

[0155] 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).

[0156] 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)

[0157]

[0158] 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 by 1H-pyrrole-2-carbonyl chloride.

[0159] MS m / z(ESI):456.0[M+1]

[0160] 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).

[0161] 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)

[0162]

[0163] 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 by 5-(4-fluorophenyl)thiophene-2-carbonyl chloride.

[0164] MS m / z(ESI):567[M+1]

[0165] 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).

[0166] 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)

[0167]

[0168] 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 by 5-(methoxymethyl)furan-2-carbonyl chloride.

[0169] MS m / z(ESI):501.5[M+1]

[0170] 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).

[0171] 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)

[0172]

[0173] 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 by benzofuran-2-carbonyl chloride.

[0174] MS m / z(ESI):507[M+1]

[0175] 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).

[0176] 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)

[0177]

[0178] 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 by thiophene-2-carbonyl chloride.

[0179] MS m / z(ESI):473[M+1]

[0180] 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).

[0181] 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)

[0182]

[0183] 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 by furan-3-carbonyl chloride.

[0184] MS m / z(ESI):457[M+1]

[0185] 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).

[0186] 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)

[0187]

[0188] 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 by 2-pyridinecarbonyl chloride.

[0189] MS m / z(ESI):468.1[M+1]

[0190] 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).

[0191] 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)

[0192]

[0193] 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 by 5-methylfuran-2-carbonyl chloride.

[0194] MS m / z(ESI):471[M+1]

[0195] 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).

[0196] 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-thiocarboxate (Compound 18)

[0197]

[0198] 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 by 2,5-dimethylfuran-3-carbonyl chloride.

[0199] MS m / z(ESI):485[M+1]

[0200] 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).

[0201] Biological tests

[0202] Experimental Example 1

[0203] BCA protein concentration determination kit was purchased from Beyotime, Aβ40 and Aβ42 detection kits were purchased from Wako, and cell culture-related reagents were purchased from Gibco.

[0204] HEK293APP / sw overexpressing cells were cultured in 48-well plates using DMEM culture medium (containing 10% FBS, 100 μg / mL G418 (Geneticin) and dual antibody (1× Penicillin, Streptomycin). 4 mM compound stock solution (prepared by dissolving the compound in DMEM culture medium) was taken, filtered through a 0.22 μm sterile filter, and stored at -20°C until use. At a cell density of 70%, 40 μL of compound test solution was added to each well to a final concentration of 400 μM and cultured for 24 hours.

[0205] The culture supernatant was collected and a portion was added to the BCA reagent. After incubation at room temperature for 30 minutes, the absorbance of each well (i.e., OD value) was measured at 570 nm on a microplate reader, and the total protein concentration was calculated based on a protein standard curve. Meanwhile, another portion of the supernatant (100 μL) was added to a pre-prepared 96-well plate and incubated overnight at 4°C. After removing the solution and washing the reagent, HRP (horseradish oxidase)-labeled antibody was added and incubated at 4°C for 2 hours. After removing and washing the reagent, TMB colorimetric solution was added and incubated at room temperature for 30 minutes. After the reaction was terminated by adding the stop solution, the absorbance of each well (i.e., OD value) was measured at 450 nm on a microplate reader, and the concentrations of Aβ40 and Aβ42 were calculated based on the standard curves for Aβ40 and Aβ42, respectively. Finally, the concentrations of Aβ40 and Aβ42 were adjusted using the total protein concentration to determine the final concentration. The test results are shown in the table below.

[0206] Compound number Aβ40 content (pmol / L) Aβ42 content (pmol / L) 1 41.18 3.32 2 37.39 3.34 5 48.94 4.92 7 35.93 5.03 8 60.96 2.31 9 42.88 2.94 13 43.76 7.21 15 37.88 10.52 <![CDATA[Blank control * > 127.81 11.08

[0207] * No compound test solution was added to the blank control.

[0208] From the above experimental results, it can be seen that the compounds of the present invention can significantly reduce the levels of Aβ42 and / or Aβ40.

[0209] Experimental Example 2. Acute toxicity test

[0210] 2.1. Experimental Purpose

[0211] The poisoning reaction and death of mice after oral administration of the test compound are observed to preliminarily evaluate the safety of the test compound.

[0212] Experimental methods

[0213] 2.2.1. Experimental materials

[0214] CMC-Na (sodium carboxymethyl cellulose) was purchased from Shanghai Sinopharm Chemical Reagent Co., Ltd.

[0215] The experimental animals were Kunming mice, weighing 18-20 g, provided by Beijing Keao Xieli Feed Co., Ltd.

[0216] Experimental procedures

[0217] 1) Preparation of 0.7% CMC-Na: Take 0.7 g of CMC-Na and add distilled water to prepare a 0.7 g / 100 mL solution.

[0218] 2) Take the compound to be tested and add 0.7% CMC-Na to prepare a 100 mg / mL suspension.

[0219] 3) Each test group consisted of 10 male mice. Each mouse was orally administered the test compound (2000 mg / kg) once daily for 15 days. Following administration, the animals were observed for the following: diet, appearance, behavior, secretions, excretions, symptoms of adverse reactions, onset, severity, duration, reversibility, and mortality. Body weights were recorded on the day of administration, 7 days, and 14 days.

[0220] 2.3 Experimental results

[0221]

[0222] After administration of the test compound, the animals showed no abnormalities and no obvious toxic reactions were observed during continuous observation, indicating that the tested compound has good safety.

[0223] Experimental Example 3. Water maze behavioral experiment

[0224] 3.1 Experimental Principle

[0225] Rodents have a strong motivation to escape aquatic environments and can do so in the fastest and most direct way possible. Learning to escape aquatic environments reflects the animals' learning abilities. Orienting themselves spatially based on their surroundings and swimming purposefully toward a safe location in the water (such as a platform) demonstrates their spatial learning and memory abilities.

[0226] Experimental methods

[0227] Experimental materials

[0228] 1) Experimental animals

[0229] The experimental animals were APP / PS1 2×Tg mice (the blank control group was C57BL / 6 wild-type mice), aged 6-8 months and weighing 20-40 g, purchased from The Jackson laboratory.

[0230] APP / PS1 mice are APP / PS1 dual transgenic Alzheimer's disease (2×Tg-AD) model mice. The appearance of Aβ deposition in 2×Tg-AD mice precedes the pathological changes of tau protein by several months, and they can more realistically simulate the clinical course and pathological changes of Alzheimer's disease.

[0231] 2) Main reagents

[0232] CMC-Na (sodium carboxymethyl cellulose) was purchased from Shanghai Sinopharm Chemical Reagent Co., Ltd.;

[0233] Positive control: BTMP (benfotiamine), produced by Shanghai Rixin Biotechnology Co., Ltd.

[0234] Reference compound 1: Prepared according to the method of Example 6 in CN201811435584.X.

[0235] 3) Main equipment

[0236]

[0237] 3.2.2 Experimental methods

[0238] 1) Drug preparation and administration information

[0239] 1.1. Drug preparation

[0240] Preparation of 0.7% CMC-Na: Take 0.7g CMC-Na and add appropriate amount of water, heat to dissolve, bring to room temperature and dilute to 100mL, and store at 4℃.

[0241] Preparation of BTMP: Add 100 mg of BTMP to 10 mL of 0.7% CMC-Na to prepare a 10 mg / mL suspension for later use.

[0242] Preparation of test sample and reference compound 1: Weigh 100 mg of the test compound and add 10 mL of 0.7% CMC-Na to prepare a 10 mg / mL suspension for later use.

[0243] 1.2. Dosage Information

[0244] The experimental mice were randomly divided into groups (9 or 10 mice in each group), and each group of mice was orally gavaged with 0.2 mL / 10 g body weight of the drug once a day for 8 consecutive weeks.

[0245] Group Drug / dosage gender Duration of medication Blank control group 0.7% CMC-Na male / female 8w Model Group 0.7% CMC-Na male / female 8w BTMP 200mg / kg male / female 8w Test compound 200mg / kg male / female 8w Reference compound 1 200mg / kg male / female 8w

[0246] 2) Experimental steps

[0247] Mice in the blank control group, model group, and experimental group were gavage-administered at the above-mentioned dosage / specification for 8 consecutive weeks. Water maze training and testing began during the final week of dosing. Water maze training and testing lasted for 6 days, with a 5-day training period and a 1-day testing period. During the 6-day water maze training and testing period (a total of 6 days), the room lighting and other conditions were maintained uniform, the room was kept quiet, and any environmental or personal interference was eliminated.

[0248] 2.1. Preparation before the experiment: Place an appropriate amount of water in the water maze pool at a temperature of 22 ± 3°C. Place the platform in a fixed position (target quadrant) 1 cm below the water surface. Add titanium dioxide until the water turns white and the platform is obscured.

[0249] 2.2. Training Period (Days 1 to 5): Before each day's first quadrant training, each mouse was placed on the platform for 15 seconds (to increase their sense of security). The mouse was then placed in the pool (with its head facing the pool wall) from the quadrant where the platform was located, and the swimming time was set to 60 seconds. If the mouse found the platform within 60 seconds and remained 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, and the mouse was guided to the platform and remained there for 20 seconds. The mouse was then removed, and training for that mouse in that quadrant was concluded.

[0250] After training in the first quadrant, proceed with the remaining three quadrants. It is not necessary to place the mouse on the platform for 15 seconds before training. Each mouse should be trained 10-15 minutes apart between two quadrants. This training method should be repeated for 5 consecutive days.

[0251] 2.3. Testing phase (Day 6): 24 hours after the last training session, the platform was removed and the mouse was dropped into the quadrant opposite the original platform (i.e., the position farthest from the platform). The time the mouse spent in the target quadrant (the quadrant where the original platform was located), the number of times it crossed the original platform (number of platform crossings), and the time to the first crossing of the original platform (latency) were recorded. These were used as indicators to assess the spatial learning and memory ability of the mouse.

[0252] Group Quantity (pieces) Incubation period (s) Number of times of crossing the platform Target quadrant time (s) Blank control group 10 <![CDATA[21.8±3.3 ## ]]> <![CDATA[2.5±0.9 ## ]]> <![CDATA[20.0±2.3 ## ]]> Model Group 10 <![CDATA[45.0±8.8 ** ]]> <![CDATA[0.9±0.6 ** ]]> <![CDATA[12.8±2.9 ** ]]>

[0253] BTMP 10 <![CDATA[27.3±1.6 *## ]]> <![CDATA[2.1±0.6 ## ]]> <![CDATA[18.0±3.5 ## ]]> Compound 1 10 <![CDATA[22.0±1.5 ## ]]> <![CDATA[2.4±0.8 ## ]]> <![CDATA[19.6±3.4 ## ]]> Compound 2 10 <![CDATA[22.7±1.1 ## ]]> <![CDATA[2.2±0.6 ## ]]> <![CDATA[18.8±2.6 ## ]]> Compound 5 9 <![CDATA[25.0±2.2 ## ]]> <![CDATA[2.2±0.7 ## ]]> <![CDATA[17.7±2.6 ## ]]> Compound 9 9 <![CDATA[22.8±1.3 ## ]]> <![CDATA[2.3±0.5 ## ]]> <![CDATA[18.6±1.6 ## ]]> Reference compound 1 10 <![CDATA[27.0±1.3 ## ]]> <![CDATA[2.1±0.6 ## ]]> <![CDATA[18.1±2.8 ## ]]>

[0254] Note: Compared with the blank control group ** P < 0.01, * P<0.05; compared with the model group ## P < 0.01, # P<0.05.

[0255] The experimental results show that the incubation period of animals in the test groups administered with the compounds of the present application (for example, the incubation period of animals in the test group administered with Compound 1 was 22.0±1.5s) was substantially comparable to the incubation period of animals in the blank control group (21.8±3.3s), and was much shorter than the incubation period of animals in the test groups administered with BTMP or Reference Compound 1 (27.3±1.6s and 27.0±1.3s, respectively). This effect achieved by the compounds of the present application was unexpected.

[0256] Experimental Example 4. Platform Jumping Experiment

[0257] 1.1. Experimental animals and reagents

[0258] The mice used in this experiment were purchased from Xipu-Bikai Laboratory Animal Co., Ltd., ICR animals, SPF grade, aged 3-4 weeks and weighing 16-18 g.

[0259] Scopolamine hydrobromide trihydrate, source: aladdin; product number: S107418; purity: 98%.

[0260] Sodium nitrite (NaNO2), source: Sinopharm Chemical Reagent Co., Ltd.; product number: 10020018; specification: analytical grade.

[0261] 1.2. Drug configuration and administration information

[0262] 1) Drug configuration

[0263] Preparation of 0.7% CMC-Na: Weigh 0.7 g of CMC-Na, add appropriate amount of purified water, heat to dissolve, bring to room temperature and dilute to 100 mL, and store at 4°C.

[0264] Preparation of test sample: Weigh 100 mg of the compound to be tested and add 10 mL of 0.7% CMC-Na to make a 10 mg / mL suspension for later use.

[0265] 2) Dosage information

[0266] The experimental mice were randomly divided into groups (9 or 10 mice in each group), and each group of mice was orally gavaged with 0.2 mL / 10 g body weight of the drug once a day for 3 consecutive weeks.

[0267] Group Drug / dosage gender Duration of medication Blank group 0.7% CMC-Na male 3w Model Group 0.7% CMC-Na male 3w Test compound 200mg / kg male 3w

[0268] Experimental procedures

[0269] The experimental animals were orally gavaged for 3 consecutive weeks according to the prescribed dosage / specifications. Training began on the last day of administration and testing was performed 24 hours later.

[0270] 1) Scopolamine-induced acute memory dysfunction model

[0271] Experimental animals were administered the drug via oral gavage for 3 weeks. Scopolamine (2 mg / kg for mice) was injected intraperitoneally 0.5 hours after the last dose. Animals were trained using a YLS-3TB platform jump recorder. Memory acquisition was tested 24 hours later. Latency (the time from the start of the timer to the first jump off the platform) and the number of errors (number of electric shocks) were recorded.

[0272] 2) Sodium nitrite-induced hypoxic memory impairment model

[0273] Animals were administered the drug via oral gavage for three weeks. One hour after the last dose, they were trained using a YLS-3TB platform jump recorder. Immediately following training, sodium nitrite (120 mg / kg for mice) was injected subcutaneously (neck). Twenty-four hours later, the platform jump test was performed. The latency (the time from the start of the timer to the first jump off the platform) and the number of errors (number of electric shocks) were recorded.

[0274] 1.4. Behavioral testing in the platform jumping experiment

[0275] The YLS-3TB jumping platform recorder consists of five compartments separated by a transparent plate. The bottom of the box is covered with a copper grid and is powered at 50V. Each compartment contains a rubber platform 3.5cm high and 3.5cm in diameter, which serves as a safe zone for mice to avoid electric shock. Before the formal experiment, the mice were trained: they were placed in a small compartment of the jumping platform box (the five compartments are connected) to familiarize themselves with the environment for 5 minutes. Then, an electrical stimulus of 50V and 1.00mA was applied (at this time, the mice were moving on the electric grid). Mice have a habit of jumping from high places, and if they jump, they receive an electric shock, which will create a memory. The power supply lasts for 5 minutes, which constitutes the training process.

[0276] Test: The animals were placed on the platform of the stepping box chamber in turn, with a time interval of 5 seconds between each animal. sImmediately after the first animal is placed on the platform, power is applied. The total power-on duration is set to 6 minutes. After power is applied, print the data, recording the latency (the time from the start of the test to the first jump off the platform) and the number of errors (the number of shocks during the test period). Since the time animals are released varies, the time difference can be subtracted from the actual release time.

[0277] Results of the platform jumping experiment in the scopolamine-induced acute memory dysfunction model

[0278] Group Quantity (pieces) Incubation period (s) Number of errors Blank group 10 <![CDATA[203.0±116.9 ## ]]> <![CDATA[0.7±0.82 ## ]]> Model Group 10 <![CDATA[68.5±80.0 ** ]]> <![CDATA[1.7±0.5 ** ]]> Compound 1 10 <![CDATA[180.0±105.9 # ]]> <![CDATA[0.8±0.8 ## ]]> Compound 2 10 <![CDATA[173.2±98.7 # ]]> <![CDATA[0.9±0.7 # ]]>

[0279] Note: Compared with the blank control group ** P < 0.01, * P<0.05; compared with AD model group ## P < 0.01, # P<0.05.

[0280] Results of the platform jumping experiment in the sodium nitrite-induced hypoxic memory impairment model

[0281] Group Quantity (pieces) Incubation period (s) Number of errors Blank group 10 <![CDATA[267.4±79.8 ## ]]> <![CDATA[0.2±0.4 ## ]]> Model Group 10 <![CDATA[93.8±90.25 ** ]]> <![CDATA[1.4±0.7 ** ]]> Compound 1 10 <![CDATA[228.8±155.9 ## ]]> <![CDATA[0.4±0.7 ## ]]> Compound 2 10 <![CDATA[210.4±117.3 # ]]> <![CDATA[0.6±0.8 # ]]> Compound 9 9 <![CDATA[209.3±110.4 # ]]> <![CDATA[0.6±0.7 # ]]>

[0282] Note: Compared with the blank control group ** P < 0.01, * P<0.05; compared with AD model group ## P < 0.01, # P<0.05.

[0283] Experimental Example 5. Behavioral Detection of Dark Avoidance Experiment

[0284] 1. Experimental Materials

[0285] 1.1. Experimental animals and reagents

[0286] The mice used in this experiment were purchased from Xipu-Bikai Laboratory Animal Co., Ltd., ICR animals, SPF grade, aged 3-4 weeks and weighing 16-18 g.

[0287] Anhydrous ethanol: Source: Shanghai Titan Technology Co., Ltd.; Product No.: G73537B; Purity: ≥99.7%.

[0288] 1.2. Drug configuration and administration information

[0289] 1) Drug configuration

[0290] Preparation of 0.7% CMC-Na: Weigh 0.7 g of CMC-Na, add appropriate amount of purified water, heat to dissolve, bring to room temperature and dilute to 100 mL, and store at 4°C.

[0291] Preparation of test sample: Weigh 100 mg of the compound to be tested and add 10 mL of 0.7% CMC-Na to make a 10 mg / mL suspension for later use.

[0292] 2) Dosage information

[0293] The experimental mice were randomly divided into groups (9 or 10 mice in each group), and each group of mice was orally gavaged with 0.2 mL / 10 g body weight of the drug once a day for 3 consecutive weeks.

[0294] Group Drug / dosage gender Duration of medication Blank group 0.7% CMC-Na male 3w Model Group 0.7% CMC-Na male 3w Test compound 200mg / kg male 3w

[0295] 2. Ethanol-induced animal memory retrieval disorder model

[0296] Experimental animals were administered the drug via oral gavage for 3 weeks. One hour after the last dose, the animals were trained using a YLS-17B dark avoidance tester. Testing was performed 24 hours later. 30 minutes before testing, the animals were given a 45% ethanol solution (0.1 mL / 10 g) via oral gavage. The animals' latency (the time from the start of the timer to the first entry into the dark chamber) and the number of errors (number of electric shocks) were recorded.

[0297] The activity box of the automatic dark avoidance tester consists of two chambers, a light chamber and a dark chamber, separated by a hole. The bottom of the chamber is covered with a copper grid, and the animals generally enter the dark chamber. Before the formal experiment, the experimental mice were trained: the animals were placed in the light chamber with their backs facing the hole. They were accustomed to the environment for 5 minutes. Then, an electrical stimulus was applied to the copper grid of the dark chamber at a voltage of 50V and a current of 1.00mA (adjustable according to actual conditions). After receiving the shock, the animals entered the light chamber or tried to move back and forth between the two chambers. The current was maintained for 5 minutes, which constituted the training process.

[0298] Test: Alcohol model mice were placed in the bright box with their backs facing the hole, with a time interval of 5 seconds between each animal. s Immediately after the first mouse is placed in the light chamber, power is applied. The total power-on duration is set to 6 minutes. At the end of the power-on period, data is printed, recording the latency (the time from the start of the test to the first entry into the dark chamber) and the number of errors (the number of shocks during the test period). Due to the varying timing of animal release, the time difference can be subtracted from the actual release time. If the experimental mouse does not enter the dark chamber within 5 minutes, its latency is recorded as 300 seconds.

[0299] Statistical analysis: All data were expressed as mean ± standard deviation and analyzed using SPSS software.

[0300] Results of the dark avoidance experiment in the ethanol-induced animal memory retrieval impairment model

[0301] Group Quantity (pieces) Incubation period (s) Number of errors Blank group 10 <![CDATA[232.2±117.1 # ]]> <![CDATA[0.3±0.48 ## ]]> Model Group 10 <![CDATA[118.4±106.9 * ]]> <![CDATA[2.4±1.7 ** ]]>

[0302] Compound 1 10 <![CDATA[229.8±90.0 # ]]> 1.0±125 Compound 2 10 <![CDATA[217.4±96.6 # ]]> 1.2±1.3 Compound 9 9 <![CDATA[216.1±76.8 # ]]> <![CDATA[1.0±1.0 # ]]>

[0303] Note: Compared with the blank control group** P < 0.01, * P<0.05; compared with AD model group ## P < 0.01, # P<0.05.

[0304] Experimental Example 6 Pharmacokinetic Study

[0305] 1.1 Experimental animals and reagents

[0306] The SD rats used in this experiment were purchased from Zhejiang Weitonglihua Experimental Animal Co., Ltd., both male and female, SPF grade, and weighed approximately 250 g.

[0307] Sodium carboxymethyl cellulose (CMC-Na), source: Sinopharm Chemical Reagent Co., Ltd.; product number: 20160704.

[0308] BTMP was produced by Shanghai Rixin Pharmaceutical Technology Co., Ltd.

[0309] Reference compound 2, Prepared according to the method described in Example 13 in CN201811435584.X.

[0310] 1.2 Drug configuration

[0311] Preparation of 0.7% CMC-Na: Accurately weigh about 7g of CMC-Na and place it in a 1L beaker. Add a magnetic stirrer to the beaker and add 1L of purified water. Stir to obtain a clear solution.

[0312] Preparation of test sample: Weigh an appropriate amount of test sample and grind it into a fine powder in a mortar. Add a certain amount of solvent to a suitable container. Add the ground test sample to the container under magnetic stirring and stir until the appearance is uniform. Gradually add the remaining solvent and then stir magnetically for at least 20 minutes to prepare a drug solution concentration of 15.353 mM.

[0313] 1.3 Experimental steps

[0314] (1) Absorption test

[0315] SD rats were divided into 3 groups, 6 rats per group, half male and half female. Each group of animals was given a single oral gavage of compound 1 (75 mg / kg free base, 15.353 mM), BTMP (71.6 mg / kg, 15.353 mM), or reference compound 2 (75 mg / kg free base, 15.353 mM). Blood was collected (approximately 200 μL / time) before administration (0 min) and 3 min, 8 min, 15 min, 30 min, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 24 h, and 48 h after administration. Blood was anticoagulated with EDTA and placed on ice after collection. For blood samples collected at various time points, 150 μL of whole blood was added to 150 μL of 5.2% perchloric acid for the determination of TM (thiamine) and TDP (thiamine diphosphate). (TM and TDP are metabolites produced in vivo after administration of Compound 1, BTMP, and Reference Compound 2.) All samples were frozen at -80°C.

[0316] (2) Brain distribution test

[0317] Male SD rats were divided into 3 groups, with 16 rats in each group (4 time points, 4 animals were sacrificed at each time point). Compound 1 (75 mg / kg free base, 15.353 mM), BTMP (71.6 mg / kg, 15.353 mM) or reference compound 2 (75 mg / kg free base, 15.353 mM) was administered orally to each group of animals. The animals were sacrificed 5 min, 1 h, 3 h, and 9 h after administration. The brains were immediately removed after the animals were sacrificed, rinsed with ice-cold water, and dried. 50 mg of brain tissue was weighed, 0.45 mL of 100 mM potassium dihydrogen phosphate (pH = 5.0) buffer was added, and homogenized. Blood was collected at the same time, anticoagulated with EDTA, and placed on ice after collection. 150 μL of whole blood was taken and 150 μL of 5.2% perchloric acid was added to measure TM. Another 4 animals were gavaged with normal saline to measure the endogenous TM concentration. All samples were frozen in a -80℃ freezer.

[0318] (3) Sample measurement

[0319] The concentrations of TM and TDP in the samples were determined by HPLC-FLD method.

[0320] (4) Data processing

[0321] The pharmacokinetic parameters of TM and TDP in rat blood were calculated using a non-compartmental model using DAS software. TM concentrations in rat brain tissue were measured after administration, and the mean and standard deviation were calculated. The area under the concentration-time curve (AUC) was calculated using the trapezoidal method.

[0322] 1.4 Experimental Results

[0323] 1.4.1 Rat plasma drug concentration and pharmacokinetic parameters in the absorption study

[0324] The pharmacokinetic parameters of compound 1, BTMP, and reference compound 2 after single oral administration to rats are summarized in Table 1.

[0325] Table 1 Pharmacokinetic parameters after oral administration in rats (calculated after deducting the concentration at zero time, Mean ± SD, n = 6)

[0326]

[0327]

[0328] From the above experimental results, it can be seen that at the same dosage, the exposure of TM and TDP in the compound 1 group was higher than that in the BTMP and reference compound 2 groups, and the t 1 / 2 In terms of t 1 / 2 Significantly higher than that of the BTMP or reference compound 2 group 1 / 2 .

[0329] 1.4.2 Changes in concentrations at different times in rat brain and whole blood during the brain distribution study

[0330] The concentrations of TM in the brain and whole blood at different times after a single oral administration of compound 1, BTMP, and reference compound 2 to rats are shown in Table 2.

[0331] Table 2 TM concentrations in brain and whole blood of rats after oral administration (Mean ± SD, n = 4)

[0332]

[0333] Based on the above data, it can be calculated that after rats were gavage-administered with compound 1, BTMP, and reference compound 2, the AUC of TM in the brain (calculated after deducting the concentration at zero time) were 1156.6 ng·h / g, 739.9 ng·h / g, and 555.9 ng·h / g, respectively. The TM AUC of the compound 1-administered group was 1.56 times and 2.08 times that of the BTMP-administered and reference compound 2-administered groups, respectively.

[0334] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

2. A pharmaceutical composition comprising a preventively or therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 2 in the preparation of a medicament for preventing or treating a neurodegenerative disease or alleviating the symptoms of a neurodegenerative disease.

4. The method of 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, Lougheed-Heilig disease, paralytic dementias and progressive disorders caused by gradual nerve cell death. The method according to claim 4 , wherein the neurodegenerative disease is Alzheimer's disease.

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