Compound containing phosphate ester group, pharmaceutical composition containing compound, preparation method and application thereof

Abstract

The present invention relates to compounds containing phosphate groups, pharmaceutical compositions containing them, processes for their preparation and uses thereof. In particular, the present invention relates to compounds of formula (I), pharmaceutical compositions comprising them, processes for their preparation and their use for the treatment of neurodegenerative diseases.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202280036116.3, filed on May 17, 2022, entitled “Compounds Containing Phosphate Groups, Pharmaceutical Compositions Comprising the Same, Methods of Making the Same, and Uses Thereof”. TECHNICAL FIELD

[0002] The present application relates to compounds containing phosphate groups, pharmaceutical compositions comprising the same, methods of making the same, and uses thereof for treating neurodegenerative diseases. BACKGROUND

[0003] Alzheimer’s disease (AD) is a progressive neurodegenerative disease with cognitive and behavioral disorders as the main clinical manifestations, mainly manifested as rapid decline in recognition ability and memory function. The main pathophysiological features are deposition of β-amyloid (Aβ) in the brain to form senile plaques, overphosphorylation 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 burden to families and society. However, there is currently no drug that can stop or slow down the progression of the disease worldwide. The drugs currently marketed for the treatment of AD are only symptomatic treatment drugs, which can only control or improve cognitive and functional symptoms for a period of time, and cannot stop or slow down the deterioration of the disease. SUMMARY

[0004] The present application provides compounds containing phosphate groups, which can be used for preventing or treating neurodegenerative diseases. In addition, the compounds of the present application also have better physicochemical properties (e.g., solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, appropriate half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and / or fewer side effects), less likely to develop resistance, and other superior properties.

[0005] One aspect of the present application 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): (I) wherein: Ring A is C 6-10 an aromatic ring or a 5-14 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 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 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 , -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 group to which they are attached form a C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic ring or 5-14 membered heteroaromatic ring; R 3 and R 4 at each occurrence are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-14 membered heteroaryl, and C 6-12 aralkyl; each occurrence of the above alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, hydrocarbon ring, heterocyclyl, heterocyclic ring, aryl, aromatic ring, heteroaryl, heteroaromatic ring, and aralkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, and 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 , -O-C 1-6 alkylene-NR 5 R 6 , and -C 1-6 alkylene-O-C 1-6 alkyl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl being further optionally 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 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, and C6-12 aralkyl; R 5 and R 6 each independently at each occurrence is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, and C 6-12 aralkyl; and n is an integer of 0, 1, 2, 3, or 4; provided that, when L 1 is a direct bond, ring A is not a phenyl ring.

[0006] Another aspect of the present application provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present application 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 application provides the use of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound or prodrug thereof or a pharmaceutical composition of the present application in the manufacture of a medicament for preventing or treating a neurodegenerative disease or alleviating a symptom of a neurodegenerative disease.

[0008] Another aspect of the present application provides a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound or prodrug thereof or a pharmaceutical composition of the present application for use in preventing or treating a neurodegenerative disease or alleviating a symptom of a neurodegenerative disease.

[0009] Another aspect of the present application provides a method of preventing or treating a neurodegenerative disease or alleviating a symptom of a neurodegenerative disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound or prodrug thereof or a pharmaceutical composition of the present application.

[0010] Another aspect of the present application provides a method of preparing a compound of the present application. DETAILED DESCRIPTION

[0011] Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Reference herein to technical terms used herein is intended to refer to the technical terms as commonly understood by those skilled in the art, including variations or substitutions of techniques or equivalents of techniques that would be apparent to those skilled in the art. Although it is believed that the following terms are well understood by one of ordinary skill in the art, the following definitions are set forth to better define the present application.

[0012] The terms "comprising," "containing," "having," "including," or "involving," and other variants as used herein are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0013] As used herein, the term "alkylene" denotes 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.

[0014] As used herein, the term "alkyl" is defined as a straight-chain or branched-chain saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6, carbon atoms. For example, as used herein, the term "C 1-6 alkyl" refers to a linear or branched-chain aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl). The term "C 1-4 alkyl" refers to a linear or branched-chain aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl). The term "C

[0015] As used herein, the term "alkylene" denotes 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.

[0016] As used herein, the term "alkylene" denotes 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. 2-6 As used herein, the term "alkylene" denotes 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.

[0017] When the compounds of the present application contain alkenylene or alkenyl groups, the compounds can exist in pure E (entgegen) form, pure Z (zusammen) form or in any mixture thereof.

[0018] As used herein, the term "alkynyl" denotes 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.

[0019] 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 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)nonanyl, (cyclo)hexenyl, and the like.

[0020] As used herein, the term "cycloalkyl" refers to saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon rings (e.g., monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononanyl, or bicyclic, including spiro, fused, or bridged systems such as bicyclo[l. l. l]pentyl, bicyclo[2.2. l]heptyl, bicyclo[3.2. l]octyl, or bicyclo[5.2.0]nonyl, decahydronaphthyl, and the like), optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-6 cycloalkyl" refers to saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) having 3 to 6 ring-forming carbon atoms, optionally substituted with 1 or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0021] As used herein, the terms "heterocyclyl," "heterocyclyl ene," and "heterocycle" refer to saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) cyclic groups having, for example, 3-10 (suitably having 3-8, more suitably having 3-6) ring atoms, at least one of which is a heteroatom selected from N, O, and S, and the remainder of which are C. For example, a "3-10 membered (hetero)cycloalkyl ene" is a saturated or partially unsaturated (hetero)alkylene 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 heterocyclyl ene and heterocycle include, but are not limited to, (hetero)cyclooxanyl, (hetero)cycloaziridinyl, (hetero)cycloazetidinyl, (hetero)cyclooxetanyl, (hetero)cyclo tetrahydrofuranyl, (hetero)cyclo dioxolinyl, (hetero)cyclopyrrolidinyl, (hetero)cyclopyrrolidonyl, (hetero)cycloimidazolidinyl, (hetero)cyclopyrazolidinyl, (hetero)cyclopyrrolinyl, (hetero)cyclo tetrahydropyranyl, (hetero)cyclo piperidinyl, (hetero)cyclo morpholinyl, (hetero)cyclo dithianyl, (hetero)cyclo thiomorpholinyl, (hetero)cyclo piperazinyl, or (hetero)cyclo trithianyl. The groups also encompass 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, and the like). Heterocyclyl ene and heterocycle can be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0022] As used herein, the terms "(hetero)aryl" and "aromatic ring" refer to all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated pi-electron system. For example, as used herein, the terms "C 6-10 (hetero)aryl" and "C 6-10 aromatic ring" mean aromatic groups containing 6 to 10 carbon atoms, such as (hetero)phenyl (benzene ring) or (hetero)naphthyl (naphthalene ring). (Hetero)aryl and aromatic ring are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, and the like).

[0023] As used herein, the terms "(hetero)aryi" and "heteroaromatic ring" mean 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 can be the same or different (the heteroatom is for example oxygen, nitrogen or sulfur), and, in addition, can in each case be benzo-fused. In particular, the "(hetero)aryi" or "heteroaromatic ring" is selected from (hetero)thiophenyl, (hetero)furyl, (hetero)pyrrolyl, (hetero)oxazolyl, (hetero)thiazolyl, (hetero)imidazolyl, (hetero)pyrazolyl, (hetero)isoxazolyl, (hetero)isothiazolyl, (hetero)oxadiazolyl, (hetero)thiadiazolyl and the like, and their benzo derivatives; or (hetero)pyridyl, (hetero)pyridazinyl, (hetero)pyrimidinyl, (hetero)pyrazinyl, (hetero)triazinyl and the like, and their benzo derivatives.

[0024] The term "arylalkyl" preferably denotes an aryl-substituted alkyl group, wherein the aryl and the alkyl are as defined herein. Typically, the aryl group can have 6 to 14 carbon atoms and the alkyl group can have 1 to 6 carbon atoms. Exemplary arylalkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.

[0025] As used herein, the term "halo" or "halogen" group is defined as including F, CI, Br or I.

[0026] As used herein, the term "alkylthio" means an alkyl group as defined above attached to the parent molecular moiety through a sulfur atom. 1-6 Representative examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, tert-butylthio and hexylthio.

[0027] As used herein, the term "nitrogen-containing heterocycle" means 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 can also optionally contain one or more (e.g., one, two, three or four) ring members selected from N, O, C=0, S, S=0 and S(=0)2; the nitrogen-containing heterocycle is attached to the remainder of the molecule through a nitrogen atom. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocycle. In particular, 3- to 14-membered nitrogen-containing heterocycles are groups having 3-14 carbon atoms and heteroatoms in the ring, at least one of which is a nitrogen atom, including but not limited to 3-membered nitrogen-containing heterocycles (such as aziridinyl), 4-membered nitrogen-containing heterocycles (such as azetidinyl), 5-membered nitrogen-containing heterocycles (such as pyrrolyl, pyrrolidinyl (pyrrolidine ring), pyrrolinyl, pyrrolidonyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), 6-membered nitrogen-containing heterocycles (such as piperidinyl (piperidine ring), morpholinyl, thiomorpholinyl, piperazinyl), 7-membered nitrogen-containing heterocycles and the like.

[0028] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0029] If a substituent is described as “optionally substituted,” then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together with independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted with independently selected optional substituents.

[0030] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0031] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, or ten.

[0032] Unless otherwise specified, as used herein, the connection point of a substituent may be located at any suitable position of the substituent.

[0033] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0034] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this 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., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.)13 N and 15 Oxygen isotopes (e.g. 15 O, 17 O and 18 Phosphorus isotopes (e.g. 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically-labeled compounds of the application (for example, those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotopes tritium, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready detection. Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of the application can generally be prepared by carrying out the procedures disclosed in the d 6 or DMSO- d 6 .

[0035] The term "stereoisomers" denotes isomers having the same molecular formula but different structures, resulting from a difference in the arrangement of atoms or groups in space. In compounds with one or more asymmetric centers, racemates of the compounds, single enanti (or optical) isomers, and mixtures of enantiomeric or optical isomers can be present. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the application can exist as mixtures of two or more different structural forms in rapid equilibrium (often 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 the scope of the 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%).

[0036] A solid line ( ), a solid wedge ( ), or a dashed wedge ( ) depict carbon-carbon bonds of the compounds of the invention. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers (e.g., particular enantiomers, racemic mixtures, etc.) are included. The use of a solid or dashed wedge to depict a bond to an asymmetric carbon atom is intended to indicate that the depicted stereoisomer is present. When present in a racemic mixture, the solid and dashed wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise specified, the compounds of the invention are intended to exist in the form of stereoisomers, which include 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 invention can exhibit more than one type of isomerism, and consist of mixtures (e.g., racemic mixtures and diastereomeric pairs) thereof.

[0037] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which can be a single polymorph or a mixture of more than one polymorph in any ratio.

[0038] It is also to be understood that certain compounds of the invention can exist in free form for treatment, or as appropriate, in the form of a pharmaceutically acceptable derivative thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which, upon administration to a patient in need thereof, are capable of providing, directly or indirectly, a compound of the invention or a metabolite or residue thereof. Accordingly, as used herein, reference to a "compound of the invention" is intended to encompass also the various derivative forms of the compound.

[0039] Pharmaceutically acceptable salts of the compounds of the invention include both acid and base addition salts thereof.

[0040] Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include 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 other similar salts.

[0041] 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.

[0042] A review of suitable salts is available in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of the compounds of the present application are known to those skilled in the art.

[0043] As used herein, the term "ester" means an ester derived from the various generic compounds of the present application, which includes physiologically hydrolysable esters (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of a compound of the present application). The compounds of the present application can also be esters themselves.

[0044] The compounds of the present application can exist in solvate (preferably hydrate) form, wherein the compound of the present application contains a polar solvent, particularly, for example, water, methanol or ethanol, as a structural element of the crystal lattice of said compound. The amount of polar solvent, particularly water, can be present in stoichiometric or non-stoichiometric amounts.

[0045] Metabolites of the compounds of the present application, i.e., species derived from the compounds of the present application in vivo, are also within the scope of the present application. Such products can result, for example, from oxidation, reduction, hydrolysis, am idation, deam idation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the present application includes metabolites of compounds of the present application, whether produced by the mammal's own metabolism or by metabolism in a reconstituted system. Such intermediates as dehydrogenated, hydroxylated or other oxidized compounds, as well as other metabolites, are within the scope of the present application.

[0046] The present application further includes within its scope prodrugs of the compounds of the application, which are certain derivatives of the compounds of the application that possess little or no pharmacological activity themselves but, following administration, are converted into compounds of the application, which are pharmaceutically active, due to enzymatic or chemical processes. In general, such prodrugs will be preservatives of functional groups present in the compounds of the application, which readily undergo transformation under in vivo conditions to yield the desired compounds of the application. For additional information on prodrugs, see "Pro-drugs as Novel Delivery Systems", Vol. 14, of the A.C.S. Symposium Series (T. Higuchi and W. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association). Prodrugs of the application can be prepared using methods known to those of ordinary skill in the art, for example, by the replacement of appropriate functionalities present in the compounds of the application with certain moieties known to those skilled in the art as "pro-moieties" (for example, as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985).

[0047] The present application also encompasses compounds of the present application containing protecting groups. During any of the processes for preparation of the compounds of the present application, it can be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned, as well as to protect the compound of the present application itself, thus forming a chemically protected form of a compound of the present application. This can be achieved by means of conventional protecting groups, for example, 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, which are incorporated herein by reference. The protecting groups can be removed at a suitable subsequent stage using methods known from the art.

[0048] As used herein, the term "about" refers to ± 10% of the indicated value, preferably ± 5%, more preferably ± 2%.

[0049] Compounds In some embodiments, the present application 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): (I) wherein: Ring A is C 6-10 an aryl ring or a 5-14 membered heteroaryl 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 is each independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 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 , -O-C 1-6alkylene-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 group to which they are attached form a C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic ring, or 5-14 membered heteroaromatic ring; R 3 and R 4 each occurrence is independently selected from the group consisting of H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, and C 6-12 aralkyl; the above alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, hydrocarbon ring, heterocyclyl, heterocyclic ring, aryl, aromatic ring, heteroaryl, heteroaromatic ring, and aralkyl are each optionally substituted at each occurrence with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 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-NR5 R 6 , -O-C 1-6 alkylene-NR 5 R 6 and -C 1-6 alkylene-O-C 1-6 alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are further 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 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl; R 5 and R 6 are each independently at each occurrence selected from the group consisting of H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl; and n is an integer of 0, 1, 2, 3 or 4; with the proviso that when L 1 is a direct bond, ring A is not a phenyl ring.

[0050] In some embodiments, the present application 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 phenyl ring or a 5-6 membered heteroaromatic ring.

[0051] In some embodiments, the present application 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 phenyl ring, a pyrrole ring, a furan ring, a thiophene ring or a pyridine ring.

[0052] In some embodiments, the present application 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 is a direct bond or -O-C 1-6 alkylene-.

[0053] In some embodiments, the present application 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 1is a direct bond, -O-CH2-, or -O-CH2CH2-.

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

[0055] In some embodiments, the present application 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 halo, C 1-6 alkyl, C 6-10 aryl, or -C 1-6 alkylene-O-C 1-6 alkyl; or two R 1 together with the group to which they are attached form a C 6-10 aromatic ring, which is optionally further substituted with -OR 5 .

[0056] In some embodiments, the present application 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 with F, or -CH2-O-CH3; or two R 1 together with the group to which they are attached form a phenyl ring, which is optionally further substituted with methoxy.

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

[0058] The present application encompasses compounds resulting from any combination of the various embodiments.

[0059] In some embodiments, the compound of Formula (I) is not: and .

[0060] In some embodiments, the present application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound or prodrug thereof, wherein the compound is:

[0061] Methods of preparation In some embodiments, the present application provides a method of preparing a compound of Formula (I): wherein: LG is a leaving group, preferably a halogen, most preferably a chlorine; the remaining groups are as defined above; The method comprises reacting a compound of Formula (I)-a with a compound of Formula (I)-b to obtain a compound of Formula (I).

[0062] The reaction is preferably carried out in the presence of a base (e.g. an inorganic base such as 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, e.g. 25 °C.

[0063] Pharmaceutical compositions and methods of treatment In some embodiments, the present application provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound or prodrug thereof and one or more pharmaceutically acceptable carriers.

[0064] In some embodiments, the present application provides the use of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound or prodrug thereof or a pharmaceutical composition of the present application in the manufacture of a medicament for preventing or treating a neurodegenerative disease or alleviating the symptoms of a neurodegenerative disease.

[0065] In some embodiments, the present application provides a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound or prodrug thereof, or a pharmaceutical composition of the present application, for use in the prevention or treatment of a neurodegenerative disease or in the alleviation of symptoms of a neurodegenerative disease.

[0066] In some embodiments, the present application provides a method of preventing or treating a neurodegenerative disease or alleviating symptoms of a neurodegenerative disease, comprising administering to an individual in need thereof an effective amount of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound or prodrug thereof, or a pharmaceutical composition of the present application.

[0067] 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-Barre syndrome, Parkinson's disease, Lou Gehrig's disease, diseases caused by progressive nerve cell death leading to palsy and progressive ataxia; preferably Alzheimer's disease.

[0068] A "pharmaceutically acceptable carrier" in the present application refers to a diluent, adjuvant, excipient, or vehicle with which a therapeutic agent is administered, and which is physiologically tolerable and nontoxic to the recipient at the dosages and concentrations employed, and which is suitable for contact with the tissues of human and / or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio as defined in reasonable medical judgment.

[0069] Pharmaceutically acceptable carriers that can be employed in the pharmaceutical compositions of the present application include, but are not limited to, sterile aqueous, nonaqueous, and mixture of aqueous and nonaqueous solutions, suspensions, and emulsions, including those that are isotonic, preservative-free, and / or buffered. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils, such as peanut oil, cottonseed oil, sesame oil, and the like, and triglycerides; and injectable organic esters such as ethyl oleate. Examples of aqueous solvents are water, alcoholic / aqueous solutions, saline, Ringer's

[0070] The pharmaceutical compositions of the present application can act systemically and / or topically. To this end, they can be administered by suitable routes, for example by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including drip infusion) or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

[0071] For these administration routes, the pharmaceutical compositions of the present application can be administered in suitable dosage forms.

[0072] The 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, syrups.

[0073] The term "effective amount" as used herein refers to the amount of a compound that, when administered, will relieve to some extent one or more of the symptoms of the disorder being treated.

[0074] Dosage regimens can be adjusted to provide the optimum 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 exigencies 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. It is to be further noted that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the

[0075] The amount of a compound of the present application that is administered will depend on the subject to be treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the judgment of the prescribing physician. In general, an effective dosage in the range from about 0.0001 to about 50 mg per kg body weight per day, such as from about 0.01 to about 10 mg / kg / day (single or divided doses) is appropriate. For a 70 kg individual, this would amount to from about 0.007 mg / day to about 3500 mg / day, such as from about 0.7 mg / day to about 700 mg / day. In some instances, dosage levels less than the lower limit of the aforesaid range can be more than adequate, while in other cases still larger doses can be employed without causing any harmful side effects, provided that they are divided into several small doses for administration throughout the day.

[0076] The content or amount of a compound of the present application in a pharmaceutical composition can be from 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, such as 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.

[0077] Unless otherwise stated, as used herein, the term “treatment” means to reverse, alleviate, or inhibit the progression of a disease or condition or one or more symptoms of such a disease or condition to which such term is applied, or to prevent such a disease or condition or one or more symptoms of such a disease or condition.

[0078] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes 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.).

[0079] In another embodiment, the pharmaceutical composition of the present invention may also contain one or more additional therapeutic or preventative agents.

[0080] Example To make the objectives and technical solutions of this invention clearer, the embodiments of this invention are described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of this invention. Unless otherwise specified, specific conditions in the examples are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased from the market.

[0081] The structure of the compound was determined by nuclear magnetic resonance (NMR). 1 The NMR was determined by either 1H NMR or mass spectrometry (MS). NMR measurements were performed using a Bruker AVANCE-500 NMR spectrometer or a Varian-400MHz NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO) as the solvent. d 6 ), deuterated methanol (CD3OD), deuterated water (D2O), etc., with tetramethylsilane (TMS) as the internal standard, and chemical shift (δ) given in parts per million (ppm).

[0082] The instrument used for MS measurements was an Agilent (ESI) mass spectrometer (manufacturer: Agilent, model: Agilent 6110).

[0083] Methods for preparing high-performance liquid chromatography separation: Instrument model: Agilent P3500, Column: Welch Ultimate XB-C18 (30 x 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 in water.

[0084] The compounds synthesized in the following examples are in accordance with the molecular formula, and the compound names are generated by ChemBioDraw software.

[0085] 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) Phosphine thiamine (1a) (83% content, 20 g, 0.04 mol, 1.0 eq.) was dissolved in water (40 mL) and stirred to dissolve. A sodium hydroxide solution (30%) was added dropwise to adjust the pH to 10.5-11.0, and stirring was continued for 30 minutes while maintaining the system temperature at 25 °C. 2-Propylvaleryl chloride (1b) (0.07 mol, 1.75 eq.) diluted in tetrahydrofuran (20 mL) was added dropwise over 20 minutes, and stirring was continued for 10 minutes. The aqueous phase was adjusted to pH 1.5, and the system became turbid. Ethyl acetate (100 mL) was added dropwise slowly. White solids were precipitated, which were filtered and dried, then dissolved in water (100 mL). NaHCO3 (1.0 eq.) was added, and a small amount of gas bubbles were generated. The water was concentrated to dryness, DCM was added and stirred to dissolve, the salt was removed by filtration, and the filtrate was concentrated to obtain the title compound 1 (white solid).

[0086] MS m / z (ESI): 489 [M+1] 1 H NMR (400 MHz, DMSO- d 6): δ 7.90 (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). 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) The title compound 2 (white solid) was prepared using the same synthetic route as Example 1 except replacing 1b in Example 1 with 2-ethylbutyryl chloride.

[0087] MS m / z (ESI): 461 [M+1] 1 H NMR (400MHz, DMSO- d 6 ) δ 9.18 (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). Example 5: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5- yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl) O-phenethyl thiocarbonate (Compound 5) The title compound 5 (off-white solid) was prepared using the same synthetic route as Example 1 except replacing 1b in Example 1 with phenethyl chloroformate.

[0088] MS m / z (ESI): 511.1 [M+1] 1 H NMR (500 MHz, DMSO- d6 ) δ 7.84 (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). Example 6: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5- yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl) O-benzyl thiocarbonate (Compound 6) The title compound 6 (off-white solid) was prepared using the same synthetic route as in Example 1 except that 1b in Example 1 was replaced by benzyl chloroformate.

[0089] MS m / z (ESI): 497.1 [M+1] 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.84 (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). 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- thiocarbonate (Compound 7) The title compound 7 (white solid) was prepared using the same synthetic route as in Example 1 except that 1b in Example 1 was replaced by 5-chlorothiophene-2- carboxylic acid chloride.

[0090] MS m / z (ESI): 507 [M+1] 1 H NMR (500 MHz, DMSO- d 6) δ 7.95 (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). 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- thioformate (Compound 8) The title compound 8 (off-white solid) was prepared using the same synthetic route as in Example 1 except replacing 1b in Example 1 with 5-methoxybenzofuran-2- carboxylic acid chloride.

[0091] MS m / z (ESI): 537 [M+1] 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.95 (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). 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-thioformate (Compound 9) The title compound 9 (off-white solid) was prepared using the same synthetic route as in Example 1 except replacing 1b in Example 1 with furan-2-carboxylic acid chloride.

[0092] MS m / z (ESI): 456.9 [M+1] 1 H NMR (500 MHz, DMSO- d 6) δ 8.02 (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). 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-thioate (Compound 10) The title compound 10 (off-white solid) was prepared using the same synthetic route as in Example 1 except replacing 1b in Example 1 with 1H-pyrrole-2-carbonyl chloride.

[0093] MS m / z (ESI): 456.0 [M+1] 1 H NMR (500 MHz, DMSO- d 6 ) δ 12.12 (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). 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- thioate (Compound 11) The title compound 11 (off-white solid) was prepared using the same synthetic route as in Example 1 except replacing 1b in Example 1 with 5-(4-fluorophenyl)thiophene-2- carbonyl chloride.

[0094] MS m / z (ESI): 567 [M+1] 1 H NMR (500 MHz, DMSO- d 6) δ 7.92 (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). 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) The title compound 12 (off-white solid) was prepared using the same synthetic route as in Example 1 except replacing 1b in Example 1 with 5-(methoxymethyl)furan-2- carboxylic acid chloride.

[0095] MS m / z (ESI): 501.5 [M+1] 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.88 (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). 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) The title compound 13 (white solid) was prepared using the same synthetic route as in Example 1 except replacing 1b in Example 1 with benzofuran-2-carboxylic acid chloride.

[0096] MS m / z (ESI): 507 [M+1] 1 H NMR (500 MHz, DMSO- d 6) δ 7.98 (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). 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) The title compound 14 (white solid) was prepared using the same synthetic route as in Example 1 except replacing 1b in Example 1 with thiophene-2-formic acid chloride.

[0097] MS m / z (ESI): 473 [M+1] 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.08 (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). 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) The title compound 15 (off-white solid) was prepared using the same synthetic route as in Example 1 except replacing 1b in Example 1 with furan-3-formic acid chloride.

[0098] MS m / z (ESI): 457 [M+1] 1 H NMR (500 MHz, DMSO- d 6) δ 8.39 (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). 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-thioate (Compound 16) The title compound 16 (off-white solid) was prepared using the same synthetic route as in Example 1 except replacing 1b in Example 1 with 2-pyridinecarboxylic acid chloride.

[0099] MS m / z (ESI): 468.1 [M+1] 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.67 (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). 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- thioate (Compound 17) The title compound 17 (off-white solid) was prepared using the same synthetic route as in Example 1 except replacing 1b in Example 1 with 5-methylfuran-2- carboxylic acid chloride.

[0100] MS m / z (ESI): 471 [M+1] 1 H NMR (500 MHz, DMSO- d 6) δ 7.86 (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). 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) The title compound 18 (off-white solid) was prepared using the same synthetic route as in Example 1 except that 1b in Example 1 was replaced by 2,5-dimethylfuran-3- formyl chloride.

[0101] MS m / z (ESI): 485 [M+1] 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.94 (s, 1H), 7.84 (s, 1H), 6.17 (s, 1H),4.47 (s, 2H), 3.83 - 3.79 (m, 2H), 2.67 (s, 2H), 2.41 (s, 3H), 2.35 (s, 3H),2.22 (s, 3H), 2.17 (s, 3H). Biological tests Experimental Example 1 BCA protein concentration assay kit was purchased from Biyun Tian, Aβ40 and Aβ42 detection kit was purchased from Wako company, and cell culture related reagents were purchased from Gibco company.

[0102] HEK293APP / sw overexpressed cells were cultured in DMEM medium (containing 10% FBS, 100 μg / mL G418 (Geneticin) and double antibiotics (1x Penicillin, Streptomycin) in a 48-well plate. Take 4 mM compound stock solution (compound dissolved in DMEM medium to prepare), filter with 0.22 μm sterile filter and store at -20℃ for standby. When the cell density is 70%, add 40 μL of compound test solution to each well, the final concentration is 400 μM, and culture for 24 hours.

[0103] Take the culture supernatant, part of which is added to the BCA reagent, and after incubation at room temperature for 30 min, the absorbance value (i.e. OD value) of each well is measured at 570 nm on a microplate reader, and the total protein concentration is calculated according to the protein standard curve; at the same time, another part of the supernatant (100 μL) is added to the prepared 96-well plate and incubated at 4°C overnight, after removing the solution and washing the reagent, HRP (horseradish oxidase) labeled antibody is added, and incubated at 4°C for 2 hours, after removing and washing the reagent, TMB color developing solution is added, and after incubation at room temperature for 30 min, the reaction is terminated by adding a stop solution, the absorbance value (i.e. OD value) of each well is measured at 450 nm on a microplate reader, and the concentrations of Aβ40 and Aβ42 are calculated according to the standard curves of Aβ40 and Aβ42 respectively, and finally the total protein concentration is used to adjust the concentrations of Aβ40 and Aβ42 to obtain the final concentrations. The test results are shown in the following table.

[0104] *No compound test solution is added in the blank control.

[0105] From the above experimental results, it can be seen that the compound of the present application can significantly reduce the level of Aβ42 or / and Aβ40.

[0106] Experimental Example 2. Acute toxicity experiment 2.1. Purpose of the experiment To observe the poisoning reaction and death of mice after intragastric administration of the test compound, and to preliminarily evaluate the safety of the test compound.

[0107] 2.2. Experimental method 2.2.1. Experimental materials CMC-Na (sodium carboxymethylcellulose), purchased from Shanghai Reagent Co., Ltd.

[0108] The experimental animals are Kunming mice, 18-20 g, provided by Beijing Kaohe Cooperation Feed Co., Ltd.

[0109] 2.2.2. Experimental steps 1) Preparation of 0.7% CMC-Na: Take 0.7 g of CMC-Na and prepare a solution of 0.7 g / 100 mL with distilled water.

[0110] 2) Take the test compound, add 0.7% CMC-Na to prepare a suspension of 100 mg / mL.

[0111] 3) Each test group contains 10 mice, all male, each mouse orally gavaged with the test compound (2000 mg / kg), once a day, for a cumulative of 15 days. The following reactions of the animals can be observed after administration: animal diet, appearance, behavior, secretions, excretions, symptoms of abnormal reactions of animals, onset time, severity, duration, reversibility, and animal death. The body weight of the mice on the day of administration, the 7th day, and the 14th day is recorded.

[0112] 2.3. Experimental results

[0113] 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.

[0114] Experimental Example 3. Water maze behavior experiment 3.1. Experimental principle Rodents have a strong motivation to escape from water environment, and can escape from water environment in the fastest and most direct way. The process of learning to escape from water environment reflects the learning ability of animals, and the spatial positioning according to the surrounding environment and the purposeful swimming to the safe place (such as platform) can reflect the spatial learning and memory ability of animals.

[0115] 3.2. Experimental method 3.2.1. Experimental materials 1) Experimental animals The experimental animals were APP / PS1 2×Tg mice (the blank control group was C57BL / 6 wild-type mice). The mice were 6-8 months old, weighing 20-40 g, and purchased from The Jackson laboratory.

[0116] The APP / PS1 mice were APP / PS1 double transgenic Alzheimer's disease (2×Tg⁃AD) model mice, which showed Aβ deposition earlier than tau protein pathological changes for several months, and could more truly simulate the clinical process and pathological changes of Alzheimer's disease.

[0117] 2) Main reagents CMC-Na (sodium carboxymethyl cellulose), purchased from Shanghai Reagent Company Limited of China National Pharmaceutical Group Corporation; Positive control: BTMP (benfoflumine), self-made by Shanghai Rixin Biological Technology Co., Ltd.

[0118] Reference compound 1: , prepared according to the method of Example 6 in CN201811435584.X.

[0119] 3) Main equipment

[0120] 3.2.2. Experimental method 1) Drug preparation and administration information 1.1. Drug preparation Preparation of 0.7% CMC-Na: Take 0.7 g of CMC-Na and add an appropriate amount of water, heat to dissolve, and let it cool to room temperature to 100 mL, and store at 4°C.

[0121] Preparation of BTMP: Add 100 mg of BTMP to 10 mL of 0.7% CMC-Na to prepare a 10 mg / mL suspension for use.

[0122] Preparation of test sample and reference compound 1: Take 100 mg of the test compound and add it to 10 mL of 0.7% CMC-Na to prepare a 10 mg / mL suspension for use.

[0123] 1.2. Administration information Randomly divide the experimental mice into groups (9 or 10 per group), and administer each group of mice orally at a dose of 0.2 mL / 10 g of body weight once a day for 8 consecutive weeks.

[0124] 2) Experimental procedure The blank control group, model group, and experimental group mice were administered orally at the above-mentioned dose / specification for 8 consecutive weeks, and the last week of administration began the water maze training and testing. The water maze training and testing lasted for 6 days, with 5 days of training and 1 day of testing. In addition, during the water maze training and testing period (a total of 6 days), the indoor light and other conditions were kept consistent, the indoor was kept quiet, and environmental and personnel interference was excluded.

[0125] 2.1. Pre-experiment preparation: Fill the water maze pool with an appropriate amount of water, keep the water temperature at 22±3°C, place the platform at a fixed position (target quadrant) and 1 cm below the water surface, and add titanium dioxide to make the water color white, so that the platform cannot be seen.

[0126] 2.2. Training period (days 1-5): Before training in the first quadrant each day, place each mouse on the platform for 15 seconds (to increase the mouse's sense of safety on the platform), then place the mouse in the pool from the quadrant where the platform is located (head facing the pool wall), and set the swimming time to 60 seconds. If the mouse finds the platform within 60 seconds and stays for 5 seconds, it is considered to have successfully found the platform. If the mouse fails to find the platform, record the time as 60 seconds, guide the mouse to the platform and let it stay for 20 seconds, then take the mouse out and end the training for this mouse in this quadrant.

[0127] After the first quadrant training, the remaining three quadrants were trained in turn, and the mice did not need to be placed on the platform for 15 s in advance. The training time interval of each mouse was 10-15 minutes. In this way, the mice were trained for 5 consecutive days.

[0128] 2.3. Test period (6th day): 24 hours after the last training, the platform was removed, and the mice were dropped in the position opposite to the original platform quadrant (i.e., the position farthest from the platform). The time of the mice in the target quadrant (the quadrant where the platform was originally located), the number of times of crossing the original platform position (crossing the platform), and the time of first crossing the original platform position (latency) were recorded, which were used as the evaluation index of the spatial learning and memory ability of the mice.

[0129] Note: compared with the blank control group, **P<0.01, *P<0.05; compared with the model group ## P<0.01, # P<0.05.

[0130] As can be seen from the experimental results, 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 s) was basically equivalent to the latency of the animals in the blank control group (21.8±3.3 s), and was much smaller than the latency of the animals in the test group administered with BTMP or Reference Compound 1 (27.3±1.6 s and 27.0±1.3 s, respectively). This effect achieved by the compound of the present application was unexpected.

[0131] Experimental Example 4. Step-down test 1.1. Experimental animals and reagents In this experiment, the mice were purchased from Supor-Bikai Experimental Animal Co., Ltd., ICR animals, SPF level, 3-4 weeks old, 16-18 g.

[0132] Scopolamine hydrobromide trihydrate, source: aladdin; product number: S107418; purity: 98%.

[0133] Sodium nitrite (NaNO2), source: National Pharmaceutical Group Chemical Reagent Co., Ltd.; product number: 10020018; specification: analytical pure.

[0134] 1.2. Drug configuration and administration information 1) Drug configuration 0.7% CMC-Na preparation: weigh 0.7 g of CMC-Na, add an appropriate amount of purified water, heat to dissolve, and let it cool to room temperature to 100 mL, and store at 4°C.

[0135] Preparation of test sample: 100 mg of the test compound was weighed and dissolved in 10 mL of 0.7% CMC-Na to prepare a 10 mg / mL suspension for use.

[0136] 2) Dosing information The experimental mice were randomly divided into groups (9 or 10 mice per group), and the mice in each group were orally administered at a dose of 0.2 mL / 10 g of body weight once a day for 3 consecutive weeks.

[0137] 1.3. Experimental procedure The experimental animals were orally administered at the specified dose / size for 3 consecutive weeks, and training was started on the last day of administration, and testing was performed 24 hours later.

[0138] 1) Scopolamine-induced acute memory dysfunction model The experimental animals were orally administered for 3 weeks, and 0.5 hours after the last administration, scopolamine (mice: 2 mg / kg) was injected intraperitoneally. The animals were trained using a YLS-3TB type jump platform recorder, and the memory acquisition function of the animals was tested 24 hours later. The latency (time from the start of the count to the first jump off the platform) and the number of errors (number of shocks) were recorded.

[0139] 2) Sodium nitrite-induced anoxic memory dysfunction model The experimental animals were orally administered for 3 weeks, and 1 hour after the last administration, the animals were trained using a YLS-3TB type jump platform recorder, and immediately after training, sodium nitrite (mice: 120 mg / kg) was injected subcutaneously (neck). The jump platform test was performed 24 hours later. The latency (time from the start of the count to the first jump off the platform) and the number of errors (number of shocks) were recorded.

[0140] 1.4. Behavioral detection of jump platform experiment The YLS-3TB type jump platform recorder was separated into 5 chambers by a transparent plate, and the bottom was a copper grid with a voltage of 50 V. Each chamber had a rubber pad platform with a height of 3.5 cm and a diameter of 3.5 cm, serving as a safe area for mice to avoid electric shock. Before the formal experiment, the experimental mice were trained: the experimental mice were placed in the jump platform chamber to familiarize themselves with the environment for 5 min (5 chambers connected), and then stimulated by electricity (at this time, the experimental mice were all moving on the electric grid), with a voltage of 50 V and a current of 1.00 mA. Mice have the habit of jumping from a high place, and if they jump down, they will be shocked to produce memory. The electricity was turned on for 5 min, which was the training process.

[0141] Test: Animals were put on the platform of the jump box chamber in turn, and each animal was put in for 5 s. The first animal was put on the platform immediately after the power was turned on. The total power-on time was set to 6 min. After the power was turned off, the data was printed, and 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 times of electric shock during the test period) were recorded. Due to the different time of animal release, the actual release time can be used to subtract the time difference.

[0142] Results of the jump test of the scopolamine-induced acute memory dysfunction model

[0143] Note: **P <0.01, *P <0.05 compared with the blank control group; P <0.01, *P <0.05 compared with the AD model group ## P <0.01, # P <0.05.

[0144] Results of the jump test of the sodium nitrite-induced hypoxic memory dysfunction model

[0145] Note: **P <0.01, *P <0.05 compared with the blank control group; P <0.01, *P <0.05 compared with the AD model group ## P <0.01, # P <0.05.

[0146] Example 5. Behavior detection by dark avoidance test 1. Experimental materials 1.1. Experimental animals and reagents The mice used in this experiment were purchased from Xipu-Bikai Experimental Animal Co., Ltd. and were ICR animals, SPF level, 3-4 weeks old, and 16-18 g.

[0147] Anhydrous ethanol: source: Shanghai Titan Science and Technology Co., Ltd.; product number: G73537B; purity: ≥99.7%.

[0148] 1.2. Drug preparation and administration information 1) Drug preparation Preparation of 0.7% CMC-Na: weigh 0.7 g of CMC-Na, add an appropriate amount of purified water, heat to dissolve, and let it cool to room temperature to 100 mL, and store at 4°C.

[0149] Preparation of test sample: weigh 100 mg of the compound to be tested, and add 10 mL of 0.7% CMC-Na to prepare a 10 mg / mL suspension for use.

[0150] 2) Administration information The experimental mice were randomly divided into groups (9 or 10 per group), and each group of mice was orally administered at a dose of 0.2 mL / 10 g of body weight once a day for 3 consecutive weeks.

[0151] 2. Ethanol-induced animal model of memory reactivation disorder The experimental animals were orally administered for 3 weeks, and 1 hour after the last administration, the animals were trained using a YLS-17B dark avoidance tester, and tested 24 hours later. Thirty minutes before testing, the animals were orally administered a 45% ethanol solution (0.1 mL / 10 g). The latency period (time from the start of the test to the first entry into the dark chamber) and the number of errors (number of electric shocks) were recorded.

[0152] The activity box of the dark avoidance automatic tester has a clear and dark chamber, with a hole between the two chambers, and the bottom of the box is connected to a copper grid, and the animal generally enters 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, and were familiar with the environment for 5 minutes, and then the copper grid of the dark chamber was electrified to stimulate the animals, with a voltage of 50 V and a current of 1.00 mA (which can be adjusted according to actual conditions). The animals were shocked and entered the light chamber, or tried to explore between the two chambers. The electricity was turned on for 5 minutes, which was the training process.

[0153] Testing: The ethanol-induced animal model mice were placed in the light chamber one by one with their backs facing the hole, with a time interval of 5 seconds for each animal. The first animal was placed in the light chamber immediately after the electricity was turned on. The total electricity duration was set to 6 minutes. After the electricity was turned off, the data was printed and the latency period (time from the start of the test to the first entry into the dark chamber) and the number of errors (number of electric shocks during the test period) were recorded. Due to the different times of animal release, the time difference can be subtracted according to the actual release time. If the experimental mice still did not enter the dark chamber within 5 minutes, their latency period was recorded as 300 seconds.

[0154] Statistical analysis: All data were expressed as mean ± standard deviation and analyzed using SPSS software.

[0155] Results of the dark avoidance experiment of the ethanol-induced animal model of memory reactivation disorder

[0156] Note: **P<0.01, *P<0.05 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] Example 6: Pharmacokinetic study 1.1 Experimental animals and reagents The SD rats used in this experiment were purchased from Zhejiang Weitong Lihua Experimental Animal Co., Ltd., and were of both sexes, SPF level, and about 250 g.

[0158] Sodium carboxymethylcellulose (CMC-Na), source: National Pharmaceutical Group Chemical Reagent Co., Ltd.; product number: 20160704.

[0159] BTMP, self-made by Shanghai Rixin Pharmaceutical Technology Co., Ltd.

[0160] Reference compound 2, , prepared according to the method described in Example 13 of CN201811435584.X.

[0161] 1.2 Drug configuration 0.7% CMC-Na configuration: about 7 g of CMC-Na was accurately weighed into a 1 L beaker, a magnetic stirrer was added into the beaker, 1 L of purified water was added, and stirring was performed to obtain a clear and transparent solution.

[0162] Test sample configuration: an appropriate amount of test sample was weighed into a mortar, ground into fine powder, and then added into a suitable container with a certain amount of solvent. The ground test sample was added into the container under magnetic stirring until the appearance was uniform. The remaining solvent was gradually added, and then magnetic stirring was performed for at least 20 min to configure a 15.353 mM drug solution.

[0163] 1.3 Experimental procedure (1) Absorption test SD rats were divided into 3 groups, 6 rats in each group, half male and half female. Each group of animals was given a single 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 (about 200 µL / time) was collected before administration (0 min) and at 3 min, 8 min, 15 min, 30 min, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 24 h, 48 h after administration. The blood was anticoagulated with EDTA and placed on ice after collection. For each time point, 150 µL of whole blood was taken and added to 150 µL of 5.2% perchloric acid to determine TM (thiamine) and TDP (thiamine diphosphate) (TM and TDP are in vivo metabolites generated after administration of compound 1, BTMP and reference compound 2). All samples were frozen at -80°C.

[0164] (2) Brain distribution test Male SD rats were randomly divided into three groups of 16 rats each (four animals were sacrificed at each of the four time points). Each group was administered 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) by gavage once. Animals were sacrificed at 5 min, 1 h, 3 h, and 9 h after administration. Immediately after sacrifice, the brain was harvested, rinsed with ice-cold water, and dried. 50 mg of brain tissue was weighed and homogenized in 0.45 mL of 100 mM dipotassium hydrogen phosphate (pH=5.0) buffer. Blood was collected simultaneously, anticoagulated with EDTA, and placed on ice. 150 µL of whole blood was added to 150 µL of 5.2% perchloric acid for TM determination. Four additional animals were administered physiological saline by gavage for determining endogenous TM concentration. All samples were frozen at -80°C.

[0165] (3) Sample determination The concentrations of TM and TDP in the sample were determined by HPLC-FLD method.

[0166] (4) Data processing The pharmacokinetic parameters of TM and TDP in rat blood after drug administration were calculated using a non-compartmental model in DAS software. The concentration of TM in rat brain tissue after drug administration was measured, and the mean and standard deviation were calculated. The area under the curve (AUC) was calculated using the trapezoidal method.

[0167] 1.4 Experimental Results 1.4.1 Blood drug concentration and pharmacokinetic parameters in rats during absorption assay Table 1 summarizes the pharmacokinetic parameters of rats after a single oral gavage administration of compound 1, BTMP, and reference compound 2.

[0168] Table 1. Pharmacokinetic parameters of rats after oral administration (calculated after subtracting the concentration at time zero, Mean ± SD, n=6)

[0169] The experimental results above show that, at the same dosage, the exposure levels of TM and TDP in the compound 1 group were higher than those in the BTMP and reference compound 2 groups, and for TDP, the t... 1 / 2 In contrast, the t in the compound 1 administration group 1 / 2 The t values ​​were significantly higher than those in the BTMP or reference compound 2 treatment group. 1 / 2 .

[0170] 1.4.2 Concentration changes in rat brain and whole blood at different times during brain distribution test The TM concentrations in brain and whole blood of rats at different times after single gavage administration of compound 1, BTMP, reference compound 2 are shown in Table 2.

[0171] Table 2 TM concentrations in brain and whole blood of rats after gavage administration (Mean ± SD, n=4)

[0172] Based on the above data, it can be calculated that after gavage administration of compound 1, BTMP, reference compound 2 to rats, the AUC of TM in the brain (calculated after deducting the concentration at zero time) is 1156.6 ng·h / g, 739.9 ng·h / g and 555.9 ng·h / g, respectively. The TM AUC of the compound 1 administration group is 1.56 times and 2.08 times that of the BTMP and reference compound 2 administration groups, respectively.

[0173] Various modifications to the application will be apparent to those skilled in the art from the foregoing description, which is intended to be illustrative only. Such modifications are intended to fall within the scope of the appended claims. Each of the references cited herein, including all patents, patent applications, journal articles, books, and any other publications, are incorporated herein in their entireties by this reference.

Claims

1. 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): ###0001### wherein: n is an integer of 0, 1, 2, 3 or 4; R1 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -ORa, -NRaRb, -C(O)Rc, -C(O)ORd, -C(O)NRcRd, -CN, -NO2, -S(O)2Rd, -S(O)2NRcRd, -NRcS(O)2Rd, -N=C(Rc)2, -N=C(Rc)ORd, -N=C(Rc)NRcRd, -N=S(Rc)2, -N=S(Rc)ORd, -N=S(Rc)NRcRd, -C=N(Rc), -C=NORd, -C=NRcRd, -C=O, -C=S, -C=CRcRd, -C=CRcORd, -C=CRcNRcRd, -C=OORd, -C=ONRcRd, -C=OS(Rc)2, -C=OS(Rc)ORd, -C=OS(Rc)NRcRd, -C=S(Rc)2, -C=S(Rc)ORd, -C=S(Rc)NRcRd, -C=OORd, -C=ONRcRd, -C=S=O, -C=OORd, -C=ONRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S=O(Rc)ORd, -C=S=O(Rc)NRcRd, -C=S=OORd, -C=S=ONRcRd, -C=S=O(Rc)2, -C=S= ， (I) ​ Ring A is C 6-10 an aromatic or 5-14 membered heteroaromatic ring; L 1 is directly bonded or -R 2 -C 1-6 alkylene-; R 2 is -O-, -NH-, -S-, -S(=O)- or -S(=O)2-; R 1 at each occurrence is selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 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 , -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 group to which they are attached form a C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic ring, or 5-14 membered heteroaromatic ring; R 3 and R 4 are each independently at each occurrence selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, and C 6-12 aralkyl; The aforementioned alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkyl, heterocyclic, heterocyclic, aryl, aromatic, heteroaryl, heteroaromatic, and aralkyl groups are each optionally substituted by one or more substituents independently selected from the following: halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl group, =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 groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are further optionally substituted by one or more substituents independently selected from: halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl groups; R 5 and R 6 each independently at each occurrence is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, and C 6-12 aralkyl; and ​ provided that when L 1 is a direct bond, ring A is not a phenyl ring. ​ ​ 4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound, or prodrug thereof, wherein L 1 is a direct bond or -O-C 1-6 alkylene-.

5. The compound of claim 4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound, or prodrug thereof, wherein L 1 is a direct bond, -O-CH2-, or -O-CH2CH2-.

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

7. The compound of claim 6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound, or prodrug thereof, wherein R 1 is -CI, methyl, phenyl optionally substituted with F, or -CH2-O-CH3; or two R 1 together with the group to which they are attached form a phenyl ring, which is optionally further substituted with methoxy.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound, or prodrug thereof, wherein is , , , , , , , , , , , , or . ​ 。 ​ ​ ​ ​ ； ​ ​ ​ ​

Images