Pyrimidine compounds, pharmaceutical compositions comprising the same, processes for their preparation and uses thereof

Abstract

The present invention relates to compounds of Formula (I), pharmaceutical compositions comprising the same, processes for their preparation and their use for the treatment of neurodegenerative diseases.

Description

Technical Field

[0001] This invention relates to pyrimidine compounds, pharmaceutical compositions comprising the same, methods for their preparation, and their use in the treatment of neurodegenerative diseases. Background Technology

[0002] Alzheimer's disease (AD), commonly known as senile dementia, is a progressive neurodegenerative disease characterized by cognitive and behavioral impairments. It is the most common form of dementia in the elderly, primarily manifesting as impaired cognitive abilities and rapid decline in memory. Its main pathophysiological features include the deposition of β-amyloid (Aβ) protein in the brain, forming senile plaques; hyperphosphorylation of tau protein, forming neurofibrillary tangles; impaired brain glucose metabolism; and loss of neurons / synapses. Due to its long course and poor self-care ability, AD places a severe emotional and economic burden on families and society. However, currently, there are no drugs worldwide that can stop or slow the progression of the disease. Currently available AD medications are only symptomatic treatments, capable of controlling or improving cognitive and functional symptoms for a period of time, but cannot stop or delay the deterioration of the disease. Summary of the Invention

[0003] This invention provides pyrimidine compounds that can be used for the prevention or treatment of neurodegenerative diseases. Furthermore, the compounds of this invention possess superior properties such as better physicochemical properties (e.g., solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, suitable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and / or fewer side effects), and less likelihood of developing 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] R is selected from H, halogen, hydroxyl, 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 groups, -C(=NH)NH2, -C(=O)R 3 -OC(=O)R3 -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 and -OC 1-6 Alkylene-NR 3 R 4 ;

[0008] L 1 and L 2 Each is independently selected from direct bonds, C 1-6 Alkylene and C 2-6 alkenyl;

[0009] R 1 and R 2 Each is independently selected from H, 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 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 -NR3 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 and -OC 1-6 Alkylene-NR 3 R 4 ;

[0010] R 3 and R 4 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl groups;

[0011] The aforementioned alkyl, alkylene, alkenyl, alkenylene, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, 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 -NR5 -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 and -OC 1-6 Alkylene-NR 5 R 6 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are further optionally substituted by one or more substituents independently selected from the following: 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;

[0012] R 5 and R 6 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl groups; and

[0013] The condition is when -L 2 -R 2 Together they constitute C 1-6 When alkyl, -L 1 -R 1 It is not an unsubstituted phenyl group; and

[0014] When -L 2 -R 2 Together they form -(CH2)2-OC(=O)-(C 1-7 When alkyl), -L 1 -R 1 It is not an unsubstituted phenyl group or an unsubstituted furanyl group.

[0015] Another aspect of the invention provides a pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug, and one or more pharmaceutically acceptable carriers.

[0016] Another aspect of the invention provides the use of the compounds of the invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs, or pharmaceutical compositions of the invention, in the preparation of medicaments for the prevention or treatment of neurodegenerative diseases or for the relief of symptoms of neurodegenerative diseases.

[0017] Another aspect of the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs of the present invention, or pharmaceutical compositions of the present invention, for the prevention or treatment of neurodegenerative diseases or the relief of symptoms of neurodegenerative diseases.

[0018] Another aspect of the present invention provides a method for preventing or treating neurodegenerative diseases or alleviating the symptoms of neurodegenerative diseases, the method comprising administering to an individual in need an effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug or pharmaceutical composition of the present invention.

[0019] Another aspect of the present invention provides a method for preparing the compounds of the present invention. Detailed Implementation

[0020] definition

[0021] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0022] The terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0023] As used herein, the term "alkylene" means 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.

[0024] As used herein, the term "alkyl" is defined as a straight-chain or branched 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" is used to refer to... 1-6 "Alkyl" refers to a linear or branched group with 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl), optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogens (in which case the group is called "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 with 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0025] As used herein, the term "alkenyl" refers to a divalent hydrocarbon group containing one or more double bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as vinylene, propenylene or allylene.

[0026] As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing a double bond and having 2–6 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.

[0027] When the compounds of the present invention contain an alkenyl group or an alkenyl group, the compounds may exist in pure E (iso-side) form, pure Z (iso-side) form, or any mixture thereof.

[0028] 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.

[0029] As used herein, the terms “cycloalkylene group,” “cycloalkylene group,” and “hydrocarbon ring” refer to a saturated (i.e., “cycloalkylene group” and “cycloalkylene group”) or unsaturated (i.e., having one or more double and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring having, for example, 3 to 10 (suitably 3 to 8, more preferably 3 to 6) cyclic carbon atoms, including but not limited to (cycloalkylene group) propyl(ring), (cycloalkylene group) butyl(ring), (cycloalkylene group) pentyl(ring), (cycloalkylene group) hexyl(ring), (cycloalkylene group) heptyl(ring), (cycloalkylene group) octyl(ring), (cycloalkylene group) nonyl(ring), (cycloalkylene group) hexenyl(ring), etc.

[0030] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated nonaromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems (such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.), 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 (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) with 3 to 6 cyclic carbon atoms, which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0031] As used herein, the term "heterocyclic group" refers to a saturated or unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring and one or more (e.g., one, two, three, or four) atoms selected from C(=O), O, S, S(=O), S(=O)2, and NR. a Groups containing heteroatoms, wherein R a Represents a hydrogen atom or C 1-6 Alkyl or halogenated -C 1-6 Alkyl group; the heterocyclic alkyl group may be attached to the remainder of the molecule by any one of the carbon atoms or a nitrogen atom (if present). In particular, a 3-10 membered heterocyclic group is a group having 3-10 carbon atoms and heteroatoms in the ring, such as, but not limited to, ethylene oxide, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolyl, pyrrolidone, imidazoalkyl, pyrazolyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazine, or trithianyl.

[0032] As used herein, the term "aryl" refers to a fully carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, the term "C 6-14 "Aryl" refers to an aromatic group containing 6 to 14 carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituented by one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C). 1-6 Alkyl groups, etc., are substituted.

[0033] The term "aralkyl" preferably refers to an aryl-substituted alkyl group, wherein the aryl group and the alkyl group are as defined herein. Typically, the aryl group may have 6-14 carbon atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0034] As used herein, the term "heteroaryl" refers to a monovalent monocyclic, bicyclic, or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and containing at least one heteroatom that may be the same or different (the heteroatom being, for example, oxygen, nitrogen, or sulfur), and additionally, in each case, may be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, etc., and their benzo[derivatives]; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo[derivatives].

[0035] As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br, or I.

[0036] As used herein, the term "alkylthio" refers to an alkyl group as defined above, which is attached to a portion of the parent molecule via a sulfur atom. C 1-6 Representative examples of alkyl thio groups include, but are not limited to, methyl thio, ethyl thio, tert-butyl thio, and hexyl thio.

[0037] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least one nitrogen atom in the ring, and optionally may also 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)2; said nitrogen-containing heterocycle is connected to the remainder of the molecule by a nitrogen atom. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring. Specifically, 3- to 14-membered nitrogen-containing heterocycles are groups having 3 to 14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to ternary nitrogen-containing heterocycles (such as aziridinyl), quaternary nitrogen-containing heterocycles (such as aziridine), pentazolidinyl, pyrrolinyl, pyrrolidone, imidazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolin ...

[0038] 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.

[0039] 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.

[0040] 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.

[0041] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, or ten.

[0042] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0043] 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.

[0044] 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 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g., ... 35 S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0045] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer 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-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0046] Solid lines may be used in this article. solid wedge Or virtual wedge The carbon-carbon bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom. Solid or imaginary wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and imaginary wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, 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, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0047] This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0048] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. 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, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0049] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.

[0050] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate / carbonate, bisulfate / sulfate, fumarate, glucohepanoate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodate / iodide, maleate, malonate, methyl sulfate, naphthylcarbamate, nicotinate, nitrate, orotate, oxalate, palmitate, and other similar salts.

[0051] Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, diethylamine salts, lysine salts, magnesium salts, meglumine salts, potassium salts, and other similar salts.

[0052] For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts for the compounds of the present invention are known to those skilled in the art.

[0053] As used herein, the term "ester" means an ester derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (the compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves also be esters.

[0054] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0055] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0056] This invention further includes, within its scope, prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity, which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that readily convert in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987 (EB Roche, editor, American Pharmaceutical Association). The prodrugs of the invention can be prepared, for example, by replacing suitable functional groups present in the compounds of the invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0057] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by 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.W. Uts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0058] As used herein, the term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0059] compound

[0060] 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):

[0061]

[0062] in

[0063] R is selected from H, halogen, hydroxyl, 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 groups, -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 and -OC 1-6 Alkylene-NR 3 R 4 ;

[0064] L 1 and L 2 Each is independently selected from direct bonds, C 1-6 Alkylene and C 2-6 alkenyl;

[0065] R 1 and R 2Each is independently selected from H, 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 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 and -OC 1-6 Alkylene-NR 3 R 4 ;

[0066] R 3 and R 4 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl groups;

[0067] The aforementioned alkyl, alkylene, alkenyl, alkenylene, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, 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, C2-6 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 and -OC 1-6 Alkylene-NR 5 R 6 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are further optionally substituted by one or more substituents independently selected from the following: 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;

[0068] R 5 and R 6 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl groups; and

[0069] The condition is when -L 2 -R2 Together they constitute C 1-6 When alkyl, -L 1 -R 1 It is not an unsubstituted phenyl group; and

[0070] When -L 2 -R 2 Together they form -(CH2)2-OC(=O)-(C 1-7 When alkyl), -L 1 -R 1 It is not an unsubstituted phenyl group or an unsubstituted furanyl group.

[0071] In some implementations, R is selected from C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-14 heteroaryl groups; preferably, R is cyclobutyl, cyclohexyl, phenyl, thiophene, or pyridyl.

[0072] 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 C 2-6 Alkenyl group.

[0073] In some implementations, L 1 It is a direct bond or a vinylidene bond.

[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 R 1 Selected from C 3-6 Cyclic hydrocarbon group, C 6-10 Aryl and 5-14 heteroaryl groups, optionally composed of one or more independently selected from halogens and -O-(C 1-6 Alkyl groups are substituted.

[0075] In some implementation schemes, R 1 It is selected from cyclohexyl, phenyl and furanyl, and is optionally substituted by one or more substituents independently selected from F, Cl, Br, I and -OCH3.

[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 -R 1 Selected from

[0077]

[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 L 2 For direct keys, C 1-4 Alkylene or C 2-4 Alkenyl group.

[0079] In some implementations, L 2 It is a direct bond, methylene, ethylene, or vinylene.

[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

[0081] R 2 Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, 3-10 membered heterocyclic, -C(=O)R 3 -OC(=O)R 3 -OR 3 -SR 3 -NR 3 -C(=O)R 4 -NR 3 -S(=O)2-R 4 -NR 3 R 4 -C(=O)NR 3 R 4 and -C(=O)OR 3 ;where R 3 and R 4 Each is independently selected from H and C. 1-6 Alkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and C 6-12 Aryl group, preferably, R 3 and R 4 Each is independently selected from H, methyl, ethyl, morpholino, phenyl (Ph), and benzyl (Bn).

[0082] In some implementation schemes, R 2The following are the possible values ​​for H, F, Cl, hydroxyl, methyl, ethyl, vinyl, -CH2CH2F, -CH2CH2Cl, -OC(=O)CH3, -OC(=O)Ph, -SCH3, -OCH3, -OCH2CH3, -OBn, -NHC(=O)CH3, -NHS(=O)2CH3, -N(CH3)Ph, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)OH, -C(=O)OCH2CH3.

[0083] 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 2 -R 2 Selected from methyl, ethyl, vinyl,

[0084] 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 the compound has the structure of formula (II) or (III):

[0085]

[0086] 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

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094] Preparation method

[0095] In some embodiments, the present invention provides a method for preparing a compound of formula (I):

[0096]

[0097] in:

[0098] Hal 1 and Hal 2 Each is independently selected from F, Cl, Br, and I;

[0099] The remaining groups are as defined above;

[0100] The method includes the following steps:

[0101] Step (I): React a compound of formula (I)-a or a salt thereof with a compound of formula (I)-b to obtain a compound of formula (I)-c.

[0102] The reaction solvent in step (I) is preferably an amide solvent (e.g., DMF), a nitrile solvent (e.g., acetonitrile), an aromatic hydrocarbon solvent (e.g., toluene or chlorobenzene), an ether solvent (e.g., dioxane), N-methylpyrrolidone, or a mixture thereof. The reaction temperature in step (I) is, for example, 80-150°C, preferably 100-110°C.

[0103] Step (II): React the compound of formula (I)-c with the compound of formula (I)-d to obtain the compound of formula (I).

[0104] The reaction in step (II) is preferably carried out in the presence of a base (e.g., an inorganic base such as sodium hydroxide or an organic base). The reaction solvent in step (II) is preferably water, dichloromethane, THF, or a mixture thereof. The reaction temperature in step (II) is preferably 0-50°C, for example, 10°C.

[0105] Pharmaceutical compositions and treatment methods

[0106] In some embodiments, the present invention provides pharmaceutical compositions comprising a preventive or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug, and one or more pharmaceutically acceptable carriers.

[0107] In some embodiments, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs, or pharmaceutical compositions of the present invention, in the preparation of medicaments for the prevention or treatment of neurodegenerative diseases or for the relief of symptoms of neurodegenerative diseases.

[0108] In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs of the present invention, or pharmaceutical compositions of the present invention, for the prevention or treatment of neurodegenerative diseases or the relief of symptoms of neurodegenerative diseases.

[0109] In some embodiments, the present invention provides a method for preventing or treating neurodegenerative diseases or alleviating symptoms of neurodegenerative diseases, the method comprising administering to an individual in need 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 or pharmaceutical composition of the present invention.

[0110] 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, Loggehrig's disease, and diseases caused by paralytic dementia and progressive dysfunction resulting from gradual neuronal death; preferably Alzheimer's disease.

[0111] In this invention, "pharmaceutically acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0112] 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, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The compositions may also contain small amounts of wetting agents, emulsifiers, or pH buffers as needed. Oral formulations may contain standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0113] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered via suitable routes, such as by injection (e.g., intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including infusion) or transdermal administration; or by oral, sublingual, nasal, transmucosal, topical, ophthalmic formulations or by inhalation.

[0114] For these routes of administration, the pharmaceutical compositions of the present invention can be administered in suitable dosage forms.

[0115] 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, and syrups.

[0116] As used in this article, the term "effective amount" refers to the amount of a compound that, when administered, will alleviate one or more symptoms of the treated condition to some extent.

[0117] The dosing regimen can be adjusted to provide the optimal required response. For example, a single bolus injection can be administered, several fractions can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. To further understand, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising its administration.

[0118] The amount of the compounds of the present invention administered will depend on the individual being treated, the severity of the condition or illness, the rate of administration, the disposal of the compounds, and the prescribing physician's judgment. Generally, the effective dose is from about 0.0001 to about 50 mg per kg of body weight per day, for example, from about 0.01 to about 10 mg / kg / day (single or divided doses). For a 70 kg person, this would total from about 0.007 mg / day to about 3500 mg / day, for example, from about 0.7 mg / day to about 700 mg / day. In some cases, dose levels not exceeding the lower limit of the foregoing range may be sufficient, while in other cases, larger doses may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses administered throughout the day.

[0119] The content or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, preferably 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.

[0120] 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.

[0121] 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.).

[0122] In another embodiment, the pharmaceutical composition of the present invention may also contain one or more additional therapeutic or preventative agents.

[0123] Example

[0124] 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.

[0125] The structure of the compound was determined by nuclear magnetic resonance (NMR). 1 Chemical shifts (δ) were determined by 1H NMR or mass spectrometry (MS). NMR measurements were performed using a Bruker AVANCE-500 or AVANCE-400 NMR spectrometer. The solvents used for the measurements were deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated water (D2O), etc. The internal standard was tetramethylsilane (TMS). Chemical shifts (δ) were given in parts per million (ppm).

[0126] The instrument used for MS measurements was an Agilent (ESI) mass spectrometer (manufacturer: Agilent, model: Agilent 6110).

[0127] Methods for preparing high performance liquid chromatography separation:

[0128] Instrument model: Elite P3500; Column: Welch Ultimate XB-C18 (30×250mm, 10μm); Column temperature: 25℃; Flow rate: 42mL / min; Detection wavelength: 254nm; Elution gradient: (0min: 10%A, 90%B; 25min: 90%A, 10%B; 35min: 90%A, 10%B; 38min: 10%A, 90%B; 40min: 10%A, 90%B); Mobile phase: A: methanol, B: 0.05% formic acid aqueous solution.

[0129] The compounds synthesized in the following examples are based on their molecular formulas, and the compound names were generated by ChemBioDraw software.

[0130] The abbreviations used in this invention have the following meanings:

[0131] Bn benzyl DCM dichloromethane DIEA / DIPEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide EA Ethyl acetate HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate <![CDATA[H2O]]> water <![CDATA[LiAlH4]]> Lithium aluminum hydride MeOH methanol MeONa Sodium methoxide MTBE Methyl tert-butyl ether NaOH Sodium hydroxide Ph Phenyl TBSCl tert-butyldimethylchlorosilane THF Tetrahydrofuran

[0132] Example 1: Synthesis of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-fluoropent-2-en-3-yl)thiobenzoate (Compound 1)

[0133]

[0134] Step 1: Dissolve compounds 1a (2.5 g, 0.088 mol) and 1b (1.3 g, 0.088 mol) in 25 g DMF, stir at 100–110 °C for 2 hours, cool to room temperature, add methyl tert-butyl ether (50 mL), the product precipitates, filter, dissolve the filter cake in 20 mL methanol, then add methyl tert-butyl ether (50 mL), the product precipitates, filter, wash the filter cake with methyl tert-butyl ether, and dry under vacuum at 40 °C to obtain 2.7 g intermediate 1c.

[0135] Step 2: Dissolve intermediate 1c (1.7g, 0.005mol) in 5g water, adjust the pH to 12 with 30% sodium hydroxide solution, stir for half an hour, cool to 10℃, add 5mL of THF solution of benzoyl chloride (1d) (0.8g, 0.005mol), maintain pH at 10-12 and stir for half an hour, add dichloromethane (50mL) for extraction, purify the organic phase by silica gel column chromatography (dichloromethane:methanol = 10:1), and concentrate under vacuum at 40℃ to obtain title compound 1 (0.3g, off-white solid).

[0136] MS m / z (ESI): 389 [M+1] + .

[0137] 1H NMR (500MHz, DMSO-d6): δ7.87 (s, 1H), 7.83 (s, 1H), 7.76-7.75 (dd, 2H), 7.72-7.69 (t, 1H), 7.56-7 .53(t, 2H), 6.68(br, 2H), 4.56(t, 1H), 4.47-4.43(m, 3H), 2.89(dt, 2H), 2.19(s, 3H), 2.18(s, 3H).

[0138] Example 2: Synthesis of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-fluoropent-2-en-3-yl)2-fluorothiobenzoate (Compound 2)

[0139]

[0140] Except for replacing benzoyl chloride in step 2 of Example 1 with o-fluorobenzoyl chloride, the same synthetic route as in Example 1 was used to prepare title compound 2 (pale yellow solid).

[0141] MS m / z (ESI): 407 [M+1] + .

[0142] 1 H NMR (500MHz, DMSO-d6) δ8.42 (s, 1H), 8.35 (s, 1H), 8.24 (t, 1H), 8.16 (dd, 1H), 7.81-7 .72(m, 2H), 6.88(br, 2H), 5.09-4.98(m, 4H), 3.44(dt, 2H), 2.74(s, 3H), 2.67(s, 3H).

[0143] Example 3: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-fluoropent-2-en-3-yl)2-bromothiobenzoate (compound 3)

[0144]

[0145] Except for replacing benzoyl chloride in step 2 of Example 1 with o-bromobenzoyl chloride, the same synthetic route as in Example 1 was used to prepare title compound 3 (pale yellow solid).

[0146] MS m / z (ESI): 467 [M+1] + ;469[M+1] + .

[0147] 1H NMR (500MHz, DMSO-d6) δ7.92 (s, 1H), 7.85 (s, 1H), 7.76-7.75 (d, 1H), 7.53-7.49 (m, 3H), 6. 76(br, 2H), 4.60-4.58(t, 1H), 4.51-4.46(m, 3H), 2.92(dt, 2H), 2.22(s, 3H), 2.19(s, 3H).

[0148] Example 4: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-fluoropent-2-en-3-yl)2-iodothiobenzoate (compound 4)

[0149]

[0150] Except for replacing benzoyl chloride in step 2 of Example 1 with o-iodobenzoyl chloride, the same synthetic route as in Example 1 was used to prepare title compound 4 (pale yellow solid).

[0151] MS m / z (ESI): 515 [M+1] + .

[0152] 1 H NMR (500MHz, DMSO-d6) δ7.99 (d, 1H), 7.93 (s, 1H), 7.85 (s, 1H), 7.55-7.52 (t, 1H), 7.47 (d, 1H), 7.33 ( t, 1H), 6.75 (br, 2H), 4.62 (t, 1H), 4.52 (t, 1H), 4.46 (s, 2H), 2.93 (dt, 2H), 2.22 (s, 3H), 2.18 (s, 3H).

[0153] Example 5: Synthesis of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-chloropent-2-en-3-yl)thiobenzoate (compound 5)

[0154]

[0155] Step 1: Compound 1a (4.0 g, 0.014 mol) and compound 5b (1.6 g, 0.01 mol) were dissolved in a mixed solution of DMF (8 mL) and acetonitrile (8 mL), and stirred at 110 °C for 3 hours. The reaction mixture was cooled to room temperature, acetonitrile was added, the product precipitated, filtered, the filter cake was washed with DCM, and dried under vacuum at 40 °C to obtain intermediate 5c (2.3 g, off-white solid).

[0156] Step 2: Add intermediate 5c (1.0 g, 0.0027 mol) and water (2 g) to the reaction flask. Adjust the pH to 10-12 with 30% sodium hydroxide solution and stir for half an hour. Add 2 mL of THF solution containing benzoyl chloride (0.25 g, 0.0017 mol) dropwise, maintaining the pH at 10-12 and stirring for another half hour. Extract with dichloromethane (50 mL). Purify the organic phase by silica gel column chromatography (dichloromethane:methanol = 30:1). Purify the obtained product by preparative liquid chromatography and freeze-dry to obtain title compound 5 (a white solid).

[0157] MS m / z (ESI): 405 [M+1] + .

[0158] 1 H NMR (500MHz, DMSO-d6) δ7.86 (s, 1H), 7.85 (s, 1H), 7.77 (d, 2H), 7.72 (t, 1H), 7.56 (t, 2H), 6.66(br, 2H), 4.44(s, 2H), 3.71(t, 2H), 2.91(t, 2H), 2.21(s, 3H), 2.18(s, 3H).

[0159] Example 6: Synthesis of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-fluoropent-2-en-3-yl)furan-2-thiocarbamate (Compound 6)

[0160]

[0161] Except for replacing benzoyl chloride in step 2 of Example 1 with 6d, the title compound 6 (pale yellow solid) was prepared by the same synthetic route as in Example 1.

[0162] MS m / z (ESI): 379 [M+1] + .

[0163] 1 H NMR (500MHz, DMSO-d6) δ8.04 (s, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.32 (d, 1H), 6.76 (d, 1H) , 6.65(br, 2H), 4.55(t, 1H), 4.45-4.41(m, 2H), 2.85(dt, 2H), 2.24(s, 3H), 2.15(s, 3H).

[0164] Example 7: Synthesis of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-fluoropent-2-en-3-yl)cyclohexylthiocarbamate (Compound 7)

[0165]

[0166] Except for replacing benzoyl chloride in step 2 of Example 1 with 7d, the title compound 7 (yellow solid) was prepared by the same synthetic route as in Example 1.

[0167] MS m / z (ESI): 395 [M+1] + .

[0168] 1 H NMR (500MHz, DMSO-d6): δ7.78 (s, 1H), 7.76-7.74 (d, 1H), 6.70 (s, 2H), 4.51-4.48 (t, 1H), 4.37 (s, 2 H), 2.78-2.67(m, 2H), 2.39(s, 1H), 2.27(s, 3H), 2.10(s, 3H), 1.81-1.55(m, 6H), 1.36-1.14(m, 5H).

[0169] Example 8: Synthesis of S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-fluoropent-2-en-3-yl)(E)-3-phenylprop-2-thioenoate (Compound 8)

[0170]

[0171] Except for replacing benzoyl chloride in step 2 of Example 1 with 8d, the title compound 8 (pale yellow solid) was prepared by the same synthetic route as in Example 1.

[0172] MS m / z (ESI): 415 [M+1] + .

[0173] 1 H NMR (500MHz, DMSO-d6) δ8.38 (s, 1H), 8.34 (s, 1H), 8.19 (d, 2H), 8.00-7.93 (m, 4H), 7 .22(d,1H),6.81(s,2H),5.07-4.95(m,4H),3.40(dt,2H),2.73(s,3H),2.70(s,3H).

[0174] Example 9: Synthesis of (Z)-4-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-3-(benzoylthio)pent-3-en-1-yl acetate (compound 9)

[0175]

[0176] Step 1: Dissolve compounds 1a (5.6 g, 0.02 mol) and 9b (3.7 g, 0.02 mol) in 10 mL of LMF, heat to 110 °C, and reflux for three hours; then cool to room temperature, add methyl tert-butyl ether dropwise, and the product precipitates to obtain crude product 9c (2.5 g, yellow oil), which is used directly in the next step of the reaction.

[0177] Step 2: Add the above crude product (2.5g) to 10g of water, stir to dissolve, adjust the pH to 10-11 with 30% sodium hydroxide solution, add tetrahydrofuran solution of benzoyl chloride (0.7g) dropwise, maintain the pH at 10-11, react for 0.5 hours, extract the reaction solution twice with dichloromethane, then concentrate to dryness to obtain a yellow oily liquid, purify it by preparative liquid chromatography, freeze-dry the product to obtain title compound 9 (0.1g, white solid).

[0178] MS m / z (ESI): 429 [M+1] + .

[0179] 1 H NMR (500MHz, DMSO-d6): δ7.85(s, 1H), 7.84(s, 1H), 7.77(d, 2H), 7.72(t, 1H), 7.56(t, 2H), 6 .68(br, 2H), 4.44(s, 2H), 4.09(t, 2H), 2.77(t, 2H), 2.19(s, 3H), 2.18(s, 3H), 2.01(s, 3H).

[0180] Example 10: Synthesis of (Z)-4-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-3-((3-bromobenzoyl)thio)pent-3-en-1-yl acetate (compound 10)

[0181]

[0182] Except for replacing benzoyl chloride in step 2 of Example 9 with m-bromobenzoyl chloride, the same synthetic route as in Example 9 was used to prepare title compound 10 (a white solid).

[0183] MS m / z (ESI): 509 [M+1] + .

[0184] 1 H NMR (500MHz, CD3OD) δ7.95 (s, 1H), 7.88-7.87 (m, 2H), 7.84-7.79 (m, 2H), 7.45 (t, 1 H), 4.57(br, 2H), 4.23(t, 2H), 2.86(t, 2H), 2.29(s, 3H), 2.25(s, 3H), 2.05(s, 3H).

[0185] Example 11: Synthesis of (Z)-4-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-3-((furan-2-carbonyl)thio)pent-3-en-1-yl acetate (compound 11)

[0186]

[0187] Except for replacing benzoyl chloride in step 2 of Example 9 with furan-2-formyl chloride, the title compound 11 (a white solid) was prepared by the same synthetic route as in Example 9.

[0188] MS m / z (ESI): 419 [M+1] + .

[0189] 1 H NMR (500MHz, DMSO-d6): δ8.03(s, 1H), 7.83(s, 2H), 7.31(dd, 1H), 6.77(dd, 1H), 6.64( br, 2H), 4.41 (s, 2H), 4.07 (t, 2H), 2.73 (t, 2H), 2.23 (s, 3H), 2.15 (s, 3H), 1.99 (s, 3H).

[0190] Example 12: Synthesis of (Z)-4-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-3-((2-methoxybenzoyl)thio)pent-3-en-1-yl acetate (compound 12)

[0191]

[0192] Except for replacing benzoyl chloride in step 2 of Example 9 with 2-methoxybenzoyl chloride, the title compound 12 (white solid) was prepared by the same synthetic route as in Example 9.

[0193] MS m / z (ESI): 459 [M+1] + .

[0194] 1H NMR (500MHz, DMSO-d6) δ7.83 (s, 1H), 7.80 (s, 1H), 7.60-7.57 (m, 2H), 7.19 (d, 1H), 7.05 (t, 1H), 6.71 ( br, 2H), 4.42 (s, 2H), 4.04 (t, 2H), 3.87 (s, 3H), 2.71 (br, 2H), 2.24 (s, 3H), 2.15 (s, 3H), 2.00 (s, 3H).

[0195] Example 13: Synthesis of (Z)-4-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-3-(cinnamoylthio)pent-3-en-1-yl acetate (compound 13)

[0196]

[0197] Except for replacing benzoyl chloride with cinnamyl chloride in step 2 of Example 9, the same synthetic route as in Example 9 was used to prepare title compound 13 (white solid).

[0198] MS m / z (ESI): 455 [M+1] + .

[0199] 1 H NMR (500MHz, DMSO-d6) δ7.84 (s, 1H), 7.83 (s, 1H), 7.75 (d, 2H), 7.50-7.44 (m, 4H), 6.88 (d, 1H) , 6.70(br, 2H), 4.42(s, 2H), 4.08(t, 2H), 2.72(t, 2H), 2.23(s, 3H), 2.14(s, 3H), 2.01(s, 3H).

[0200] Example 14: Synthesis of (Z)-4-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-3-(benzoylthio)pent-3-en-1-ylbenzoate (compound 14).

[0201]

[0202] Step 1: Add compound 14a (34g, 0.1mol) to 200mL DMF, stir, add DIPEA (26g, 0.2mol) dropwise, cool to 0℃, react for 0.5 hours, add TBSCl (23g, 0.15mol) dropwise, then keep warm at 0-5℃ and react for 16 hours, add 500mL MTBE, continue stirring for 2 hours, filter, wash the filter cake with MTBE, and then dry at 40℃ to obtain white solid 14b (30g).

[0203] Step 2: 14b (30 g, 0.072 mol) was added to 30 mL of water and 60 mL of tetrahydrofuran, stirred, and 30% NaOH solution was added dropwise to adjust the pH to 10⁻¹1. The reaction was allowed to proceed for 0.5 hours. Then, benzoyl chloride (31 g, 0.216 mol) was added dropwise at 0-5 °C while maintaining the pH at 10⁻¹1. The reaction was allowed to proceed for 1 hour. The mixture was extracted, and the organic phase was purified by silica gel column chromatography (methanol:dichloromethane = 1:20) to obtain title compound 14 (0.3 g, white solid).

[0204] MS m / z (ESI): 491 [M+1] + .

[0205] 1 H NMR (500MHz, DMSO-d6) δ7.93 (dd, 2H), 7.85 (s, 1H), 7.79 (s, 1H), 7.74-7.65 (m, 4H), 7.5 4-7.51 (m, 4H), 6.65 (s, 2H), 4.44-4.37 (m, 4H), 2.92 (t, 2H), 2.19 (s, 3H), 2.13 (s, 3H).

[0206] Example 15: Synthesis of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-methoxypent-2-en-3-yl)thiobenzoate (compound 15)

[0207]

[0208] Step 1: Add 1a (2.0 g, 0.007 mol) and 15b (1.0 g, 0.006 mol) to 5 mL of DMF and stir at 110 °C for 2 hours. Cool the reactants to room temperature, add acetonitrile, the product precipitates, filter, wash the filter cake with DCM, and dry under vacuum at 40 °C to obtain intermediate 15c (1.5 g).

[0209] Step 2: Add 15c (1.5g, 0.004mol) to a 100mL single-necked flask, add 3g H2O and 30% sodium hydroxide solution to adjust the pH to 12, stir for half an hour, cool to 10℃, add 4mL of benzoyl chloride (0.4g, 0.0028mol) in THF solution, maintain pH at 10-12 and stir for half an hour. Add dichloromethane (50mL) for extraction, purify the organic phase by silica gel column chromatography (dichloromethane:methanol = 20:1), and concentrate under vacuum at 40℃ to obtain title compound 15 (0.3g, off-white solid).

[0210] MS m / z (ESI): 401 [M+1] + .

[0211] 1 H NMR (500MHz, DMSO-d6) δ7.84 (s, 1H), 7.83 (s, 1H), 7.76 (d, 2H), 7.70 (t, 1H), 7.54 (t, 2H), 6 .67(br, 2H), 4.41(s, 2H), 3.38(t, 2H), 3.21(s, 3H), 2.66(t, 2H), 2.21(s, 3H), 2.16(s, 3H).

[0212] Example 16: Synthesis of the hydrochloride salt of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-methoxypent-2-en-3-yl)thiobenzoate (compound 15)

[0213]

[0214] Compound 15, prepared as in Example 15, was added to ethyl acetate (10 mL) and stirred in an ice-salt bath until completely dissolved. An appropriate amount of isopropanol hydrochloride solution was added dropwise until a white solid precipitated. The mixture was filtered, and the filter cake was dried under vacuum at 50 °C to obtain the hydrochloride salt of compound 15 (a white solid).

[0215] MS m / z (ESI): 401 [M+1] + .

[0216] 1 H NMR (500MHz, DMSO-d6) δ14.45 (br, 1H), 9.14 (br, 1H), 8.20 (s, 1H), 8.04 (br, 1H), 7.93 (s, 1H), 7.75-7. 70(m, 3H), 7.56(t, 2H), 4.53(s, 2H), 3.42(t, 2H), 3.22(s, 3H), 2.66(t, 2H), 2.28(s, 3H), 2.23(s, 3H).

[0217] Example 17: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-methoxypent-2-en-3-yl)2-methoxythiobenzoate (Compound 17)

[0218]

[0219] Except for replacing benzoyl chloride in step 2 of Example 15 with o-methoxybenzoyl chloride, the same synthetic route as in Example 15 was used to obtain title compound 17 (white solid).

[0220] MS m / z (ESI): 431 [M+1] + .

[0221] 1 H NMR (500MHz, DMSO-d6) δ7.82 (s, 1H), 7.80 (s, 1H), 7.60-7.56 (m, 2H), 7.19 (d, 1H), 7.04 (t, 1H), 6.71 (s, 2H), 4.40 (s, 2H), 3.87 (s, 3H), 3.36 (t, 2H), 3.21 (s, 3H), 2.61 (br, 2H), 2.26 (s, 3H), 2.13 (s, 3H).

[0222] Example 18: Synthesis of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-methoxypent-2-en-3-yl)3-bromothiobenzoate (compound 18)

[0223]

[0224] Except for replacing benzoyl chloride in step 2 of Example 15 with m-bromobenzoyl chloride, the same synthetic route as in Example 15 was used to obtain title compound 18 (white solid).

[0225] MS m / z (ESI): 481 [M+1] + .

[0226] 1 H NMR (500MHz, CDCl3) δ7.93-7.92(m, 2H), 7.84(s, 1H), 7.73-7.69(m, 2H), 7.32(t, 1 H), 5.94(s, 2H), 3.45(t, 2H), 3.31(s, 3H), 2.71(br, 2H), 2.41(s, 3H), 2.17(s, 3H)

[0227] Example 19: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-methoxypent-2-en-3-yl)furan-2-thiocarbamate (Compound 19)

[0228]

[0229] Except for replacing benzoyl chloride in step 2 of Example 15 with furan-2-formyl chloride, the same synthetic route as in Example 15 was used to obtain title compound 19 (white solid).

[0230] MS m / z (ESI): 391 [M+1]+ .

[0231] 1 H NMR (500MHz, DMSO-d6) δ8.03 (s, 1H), 7.83 (s, 1H), 7.81 (s, 1H), 7.30 (d, 1H), 6.75 (d, 1H), 6 .66(br, 2H), 4.39(s, 2H), 3.36(t, 2H), 3.19(s, 3H), 2.62(t, 2H), 2.26(s, 3H), 2.13(s, 3H).

[0232] Example 20: Synthesis of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-methoxypent-2-en-3-yl)cyclohexylthiocarbamate (Compound 20)

[0233]

[0234] Except for replacing benzoyl chloride with cyclohexyl chloride in step 2 of Example 15, the same synthetic route as in Example 15 was used to obtain title compound 20 (white solid).

[0235] MS m / z (ESI): 407 [M+1] + .

[0236] 1 H NMR (500MHz, DMSO-d6) δ7.78 (s, 1H), 7.71 (s, 1H), 6.69 (br, 2H), 4.36 (s, 2H), 3.31 (t, 2H), 3.18 (s, 3H), 2.52 (t, 2H), 2.38(br, 1H), 2.28(s, 3H), 2.08(s, 3H), 1.76-1.71(m, 2H), 1.68-1.62(m, 2H), 1.57-1.55(m, 1H), 1.28-1.14(m, 5H).

[0237] Example 21: Synthesis of S-((Z)-2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-methoxypent-2-en-3-yl)(E)-3-phenylprop-2-thioenoate (compound 21)

[0238]

[0239] Except for replacing benzoyl chloride with cinnamyl chloride in step 2 of Example 15, the same synthetic route as in Example 15 was used to obtain title compound 21 (white solid).

[0240] MS m / z (ESI): 427 [M+1] + .

[0241] 1 H NMR (500MHz, DMSO-d6) δ7.82 (s, 1H), 7.81 (s, 1H), 7.77-7.71 (m, 2H), 7.49-7.42 (m, 4H), 6.85 (d, 1H), 6.66(s, 2H), 4.39(s, 2H), 3.37(t, 2H), 3.20(s, 3H), 2.62(t, 2H), 2.23(s, 3H), 2.11(s, 3H).

[0242] Example 22: Synthesis of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-ethoxypent-2-en-3-yl)thiobenzoate (compound 22)

[0243]

[0244] Except for replacing 15b with 22b in step 1 of Example 15, the title compound 22 (a white solid) was prepared by the same synthetic route as in Example 15.

[0245] MS m / z (ESI): 415 [M+1] + .

[0246] 1 H NMR (500MHz, DMSO-d6) δ7.84 (s, 2H), 7.76 (d, 2H), 7.69 (t, 1H), 7.54 (t, 2H), 6.71 (d, 2H), 4 .42(s, 2H), 3.42(t, 2H), 3.37(q, 2H), 2.65(t, 2H), 2.21(s, 3H), 2.16(s, 3H), 1.08(t, 3H).

[0247] Example 23: Synthesis of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-ethoxypent-2-en-3-yl)3-bromothiobenzoate (compound 23)

[0248]

[0249] Except for replacing benzoyl chloride in step 2 of Example 22 with m-bromobenzoyl chloride, the same synthetic route as in Example 22 was used to prepare title compound 23 (white solid).

[0250] MS m / z (ESI): 495 [M+1]+ .

[0251] 1 H NMR (500MHz, DMSO-d6) δ7.91 (dd, 1H), 7.83 (s, 1H), 7.81 (s, 1H), 7.78 (t, 1H), 7.76 (d, 1H), 7.50 (t, 1H), 6.66(d, 2H), 4.41(s, 2H), 3.42(t, 2H), 3.36(q, 2H), 2.63(t, 2H), 2.19(s, 3H), 2.16(s, 3H), 1.07(t, 3H).

[0252] Example 24: Synthesis of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-ethoxypent-2-en-3-yl)2-methoxythiobenzoate (compound 24)

[0253]

[0254] Except for replacing benzoyl chloride in step 2 of Example 22 with o-methoxybenzoyl chloride, the title compound 24 (white solid) was prepared by the same synthetic route as in Example 22.

[0255] MS m / z (ESI): 445 [M+1] + .

[0256] 1 H NMR (500MHz, CD3OD) δ7.92 (s, 1H), 7.83 (s, 1H), 7.66 (dd, 1H), 7.58-7.52 (m, 1H), 7.14 (d, 1H), 7.02 (t, 1H), 4.52(br, 2H), 3.93(s, 3H), 3.53(t, 2H), 3.48(q, 2H), 2.72(br, 2H), 2.28(s, 3H), 2.23(s, 3H), 1.19(t, 3H).

[0257] Example 25: Synthesis of S-((Z)-2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-ethoxypent-2-en-3-yl)(E)-3-phenylprop-2-thioenoate (compound 25)

[0258]

[0259] Except for replacing benzoyl chloride with cinnamyl chloride in step 2 of Example 22, the same synthetic route as in Example 22 was used to prepare title compound 25 (white solid).

[0260] MS m / z (ESI): 441 [M+1] + .

[0261] 1 H NMR (500MHz, DMSO-d6) δ7.82 (s, 2H), 7.76 (d, 2H), 7.50-7.44 (m, 4H), 6.86 (d, 1H), 6.68 (br , 2H), 4.40(s, 2H), 3.41-3.38(m, 4H), 2.62(t, 2H), 2.24(s, 3H), 2.12(s, 3H), 1.08(t, 3H).

[0262] Example 26: Synthesis of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-ethoxypent-2-en-3-yl)furan-2-thiocarbamate (Compound 26)

[0263]

[0264] Except for replacing benzoyl chloride in step 2 of Example 22 with furan-2-formyl chloride, the same synthetic route as in Example 22 was used to prepare title compound 26 (white solid).

[0265] MS m / z (ESI): 405 [M+1] + .

[0266] 1 H NMR (500MHz, DMSO-d6) δ8.03 (d, 1H), 7.82 (s, 1H), 7.82 (s, 1H), 7.81 (s, 1H), 7.30 (d, 1H), 6.75 (dd, 3H), 6 .65(br, 2H), 4.40(s, 2H), 3.40(t, 2H), 3.36(q, 2H), 2.61(t, 2H), 2.24(s, 3H), 2.13(s, 3H), 1.07(t, 3H).

[0267] Example 27: Synthesis of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-ethoxypent-2-en-3-yl)cyclohexylthiocarbamate (Compound 27)

[0268]

[0269] Except for replacing benzoyl chloride with cyclohexyl chloride in step 2 of Example 22, the same synthetic route as in Example 22 was used to prepare title compound 27 (white solid).

[0270] MS m / z (ESI): 421 [M+1] + .

[0271] 1 H NMR (500MHz, DMSO-d6) δ7.77 (s, 1H), 7.70 (s, 1H), 6.70 (br, 2H), 4.36 (s, 2H), 3.37-3.32 (m, 4H), 2.52 (br, 2H), 2.38 (br, 1H), 2. 27(s, 3H), 2.08(s, 3H), 1.77-1.71(m, 2H), 1.68-1.62(m, 2H), 1.57-1.55(m, 1H), 1.26-1.21(m, 4H), 1.14(br, 1H), 1.07(t, 3H).

[0272] Example 28: Synthesis of the hydrochloride salt of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-ethoxypent-2-en-3-yl)thiobenzoate (compound 22)

[0273]

[0274] Compound 22 (0.1 g, 0.0146 mol) prepared in Example 22 was added to ethyl acetate (3 mL) and stirred until dissolved. Then, an isopropanol solution of hydrogen chloride was added dropwise while stirring until the pH reached 1-2 (approximately 0.5 mL was added). After the addition was complete, the mixture was stirred for 30 min, and the solvent was removed by rotary evaporation at 40 °C to obtain an oily substance. Deionized water (50 mL) was added to the oily substance, and after the oily substance dissolved, it was frozen and lyophilized to obtain the hydrochloride salt of compound 22 (0.08 g, off-white solid).

[0275] MS m / z (ESI): 415 [M+1] + .

[0276] 1 H NMR (500MHz, DMSO-d6): δ14.76 (s, 1H), 9.13 (s, 1H), 8.22 (s, 1H), 8.05 (s, 1H), 7.93 (s, 1H), 7.76-7.70 (m, 3H), 7.58-7.54 ( t, 2H), 4.55 (s, 2H), 3.48-3.44 (t, 2H), 3.41-3.36 (q, 2H), 2.67-2.64 (t, 2H), 2.29 (s, 3H), 2.23 (s, 3H), 1.08-1.05 (t, 3H).

[0277] Example 30: Synthesis of (Z)-5-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-4-((2-methoxybenzoyl)thio)hex-4-enoic acid (compound 30)

[0278]

[0279] Step 1: In a 100mL single-necked flask, add 1a (1.54g), 30b (1.67g), anhydrous acetonitrile (2g), and anhydrous DMF (6g) in sequence and stir. Heat to 110℃ and reflux for 3h until the reaction is complete. Cool to room temperature, add 100mL of anhydrous acetonitrile, filter, dissolve the filter cake with MEOH / CH3CN, concentrate under reduced pressure to remove the solvent, and obtain product 30c (1.25g).

[0280] Step 2: In a 100 mL single-necked flask, 30 C (1.25 g) and H2O (3 g) were added sequentially and stirred until dissolved. The pH was adjusted to 10-12 by adding 30% NaOH dropwise and stirred for 0.5 h. 2-Methoxybenzoyl chloride (0.189 g) was added dropwise. HPLC detection showed that the reaction was complete. The pH was adjusted to 4-5 by adding 36% HCl dropwise. DCM was added and stirred for 10 min. After standing, the organic phase was separated. The aqueous phase was washed twice with DCM. The organic phases were combined, evaporated to dryness, dissolved in MeOH, purified by preparative chromatography, and lyophilized to obtain the title compound 30 (white solid).

[0281] MS m / z (ESI): 445 [M+1] + .

[0282] 1 H NMR (500MHz, DMSO-d6) δ7.82 (s, 1H), 7.79 (s, 1H), 7.58-7.55 (m, 2H), 7.19 (d, 1H), 7.05 (t, 1H) , 6.71(br, 2H), 4.39(s, 2H), 3.86(s, 3H), 2.60(t, 2H), 2.33(t, 2H), 2.27(s, 3H), 2.13(s, 3H).

[0283] Example 31: Synthesis of (Z)-5-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-4-((3-bromobenzoyl)thio)hex-4-enoic acid (compound 31)

[0284]

[0285] Except for replacing 2-methoxybenzoyl chloride with m-bromobenzoyl chloride in step 2 of Example 30, the title compound (off-white solid) was prepared by the same synthetic route as in Example 30.

[0286] MS m / z (ESI): 493 [M+1] + .

[0287] 1 H NMR (500MHz, DMSO-d6) δ7.92-7.88(m, 1H), 7.86(s, 1H), 7.85(s, 1H), 7.77(t, 1H), 7.76-7.72(m, 1 H), 7.50(t, 1H), 6.77(br, 2H), 4.40(br, 2H), 2.64(t, 2H), 2.37(t, 2H), 2.18(s, 3H), 2.17(s, 3H).

[0288] Example 32: Synthesis of (Z)-5-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-4-(benzoylthio)hex-4-enoic acid ethyl ester (compound 32)

[0289]

[0290] Add 30c (1.45g) and 4.0g H2O to a 100mL single-necked flask, and stir until dissolved. Add 30% NaOH dropwise to adjust the pH to about 10-12 until the pH remains stable. Controlling the pH at 10-12, add benzoyl chloride (0.336g, 0.0024mol) / THF dropwise, react for 10min, add DCM, stir to separate the layers, dry the organic phase by rotary evaporation, and purify by chromatography to obtain the title compound 32 (white solid).

[0291] MS m / z (ESI): 443 [M+1] + .

[0292] 1 H NMR (500MHz, DMSO-d6) δ7.84(s, 1H), 7.83(s, 1H), 7.76(d, 2H), 7.70(t, 1H), 7.56(t, 2H), 6.68(br , 2H), 4.41(s, 2H), 4.06(q, 2H), 2.69(t, 2H), 2.46(t, 2H), 2.20(s, 3H), 2.18(s, 3H), 1.18(t, 3H).

[0293] Example 33: Synthesis of (Z)-5-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-4-((2-methoxybenzoyl)thio)hex-4-enoic acid ethyl ester (compound 33)

[0294]

[0295] Except that benzoyl chloride in Example 32 was replaced with 2-methoxybenzoyl chloride, the title compound 33 (white solid) was prepared by the same synthetic route as in Example 32.

[0296] MS m / z (ESI): 473 [M+1] + .

[0297] 1 H NMR (500MHz, DMSO-d6) δ7.80 (s, 1H), 7.78 (s, 1H), 7.58-7.56 (m, 2H), 7.19 (d, 1H), 7.05 (t, 1H), 6.68 (s, 2H ), 4.38(s, 2H), 4.06(t, 2H), 3.86(s, 3H), 2.64(t, 2H), 2.40(t, 2H), 2.27(s, 3H), 2.14(s, 3H), 1.18(t, 3H).

[0298] Example 34: Synthesis of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-morpholinopent-2-en-3-yl)thiobenzoate (compound 34)

[0299]

[0300] Except for replacing 1b with 34b in step 1 of Example 1, the same synthetic route as in Example 1 was used to obtain title compound 34 (white solid).

[0301] MS m / z (ESI): 456 [M+1] + .

[0302] 1 H NMR (500MHz, DMSO-d6) δ7.85 (s, 1H), 7.84 (s, 1H), 7.76 (d, 2H), 7.71 (t, 1H), 7.56 (t, 2H), 6.67 (br, 2H), 4.42 (s, 2H), 3.54 (br, 4H), 2.57 (t, 2H), 2.38-2.33 (m, 6H), 2.21 (s, 3H), 2.16 (s, 3H).

[0303] Example 35: Synthesis of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-morpholinopent-2-en-3-yl)2-methoxythiobenzoate (compound 35)

[0304]

[0305] Except for replacing benzoyl chloride in step 2 of Example 34 with o-methoxybenzoyl chloride, the title compound 35 (white powder solid) was prepared by the same synthetic route as in Example 34.

[0306] MS m / z (ESI): 486 [M+1] + .

[0307] 1 H NMR (500MHz, CD3OD): δ7.93 (s, 1H), 7.84 (s, 1H), 7.65 (dd, 1H), 7.59-7.53 (m, 1H), 7.14 (d, 1H), 7.03 (t, 1H), 4.55(br, 2H), 3.93(s, 3H), 3.70(t, 4H), 2.68(t, 2H), 2.54-2.44(m, 6H), 2.28(s, 3H), 2.24(s, 3H).

[0308] Example 36: Synthesis of the formate salt of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(4-phenylpiperazin-1-yl)pent-2-en-3-yl)2-fluorothiobenzoate (compound 36)

[0309]

[0310] Step 1: Add 1a (2.1g), 36b (1.0g), acetonitrile (20g), and N,N-dimethylformamide (6g) to a 100mL single-necked flask, heat to 100-110℃ and stir for 3 hours. Cool the reactants to room temperature, the product precipitates, filter, and slurry the filter cake with 20mL of acetonitrile, filter again, and vacuum dry the filter cake at 40℃ to obtain intermediate 36c.

[0311] Step 2: Add 36c (2.1g) and water (5.0g) to a 100mL single-necked flask, adjust the pH to 11.0 with 30% NaOH, stir for 30 minutes, and retest the pH to be greater than 11.0; add o-fluorobenzoyl chloride / tetrahydrofuran (0.38g / 2mL), add 5mL of ethyl acetate, separate the liquid and water, extract the aqueous phase twice with 5mL of ethyl acetate, combine the organic phases, dry, evaporate to dryness, dissolve in methanol, and prepare the formate salt (white solid) of the title compound 36 by chromatographic purification.

[0312] MS m / z (ESI): 549 [M+1] + .

[0313] 1H NMR (500MHz, CD3OD) δ8.29 (s, 1H), 7.97 (s, 1H), 7.90 (s, 1H), 7.74 (t, 1H), 7.65 (d, 1H), 7.34-7.20 (m, 4H), 6.96(d, 2H), 6.85(t, 1H), 4.55(br, 2H), 3.25(t, 4H), 2.91(t, 4H), 2.82(s, 4H), 2.27(s, 3H), 2.15(s, 3H).

[0314] Example 37: Synthesis of S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-((2S,6R)-2,6-dimethylmorpholino)pent-2-en-3-yl)2-fluorothiobenzoate (compound 37)

[0315]

[0316] Step 1: Dissolve 37b (1.8 g, 0.0075 mol) and 1a (3.2 g, 0.0125 mol) in a mixed solution of DMF (15 g) and acetonitrile (5 g), and heat in an oil bath to 110 °C for 3 hours. Cool the reaction solution to room temperature, filter, wash the filter cake with acetonitrile, and dry the filter cake to obtain a light grayish-yellow solid 37c (2.71 g).

[0317] Step 2: Dissolve 37c (5.56 g, 0.0106 mol) in water (20 mL) and stir until dissolved. Add 30% sodium hydroxide solution dropwise to the reaction solution to adjust the pH to 10-11. Cool to 10°C in an ice bath and maintain the temperature for 10 minutes. Add 5 mL of tetrahydrofuran solution of o-fluorobenzoyl chloride dropwise at 10°C, controlling the pH to 10-11 during the addition. After the addition is complete, maintain the temperature and pH for another 15 minutes. Adjust the pH of the reaction solution to 7-8. Extract three times with dichloromethane. Dry the dichloromethane layer with anhydrous sodium sulfate to remove the solvent. Purify the crude product by column chromatography. Dissolve the purified product in purified water and freeze-dry to obtain the target compound 37 (0.055 g, off-white solid).

[0318] MS m / z (ESI): 502 [M+1] + .

[0319] 1H NMR (500MHz, DMSO-d6): δ7.80 (s, 2H), 7.70-7.60 (m, 2H), 7.36-7.30 (m, 2H), 6.65 (br, 2H), 4.39 (s, 2H), 3.5 3-3.42 (m, 2H), 2.67 (d, 2H), 2.52 (d, 2H), 2.32 (t, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 1.58 (t, 2H), 1.00 (d, 6H).

[0320] Example 38: Synthesis of the formate salt of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(4-(methanesulfonyl)piperazin-1-yl)pent-2-en-3-yl)2-fluorothiobenzoate (compound 38)

[0321]

[0322] Step 1: Add 1a (1.4g), 38b (0.7g), acetonitrile (2.0g), and N,N-dimethylformamide (6.0g) to a 100mL single-necked flask, heat to 100-110℃ and stir for 3 hours. Cool the reaction mixture to room temperature, add acetone, the product precipitates, filter, and the filter cake is slurried with 20mL of acetonitrile, filtered, and the filter cake is dried under vacuum at 40℃ to obtain intermediate 38c (3.3g).

[0323] Step 2: Add intermediate 38c (3.3g) and water (4.4g) to a 100mL single-necked flask, adjust the pH to 11.0 with 30% NaOH, stir for 10 minutes, and retest the pH to be greater than 11.0; add o-fluorobenzoyl chloride / tetrahydrofuran (0.3g / 2mL), add 5mL of ethyl acetate, separate the liquid and water, extract the aqueous phase twice with 5mL of ethyl acetate, combine the organic phases, dry, evaporate to dryness, dissolve in methanol, and prepare the formate salt of compound 38 (white solid) by chromatographic purification.

[0324] MS m / z (ESI): 551 [M+1] + .

[0325] 1 H NMR (500MHz, DMSO-d6) δ8.15(s, 1H), 7.84(s, 1H), 7.82(s, 1H), 7.69(t, 2H), 7.38-7.32(m, 2H), 6.69(s , 2H), 4.40(s, 2H), 3.05(t, 4H), 2.87(s, 3H), 2.55(t, 2H), 2.43-2.40(m, 6H), 2.17(s, 3H), 2.14(s, 3H).

[0326] Example 39: Synthesis of (Z)-S-(5-acetamido-2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)pent-2-en-3-yl)thiobenzoate (compound 39)

[0327]

[0328] Step 1: Add 39b (1.8 g, 0.01 mol) and 1a (5.6 g, 0.02 mol) to 8 mL of LDMF, heat to 110 °C, and stir for 2 hours; cool to 0–10 °C, add MTBE to precipitate the product, filter, wash the filter cake with MTBE, and dry the filter cake to obtain the crude intermediate product 39c (5.5 g, yellow solid).

[0329] Step 2: Add crude product 39c (3.4 g, 0.01 mol) to 6.8 g of water, stir to dissolve, adjust the pH to 10-11 with 30% sodium hydroxide solution, add benzoyl chloride (1.4 g, 0.01 mol) in tetrahydrofuran solution dropwise, maintain pH at 10-11 and react for 0.5 hours. Extract the reaction solution twice with dichloromethane, then concentrate to dryness, and then separate by column chromatography. The product is eluted by dichloromethane:methanol = 10:1. Purify the crude product by preparative chromatography, freeze-dry the product to obtain the title compound (0.1 g, white solid).

[0330] MS m / z (ESI): 428 [M+1] + .

[0331] 1 H NMR (500MHz, DMSO-d6): δ7.91 (s, 1H), 7.88 (t, 1H), 7.83 (s, 1H), 7.73-7.67 (m, 3H), 7.54 (t, 2H) ), 6.63(br, 2H), 4.39(s, 2H), 3.17(q, 2H), 2.52(t, 2H), 2.12(s, 3H), 2.11(s, 3H), 1.78(s, 3H).

[0332] Example 40: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(methyl(phenyl)amino)pent-2-en-3-yl)2-fluorothiobenzoate (compound 40)

[0333]

[0334] Step 1: Add 40b (1.0 g, 0.0043 mol) to 5 mL of DMF, then add 1a (1.6 g, 0.0057 mol), heat to 110 °C and reflux for 3 hours, then cool to room temperature, filter, wash the filter cake with acetonitrile, and dry under reduced pressure to obtain intermediate 40c (1.7 g, white solid).

[0335] Step 2: Dissolve 40c (1.7g, 0.004mol) in 15g of water and stir to dissolve. Begin adding sodium hydroxide solution (30%) dropwise to adjust the pH to 10-12. Stir for 10 minutes, retest the pH, and adjust the pH to 10-12 until it remains stable. Stir for 0.1 hours, and add o-fluorobenzoyl chloride (0.7g, 0.0044mol) and 10mL of tetrahydrofuran solution dropwise while maintaining the temperature below 10°C. Add sodium hydroxide solution during the dropwise addition to maintain the pH at 10-12. After the dropwise addition is complete, keep the reaction at this temperature for 0.5 hours. Extract twice with dichloromethane. Purify the organic phase by silica gel column chromatography (methanol:dichloromethane = 1:20) to obtain the title compound 40 (0.13g, yellow solid).

[0336] MS m / z (ESI): 494 [M+1] + .

[0337] 1 H NMR (500MHz, DMSO-d6): δ7.83 (s, 1H), 7.72-7.68 (m, 1H), 7.67-7.62 (m, 2H), 7.41-7.34 (m, 2H), 7.14 (t, 2H) ), 6.68(d, 2H), 6.60(t, 1H), 4.39(s, 2H), 3.49(t, 2H), 2.80(s, 3H), 2.63(t, 2H), 2.16(s, 3H), 2.07(s, 3H).

[0338] Example 41: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(methanesulfonamido)pent-2-en-3-yl)2-fluorothiobenzoate (compound 41)

[0339]

[0340] Step 1: Dissolve 41b (1.8 g, 0.0088 mol) and 1a (3.2 g, 0.0125 mol) in a mixed solution of DMF (15 g) and acetonitrile (5 g), and heat in an oil bath to 110 °C for 3 hours. Cool the reaction solution to room temperature, filter, wash the filter cake with acetonitrile, and dry the filter cake to obtain intermediate 41c (2.71 g, light grayish-yellow solid).

[0341] Step 2: Dissolve intermediate 41c (2.71 g) in water (20 mL) with stirring. Add 30% sodium hydroxide solution dropwise to the reaction solution to adjust the pH to 10-11. Cool to 10°C in an ice bath and maintain the temperature for 10 minutes. Add tetrahydrofuran (5 mL) solution of o-fluorobenzoyl chloride dropwise at 10°C, controlling the pH to 10-11 during the addition. After the addition is complete, maintain the temperature and pH for another 15 minutes. Adjust the pH of the reaction solution to 7-8. Extract three times with dichloromethane. Dry the dichloromethane layer with anhydrous sodium sulfate to remove the solvent. Purify the crude product by column chromatography. Dissolve the purified product in purified water and freeze-dry to obtain title compound 41 (0.31 g, off-white solid).

[0342] MS m / z (ESI): 482 [M+1] + .

[0343] 1 H NMR (500MHz, DMSO-d6): δ7.92(s, 1H), 7.82(s, 1H), 7.68-7.63(m, 2H), 7.36-7.31(m, 2H), 7.07(br , 1H), 6.65(br, 2H), 4.38(s, 2H), 3.05(q, 2H), 2.86(s, 3H), 2.58(t, 2H), 2.16(s, 3H), 2.08(s, 3H).

[0344] Example 42: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-6-(methylamino)-6-oxohex-2-en-3-yl)thiobenzoate (compound 42)

[0345]

[0346] Step 1: In a 100mL single-necked flask, add 1a (1.54g), 42b (1.67g), anhydrous acetonitrile (2g) and anhydrous DMF (6g) in sequence, stir, heat to 110℃ and reflux for 3h until the reaction is complete, cool to room temperature, add 100mL of anhydrous acetonitrile, filter, dissolve the filter cake with MeOH / CH3CN, concentrate under reduced pressure to remove the solvent, and obtain intermediate product 42c (1.25g).

[0347] Step 2: In a 100 mL single-necked flask, add 42c (1.25 g) and H2O (3 g) sequentially, stir and dissolve. Adjust the pH to 10-12 by adding 30% NaOH dropwise, stir for 0.5 h, add benzoyl chloride (0.189 g), detect by HPLC, add DCM, stir for 10 min, let stand, separate the organic phase, wash the aqueous phase twice with DCM, combine the organic phases, evaporate to dryness, dissolve in MeOH, purify by preparative chromatography, freeze dry, and obtain the title compound 42 (white solid).

[0348] MS m / z (ESI): 428 [M+1] + .

[0349] 1 H NMR (500MHz, DMSO-d6): δ7.84(s, 1H), 7.82(s, 1H), 7.78(q, 1H), 7.76(d, 1H), 7.70-7.69(t, 1H), 7 .56(t, 2H), 6.67(br, 2H), 4.40(s, 2H), 2.65(t, 2H), 2.55(d, 3H), 2.21-2.19(m, 5H), 2.15(s, 3H).

[0350] Example 43: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-6-(dimethylamino)-6-oxohex-2-en-3-yl)thiobenzoate (compound 43)

[0351]

[0352] Except for replacing 42b with 43b in step 1 of Example 42, the same synthetic route as in Example 42 was used to obtain title compound 43 (white solid).

[0353] MS m / z (ESI): 442 [M+1] + .

[0354] 1 H NMR (500MHz, DMSO-d6) δ7.84(s, 1H), 7.82(s, 1H), 7.75(d, 2H), 7.68(t, 1H), 7.55(t, 2H), 6.67(br , 2H), 4.39(s, 2H), 2.90(s, 3H), 2.80(s, 3H), 2.65(t, 2H), 2.43(t, 2H), 2.18(s, 3H), 2.15(s, 3H).

[0355] Example 44: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)pent-2-en-3-yl)thiobenzoate (compound 44)

[0356]

[0357] Step 1: Add acetonitrile, 1a (0.0079 mol), and 44b (0.0079 mol) to a 100 mL single-necked flask, heat to 110 °C and reflux for 2 h. A solid precipitates out. Filter the solid and concentrate it under reduced pressure to remove the solvent. Dissolve the solid in a small amount of MeOH, add EA, and the solid precipitates out. Filter the solid and concentrate it under reduced pressure to remove the solvent to obtain intermediate 44c (2.0 g).

[0358] Step 2: In a 100mL single-necked flask, add 2.0g of intermediate 44c and 4.0g of H2O at once, and stir until dissolved; add 30% NaOH dropwise and react for 30min, controlling the pH at 10-12; add 0.20g (0.00141mol) of benzoyl chloride dropwise and react for 1h; adjust the pH to 4.0, the solid precipitates, filter, and the filter cake is pulped with EA, then pulped with MeOH, and dried to obtain the title compound 44 (a white solid).

[0359] MS m / z (ESI): 371 [M+1] + .

[0360] 1 H NMR (500MHz, DMSO-d6) δ7.85 (s, 1H), 7.84 (s, 1H), 7.76 (d, 2H), 7.71 (t, 1H), 7.55 (t , 2H), 6.68(s, 2H), 4.40(s, 2H), 2.43(t, 2H), 2.20(s, 3H), 2.14(s, 3H), 0.98(t, 3H).

[0361] Example 45: Synthesis of (Z)-S-(3-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)but-2-en-2-yl)thiobenzoate (compound 45)

[0362]

[0363] Except for replacing 44b with 45b in step 1 of Example 44, the title compound 45 (white solid) was prepared by the same synthetic route as in Example 44.

[0364] MS m / z (ESI): 357 [M+1] + .

[0365] 1 H NMR (500MHz, DMSO-d6): δ7.87(s, 1H), 7.85(s, 1H), 7.74(d, 2H), 7.71(t, 1H), 7 .55(t, 2H), 6.71(br, 2H), 4.41(s, 2H), 2.17(s, 3H), 2.13(s, 3H), 2.07(s, 3H).

[0366] Example 46: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(methylthio)pent-2-en-3-yl)thiobenzoate (compound 46)

[0367]

[0368] Step 1: Add 1.4 g of 46b and 4.4 g of 1a to 10 mL of DMF, heat to 110 °C, and reflux for three hours. Then cool the reaction mixture to room temperature, add methyl tert-butyl ether dropwise, and the product precipitates to give 1.8 g of a yellow oil. Use this crude product directly in the next step of the reaction.

[0369] Step 2: Add the crude product (1.8 g) to 10 g of water and stir to dissolve. Adjust the pH to 10-11 with 30% sodium hydroxide solution. Add benzoyl chloride in tetrahydrofuran solution dropwise, maintain the pH at 10-11, and react for 0.5 hours. Extract the reaction solution twice with dichloromethane, then concentrate to dryness to obtain a yellow oily liquid. Purify by preparative liquid chromatography, and freeze-dry the product to obtain the title compound 46 (0.03 g, off-white solid).

[0370] MS m / z (ESI): 417 [M+1] + .

[0371] 1 H NMR (500MHz, DMSO-d6): δ7.90-7.88 (m, 3H), 7.78 (s, 1H), 7.74 (t, 1H), 7.59 (t, 2H), 6.76 (br, 2H), 3.64 (br, 2H), 2.80 (s, 3H), 2.70 (t, 2H), 2.59 (t, 2H), 2.26 (s, 3H), 2.10 (s, 3H).

[0372] Example 47: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(benzyloxy)pent-2-en-3-yl)thiobenzoate (compound 47)

[0373]

[0374] Step 1: Dissolve 2.02 g of compound 1a and 2.3 g of compound 47b in 6.9 g of DMF, heat to 110 °C and react for 4 h. After cooling, add 20 mL of acetonitrile and stir to precipitate a solid. Filter, wash the filter cake with acetonitrile, and dry to obtain 3.4 g of crude product.

[0375] Step 2: Dissolve 3.4g of the crude product in 10g of water and stir until dissolved. Adjust the pH to 10⁻¹¹ by adding sodium hydroxide solution (30%) dropwise. Stabilize the pH at 10⁻¹¹, cool in an ice bath, and stir for 10 min. Add a tetrahydrofuran solution of benzoyl chloride dropwise while maintaining the temperature below 10℃, adding sodium hydroxide solution during the addition to keep the pH at 10⁻¹¹. After the addition is complete, maintain the temperature for 10 min. Extract twice with dichloromethane, discard the organic phase, concentrate to obtain the crude product, prepare HPL purification, and lyophilize to obtain title compound 47 (a white solid).

[0376] MS m / z (ESI): 477 [M+1] + .

[0377] 1 H NMR (400MHz, DMSO-d6): δ7.82 (s, 2H), 7.73-7.68 (m, 3H), 7.55 (t, 2H), 7.34-7.27 (m, 5H ), 6.67(br, 2H), 4.43-4.41(m, 4H), 3.51(t, 2H), 2.72(t, 2H), 2.18(s, 3H), 2.16(s, 3H).

[0378] Example 48: Synthesis of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-hydroxypent-2-en-3-yl)thiobenzoate (compound 48)

[0379]

[0380] Add VB1 (33.7 g, 0.1 mol) to 100 mL of water, stir until dissolved, and adjust the pH to 10⁻¹² by adding 30% NaOH solution dropwise. React for 0.5 hours, then add benzoyl chloride (14.2 g, 0.1 mol) dropwise at 0-5 °C while maintaining pH at 10⁻¹². React for 1 hour, extract, and purify by organic phase silica gel column chromatography (methanol:dichloromethane = 1:20). Concentrate to obtain a white solid (12.8 g, yield 33.1%).

[0381] MS m / z (ESI): 387 [M+1] + .

[0382] 1H NMR (500MHz, CD3OD): δ8.01 (s, 1H), 7.85 (s, 1H), 7.80 (dd, 2H), 7.67-7.63 (m, 1H), 7 .51-7.47(m, 2H), 4.56(br, 2H), 3.71(t, 2H), 2.75(t, 2H), 2.27(s, 3H), 2.19(s, 3H).

[0383] Example 49: Synthesis of (Z)-S-(2-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)pent-1,3-dien-3-yl)thiobenzoate (compound 49)

[0384]

[0385] Step 1: Add 1a (2.8 g, 0.01 mol) and 49b (1.2 g, 0.01 mol) to a mixed solution of 12 mL DMF and 4 mL acetonitrile, and react at 110 °C for 2 h. After cooling, add acetonitrile, precipitate a solid, filter, and obtain approximately 1.2 g of crude product.

[0386] Step 2: Add 3g of water to the crude product from Step 1, adjust the pH to 10-12 with 30% sodium hydroxide solution, stir for half an hour, add 2mL of tetrahydrofuran solution containing 0.4g of benzoyl chloride, maintain the pH at 10-12, and stir for another half hour. Extract with 50mL of dichloromethane, dry with anhydrous sodium sulfate, and purify by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain 32mg of crude product. Then purify by preparative liquid chromatography and freeze-dry to obtain the title compound 49 (10mg, yellow solid).

[0387] MS m / z (ESI): 369 [M+1] + .

[0388] 1 H NMR (500MHz, DMSO-d6) δ7.91 (s, 1H), 7.86 (s, 1H), 7.81 (d, 2H), 7.71 (t, 1H), 7.56 (t, 2H), 6. 97(dd, 1H), 6.67(br, 2H), 5.46(d, 1H), 5.31(d, 1H), 4.49(s, 2H), 2.30(s, 3H), 2.22(s, 3H).

[0389] Example 50: Synthesis of (Z)-S-(6-amino-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-6-oxohex-2-en-3-yl)thiobenzoate (Compound 50)

[0390]

[0391] Except for replacing 49b with 50b in step 1 of Example 49, the title compound 50 (white solid) was prepared by the same synthetic route as in Example 49.

[0392] MS m / z (ESI): 414 [M+1] + .

[0393] 1H NMR (500MHz, DMSO-d6): δ7.86 (s, 1H), 7.84 (s, 1H), 7.76 (d, 2H), 7.56 (t, 1H ), 7.53(t, 2H), 6.67(br, 2H), 4.40(s, 2H), 2.65(t, 2H), 2.23-2.16(m, 8H).

[0394] Example 51: Synthesis of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-6-morpholino-6-oxohex-2-en-3-yl)3-bromothiobenzoate (compound 51)

[0395]

[0396] Compound 31 (0.20 g, 0.4 mmol, 1.0 eq.), dichloromethane (10 mL), morpholine (0.035 g, 0.4 mmol, 1.0 eq.), HATU (0.18 g, 0.48 mmol, 1.2 eq.), and N,N-diisopropylethylamine (0.10 g, 0.8 mmol, 2.0 eq.) were added sequentially to a reaction flask. The resulting reaction solution was stirred at room temperature for 16 hours, concentrated under reduced pressure, and purified by preparative HPLC. The target fraction was collected and lyophilized to give title compound 51 (90 mg, off-white solid, yield: 40%).

[0397] MS m / z (ESI): 562,564 [M+1] + .

[0398] 1 H NMR (400Hz, DMSO-d6): δ7.90-7.84(m, 3H), 7.76-7.72(m, 2H), 7.49(t, 1H), 6.83(br, 2H), 4.39(b r, 2H), 3.54-3.50 (m, 4H), 3.39-3.36 (m, 4H), 2.64 (t, 2H), 2.47 (t, 2H), 2.17 (s, 3H), 2.16 (s, 3H).

[0399] Example 52: Synthesis of (Z)-S-(2-(N-(((4-amino-2-phenylpyrimidin-5-yl)methyl)formamido)-5-methoxypent-2-en-3-yl)thiobenzoate (compound 52)

[0400]

[0401] Step 1: Add 52a (31.3 g, 0.2 mol) to 200 mL of anhydrous ethanol, add sodium methoxide (10.8 g, 0.2 mol) and stir for 3 hours; filter, add the filtrate to a 500 mL reaction flask, and cool to 0–10 °C; add ethoxymethylene malononitrile (24.4 g, 0.2 mol), a yellow solid precipitates, stir at room temperature for 12 hours, filter, wash the filter cake twice with anhydrous ethanol, and dry the filter cake under vacuum at 40 °C to obtain 52b (23.5 g, 60% yield).

[0402] Step 2: Add 23.5g of 52b and 24.5g of RaneyNi to 125g of formic acid and 24.5g of water, heat to 60°C, and reflux for three hours. Filter the reaction mixture, and wash the filter cake with formic acid. Cool the filtrate to 0°C, add ammonia dropwise, and the product precipitates. Stir for 1 hour; filter, and vacuum dry the filter cake to obtain 25g of pale yellow crude product. Add the crude product to 150mL of methanol, cool to 0°C in a cold water bath, and add sodium borohydride (4.8g, 0.126mol) in portions. Stir for 3 hours. LC-MS monitoring showed that the reaction was complete. Purify by silica gel column chromatography (dichloromethane:methanol = 10:1), and concentrate under vacuum at 40°C to obtain 13.5g of white solid (50% yield).

[0403] Step 3: Add 52C (6.1 g, 0.03 mol) and DMAP (6.6 g, 0.054 mol) to 100 mL of dichloromethane, cool to 0 °C using a cold water bath, add methanesulfonyl chloride (5.2 g, 0.045 mol) dropwise, and stir for 2 hours. Concentrate under reduced pressure and evaporate the solvent to dryness.

[0404] Step 4: Add 20 mL of DMF and 4.7 g (0.03 mol) of 5-(2-methoxyethyl)-4-methylthiazole to the product from Step 3, heat to 110 °C and reflux for 3 hours. LC-MS monitoring showed that the reaction was complete. Cool to room temperature, add MTBE to precipitate the product, separate the supernatant, and concentrate the residue under reduced pressure to obtain an oily liquid 52e (14 g), which was used directly in the next step of the reaction without further purification.

[0405] Step 5: Add the crude product 52e (4.3g, 0.01mol) from Step 4 to 30g of water, stir to dissolve, adjust the pH to 10-11 with 30% sodium hydroxide solution, add tetrahydrofuran solution of benzoyl chloride dropwise, maintain the pH at 10-11 and react for 0.5 hours, extract the reaction solution twice with dichloromethane, and then concentrate to dryness to obtain a yellow oily liquid, which is purified by preparative liquid chromatography, and the product is lyophilized to obtain the title compound 52 (0.06g, white solid).

[0406] MS m / z (ESI): 463.0 [M+1] + .

[0407] 1 H NMR (400MHz, DMSO-d6): δ8.21(dd, 2H), 8.07(s, 1H), 7.87(s, 1H), 7.66-7.62(m, 3H), 7.45-7 .40(m, 5H), 6.82(br, 2H), 4.51(s, 2H), 3.39(t, 2H), 3.21(s, 3H), 2.66(t, 2H), 2.20(s, 3H).

[0408] Example 53: Synthesis of (Z)-S-(2-(N-(((4-amino-2-phenylpyrimidin-5-yl)methyl)formamido)-5-methoxypent-2-en-3-yl)furan-2-thiocarbamate (Compound 53)

[0409]

[0410] Except for replacing benzoyl chloride with 53b in step 5 of Example 52, the title compound 53 (a white solid) was prepared using the same synthetic route as in Example 52.

[0411] MS m / z (ESI): 453.0 [M+1] + .

[0412] 1 H NMR (500MHz, DMSO-d6) δ8.25-8.23 (m, 2H), 8.06 (s, 1H), 7.96 (d, 1H), 7.86 (s, 1H), 7.46-7.45 (m, 3H), 7. 19(d, 1H), 6.82(br, 2H), 6.69(dd, 1H), 4.48(s, 2H), 3.38(t, 2H), 3.20(s, 3H), 2.63(t, 2H), 2.17(s, 3H).

[0413] Example 54: Synthesis of (Z)-S-(2-(N-((4-amino-2-(pyridin-2-yl)pyrimidin-5-yl)methyl)formamido)-5-methoxypent-2-en-3-yl)thiobenzoate (compound 54)

[0414]

[0415] Step 1: Add 54a (50.0 g, 318.5 mmol, 1.0 eq) and methanol (500 mL) to a 500 mL single-necked flask, add MeONa (18 g, 333.3 mmol, 1.05 eq) while stirring, stir at room temperature for 0.5 hours, add ethoxymethylene malononitrile (38.8 g, 318.5 mmol, 1.0 eq), stir at room temperature for 2 hours, filter, and dry the filter cake to obtain 54b (yellow solid, 40 g, yield: 63.7%).

[0416] Step 2: Add 54b (40g, 203mmol, 1.0eq), 30% NaOH (200mL), and methanol (200mL) to a 250mL three-necked flask. Heat to 90℃ and stir for 4 hours. Cool to room temperature, adjust pH to 5 with 2M HCl, filter, and dry the filter cake to obtain 32g of white solid. Transfer the white solid to a 1000mL three-necked flask, add methanol (1000mL) and thionyl chloride (19.8g, 167mmol, 1.2eq), heat to 90℃ and stir for 4 hours. Cool to room temperature, adjust pH to 7-8 with saturated sodium bicarbonate, filter, and dry the filter cake to obtain 54c (yellow solid, 25g).

[0417] Step 3: Add 54c (10.0 g, 43.5 mmol, 1.0 eq) to a 500 mL single-necked flask, add THF (100 mL) under nitrogen protection, cool in an ice bath, add LiAlH4 (52 mL, 52 mmol, 1.2 eq) dropwise, stir for 2 hours, quench with water, extract with EA, dry the organic phase with anhydrous sodium sulfate, concentrate to obtain crude product, and purify by silica gel column chromatography (eluent: DCM:MeOH = 20:1 to 5:1) to obtain 54d (yellow solid, 8.9 g).

[0418] Step 4: Add 54d (6g, 29.7mmol, 1.0eq) and 33% HBr acetic acid solution (18g) to a 100mL single-necked flask, heat to 100℃ and stir for 2 hours, cool, add acetonitrile, and filter to obtain 54e (yellow solid, 6.5g, yield 82.5%).

[0419] Step 5: Add 5-(2-methoxyethyl)-4-methylthiazole (2.67 g, 17 mmol, 1.5 eq), 54e (3.0 g, 11.4 mmol, 1.0 eq), and DMF (30 mL) to a 100 mL single-necked flask, heat to 110 °C and stir for 3 hours, cool, add acetonitrile, stir and filter, dry the filter cake to obtain 54f (yellow solid, 2.6 g, yield 54%).

[0420] Step 6: Dissolve 54f (2.6g, 6.4mmol, 1.0eq) in 10g of water, add 30% sodium hydroxide solution to adjust the pH to 10-12, stir for 1 hour, retest the pH, adjust the pH to 10-12 until stable, keep below 10℃ and add benzoyl chloride (0.89g, 6.4mmol, 1.0eq), after the addition is complete, keep the reaction at 10 minutes, adjust the pH to 6, add ethyl acetate, separate the liquid and adjust the pH of the aqueous phase to 4, filter, concentrate the filtrate to obtain crude product, the crude product is purified by preparative HPLC separation (eluent: 0.1% formic acid aqueous solution: MeOH = 10%~80%), collect the target component and freeze dry to obtain the title compound (54, reddish-brown solid).

[0421] MS m / z (ESI): 464 [M+1] + .

[0422] 1 H NMR (400MHz, DMSO-d6) δ8.65 (d, 1H), 8.18-8.11 (m, 2H), 7.88-7.82 (m, 2H), 7.68-7.60 (m, 3H), 7. 49-7.36(m, 3H), 6.97(br, 2H), 4.52(s, 2H), 3.36(t, 2H), 3.18(s, 3H), 2.64(t, 2H), 2.19(s, 3H).

[0423] Example 55: (Z)-S-(2-(N-((4-amino-2-(thien-2-yl)pyrimidin-5-yl)methyl)formamido)-5-methoxypent-2-en-3-yl)thiobenzoate (Compound 55)

[0424]

[0425] Step 1: Add 55a (50.0 g, 458.7 mmol, 1.0 eq) and methanol (50 mL) to a 500 mL single-necked flask. While stirring, add 350 g of 20% HCl dioxane solution and stir at room temperature for 12 hours. Then add sodium methoxide (49.5 g, 917.4 mmol, 2.0 eq) and stir for 2 hours. Add NH3 methanol solution (100 mL) and stir at room temperature for 0.5 hours. Concentrate and remove the solvent. Then, methanol (100 mL) and sodium methoxide (49.5 g, 917.4 mmol, 2.0 eq) were added, and the mixture was stirred at room temperature for 0.5 hours. Ethoxymethylene malononitrile (56 g, 458.7 mmol, 1.0 eq) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was then purified by silica gel column chromatography (eluent: DCM:MeOH = 30:1–10:1) to give 55b (yellow solid, 26 g, yield: 28.1%).

[0426] Step 2: Except that 52b in Step 2 of Example 52 is replaced with 55b, 55c (yellow solid) is prepared using the same synthetic route.

[0427] Steps 3 to 5: Except for replacing 54d with 55c in step 4 of Example 54, the same synthesis steps and methods as in steps 4 to 6 of Example 54 were used to obtain title compound 55 (white solid).

[0428] MS m / z (ESI): 469 [M+1] + .

[0429] 1 H NMR (400MHz, DMSO-d6) δ7.97 (s, 1H), 7.86 (s, 1H), 7.73-7.61 (m, 5H), 7.42 (t, 2H), 7.13 (t, 1H), 6.91 (br, 2H), 4.47 (s, 2H), 3.38 (t, 2H), 3.18 (s, 3H), 2.64 (t, 2H), 2.18 (s, 3H).

[0430] Example 56: Synthesis of (Z)-S-(2-(N-((4-amino-2-cyclohexylpyrimidin-5-yl)methyl)formamido)-5-methoxypent-2-en-3-yl)thiobenzoate (compound 56)

[0431]

[0432] Except for replacing 55a in step 1 of Example 55 with cyclohexanenitrile, title compound 56 (a white solid) was prepared using the same synthetic route as in Example 55.

[0433] MS m / z (ESI): 469 [M+1] + .

[0434] 1 H NMR (400MHz, CD3OD): δ7.93 (d, 2H), 7.75 (d, 2H), 7.63 (t, 1H), 7.47 (t, 2H), 4.54 (br, 2H), 3.48 (t, 2 H), 3.29 (s, 3H), 2.75 (t, 2H), 2.48-2.41 (m, 1H), 2.22 (s, 3H), 1.77-1.67 (m, 5H), 1.43-1.17 (m, 5H).

[0435] Example 57: Synthesis of (Z)-S-(2-(N-((4-amino-2-cyclobutylpyrimidin-5-yl)methyl)formamido)-5-methoxypent-2-en-3-yl)thiobenzoate (compound 57)

[0436]

[0437] Except for replacing 55a in step 1 of Example 55 with cyclobutadiene nitrile, the title compound 57 (white solid) was prepared using the same synthetic route as in Example 55.

[0438] MS m / z (ESI): 441 [M+1] + .

[0439] 1 H NMR (400MHz, DMSO-d6) δ7.87 (s, 1H), 7.82 (s, 1H), 7.73-7.66 (m, 3H), 7.51 (t, 2H), 6.64 (br, 2H), 4.40 (s, 2 H), 3.37-3.33(m, 3H), 3.19(s, 3H), 2.64(t, 2H), 2.26-2.02(m, 7H), 1.94-1.84(m, 1H), 1.77-1.71(m, 1H).

[0440] Biological tests

[0441] Experimental Example 1

[0442] The BCA protein concentration assay kit was purchased from Beyotime, the Aβ40 and Aβ42 assay kits were purchased from Wako, and all cell culture-related reagents were purchased from Gibco.

[0443] HEK293APP / sw overexpressing cells were cultured in 48-well plates using DMEM medium (containing 10% FBS, 100 μg / mL G418 (Geneticin), and a penicillin antibiotic (1×Penicillin, Streptomycin). 4 mM of the compound stock solution (prepared by dissolving the compound in DMEM medium) was filtered through a 0.22 μm sterile filter and stored at -20°C for later use. At 70% cell density, 40 μL of the compound test solution was added to each well, resulting in a final concentration of 400 μM, and the cells were incubated for 24 hours.

[0444] Take a portion of the culture supernatant, add BCA reagent, incubate at room temperature for 30 min, and then measure the absorbance (OD value) of each well at 570 nm using a microplate reader. Calculate the total protein concentration based on the protein standard curve. Simultaneously, add another portion of the supernatant (100 μL) to a prepared 96-well plate and incubate overnight at 4°C. After removing the solution and washing off the reagents, add HRP (horseradish peroxidase)-labeled antibody and incubate at 4°C for 2 hours. After removing and washing off the reagents, add TMB chromogenic solution and incubate at room temperature for 30 min. Add stop solution to terminate the reaction, and measure the absorbance (OD value) of each well at 450 nm using a microplate reader. Calculate the concentrations of Aβ40 and Aβ42 based on the Aβ40 and Aβ42 standard curves, respectively. Finally, adjust the concentrations of Aβ40 and Aβ42 using the total protein concentration to obtain the final concentration. The test results are shown in the table below.

[0445] 5 46.68 4.5 7 46.6 4.78 8 46.9 3.93 9 47.77 4.69 15 38.18 3.42 21 42.8 4.4 22 41.77 4.2 23 31.37 4.43 24 34.6 3.28 26 39.65 4.1 34 39.5 1.9 35 49.45 3.76 36% formate 40.09 3.36 44 38.59 3.6 45 33.95 4.13 48 68.41 4.45 52 58.05 5.23 Blank control* 127.81 11.08

[0446] * No compound test solution is added to the blank control.

[0447] As can be seen from the above experimental results, the compounds of the present invention can significantly reduce the levels of Aβ42 and / or Aβ40.

[0448] Experimental Example 2. Toxicity Test

[0449] 2.1 Experimental Objective

[0450] This embodiment uses a CCK-8 assay kit to test the toxicity of the compound. The CCK-8 kit is a assay kit based on WST-8 (chemical name 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonylbenzene)-2H-tetrazole monosodium salt) for the detection of cell proliferation and toxicity. Its detection principle is that in the presence of an electron coupling reagent, WST-8 can be reduced by mitochondrial dehydrogenases to generate a highly water-soluble orange-yellow formazan product. The intensity of the color is directly proportional to the number of viable cells and inversely proportional to cytotoxicity. The OD value is measured at a wavelength of 450 nm using a microplate reader to reflect the level of cell proliferation and toxicity.

[0451] 2.2. Experimental Methods

[0452] 2.2.1 Experimental Materials

[0453] CCK-8 reagent kit MK MX3008 DMSO sigma D2650-100ML DMEM(1×) gibco 11995-065 DPBS basic (1×) gibco C14190500BT 0.25% Typsin-EDTA (1×) gibco 25200-056 CO2 incubator Panasonic Health Medical Devices Co., Ltd. MCO-18AC-PC

[0454] centrifuge Anting TDL-80-2B

[0455] 2.2.2 Experimental Procedure

[0456] 1) Cell plating

[0457] 1.1 When the HEK293-APP cell density reaches 80%–90%, collect the cells by digestion and centrifugation, remove the supernatant, add 5 ml of culture medium and mix well.

[0458] 1.2 After thoroughly mixing, take 20 μL of cell suspension and add it to 180 μL of culture medium to dilute it 10 times, and count the cells.

[0459] 1.3 Take another 15ml portion of DMEM complete medium and place it in a centrifuge tube. Add the cell suspension to the medium to adjust the cell count, so that the final dilution concentration of each cell is 2.4 × 10⁻⁶. 5 pcs / ml;

[0460] 1.4 To prevent liquid evaporation, 100 μl of sterile PBS should be added to the edge wells of the 96-well plate.

[0461] 1.5 Add culture medium to the sample well and gently pipette to spread 100 μL per well, achieving a cell count of 2.4 × 10⁻⁶ cells per well. 4 indivual.

[0462] 1.6 Place the inoculated cell culture plate into an incubator for culture.

[0463] 2) Add the test compound

[0464] 2.1 Prepare a 4 mM stock solution of the compound to be tested using DMEM culture medium, filter it through a 0.22 μm sterile filter, and store it at -20℃ for later use.

[0465] 2.2 After the cells have completely adhered to the well, add the above 4mM stock solution, 10μL per well, for a final concentration of 400μM, and set up 3 replicates.

[0466] 2.3 Incubate the cell culture plates at 5% CO2 and 37°C for 24 hours.

[0467] 3) Add CCK-8 reagent

[0468] 3.1 Add 10 μL of CCK-8 reagent to each well and continue culturing for 1 h.

[0469] 3.2 After 1 hour of incubation, the absorbance was measured at 450 nm.

[0470] 2.3. Experimental Results

[0471] Inhibition rate = (1 - absorbance of test group / absorbance of control group) * 100%, and the experimental results are shown in the table below.

[0472] 4 -3.02％ 5 1.49％ 7 -3.10％ 8 -6.81％ 9 -10.30％ 15% hydrochloride -2.60％ 23 1.95％ 24 -0.43％ 26 2.70％ 32 -8.65％ 33 -14.22％ 34 -6.19％ 35 -11.13％ 36% formate -7.41％ 38% formate -14.26％ 43 -0.27％ 44 4.98％

[0473] Experimental results show that the compounds of this invention have good safety.

[0474] In addition to those described herein, various modifications to the invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 。 2. A pharmaceutical composition comprising a preventive 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 the prevention or treatment of neurodegenerative diseases or for the relief of symptoms of neurodegenerative diseases, wherein the neurodegenerative disease is Alzheimer's disease.

Images