CN117545742A

CN117545742A - Pyrimidine compound, pharmaceutical composition containing same, preparation method and application thereof

Info

Publication number: CN117545742A
Application number: CN202280041466.9A
Authority: CN
Inventors: 张寰; 景何凤; 孟丽娟
Original assignee: Shanghai Rixin Pharmaceutical Technology Co ltd
Current assignee: Shanghai Rixin Pharmaceutical Technology Co ltd
Priority date: 2021-06-11
Filing date: 2022-06-06
Publication date: 2024-02-09
Also published as: WO2022257875A1

Description

Pyrimidine compound, pharmaceutical composition containing same, preparation method and application thereof

Technical Field

The invention relates to pyrimidine compounds, a pharmaceutical composition containing the same, a preparation method of the pyrimidine compounds and application of the pyrimidine compounds in treatment of neurodegenerative diseases.

Background

Alzheimer's Disease (AD) is a progressive neurodegenerative disease with cognitive and behavioral disorders as the main clinical manifestations, and is the most common senile dementia, mainly manifested by cognitive dysfunction and rapid decline of memory function. The main pathophysiological features are the formation of senile plaques by beta-amyloid (aβ) deposition in the brain, neurofibrillary tangles by hyperphosphorylation of tau protein, brain glucose metabolism disorders and neuronal/synaptic loss. The long course of disease and the poor self-care ability of the life of the patient bring serious mental and economic burden to the family and society. However, there is no drug currently available worldwide that can prevent or delay the progression of the disease, and the drugs currently marketed for the treatment of AD are symptomatic drugs only, can control or improve cognitive and functional symptoms for a period of time, and cannot prevent or delay the progression of the disease.

Disclosure of Invention

The present invention provides pyrimidine compounds, which are useful for preventing or treating neurodegenerative diseases. In addition, the compounds of the present invention have superior properties such as better physicochemical properties (e.g., solubility, physical and/or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, proper half-life, and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and/or fewer side effects), less susceptibility to developing drug resistance, and the like.

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):

wherein the method comprises the steps of

R is selected from H, halogen, hydroxy, amino, cyano, nitro, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, -C (=nh) NH ₂ 、-C(＝O)R ³ 、-OC(＝O)R ³ 、-C(＝O)OR ³ 、-OR ³ 、-SR ³ 、-S(＝O)R ³ 、-S(＝O) ₂ R ³ 、-S(＝O) ₂ NR ³ R ⁴ 、-NR ³ R ⁴ 、-C(＝O)NR ³ R ⁴ 、-NR ³ -C(＝O)R ⁴ 、-NR ³ -C(＝O)OR ⁴ 、-NR ³ -S(＝O) ₂ -R ⁴ 、-NR ³ -C(＝O)-NR ³ R ⁴ 、-C _1-6 alkylene-NR ³ R ⁴ and-O-C _1-6 alkylene-NR ³ R ⁴ ；

L ¹ And L ² Each independently selected from direct bond, C _1-6 Alkylene and C _2-6 Alkenylene;

R ¹ and R is ² Each independently selected from H, halogen, hydroxy, oxo, amino, cyano, nitro, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, =n-OR ³ 、-C(＝NH)NH ₂ 、-C(＝O)R ³ 、-OC(＝O)R ³ 、-C(＝O)OR ³ 、-OR ³ 、-SR ³ 、-S(＝O)R ³ 、-S(＝O) ₂ R ³ 、-S(＝O) ₂ NR ³ R ⁴ 、-NR ³ R ⁴ 、-C(＝O)NR ³ R ⁴ 、-NR ³ -C(＝O)R ⁴ 、-NR ³ -C(＝O)OR ⁴ 、-NR ³ -S(＝O) ₂ -R ⁴ 、-NR ³ -C(＝O)-NR ³ R ⁴ 、-C _1-6 alkylene-NR ³ R ⁴ and-O-C _1-6 alkylene-NR ³ R ⁴ ；

R ³ And R is ⁴ Each at each occurrence is independently selected from H, C _1-6 Alkyl, C _3-10 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 An aralkyl group;

the above alkyl, alkylene, alkenyl, alkenylene, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl groups are each optionally substituted at each occurrence with one or more substituents independently selected from the group consisting of: halogen, hydroxy, oxo, amino, cyano, nitro, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, =n-OR ⁵ 、-C(＝NH)NH ₂ 、-C(＝O)R ⁵ 、-OC(＝O)R ⁵ 、-C(＝O)OR ⁵ 、-OR ⁵ 、-SR ⁵ 、-S(＝O)R ⁵ 、-S(＝O) ₂ R ⁵ 、-S(＝O) ₂ NR ⁵ R ⁶ 、-NR ⁵ R ⁶ 、-C(＝O)NR ⁵ R ⁶ 、-NR ⁵ -C(＝O)R ⁶ 、-NR ⁵ -C(＝O)OR ⁶ 、-NR ⁵ -S(＝O) ₂ -R ⁶ 、-NR ⁵ -C(＝O)-NR ⁵ R ⁶ 、-C _1-6 alkylene-NR ⁵ R ⁶ and-O-C _1-6 alkylene-NR ⁵ R ⁶ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl groups are further optionally substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxy, oxo, amino, cyano, nitro, C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 An aralkyl group;

R ⁵ and R is ⁶ Each at each occurrence is independently selected from H, C _1-6 Alkyl, C _3-10 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 An aralkyl group; and is also provided with

Provided that when-L ² -R ² Together form C _1-6 In the case of alkyl radicals, -L ¹ -R ¹ Not unsubstituted phenyl; and is also provided with

when-L ² -R ² Together form- (CH) ₂ ) ₂ -OC(＝O)-(C _1-7 Alkyl), -L ¹ -R ¹ Not unsubstituted phenyl and unsubstituted furyl.

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

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

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

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

In another aspect, the invention provides a process for the preparation of the compounds of the invention.

Detailed Description

Definition of the definition

Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

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

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.

As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6 carbon atoms. For example, as used herein, the term "C _1-6 Alkyl "refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted with 1 or more (such as 1 to 3) suitable substituents such as halogen (this group is referred to as" haloalkyl ") (e.g., CF) ₃ 、C ₂ F ₅ 、CHF ₂ 、CH ₂ F、CH ₂ CF ₃ 、CH ₂ Cl or-CH ₂ CH ₂ CF ₃ Etc.). The term "C _1-4 Alkyl "refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

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

As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon radical containing one double bond and having 2 to 6 carbon atoms ("C _2-6 Alkenyl "). The alkenyl group is, for example, vinyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.

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

As used herein, the term "alkynyl" means 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.

As used herein, the terms "cycloalkylene", "cyclic hydrocarbon" and "hydrocarbon ring" refer to a saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double and/or triple bonds within the ring) mono-or polycyclic hydrocarbon ring having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including, but not limited to, cyclopropyl (cyclo), (cyclobutyl (cyclo) ene, (cyclopentyl (cyclo) ene), (cyclohexyl (cyclo) ene), (cycloheptyl (cyclo), (cyclooctyl (cyclo), (cyclonon) (cyclohexenyl (cyclo) ene), and the like.

As used herein, the term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclic [ 1.1.1:1:]amyl, bicyclo [2.2.1]Heptyl, bicyclo [3.2.1]Octyl or bicyclo [5.2.0]Nonyl, decalyl, etc.), optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C _3-6 Cycloalkyl "refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), optionally substituted with 1 or more (such as 1 to 3) suitable substituents, for example methyl-substituted cyclopropyl.

As used herein, the term "heterocyclyl" 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) selected from C (=o), O, S, S (=o), S (=o) ₂ And NR ^a Wherein R is a heteroatom-containing group ^a Represents a hydrogen atom or C _1-6 Alkyl or halo-C _1-6 An alkyl group; the heterocycloalkyl ringThe radical may be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present. In particular, 3-10 membered heterocyclyl groups are groups having 3-10 carbon atoms and heteroatoms in the ring such as, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.

As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term "C _6-14 Aryl "means an aromatic group containing 6 to 14 carbon atoms such as phenyl or naphthyl. Aryl is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO) ₂ 、C _1-6 Alkyl, etc.) substitution.

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

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 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom (which may be the same or different, such as oxygen, nitrogen or sulfur) and which may additionally be benzo-fused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like, and benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and their benzo derivatives.

As used herein, the term "halo" or "halogen" group is defined to include F, cl, br or I.

As used herein, the term "alkylthio" means an alkyl group, as defined above, appended to the parent molecular moiety through a sulfur atom. C (C) _1-6 Representative examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, t-butylthio, and hexylthio.

As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated mono-or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least one nitrogen atom in the ring, which may optionally further comprise one or more (e.g., one, two, three, or four) selected from N, O, C = O, S, S =o and S (=o) ₂ Ring members of (a); the nitrogen-containing heterocycle is attached to the remainder of the molecule through a nitrogen atom. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring. In particular, 3 to 14 membered nitrogen-containing heterocycles are groups having 3 to 14 carbon atoms and heteroatoms in the ring (at least one of which is a nitrogen atom), which include, but are not limited to, ternary nitrogen-containing heterocycles (such as aziridinyl), quaternary nitrogen-containing heterocycles (such as azetidinyl), five-membered nitrogen-containing heterocycles (such as pyrrolyl, pyrrolidinyl (pyrrolidinyl), pyrrolinyl, pyrrolonyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), six-membered nitrogen-containing heterocycles (such as piperidinyl (piperidyl), morpholinyl, thiomorpholinyl, piperazinyl), seven-membered nitrogen-containing heterocycles, and the like.

The term "substitution" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

If a substituent is described as "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent any hydrogens are present) may be replaced with an independently selected optional substituent, alone and/or together. If the nitrogen of a substituent is described as optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogens are present) may each be replaced with an independently selected optional substituent.

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

The term "one or more" as used herein means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.

As used herein, unless indicated, the point of attachment of a substituent may be from any suitable position of the substituent.

When the bond of a substituent is shown as a bond through the ring connecting two atoms, then such substituent may be bonded to any ring-forming atom in the substitutable ring.

The invention also includes all pharmaceutically acceptable isotopically-labelled compounds which are identical to those of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, ² h) Tritium (T, ³ h) A) is provided; isotopes of carbon (e.g ¹¹ C、 ¹³ C, C is a metal alloy ¹⁴ C) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of chlorine (e.g ³⁶ Cl); isotopes of fluorine (e.g ¹⁸ F) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of iodine (e.g ¹²³ I, I ¹²⁵ I) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of nitrogen (e.g ¹³ N is N ¹⁵ N); isotopes of oxygen (e.g ¹⁵ O、 ¹⁷ O and O ¹⁸ O); isotopes of phosphorus (e.g ³² P) is as follows; isotopes of sulfur (example) Such as ³⁵ S). Certain isotopically-labeled compounds of the present invention (e.g., those into which a radioisotope is incorporated) are useful in pharmaceutical and/or substrate tissue distribution studies (e.g., assays). Radioisotope tritium (i.e ³ H) Carbon-14 (i.e ¹⁴ C) Are particularly useful for this purpose because of easy incorporation and easy detection. Using positron-emitting isotopes (e.g ¹¹ C、 ¹⁸ F、 ¹⁵ O and O ¹³ N) substitution can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labeled compounds of the present invention can be prepared by processes analogous to those described in the accompanying schemes and/or in the examples and preparations by substituting an appropriate isotopically-labeled reagent for the non-labeled reagent previously employed. Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g., D ₂ O, acetone-d ₆ Or DMSO-d ₆ 。

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

Solid lines may be used hereinSolid wedge shapeOr virtual wedge shapeDepicting the carbon-carbon bonds of the compounds of the present invention. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom (e.g., particular enantiomers, racemic mixtures, etc.) are included. The use of a solid or virtual wedge to depict a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown. When present in a racemic mixture, real and imaginary wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

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

It will also be appreciated that certain compounds of the invention may exist in free form for use in therapy or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs which, upon administration to a patient in need thereof, are capable of providing the compounds of the present invention or metabolites or residues thereof, either directly or indirectly. Thus, when reference is made herein to "a compound of the invention" it is also intended to encompass the various derivative forms of the compounds described above.

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

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

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.

For a review of suitable salts see Stahl, wermpuh, "Handbook of Pharmaceutical Salts: properties, selection, and Use (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

As used herein, the term "ester" means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (compounds of the present invention that can be hydrolyzed under physiological conditions to release the free acid or alcohol form). The compounds of the invention may themselves be esters.

The compounds of the invention may be present in the form of solvates (preferably hydrates) wherein the compounds of the invention comprise a polar solvent as a structural element of the compound lattice, in particular for example water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.

Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances that form in vivo upon administration of the compounds of the invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic hydrolysis, etc. of the compound being administered. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by a process of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.

The invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity, which, when administered into or onto the body, may be converted into the compounds of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Additional 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. Stilla) and "Bioreversible Carriers in Drug Design," Pergamon Press,1987 (E. B. Roche eds., american Pharmaceutical Association). Prodrugs of the invention may be prepared, for example, by replacing the appropriate functional groups present in the compounds of the invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g. "Design of Prodrugs", described in h. Bundegaard (Elsevier, 1985) ".

The invention also encompasses compounds of the invention containing a protecting group. During any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, in Protective Groups in Organic Chemistry, ed.J.F.W.McOmie, plenum Press,1973; and those described in T.W.Greene & P.G.M.Wuts, protective Groups in Organic Synthesis, john Wiley & Sons,1991, which are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.

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

Compounds of formula (I)

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):

wherein the method comprises the steps of

the above alkyl, alkylene, alkenyl, alkenylene, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl groups are each optionally substituted at each occurrence with one or more substituents independently selected from the group consisting of: halogen, hydroxy, oxo, amino, cyano, nitro, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, =n-OR ⁵ 、-C(＝NH)NH ₂ 、-C(＝O)R ⁵ 、-OC(＝O)R ⁵ 、-C(＝O)OR ⁵ 、-OR ⁵ 、-SR ⁵ 、-S(＝O)R ⁵ 、-S(＝O) ₂ R ⁵ 、 -S(＝O) ₂ NR ⁵ R ⁶ 、-NR ⁵ R ⁶ 、-C(＝O)NR ⁵ R ⁶ 、-NR ⁵ -C(＝O)R ⁶ 、-NR ⁵ -C(＝O)OR ⁶ 、-NR ⁵ -S(＝O) ₂ -R ⁶ 、-NR ⁵ -C(＝O)-NR ⁵ R ⁶ 、-C _1-6 alkylene-NR ⁵ R ⁶ and-O-C _1-6 alkylene-NR ⁵ R ⁶ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl groups are further optionally substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxy, oxo, amino, cyano, nitro, C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 An aralkyl group;

In some embodiments, R is selected from C _3-6 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl and 5-14 membered heteroaryl; preferably, R is cyclobutyl, cyclohexyl, phenyl, thienyl or pyridyl.

In some embodiments, the invention provides the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound, or prodrug thereof, wherein L ¹ Is a direct bond or C _2-6 Alkenyl groups.

In some embodiments, L ¹ Is a direct bond or vinylidene.

In some embodiments, the invention provides the 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 radicals, C _6-10 Aryl and 5-14 membered heteroaryl, optionally substituted with one or more substituents independently selected from halogen and-O- (C) _1-6 Alkyl).

In some embodiments, R ¹ Selected from the group consisting of cyclohexenyl, phenyl, and furyl, optionally one or more of which are independently selected from F, cl, br, I and-OCH ₃ Is substituted by a substituent of (a).

In some embodiments, the 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 the group consisting of

In some embodiments, the present invention provides the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvent thereofCompounds, metabolites, isotopically-labeled compounds, or prodrugs, wherein L ² Is a direct bond, C _1-4 Alkylene or C _2-4 Alkenylene radicals.

In some embodiments, L ² Is a direct bond, methylene, ethylene or vinylidene.

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 ² Selected from H, halogen, hydroxy, C _1-6 Alkyl, C _2-6 Alkenyl, C _1-6 Haloalkyl, 3-10 membered heterocyclyl, -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 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ³ And R is ⁴ Each independently selected from H, C _1-6 Alkyl, 3-10 membered heterocyclyl, C _6-10 Aryl and C _6-12 Aralkyl, preferably R ³ And R is ⁴ Each independently selected from H, methyl, ethyl, morpholinyl, phenyl (Ph) and benzyl (Bn).

In some embodiments, R ² H, F, cl, hydroxy, methyl, ethyl, vinyl, -CH ₂ CH ₂ F、-CH ₂ CH ₂ Cl、-OC(＝O)CH ₃ 、-OC(＝O)Ph、-SCH ₃ 、-OCH ₃ 、-OCH ₂ CH ₃ 、-OBn、-NHC(＝O)CH ₃ 、-NHS(＝O) ₂ CH ₃ 、-N(CH ₃ )Ph、-C(＝O)NH ₂ 、-C(＝O)NHCH ₃ 、-C(＝O)N(CH ₃ ) ₂ 、-C(＝O)OH、-C(＝O)OCH ₂ CH ₃ 、

In some embodiments, the 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,

In some embodiments, the invention provides the 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 formula (III):

in some embodiments, the 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

Preparation method

In some embodiments, the present invention provides a process for the preparation of a compound of formula (I):

wherein:

Hal ¹ and Hal ² Each independently ofThe site is selected from F, cl, br and I;

the remaining groups are as defined above;

the method comprises the following steps:

step (I): reacting 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.

The reaction solvent of step (I) is preferably an amide-based solvent (e.g., DMF), a nitrile-based solvent (e.g., acetonitrile), an aromatic hydrocarbon solvent (e.g., toluene or chlorobenzene), an ether-based solvent (e.g., dioxane), N-methylpyrrolidone, or a mixture thereof. The reaction temperature in step (I) is, for example, 80 to 150℃and preferably 100 to 110 ℃.

Step (II): reacting a compound of formula (I) -c with a compound of formula (I) -d to obtain a compound of formula (I).

The reaction of step (II) is preferably carried out in the presence of a base, such as an inorganic base (e.g. sodium hydroxide) or an organic base. The reaction solvent of step (II) is preferably water, dichloromethane, THF or a mixture thereof. The reaction temperature in step (II) is preferably from 0 to 50℃e.g.10℃.

Pharmaceutical compositions and methods of treatment

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

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

In some embodiments, the invention provides a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound or prodrug thereof, or a pharmaceutical composition of the invention, for use in preventing or treating a neurodegenerative disease or alleviating a symptom of a neurodegenerative disease.

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

In some embodiments, the neurodegenerative disease is selected from the group consisting of alzheimer's disease, creutzfeldt-jakob disease, huntington's disease, multiple sclerosis, guillain-barre syndrome, parkinson's disease, lobed-herly disease, paralytic dementia resulting from progressive neuronal cell death, and diseases caused by progressive disorders; preferably Alzheimer's disease.

By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting the tissues of humans and/or other animals within the scope of sound medical judgment without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, in particular for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may also contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents, as desired. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

The pharmaceutical compositions of the present invention may act systematically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection (e.g. intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of an ophthalmic formulation or by inhalation.

For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms.

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

The term "effective amount" as used herein refers to the amount of a compound that, upon administration, will alleviate to some extent one or more symptoms of the disorder being treated.

The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the doses may be proportionally reduced or increased as indicated by the urgent need for a therapeutic situation. It is noted that the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.

The amount of the compound of the invention administered will depend on the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. Generally, an effective dose is about 0.0001 to about 50mg, for example about 0.01 to about 10 mg/kg/day per kg body weight per day (single or divided administration). For a 70kg human, this amounts to about 0.007 mg/day to about 3500 mg/day, for example about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforementioned range may be sufficient, while in other cases larger doses may still be employed without causing any adverse side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.

The compounds of the invention may be present in the pharmaceutical composition in an amount or in an amount of from about 0.01mg to about 1000mg, suitably from 0.1 to 500mg, preferably from 0.5 to 300mg, more preferably from 1 to 150mg, particularly preferably from 1 to 50mg, for example 1.5mg, 2mg, 4mg, 10mg, 25mg etc.

As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing such a disorder or condition, or one or more symptoms of such a disorder or condition.

As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

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

Examples

In order to make the objects and technical solutions of the present invention more apparent, embodiments of the present invention will be described in detail with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The specific conditions not specified in the examples were either conventional or manufacturer-recommended. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.

The structure of the compound is that nuclear magnetic resonance is adopted ¹ H NMR) or Mass Spectrometry (MS). NMR was performed using Bruker AVANCE-500 nuclear magnetic resonance apparatus or AVANCE-400 nuclear magnetic resonance apparatus, with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated methanol (CD) ₃ OD), deuterated water (D ₂ O), etc., the internal standard being Tetramethylsilane (TMS), the chemical shift (δ) being given in parts per million (ppm).

The measuring instrument of MS is Agilent (ESI) mass spectrometer (manufacturer: agilent, model: agilent 6110).

The preparation method of the high performance liquid chromatography separation comprises the following steps:

instrument model: irinotet P3500, chromatographic column: welch Ultimate XB-C18 (30X 250mm,10 μm); chromatographic column temperature, 25 ℃; flow rate: 42mL/min; detection wavelength: 254nm; elution gradient: (0 min: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 in water.

The compounds synthesized in the examples below are based on compounds represented by the formula, the compound names being generated by chembiosdraw software.

Abbreviations in the present invention have the following meanings:

abbreviations (abbreviations)	Meaning of
Bn	Benzyl group
DCM	Dichloromethane (dichloromethane)
DIEA/DIPEA	N, N-diisopropylethylamine
DMAP	4-dimethylaminopyridine
DMF	N, N-dimethylformamide
EA	Acetic acid ethyl ester
HATU	O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate
H ₂ O	Water and its preparation method
LiAlH ₄	Lithium aluminum hydride
MeOH	Methanol
MeONa	Sodium methoxide
MTBE	Methyl tert-butyl ether
NaOH	Sodium hydroxide
Ph	Phenyl group
TBSCl	T-butyldimethylchlorosilane
THF	Tetrahydrofuran (THF)

Example 1: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-fluoropent-2-en-3-yl) thiobenzoate (Compound 1)

Step 1: compound 1a (2.5 g,0.088 mol) and 1b (1.3 g,0.088 mol) were dissolved in 25g DMF, stirred at 100-110℃for 2 hours, cooled to room temperature, methyl tert-butyl ether (50 mL) was added, the product precipitated, filtered, the filter cake was dissolved with 20mL methanol, then methyl tert-butyl ether (50 mL) was added, the product precipitated, filtered, the filter cake washed with methyl tert-butyl ether and dried under vacuum at 40℃to give 2.7g intermediate 1c.

Step 2: intermediate 1c (1.7 g,0.005 mol) was dissolved in 5g water, adjusted to pH 12 with 30% sodium hydroxide solution, stirred for half an hour, cooled to 10 ℃, benzoyl chloride (1 d) (0.8 g,0.005 mol) in THF (5 mL) was added dropwise, kept at pH 10-12 for half an hour with stirring, dichloromethane (50 mL) was added for extraction, and the organic phase was purified by silica gel column chromatography (dichloromethane: methanol=10:1) and concentrated in vacuo at 40 ℃ to give the title compound 1 (0.3 g, off-white solid).

MS m/z(ESI)：389[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )：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).

Example 2: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-fluoropent-2-en-3-yl) 2-fluorothiobenzoate (Compound 2)

The same synthetic route as in example 1 was followed except that benzoyl chloride in step 2 of example 1 was replaced with o-fluorobenzoyl chloride to prepare the title compound 2 (pale yellow solid).

MS m/z(ESI)：407[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 3: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-fluoropent-2-en-3-yl) 2-bromothiobenzoate (Compound 3)

The same synthetic route as in example 1 was followed, except that benzoyl chloride in step 2 of example 1 was replaced with o-bromobenzoyl chloride, to prepare the title compound 3 (pale yellow solid).

MS m/z(ESI)：467[M+1] ⁺ ；469[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 4: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-fluoropent-2-en-3-yl) 2-iodothiobenzoate (Compound 4)

The same synthetic route as in example 1 was followed except that benzoyl chloride in step 2 of example 1 was replaced with o-iodobenzoyl chloride to prepare the title compound 4 (pale yellow solid).

MS m/z(ESI)：515[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 5: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-chloropent-2-en-3-yl) thiobenzoate (Compound 5)

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℃for 3 hours. The reaction was cooled to room temperature, acetonitrile was added, the product precipitated, filtered, and the filter cake washed with DCM and dried under vacuum at 40 ℃ to afford intermediate 5c (2.3 g, off-white solid).

Step 2: to the reaction flask were added intermediate 5c (1.0 g,0.0027 mol) and water (2 g), a 30% sodium hydroxide solution was added to adjust the pH to 10 to 12, stirred for half an hour, a solution of benzoyl chloride (0.25 g,0.0017 mol) in THF (2 mL) was added dropwise, and the pH was kept at 10 to 12 and stirred for half an hour. Dichloromethane (50 mL) was added for extraction, the organic phase was purified by silica gel column chromatography (dichloromethane: methanol=30:1), the resulting product was further purified by liquid phase preparation chromatography and lyophilized to give the title compound 5 (off-white solid).

MS m/z(ESI)：405[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 6: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-fluoropent-2-en-3-yl) furan-2-thiocarboxylate (Compound 6)

The title compound 6 (pale yellow solid) was obtained by the same synthetic route as in example 1, except that benzoyl chloride in step 2 of example 1 was replaced with 6 d.

MS m/z(ESI)：379[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 7: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-fluoropent-2-en-3-yl) cyclohexyl thiocarboxylate (Compound 7)

The title compound 7 (yellow solid) was obtained by the same synthetic route as in example 1 except that benzoyl chloride in step 2 of example 1 was replaced with 7 d.

MS m/z(ESI)：395[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )：δ7.78(s，1H)，7.76-7.74(d，1H)，6.70(s，2H)，4.51-4.48(t，1H)，4.37(s，2H)，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).

Example 8: synthesis of S- ((Z) -2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-fluoropent-2-en-3-yl) (E) -3-phenylpropan-2-thioacrylate (Compound 8)

The title compound 8 (pale yellow solid) was obtained by the same synthetic route as in example 1, except that the benzoyl chloride in step 2 of example 1 was replaced with 8 d.

MS m/z(ESI)：415[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 9: synthesis of (Z) -4- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -3- (benzoylthio) pent-3-en-1-yl acetate (Compound 9)

Step 1: compounds 1a (5.6 g,0.02 mol) and 9b (3.7 g,0.02 mol) were dissolved in 10 mM LDMF, heated to 110℃and refluxed for three hours; then cooled to room temperature, methyl tert-butyl ether was added dropwise, and the product precipitated to give crude product 9c (2.5 g, yellow oil), which was used directly in the next reaction.

Step 2: the above crude product (2.5 g) was added to 10g of water, stirred and dissolved, a solution of benzoyl chloride (0.7 g) in tetrahydrofuran was added dropwise to adjust the pH to 10-11, the pH was kept at 10-11, and the reaction was carried out for 0.5 hours, the reaction solution was extracted twice with methylene chloride, and then concentrated to dryness to give a yellow oily liquid, which was purified by preparative liquid chromatography, and the product was lyophilized to give the title compound 9 (0.1 g, white solid).

MS m/z(ESI)：429[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )：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)。

Example 10: synthesis of (Z) -4- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -3- ((3-bromobenzoyl) thio) pent-3-en-1-yl acetate (Compound 10)

The same synthetic route as in example 9 was followed, except that benzoyl chloride in step 2 of example 9 was replaced with m-bromobenzoyl chloride, to prepare the title compound 10 (off-white solid).

MS m/z(ESI)：509[M+1] ⁺ .

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

Example 11: synthesis of (Z) -4- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -3- ((furan-2-carbonyl) thio) pent-3-en-1-yl acetate (Compound 11)

The same synthesis as in example 9 was followed except that benzoyl chloride in step 2 of example 9 was replaced with furan-2-carbonyl chloride to afford title compound 11 (off-white solid).

MS m/z(ESI)：419[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )：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)。

Example 12: synthesis of (Z) -4- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -3- ((2-methoxybenzoyl) thio) pent-3-en-1-yl acetate (Compound 12)

The same synthetic route as in example 9 was followed, except that benzoyl chloride in step 2 of example 9 was replaced with 2-methoxybenzoyl chloride, to prepare the title compound 12 (white solid).

MS m/z(ESI)：459[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 13: synthesis of (Z) -4- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -3- (cinnamoylthio) pent-3-en-1-yl acetate (Compound 13)

The same synthetic route as in example 9 was followed, except that benzoyl chloride in step 2 of example 9 was replaced with cinnamoyl chloride, to prepare the title compound 13 (white solid).

MS m/z(ESI)：455[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 14: synthesis of (Z) -4- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -3- (benzoylthio) pent-3-en-1-ylbenzoate (Compound 14).

Step 1: compound 14a (34 g,0.1 mol) was added to 200mL of DMF, stirred, DIPEA (26 g,0.2 mol) was added dropwise, cooled to 0℃and reacted for 0.5 h, TBSCl (23 g,0.15 mol) was added dropwise, then incubated at 0-5℃and reacted for 16 h, MTBE500mL was added, stirring was continued for 2 h, filtration was continued, the filter cake was washed with MTBE, and then dried at 40℃to give white solid 14b (30 g).

Step 2: 14b (30 g,0.072 mol) was added to 30mL of water and 60mL of tetrahydrofuran, stirred, adjusted to pH=10-11 by dropwise addition of 30% NaOH solution, reacted for 0.5 hours, then benzoyl chloride (31 g,0.216 mol) was added dropwise to maintain pH=10-11 at 0-5℃for 1 hour, extracted, and the organic phase was purified by silica gel column chromatography (methanol: dichloromethane=1:20) to give the title compound 14 (0.3 g, white solid).

MS m/z(ESI)：491[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )δ7.93(dd，2H)，7.85(s，1H)，7.79(s，1H)，7.74-7.65(m，4H)，7.54-7.51(m，4H)，6.65(s，2H)，4.44-4.37(m，4H)，2.92(t，2H)，2.19(s，3H)，2.13(s，3H)。

Example 15: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-methoxypent-2-en-3-yl) thiobenzoate (Compound 15)

Step 1: 1a (2.0 g, 0.0070 mol) and 15b (1.0 g, 0.006mol) were added to 5mL of DMF and stirred at 110℃for 2 hours. The reaction was cooled to room temperature, acetonitrile was added, the product precipitated, filtered, and the filter cake washed with DCM and dried under vacuum at 40 ℃ to afford intermediate 15c (1.5 g).

Step 2: 15c (1.5 g,0.004 mol) was added to a 100mL single port bottle, 3g H was added ₂ O and 30% sodium hydroxide solution were adjusted to pH 12, stirred for half an hour, cooled to 10deg.C, benzoyl chloride (0.4 g,0.0028 mol) in THF (4 mL) was added dropwise, and the pH was kept at 10-12 and stirred for half an hour. Dichloromethane (50 mL) was added for extraction and the organic phase was purified by column chromatography on silica gel (dichloromethane: methanol=20:1) and concentrated in vacuo at 40 ℃ to give the title compound 15 (0.3 g, off-white solid).

MS m/z(ESI)：401[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 16: synthesis of hydrochloride salt of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-methoxypent-2-en-3-yl) thiobenzoate (Compound 15)

The compound 15 prepared as in example 15 was added to ethyl acetate (10 mL), stirred under ice salt bath until complete dissolution, and an appropriate amount of isopropanol hydrochloride solution was added dropwise until white solid precipitated, filtered, and the filter cake was dried under vacuum at 50 ℃ to give the hydrochloride salt of compound 15 (off-white solid).

MS m/z(ESI)：401[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 17: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-methoxypent-2-en-3-yl) 2-methoxythiobenzoate (Compound 17)

The same synthetic route as in example 15 was followed, except that benzoyl chloride in step 2 of example 15 was replaced with o-methoxy benzoyl chloride, to obtain the title compound 17 (white solid).

MS m/z(ESI)：431[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 18: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-methoxypent-2-en-3-yl) 3-bromothiobenzoate (Compound 18)

The title compound 18 (white solid) was obtained by the same synthetic route as in example 15, except that benzoyl chloride in step 2 of example 15 was replaced with m-bromobenzoyl chloride.

MS m/z(ESI)：481[M+1] ⁺ .

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

Example 19: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-methoxypent-2-en-3-yl) furan-2-thiocarboxylate (Compound 19)

The title compound 19 (white solid) was obtained by the same synthetic route as in example 15, except that benzoyl chloride in step 2 of example 15 was replaced with furan-2-carbonyl chloride.

MS m/z(ESI)：391[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 20: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-methoxypent-2-en-3-yl) cyclohexyl thiocarboxylate (Compound 20)

The title compound 20 (white solid) was obtained by the same synthetic route as in example 15, except that benzoyl chloride in step 2 of example 15 was replaced with cyclohexanechloride.

MS m/z(ESI)：407[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 21: synthesis of S- ((Z) -2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-methoxypent-2-en-3-yl) (E) -3-phenylpropan-2-thioacrylate (Compound 21)

The same synthetic route as in example 15 was followed, except that benzoyl chloride in step 2 of example 15 was replaced with cinnamoyl chloride, to give the title compound 21 (white solid).

MS m/z(ESI)：427[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 22: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-ethoxypent-2-en-3-yl) thiobenzoate (Compound 22)

The title compound 22 (off-white solid) was obtained by the same synthetic route as in example 15 except that 15b in step 1 of example 15 was replaced with 22 b.

MS m/z(ESI)：415[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 23: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-ethoxypent-2-en-3-yl) 3-bromothiobenzoate (Compound 23)

The title compound 23 (white solid) was obtained by the same procedures as in example 22 except that the benzoyl chloride in step 2 of example 22 was replaced with m-bromobenzoyl chloride.

MS m/z(ESI)：495[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 24: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-ethoxypent-2-en-3-yl) 2-methoxythiobenzoate (Compound 24)

The title compound 24 (white solid) was obtained by the same procedures as in example 22 except that benzoyl chloride in step 2 of example 22 was replaced with o-methoxybenzoyl chloride.

MS m/z(ESI)：445[M+1] ⁺ .

¹ H NMR(500MHz，CD ₃ OD)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).

Example 25: synthesis of S- ((Z) -2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-ethoxypent-2-en-3-yl) (E) -3-phenylpropan-2-thioacrylate (Compound 25)

The same synthesis as in example 22 was followed except that benzoyl chloride in step 2 of example 22 was replaced with cinnamoyl chloride to prepare the title compound 25 (white solid).

MS m/z(ESI)：441[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 26: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-ethoxypent-2-en-3-yl) furan-2-thiocarboxylate (Compound 26)

The same synthesis as in example 22 was followed except that benzoyl chloride in step 2 of example 22 was replaced with furan-2-carbonyl chloride to afford title compound 26 (white solid).

MS m/z(ESI)：405[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 27: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-ethoxypent-2-en-3-yl) cyclohexyl thiocarboxylate (Compound 27)

The title compound 27 (white solid) was obtained by the same procedures as in example 22 except that benzoyl chloride in step 2 of example 22 was replaced with cyclohexanecarbonyl chloride.

MS m/z(ESI)：421[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 28: synthesis of hydrochloride of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-ethoxypent-2-en-3-yl) thiobenzoate (Compound 22)

The compound 22 (0.1 g,0.0146 mol) prepared in example 22 was added to ethyl acetate (3 mL), dissolved by stirring, and then a solution of hydrogen chloride in isopropanol was added dropwise with stirring to a pH of 1-2 (about 0.5 mL). After the completion of the dropwise addition, the mixture was stirred for 30 minutes, and the solvent was removed by rotary evaporation at 40℃to give an oil. Deionized water (50 mL) was added to the oil, and after dissolution of the oil, the oil was frozen and lyophilized to give the hydrochloride salt of compound 22 (0.08 g, off-white solid).

MS m/z(ESI)：415[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )：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)。

Example 30: synthesis of (Z) -5- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -4- ((2-methoxybenzoyl) thio) hex-4-enoic acid (Compound 30)

Step 1: sequentially adding 1a (1.54 g), 30b (1.67 g), anhydrous acetonitrile (2 g) and anhydrous DMF (6 g) into a 100mL single-port bottle, stirring, heating to 110 ℃ for reflux reaction for 3h, cooling to room temperature, adding 100mL of anhydrous acetonitrile, filtering, and using MEOH/CH as a filter cake ₃ CN soluble clear, concentrated under reduced pressure to remove solvent, to give product 30c (1.25 g).

Step 2: in a 100mL single-necked flask, 30c (1.25 g) and H were sequentially added ₂ O (3 g), stirring the solution, dropping 30% NaOH to adjust the pH to 10-12, stirring for 0.5h, dropping 2-methoxybenzoyl chloride (0.189 g), HPLC detection shows that the reaction is completed, dropping 36% HCl to adjust the pH to 4-5, adding DCM, stirring for 10min, standing, separating out an organic phase, washing an aqueous phase with DCM twice, combining the organic phases, spin-drying, dissolving the MeOH solution, purifying by preparative chromatography, and freeze-drying to obtain the title compound 30 (white solid).

MS m/z(ESI)：445[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 31: synthesis of (Z) -5- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -4- ((3-bromobenzoyl) thio) hex-4-enoic acid (Compound 31)

The title compound (off-white solid) was obtained by the same procedures as in example 30 except that 2-methoxybenzoyl chloride in step 2 of example 30 was replaced with m-bromobenzoyl chloride.

MS m/z(ESI)：493[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )δ7.92-7.88(m，1H)，7.86(s，1H)，7.85(s，1H)，7.77(t，1H)，7.76-7.72(m，1H)，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).

Example 32: synthesis of ethyl (Z) -5- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -4- (benzoylthio) hex-4-enoate (Compound 32)

To a 100mL single-necked flask, 30c (1.45 g) and 4.0. 4.0g H were successively added ₂ O, stirring and dissolving; dropwise adding 30% NaOH, and regulating the pH to about 10-12 until the pH is stable and unchanged; benzoyl chloride (0.336 g,0.0024 mol)/THF was added dropwise at pH 10-12 and reacted for 10min, DCM was added, the layers were stirred, the organic phase was dried and spun dry and purified by preparative chromatography to give title compound 32 (white solid).

MS m/z(ESI)：443[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 33: synthesis of ethyl (Z) -5- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -4- ((2-methoxybenzoyl) thio) hex-4-enoate (Compound 33)

The same synthesis as in example 32 was followed except that benzoyl chloride in example 32 was replaced with 2-methoxybenzoyl chloride to prepare the title compound 33 (white solid).

MS m/z(ESI)：473[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 34: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-morpholino pent-2-en-3-yl) thiobenzoate (Compound 34)

The title compound 34 (white solid) was obtained by the same synthetic route as in example 1 except that 1b in step 1 of example 1 was replaced with 34 b.

MS m/z(ESI)：456[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 35: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-morpholino pent-2-en-3-yl) 2-methoxythiobenzoate (Compound 35)

The same synthesis as in example 34 was used, except that benzoyl chloride in step 2 of example 34 was replaced with o-methoxybenzoyl chloride, to prepare the title compound 35 (white powdery solid).

MS m/z(ESI)：486[M+1] ⁺ .

¹ H NMR(500MHz，CD ₃ OD)：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)。

Example 36: synthesis of formate salt of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5- (4-phenylpiperazin-1-yl) pent-2-en-3-yl) 2-fluorothiobenzoate (Compound 36)

Step 1: to a 100mL single flask were added 1a (2.1 g), 36b (1.0 g), acetonitrile (20 g) and N, N-dimethylformamide (6 g), and the mixture was heated to 100℃to 110℃and stirred for 3 hours. The reaction was cooled to room temperature, the product precipitated, filtered, the filter cake was slurried with 20mL acetonitrile, filtered, and the filter cake was dried under vacuum at 40℃to afford intermediate 36c.

Step 2: 36c (2.1 g) and water (5.0 g) are added into a 100mL single-port bottle, 30% NaOH is added dropwise to adjust the pH to 11.0, and the mixture is stirred for 30 minutes, wherein the pH is greater than 11.0; o-fluorobenzoyl chloride/tetrahydrofuran (0.38 g/2 mL) was added dropwise, ethyl acetate 5mL was added, the mixture was separated, the aqueous phase was extracted twice with 5mL ethyl acetate, the organic phases were combined, dried, spun-dried and then dissolved in methanol to give the formate salt of title compound 36 (white solid) which was purified by preparative chromatography.

MS m/z(ESI)：549[M+1] ⁺ .

¹ H NMR(500MHz，CD ₃ OD)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).

Example 37: synthesis of S- ((Z) -2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5- ((2S, 6R) -2, 6-dimethylmorpholino) pent-2-en-3-yl) 2-fluorothiobenzoate (Compound 37)

Step 1: 37b (1.8 g,0.0075 mol) and 1a (3.2 g,0.0125 mol) were dissolved in a mixed solution of DMF (15 g) and acetonitrile (5 g) and the oil bath was heated to 110℃for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with acetonitrile, and the filter cake was dried to give a pale-off-yellow solid 37c (2.71 g).

Step 2: 37c (5.56 g,0.0106 mol) was dissolved in water (20 mL) with stirring; dropwise adding 30% sodium hydroxide solution into the reaction solution, adjusting the pH to 10-11, cooling to 10 ℃ in an ice bath, and preserving heat for 10 minutes. Tetrahydrofuran (5 mL) solution of o-fluorobenzoyl chloride is added dropwise at the temperature of 10 ℃, and the pH is controlled to be 10-11 in the process of adding dropwise. After the completion of the dropwise addition, the reaction was continued for 15 minutes with maintaining the pH at a constant temperature, the pH of the reaction solution was adjusted to 7 to 8, extraction was performed three times with methylene chloride, the methylene chloride layer was dried over anhydrous sodium sulfate, the solvent was removed, and the crude product was purified by column chromatography. The purified product was dissolved in purified water and lyophilized to give the target compound 37 (0.055 g, off-white solid).

MS m/z(ESI)：502[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )：δ7.80(s，2H)，7.70-7.60(m，2H)，7.36-7.30(m，2H)，6.65(br，2H)，4.39(s，2H)，3.53-3.42(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)。

Example 38: synthesis of formate salt of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5- (4- (methylsulfonyl) piperazin-1-yl) pent-2-en-3-yl) 2-fluorothiobenzoate (Compound 38)

Step 1: to a 100mL single flask were added 1a (1.4 g), 38b (0.7 g), acetonitrile (2.0 g) and N, N-dimethylformamide (6.0 g), and the mixture was heated to 100℃to 110℃and stirred for 3 hours. The reaction was cooled to room temperature, acetone was added, the product precipitated, filtered, the filter cake was slurried with 20mL of acetonitrile, filtered, and the filter cake was dried under vacuum at 40℃to afford intermediate 38c (3.3 g).

Step 2: in a 100mL single-necked flask, adding intermediate 38c (3.3 g), water (4.4 g), dropwise adding 30% NaOH to adjust the pH to 11.0, stirring for 10 minutes, and re-measuring the pH to be more than 11.0; o-fluorobenzoyl chloride/tetrahydrofuran (0.3 g/2 mL) was added dropwise, ethyl acetate 5mL was added, the mixture was separated, the aqueous phase was extracted twice with 5mL ethyl acetate, the organic phases were combined, dried, spun-dried and then dissolved in methanol to give the formate salt of compound 38 (white solid) which was purified by preparative chromatography.

MS m/z(ESI)：551[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 39: synthesis of (Z) -S- (5-acetamido-2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) pent-2-en-3-yl) thiobenzoate (Compound 39)

Step 1: 39b (1.8 g,0.01 mol) and 1a (5.6 g,0.02 mol) were added to 8 mM DMF, heated to 110℃and then stirred for 2 hours; cooling to 0-10 ℃, adding MTBE to precipitate a product, filtering, washing a filter cake with MTBE, and drying the filter cake to obtain an intermediate crude product 39c (5.5 g, yellow solid)

Step 2: the crude product 39c (3.4 g,0.01 mol) was added to 6.8g of water, dissolved with stirring, pH was adjusted to 10-11 with 30% sodium hydroxide solution, a solution of benzoyl chloride (1.4 g,0.01 mol) in tetrahydrofuran was added dropwise, pH 10-11 was kept for 0.5 hours, the reaction solution was extracted twice with dichloromethane, then concentrated to dryness, and then the product was eluted by column chromatography, dichloromethane: methanol=10:1, and the crude product was purified by preparative chromatography, and the product was lyophilized to give the title compound (0.1 g, white solid).

MS m/z(ESI)：428[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )：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)。

Example 40: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5- (methyl (phenyl) amino) pent-2-en-3-yl) 2-fluorothiobenzoate (Compound 40)

Step 1: 40b (1.0 g,0.0043 mol) was added to 5mL of DMF, followed by 1a (1.6 g,0.0057 mol), heated to 110℃under reflux for 3 hours, then cooled to room temperature, filtered, the filter cake washed with acetonitrile and dried under reduced pressure to give intermediate 40c (1.7 g, white solid).

Step 2: 40c (1.7 g, 0.004mol) was dissolved in 15g of water, stirred for dissolution, dropwise addition of sodium hydroxide solution (30%) was started to adjust pH to 10-12, stirred for 10 minutes, pH was retested, pH was adjusted to 10-12 until stable, stirred for 0.1 hour, solution of o-fluorobenzoyl chloride (0.7 g,0.0044 mol) and 10mL of tetrahydrofuran was added dropwise at 10℃or below, pH was maintained at 10-12 by adding sodium hydroxide solution during the dropwise addition, the reaction was continued for 0.5 hour after completion of dropwise addition, dichloromethane was extracted twice, and the organic phase was purified by silica gel column chromatography (methanol: dichloromethane=1:20) to give the title compound 40 (0.13 g, yellow solid).

MS m/z(ESI)：494[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )：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)。

Example 41: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5- (methylsulfonyl) pent-2-en-3-yl) 2-fluorothiobenzoate (Compound 41)

Step 1: 41b (1.8 g,0.0088 mol) and 1a (3.2 g,0.0125 mol) were dissolved in a mixed solution of DMF (15 g) and acetonitrile (5 g) and the oil bath was heated to 110℃for 3 hours. The reaction solution was cooled to room temperature, filtered, the filter cake was washed with acetonitrile, the filter cake was dried to give intermediate 41c (2.71 g, pale greyish yellow solid).

Step 2: intermediate 41c (2.71 g) was dissolved in water (20 mL) and stirred for dissolution; dropwise adding 30% sodium hydroxide solution into the reaction solution, adjusting the pH to 10-11, cooling to 10 ℃ in an ice bath, and preserving heat for 10 minutes. Tetrahydrofuran (5 mL) solution of o-fluorobenzoyl chloride is added dropwise at the temperature of 10 ℃, and the pH is controlled to be 10-11 in the process of adding dropwise. After the dropwise addition, the reaction is continued for 15 minutes while keeping the temperature and the pH value, the pH of the reaction solution is adjusted to 7-8, the reaction solution is extracted three times by using methylene dichloride, a methylene dichloride layer is dried by using anhydrous sodium sulfate, the solvent is removed, and the crude product is purified by column chromatography. The purified product was dissolved in purified water and lyophilized to give the title compound 41 (0.31 g, off-white solid).

MS m/z(ESI)：482[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )：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)。

Example 42: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -6- (methylamino) -6-oxohex-2-en-3-yl) thiobenzoate (Compound 42)

Step 1: in a 100mL single-port flask, add 1a (1.54 g), 42b (1.67 g), anhydrous acetonitrile (2 g) and anhydrous DMF (6 g) in turn, stir, heat to 110 ℃ and reflux for 3h, react completely, cool to room temperature, add anhydrous acetonitrile 100mL, filter cake with MeOH/CH ₃ CN soluble clear, concentrated under reduced pressure to remove solvent, intermediate 42c (1.25 g).

Step 2: in a 100mL single-necked flask, 42c (1.25 g) and H were sequentially added ₂ O (3 g) was stirred to dissolve, 30% NaOH was added dropwise to adjust the pH to 10-12, stirred for 0.5h, benzoyl chloride (0.189 g) was added dropwise, HPLC was performed, DCM was added, stirred for 10min and allowed to stand, the organic phase was separated, the aqueous phase was washed twice with DCM, the organic phases were combined, dried by spinning, meOH was dissolved, purified by preparative chromatography, and lyophilized to give the title compound 42 (white solid).

MS m/z(ESI)：428[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )：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).

Example 43: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -6- (dimethylamino) -6-oxohex-2-en-3-yl) thiobenzoate (Compound 43)

The title compound 43 (white solid) was obtained by the same synthetic route as in example 42 except that 42b in step 1 of example 42 was replaced with 43 b.

MS m/z(ESI)：442[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 44: synthesis of methyl (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) pent-2-en-3-yl) thiobenzoate (Compound 44)

Step 1: acetonitrile, 1a (0.0079 mol) and 44b (0.0079 mol) were added to a 100mL single-necked flask, heated to 110℃under reflux, and reacted for 2 hours under reflux, whereupon solid was precipitated, filtered to obtain a solid, which was concentrated under reduced pressure to remove the solvent, dissolved with a small amount of MeOH, added EA, precipitated, filtered, and concentrated under reduced pressure to remove the solvent to obtain intermediate 44c (2.0 g).

Step 2: in the followingIn a 100mL single-necked flask, 2.0g of intermediate 44c and 4.0g of intermediate g H were added at a time ₂ O, stirring and dissolving; dropwise adding 30% NaOH to react for 30min, and controlling the pH to 10-12; 0.20g (0.00141 mol) of benzoyl chloride is added dropwise for reaction for 1h; the pH was adjusted to 4.0 and the solids precipitated, filtered, and the filter cake was slurried with EA, followed by MeOH and oven drying to afford title compound 44 (off-white solid).

MS m/z(ESI)：371[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 45: synthesis of (Z) -S- (3- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) but-2-en-2-yl) thiobenzoate (Compound 45)

The title compound 45 (white solid) was obtained by the same synthetic route as in example 44 except that 44b in step 1 of example 44 was replaced with 45 b.

MS m/z(ESI)：357[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )：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)。

Example 46: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5- (methylthio) pent-2-en-3-yl) thiobenzoate (Compound 46)

Step 1: 46b (1.4 g) and 1a (4.4 g) were added to 10mL of DMF and heated to 110℃and refluxed for three hours. The reaction was then cooled to room temperature and methyl tert-butyl ether was added dropwise, the product precipitated to give 1.8g of a yellow oil, which was used directly in the next reaction.

Step 2: the above crude product (1.8 g) was added to 10g of water and dissolved with stirring. The pH was adjusted to 10-11 with 30% sodium hydroxide solution. Tetrahydrofuran solution of benzoyl chloride was added dropwise, the pH was kept at 10-11 for 0.5 hours, the reaction solution was extracted twice with dichloromethane, then concentrated to dryness to give a yellow oily liquid, which was purified by preparative liquid chromatography, and the product was lyophilized to give the title compound 46 (0.03 g, off-white solid).

MS m/z(ESI)：417[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )：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).

Example 47: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5- (benzyloxy) pent-2-en-3-yl) thiobenzoate (Compound 47)

Step 1: 2.02g of compound 1a and 2.3g of compound 47b were dissolved in 6.9g of DMF, heated to 110℃and reacted for 4h, cooled, then 20mL of acetonitrile was added and the mixture was stirred to precipitate a solid. The mixture was filtered, and the cake was rinsed with acetonitrile and dried to give 3.4g of crude product.

Step 2: 3.4g of the crude product was dissolved in 10g of water with stirring. Sodium hydroxide solution (30%) was added dropwise to adjust the pH to 10-11. Stabilizing pH at 10-11, cooling with ice bath, and stirring for 10min; and dropwise adding a tetrahydrofuran solution of benzoyl chloride at the temperature of below 10 ℃, and adding a sodium hydroxide solution in the dropwise adding process to keep the pH at 10-11. The dripping is completed, and the reaction is carried out for 10min under the heat preservation. Dichloromethane was added to extract twice, the organic phase was discarded, concentrated to give crude product, purified by HPL, and lyophilized to give the title compound 47 (off-white solid).

MS m/z(ESI)：477[M+1] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )：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).

Example 48: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5-hydroxypent-2-en-3-yl) thio benzoate (Compound 48)

VB1 (33.7 g,0.1 mol) was added to 100mL of water, the solution was stirred, 30% NaOH solution was added dropwise to adjust pH=10-12, the reaction was carried out for 0.5 hours, then benzoyl chloride (14.2 g,0.1 mol) was added dropwise with maintaining pH=10-12 at 0-5℃for 1 hour, extraction was carried out, and organic phase silica gel column chromatography (methanol: dichloromethane=1:20) was purified, and the mixture was concentrated to give a white solid (12.8 g, yield 33.1%).

MS m/z(ESI)：387[M+1] ⁺ .

¹ H NMR(500MHz，CD ₃ OD)：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)。

Example 49: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) penta-1, 3-dien-3-yl) thiobenzoate (Compound 49)

Step 1: 1a (2.8 g,0.01 mol) and 49b (1.2 g,0.01 mol) were added to a mixed solution of 12mL DMF and 4mL acetonitrile and reacted at 110℃for 2h. After cooling, acetonitrile was added, and a solid was precipitated and filtered to obtain about 1.2g of a crude product.

Step 2: 3g of water and 30% sodium hydroxide solution are added to the crude product obtained in the step 1 to adjust the pH value to 10-12, the mixture is stirred for half an hour, a solution of benzoyl chloride (0.4 g) in tetrahydrofuran (2 mL) is added dropwise, and the mixture is stirred for half an hour while maintaining the pH value to 10-12. 50mL of dichloromethane was added for extraction, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (dichloromethane: methanol=30:1) to give 32mg of crude product, which was then purified by liquid phase preparative chromatography and lyophilized to give the title compound 49 (10 mg, yellow solid).

MS m/z(ESI)：369[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 50: synthesis of (Z) -S- (6-amino-2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -6-oxohex-2-en-3-yl) thiobenzoate (Compound 50)

The title compound 50 (white solid) was obtained by the same synthetic route as in example 49 except that 49b in step 1 of example 49 was replaced with 50 b.

MS m/z(ESI)：414[M+1] ⁺ .

1H NMR(500MHz，DMSO-d ₆ )：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)。

Example 51: synthesis of (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -6-morpholino-6-oxohex-2-en-3-yl) 3-bromothiobenzoate (Compound 51)

To the reaction flask were added compound 31 (0.20 g,0.4mmol,1.0 eq.), dichloromethane (10 mL), morpholine (0.035g,0.4 mmol,1.0eq.), HATU (0.18 g,0.48mmol,1.2 eq.) and N, N-diisopropylethylamine (0.10 g,0.8mmol,2.0 eq.) in this order. The obtained reaction solution was stirred at room temperature for 16 hours, concentrated under reduced pressure, and then separated and purified by preparative HPLC, and the objective component was collected and lyophilized to give the title compound 51 (90 mg, off-white solid, yield: 40%).

MS m/z(ESI)：562，564[M+1] ⁺ .

¹ H NMR(400Hz，DMSO-d ₆ )：δ7.90-7.84(m，3H)，7.76-7.72(m，2H)，7.49(t，1H)，6.83(br，2H)，4.39(br，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).

Example 52: synthesis of (Z) -S- (2- (N- ((4-amino-2-phenylpyrimidin-5-yl) methyl) carboxamido) -5-methoxypent-2-en-3-yl) thiobenzoate (Compound 52)

Step 1: 52a (31.3 g,0.2 mol) was added to 200mL of absolute ethanol, sodium methoxide (10.8 g,0.2 mol) was added and stirred for 3 hours; filtering, adding the filtrate into a 500mL reaction bottle, and cooling to 0-10 ℃; ethoxymethylenemalononitrile (24.4 g,0.2 mol) was added, a yellow solid precipitated, stirred at room temperature for 12h, filtered, the filter cake washed 2 times with absolute ethanol, and the filter cake dried under vacuum at 40 ℃ to give 52b (23.5 g,60% yield).

Step 2: 52b (23.5 g) and RaneyNi (24.5 g) were added to 125g formic acid and 24.5g water, heated to 60℃and refluxed for three hours. The reaction was filtered and the filter cake was washed with formic acid. Cooling the filtrate to 0 ℃, dropwise adding ammonia water, separating out a product, and stirring for 1 hour; filtration and vacuum drying of the filter cake gave 25g of pale yellow crude product. The crude product was added to 150mL of methanol, cooled to 0 ℃ with a cold water bath, sodium borohydride (4.8 g,0.126 mol) was added in portions, stirred for 3 hours, and LC-MS monitoring indicated the reaction was complete, purified by silica gel column chromatography (dichloromethane: methanol=10:1), concentrated in vacuo at 40 ℃ to give 52c (13.5 g of white solid, yield 50%).

Step 3: 52c (6.1 g,0.03 mol) and DMAP (6.6 g,0.054 mol) were added to 100mL of methylene chloride, cooled to 0℃in a cold water bath, methanesulfonyl chloride (5.2 g,0.045 mol) was added dropwise, and then stirred for 2 hours. Concentrating under reduced pressure, and evaporating the solvent.

Step 4: to the product of step 3, 20mL of DMF and 5- (2-methoxyethyl) -4-methylthiazole (4.7 g,0.03 mol) were added, heated to 110℃under reflux for 3 hours, LC-MS monitoring indicated completion of the reaction, cooled to room temperature, MTBE was added to precipitate the product, the supernatant was separated, and the residue was concentrated under reduced pressure to give oily liquid 52e (14 g) which was used directly in the next reaction without further purification.

Step 5: the crude product 52e (4.3 g,0.01 mol) in step 4 was added to 30g of water, stirred and dissolved, a solution of benzoyl chloride in tetrahydrofuran was added dropwise thereto, the pH was kept at 10-11 for 0.5 hours, the reaction solution was extracted twice with methylene chloride, and then concentrated to dryness to give a yellow oily liquid, which was purified by preparative liquid chromatography, and the product was lyophilized to give the title compound 52 (0.06 g, white solid).

MS m/z(ESI)：463.0[M+1] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )：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).

Example 53: synthesis of (Z) -S- (2- (N- ((4-amino-2-phenylpyrimidin-5-yl) methyl) carboxamido) -5-methoxypent-2-en-3-yl) furan-2-carbothioic acid ester (Compound 53)

The title compound 53 (off-white solid) was obtained by the same synthetic route as in example 52 except that benzoyl chloride was replaced with 53b in step 5 of example 52

MS m/z(ESI)：453.0[M+1] ⁺ .

¹ H NMR(500MHz，DMSO-d ₆ )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).

Example 54: synthesis of (Z) -S- (2- (N- ((4-amino-2- (pyridin-2-yl) pyrimidin-5-yl) methyl) carboxamido) -5-methoxypent-2-en-3-yl) thiobenzoate (Compound 54)

Step 1: 54a (50.0 g,318.5mmol,1.0 eq) and methanol (500 mL) were added to a 500mL single port flask, meONa (18 g,333.3mmol,1.05 eq) was added with stirring, stirring was performed at room temperature for 0.5 hour, ethoxymethylenemalononitrile (38.8 g,318.5mmol,1.0 eq) was added, stirring was performed at room temperature for 2 hours, filtering, and drying the filter cake to give 54b (yellow solid, 40g, yield: 63.7%).

Step 2: 54b (40 g,203mmol,1.0 eq), 30% naoh (200 mL) and methanol (200 mL) were added to a 250mL three-necked flask, the temperature was raised to 90 ℃ and the reaction was stirred for 4 hours, cooled to room temperature, ph=5 was adjusted with 2M HCl, filtered and the filter cake was dried to give 32g of white solid. The white solid was transferred to a 1000mL three-necked flask, methanol (1000 mL) and thionyl chloride (19.8 g,167mmol,1.2 eq) were added, the temperature was raised to 90 ℃ and the reaction was stirred for 4 hours, cooled to room temperature, saturated sodium bicarbonate adjusted ph=7-8, filtered and the filter cake dried to give 54c (yellow solid, 25 g).

Step 3:in a 500mL single flask was added 54c (10.0 g,43.5mmol,1.0 eq), THF (100 mL) was added under nitrogen protection, cooled in an ice bath, and LiAlH was added dropwise ₄ (52 mL,52mmol,1.2 eq) and stirring for 2 hours, quenched with water, extracted with EA and the organic phase dried over anhydrous sodium sulfate and concentrated to give the crude product which is purified by column on silica gel (eluent DCM: meOH=20:1 to 5:1) to give 54d (yellow solid, 8.9 g).

Step 4: to a 100mL single flask were added 54d (6 g,29.7mmol,1.0 eq) and 33% HBr acetic acid solution (18 g), and the mixture was stirred at 100℃for 2 hours, cooled, acetonitrile was added, and 54e (yellow solid, 6.5g, yield 82.5%) was obtained by filtration.

Step 5: in a 100mL single flask were added 5- (2-methoxyethyl) -4-methylthiazole (2.67 g,17mmol,1.5 eq), 54e (3.0 g,11.4mmol,1.0 eq) and DMF (30 mL), and the mixture was stirred for 3 hours at 110℃and cooled, acetonitrile was added and filtered with stirring, and the filter cake was dried to give 54f (yellow solid, 2.6g, yield 54%).

Step 6: 54f (2.6 g,6.4mmol,1.0 eq) was dissolved in 10g water, 30% sodium hydroxide solution was added dropwise to adjust pH to 10-12, stirred for 1 hour, pH was retested, pH was adjusted to 10-12 until stable, benzoyl chloride (0.89 g,6.4mmol,1.0 eq) was added dropwise at 10℃and reacted for 10 minutes after addition, ethyl acetate was added, the solution was separated, pH of the aqueous phase was adjusted to 4, filtration was carried out, and the filtrate was concentrated to give a crude product which was isolated and purified by preparative HPLC (eluent: 0.1% aqueous formic acid: meOH=10% -80%), and the title compound (54, reddish brown solid) was collected by freeze-drying.

MS m/z(ESI)：464[M+1] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )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).

Example 55: (Z) -S- (2- (N- ((4-amino-2- (thiophen-2-yl) pyrimidin-5-yl) methyl) carboxamido) -5-methoxypent-2-en-3-yl) thiobenzoate (compound 55)

Step 1: to a 500mL single flask were added 55a (50.0 g,458.7mmol,1.0 eq) and methanol (50 mL), and, with stirring, 350g of 20% HCl dioxane solution was added and stirred at room temperature for 12 hours. Sodium methoxide (49.5 g,917.4mmol,2.0 eq) was then added and stirred for 2 hours, NH was added ₃ Methanol solution (100 mL) was stirred at room temperature for 0.5 h, concentrated, and the solvent was removed. Methanol (100 mL) and sodium methoxide (49.5 g,917.4mmol,2.0 eq) were then added, stirred at room temperature for 0.5 hour, ethoxymethylenemalononitrile (56 g,458.7mmol,1.0 eq) was added, stirred at room temperature for 2 hours, filtered, the filtrate concentrated to give crude product which was purified by column chromatography over silica gel (eluent: DCM: meOH=30:1-10:1) to give 55b (yellow solid, 26g, yield: 28.1%)

Step 2: 55c (yellow solid) was prepared by the same synthetic route as that except that 52b in step 2 of example 52 was replaced with 55 b.

Step 3 to step 5: the title compound 55 (white solid) was obtained by the same synthesis procedures and methods as in step 4 to step 6 in example 54, except that 54d in step 4 in example 54 was replaced with 55 c.

MS m/z(ESI)：469[M+1] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )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).

Example 56: synthesis of (Z) -S- (2- (N- ((4-amino-2-cyclohexylpyrimidin-5-yl) methyl) carboxamido) -5-methoxypent-2-en-3-yl) thiobenzoate (Compound 56)

The title compound 56 (off-white solid) was prepared by the same synthetic route as in example 55 except that 55a in step 1 of example 55 was replaced with cyclohexanecarbonitrile.

MS m/z(ESI)：469[M+1] ⁺ .

¹ H NMR(400MHz，CD ₃ OD)：δ7.93(d，2H)，7.75(d，2H)，7.63(t，1H)，7.47(t，2H)，4.54(br，2H)，3.48(t，2H)，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)。

Example 57: synthesis of (Z) -S- (2- (N- ((4-amino-2-cyclobutylpyrimidin-5-yl) methyl) carboxamido) -5-methoxypent-2-en-3-yl) thiobenzoate (Compound 57)

The title compound 57 (white solid) was prepared by the same synthetic route as in example 55 except that 55a in step 1 of example 55 was replaced with cyclobutanenitrile

MS m/z(ESI)：441[M+1] ⁺ .

¹ H NMR(400MHz，DMSO-d ₆ )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，2H)，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).

Biological testing

Experimental example 1

The BCA protein concentration determination kit is purchased from Biyun, the Abeta 40 and Abeta 42 detection kits are purchased from wako company, and the cell culture related reagents are purchased from Gibco company.

HEK293APP/sw overexpressing cells were incubated in 48 well plates with DMEM medium (10% FBS, 100. Mu.g/mL G418 (Geneticin, geneticin) and double antibody (1 XPenicillin, streptomycin), 4mM stock of compound (compound prepared by dissolving in DMEM medium), filtered with a 0.22 μm sterile filter and stored at-20℃for use at 70% cell density, 40. Mu.L of compound test solution was added to each well at a final concentration of 400. Mu.M for 24 hours.

Taking a supernatant of the culture solution, adding BCA reagent into one part of the supernatant, incubating the mixture at room temperature for 30min, measuring each Kong Xiguang value (namely OD value) at 570nm of an enzyme-labeled instrument, and calculating the total protein concentration according to a protein standard curve; meanwhile, adding the other part of supernatant (100 mu L) into a prepared 96-well plate, incubating overnight at 4 ℃, removing the solution, cleaning the reagent, adding HRP (horseradish oxidase) labeled antibody, incubating at 4 ℃ for 2 hours, removing and cleaning the reagent, adding TMB color development liquid, incubating at room temperature for 30 minutes, adding a stop solution to stop the reaction, measuring each Kong Xiguang value (namely OD value) at 450nm of an enzyme marker instrument, respectively calculating the concentration of Abeta 40 and Abeta 42 according to the standard curve of Abeta 40 and Abeta 42, and finally adjusting the concentration of Abeta 40 and Abeta 42 by using the total protein concentration to obtain the final concentration. The test results are shown in the following table.

Numbering of compounds	Aβ40 content (pmol/L)	Aβ42 content (pmol/L)
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 salt of	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

* No compound test solution was added to the blank.

From the above experimental results, it can be seen that the compounds of the present invention can significantly reduce the level of aβ42 or/and aβ40.

Experimental example 2 toxicity experiment

2.1 purpose of experiment

This example tested compound toxicity by CCK-8 kit. The CCK-8 kit is a kit for cell proliferation and toxicity detection based on WST-8 (chemical name is 2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfophenyl) -2H-tetrazolium monosodium salt). The detection principle is that WST-8 can be reduced by dehydrogenase in mitochondria to generate a highly water-soluble orange-yellow formazan product (formazan) in the presence of an electron coupling reagent. The shade of color is proportional to the number of living cells and inversely proportional to cytotoxicity. Cell proliferation and toxicity levels were reflected by measuring OD values by a microplate reader at a wavelength of 450 nm.

2.2. Experimental method

2.2.1 Experimental materials

Reagent name	Branding	Goods number
CCK-8 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
Carbon dioxide incubator	Panasonic Health Medical Devices Co.,Ltd.	MCO-18AC-PC

Biological safety cabinet	SU JIE MEDICAL EQUIPMENT (SUZHOU) Co.,Ltd.	BSC-1300IIA2
Centrifugal machine	An Ting	TDL-80-2B

2.2.2 Experimental procedures

1) Cell plating

1.1 after HEK293-APP cell density was grown to 80% -90%, collected by digestion and centrifugation, the supernatant was removed, 5ml of medium was added and mixed well.

1.2 after complete mixing 20. Mu.L of cell suspension was diluted 10-fold with 180. Mu.L of medium and the cells were counted.

1.3 adding the corresponding DMEM complete culture medium into a 15ml centrifuge tube, adding the cell suspension into the culture medium to adjust the cell number so that the final dilution concentration of each cell is 2.4X10 ⁵ Individual/ml;

1.4 to prevent evaporation of liquid sterile 100 μl PBS was added to the 96 well plate edge wells for filling.

1.5 adding the culture Medium into the sample addition tank, and plating with 100. Mu.L/well to give a cell count of 2.4X10 ⁴ And each.

1.6 placing the inoculated cell culture plates into an incubator for culture.

2) Adding a test compound

2.1 preparation of 4mM stock solution of test compound in DMEM medium, filtration with 0.22 μm sterile filter and storage at-20deg.C.

2.2 after complete adherence of the cells, the 4mM stock solution was added at a final concentration of 400. Mu.M per well of 10. Mu.L, and 3 multiplex wells were set.

2.3 cell culture plates were incubated at 5% CO ₂ Incubation was carried out at 37℃for 24h.

3) Adding CCK-8 reagent

3.1 10. Mu.L of CCK-8 reagent was added per well and incubation was continued for 1h.

3.2 after 1h of incubation, absorbance was measured at 450 nm.

2.3. Experimental results

Inhibition = (1-test group absorbance/control group absorbance) = 100%, experimental results are shown in the following table.

Numbering of compounds	Inhibition rate
4	-3.02％
5	1.49％
7	-3.10％
8	-6.81％
9	-10.30％
15 hydrochloride of	-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 salt of	-7.41％
38 formate salt of 38	-14.26％
43	-0.27％
44	4.98％

Experimental results show that the compound of the invention has good safety.

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

Claims

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):

wherein the method comprises the steps of

R is selected from H, halogen, hydroxy, amino, cyano, nitro, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, -C (=nh) NH ₂ 、-C(＝O)R ³ 、-OC(＝O)R ³ 、-C(＝O)OR ³ 、-OR ³ 、-SR ³ 、-S(＝O)R ³ 、-S(＝O) ₂ R ³ 、-S(＝O) ₂ NR ³ R ⁴ 、-NR ³ R ⁴ 、-C(＝O)NR ³ R ⁴ 、-NR ³ -C(＝O)R ⁴ 、-NR ³ -C(＝O)OR ⁴ 、-NR ³ -S(＝O) ₂ -R ⁴ 、-NR ³ -C(＝O)-NR ³ R ⁴ 、-C _1-6 alkylene-NR ³ R ⁴ and-O-C _1-6 alkylene-NR ³ R ⁴ ；

L ¹ And L ² Each independently selected from direct bond, C _1-6 Alkylene and C _2-6 Alkenylene;

R ¹ and R is ² Each independently selected from H, halogen, hydroxy, oxo, amino, cyano, nitro, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, =n-OR ³ 、-C(＝NH)NH ₂ 、-C(＝O)R ³ 、-OC(＝O)R ³ 、-C(＝O)OR ³ 、-OR ³ 、-SR ³ 、-S(＝O)R ³ 、-S(＝O) ₂ R ³ 、-S(＝O) ₂ NR ³ R ⁴ 、-NR ³ R ⁴ 、-C(＝O)NR ³ R ⁴ 、-NR ³ -C(＝O)R ⁴ 、-NR ³ -C(＝O)OR ⁴ 、-NR ³ -S(＝O) ₂ -R ⁴ 、-NR ³ -C(＝O)-NR ³ R ⁴ 、-C _1-6 alkylene-NR ³ R ⁴ and-O-C _1-6 alkylene-NR ³ R ⁴ ；

R ³ And R is ⁴ Each at each occurrence is independently selected from H, C _1-6 Alkyl, C _3-10 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 An aralkyl group;

the above alkyl, alkylene, alkenyl, alkenylene, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl radicals are each optionally substituted at each occurrenceOne or more substituents independently selected from the group consisting of: halogen, hydroxy, oxo, amino, cyano, nitro, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, =n-OR ⁵ 、-C(＝NH)NH ₂ 、-C(＝O)R ⁵ 、-OC(＝O)R ⁵ 、-C(＝O)OR ⁵ 、-OR ⁵ 、-SR ⁵ 、-S(＝O)R ⁵ 、-S(＝O) ₂ R ⁵ 、-S(＝O) ₂ NR ⁵ R ⁶ 、-NR ⁵ R ⁶ 、-C(＝O)NR ⁵ R ⁶ 、-NR ⁵ -C(＝O)R ⁶ 、-NR ⁵ -C(＝O)OR ⁶ 、-NR ⁵ -S(＝O) ₂ -R ⁶ 、-NR ⁵ -C(＝O)-NR ⁵ R ⁶ 、-C _1-6 alkylene-NR ⁵ R ⁶ and-O-C _1-6 alkylene-NR ⁵ R ⁶ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl groups are further optionally substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxy, oxo, amino, cyano, nitro, C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 An aralkyl group;

R ⁵ and R is ⁶ Each at each occurrence is independently selected from H, C _1-6 Alkyl, C _3-10 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 An aralkyl group;

provided that when-L ² -R ² Co-isostructural systemC is formed into _1-6 In the case of alkyl radicals, -L ¹ -R ¹ Not unsubstituted phenyl; and is also provided with

when-L ² -R ² Together form- (CH) ₂ ) ₂ -OC(＝O)-(C _1-7 Alkyl), -L ¹ -R ¹ Not unsubstituted phenyl and unsubstituted furyl.
The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound, or prodrug thereof, wherein L ¹ Is a direct bond or C _2-6 Alkenyl groups are preferably direct bonds or vinylidene groups.
The compound of claim 1 or 2, 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 radicals, C _6-10 Aryl and 5-14 membered heteroaryl, optionally substituted with one or more substituents independently selected from halogen and-O- (C) _1-6 Alkyl);

preferably, R ¹ Selected from the group consisting of cyclohexenyl, phenyl, and furyl, optionally one or more of which are independently selected from F, cl, br, I and-OCH ₃ Is substituted by a substituent of (a).
A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound or prodrug thereof, wherein-L ¹ -R ¹ Selected from the group consisting of
The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound, or prodrug thereof, wherein L ² Is a direct bond, C _1-4 Alkylene or C _2-4 Alkenylene;

preferably L ² Is a direct bond, methylene, ethylene or vinylidene.
The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound, or prodrug thereof, wherein

R ² Selected from H, halogen, hydroxy, C _1-6 Alkyl, C _2-6 Alkenyl, C _1-6 Haloalkyl, 3-10 membered heterocyclyl, -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 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ³ And R is ⁴ Each independently selected from H, C _1-6 Alkyl, 3-10 membered heterocyclyl, C _6-10 Aryl and C _6-12 Aralkyl, preferably R ³ And R is ⁴ Each independently selected from H, methyl, ethyl, morpholinyl, phenyl (Ph) and benzyl (Bn);

most preferably, R ² H, F, cl, hydroxy, methyl, ethyl, vinyl, -CH ₂ CH ₂ F、-CH ₂ CH ₂ Cl、-OC(＝O)CH ₃ 、-OC(＝O)Ph、-SCH ₃ 、-OCH ₃ 、-OCH ₂ CH ₃ 、-OBn、-NHC(＝O)CH ₃ 、-NHS(＝O) ₂ CH ₃ 、-N(CH ₃ )Ph、-C(＝O)NH ₂ 、-C(＝O)NHCH ₃ 、-C(＝O)N(CH ₃ ) ₂ 、-C(＝O)OH、-C(＝O)OCH ₂ CH ₃ 、
The compound of any one of claims 1-6, 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,
The compound of claim 1, 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 formula (III):
the compound of any one of claims 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound, or prodrug thereof, wherein the compound is
A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of any one of claims 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound or prodrug thereof, and one or more pharmaceutically acceptable carriers.
Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound or prodrug thereof, or a pharmaceutical composition according to claim 10, for the manufacture of a medicament for the prevention or treatment of a neurodegenerative disease or for alleviating symptoms of a neurodegenerative disease.
The use of claim 11, wherein the neurodegenerative disease is selected from the group consisting of alzheimer's disease, creutzfeld-jakob disease, huntington's disease, multiple sclerosis, guillain-barre syndrome, parkinson's disease, lobehrlichia disease, paralytic dementia caused by progressive neuronal cell death, and diseases caused by progressive disorders; preferably Alzheimer's disease.
A process for the preparation of a compound of formula (I):

wherein:

Hal ¹ and Hal ² Each independently selected from F, cl, br and I;

the remaining groups are as defined in any one of claims 1 to 9;

the method comprises the following steps:

step (I): reacting 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; and

step (II): reacting a compound of formula (I) -c with a compound of formula (I) -d to obtain a compound of formula (I).