Donepezil derivative and application thereof in medicine

Abstract

The invention relates to a donepezil derivative and application thereof in drugs, in particular to a compound which is a compound shown in a formula I or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound shown in the formula I, the compound can play a long-acting role in inhibiting the expression of acetylcholinesterase, so that the Alzheimer's disease can be prevented and / or treated for a longer time. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology. Specifically, the present invention relates to a donepezil prodrug compound and a pharmaceutical composition thereof, and further relates to the use of the compound or the pharmaceutical composition in the preparation of a drug, especially in the preparation of a drug for treating Alzheimer's disease. Background Art

[0002] Alzheimer's disease (AD) is a central nervous system degenerative disease with insidious onset and a chronic progressive course. The main manifestations are progressive memory impairment, cognitive dysfunction, personality changes, and language disorders and other neuropsychiatric symptoms, which seriously affect social, occupational, and life functions. The cholinergic hypothesis holds that the pathophysiology of cognitive impairment associated with AD is attributed to the destruction or loss of cholinergic neurons, resulting in a decrease in acetylcholine levels, thereby leading to a series of pathological features such as cognitive dysfunction. Acetylcholinesterase (AChE) is a highly efficient hydrolase that catalyzes the hydrolysis of acetylcholine to produce choline and acetate ions. By reversibly inhibiting the activity of acetylcholinesterase and reducing the hydrolysis of acetylcholine, the content of acetylcholine at the receptor site can be increased, which can improve the symptoms of Alzheimer's disease.

[0003] As an acetylcholinesterase inhibitor, donepezil is suitable for Alzheimer's disease and has the advantages of high bioavailability, easy absorption, and low toxicity. However, after administration, the blood drug concentration increases, which easily causes side effects such as vomiting and diarrhea. In addition, the marketed dosage form of donepezil is an oral tablet, which needs to be taken daily. Most Alzheimer's disease patients are elderly, and the drug compliance is poor, which easily causes missed or wrong doses.

[0004] Therefore, there is a need to develop a more long-acting parenteral drug dosage form. Summary of the Invention

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art to some extent. The present invention provides a donepezil prodrug compound, which has a lower solubility than the solubility of the donepezil prototype and can also be metabolized into the prototype more quickly, and is suitable as a long-acting preparation.

[0006] In a first aspect of the present invention, the present invention provides a compound, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula I:

[0007]

[0008] Selected from a single bond or a double bond;

[0009] Y is selected from -O- or =N-;

[0010] Z is -C(=O)--R 1 , -CH 2 O-R 1a , -OC(=O)-R 1b , -C 1-4 alkylene-C(=O)-C 1-4 alkyl, -O-C 1-6 alkylene C(=O)-C 1-4 alkyl or -NHC(=O)-C 1-4 alkyl, wherein the -O-C 1-6 alkylene C(=O)-C 1-4 alkyl and -NHC(=O)-C 1-4 alkyl are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 R W substituents;

[0011] R 1 is selected from C 2-4 alkyl, C 1-6 alkyloxy, C 2-6 alkenyl, a six-membered heterocyclic group, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, benzyloxy, phenylamino, -(CH 2 ) 2 -phenyl, -CH=CH-phenyl, -CH 2 -OC(=O)C 1-4 alkyl, -OCH 2 -OC(=O)-phenyl, benzyl, phenyl, -CH 2 COOH, -(CH 2 ) 2 -COOH, -(CH 2 ) 4 -COOH or C 1-5 alkylamino, wherein the C 1-6 alkyloxy, C 2-6 alkenyl, a six-membered heterocyclic group, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, benzyloxy, phenylamino, -(CH 2 ) 2 -phenyl, -CH=CH-phenyl, -CH 2 -OC(=O)C 1-4 alkyl, -OCH 2 -OC(=O)-phenyl and benzyl are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 R W1 substituents, and the phenyl is substituted by 1, 2, 3 or 4 RW2 replace;

[0012] R 1a Selected from benzyl, -C(=O)OC 1-4 Alkyl, -C(=O)-C 1-4 alkyl or -C(=O)O-benzyl, wherein the benzyl, -C(=O)OC 1-4 Alkyl, -C(=O)-C 1-4 Alkyl and -C(=O)O-benzyl are each independently optionally unsubstituted or substituted with 1, 2, 3 or 4 R W3 replace;

[0013] R 1b Selected from C 1-6 Alkyl or phenyl, wherein the C 1-6 Alkyl and phenyl are each independently optionally unsubstituted or substituted with 1, 2, 3 or 4 R W4 replace;

[0014] R W , R W1 , R W2 , R W3 and R W4 Each independently selected from -OH, -F, -Cl, -Br, -I, =O, C 1-4 Alkyl or C 1-4 Alkoxy.

[0015] In some embodiments of the present invention, Z is -C(=O)-R 1 、-CH 2 OR 1a 、-OC(=O)-R 1b , -C 1-4 Alkylene-C(=O)C 1-4 Alkyl, -OC 1-4 Alkylene C(=O)-C 1-4 Alkyl or -NHC(=O)-C 1-4 Alkyl, wherein the -OC 1-4 Alkylene C(=O)-C 1-4 Alkyl and -NHC(=O)-C 1-4 Each alkyl group is independently optionally unsubstituted or substituted with 1, 2, 3 or 4 R W Replacement, wherein each R W Has the meaning as described in the present invention.

[0016] In some embodiments of the present invention, Z is -C(=O)-R 1 、-CH 2 OR 1a 、-OC(=O)-R 1b, -CH 2 -C(=O)-C 1-4 alkyl, -(CH 2 ) 2 -C(=O)-C 1-4 alkyl, -CH(CH 3 )-C(=O)-C 1-4 alkyl, -(CH 2 ) 3 -C(=O)-C 1-4 alkyl, -(CH 2 ) 4 -C(=O)-C 1-4 alkyl, -O-C 1-4 alkylene C(=O)-C 1-4 alkyl or -NHC(=O)-C 1-4 alkyl, wherein the -O-C 1-4 alkylene C(=O)-C 1-4 alkyl and -NHC(=O)-C 1-4 alkyl are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 R W , where each R W , R 1 , R 1a and R 1b has the meaning described in the present invention.

[0017] In some embodiments of the present invention, Z as described in the present invention is -C(=O)-R 1 , -CH 2 O-R 1a , -OC(=O)-R 1b , -CH 2 -C(=O)-methyl, -CH 2 -C(=O)-ethyl, -CH 2 -C(=O)-n-propyl, -CH 2 -C(=O)-isopropyl, -CH 2 -C(=O)-n-butyl, -CH 2 -C(=O)-isobutyl, -CH 2 -C(=O)-tert-butyl, -(CH 2 ) 2 -C(=O)-methyl, -CH(CH 3 )-C(=O)-methyl, -(CH 2 ) 2 -C(=O)-ethyl, -(CH 2 ) 2 -C(=O)-n-propyl, -(CH 2 ) 2-C(=O)-isopropyl, -(CH 2 ) 2 -C(=O)-n-butyl, -(CH 2 ) 2 -C(=O)-isobutyl, -(CH 2 ) 2 -C(=O)-tert-butyl, -(CH 2 ) 3 -C(=O)-methyl, -(CH 2 ) 3 -C(=O)-ethyl, -(CH 2 ) 3 -C(=O)-n-propyl, -(CH 2 ) 3 -C(=O)-isopropyl, -(CH 2 ) 3 -C(=O)-n-butyl, -(CH 2 ) 3 -C(=O)-isobutyl, -(CH 2 ) 3 -C(=O)-tert-butyl, -(CH 2 ) 4 -C(=O)-methyl, -(CH 2 ) 4 -C(=O)-ethyl, -(CH 2 ) 4 -C(=O)-n-propyl, -(CH 2 ) 4 -C(=O)-isopropyl, -(CH 2 ) 4 -C(=O)-n-butyl, -(CH 2 ) 4 -C(=O)-isobutyl, -(CH 2 ) 4 -C(=O)-tert-butyl, -O-C 1-4 alkylene C(=O)-C 1-4 alkyl or -NHC(=O)-C 1-4 alkyl, wherein said -O-C 1-4 alkylene C(=O)-C 1-4 alkyl and -NHC(=O)-C 1-4 alkyl are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 R W groups, wherein each R W , R 1 , R 1a and R 1b has the meaning as defined in the present invention.

[0018] In some embodiments of the present invention, Z in the present invention is -C=O-R 1 , -CH 2 O-R 1a , -OC(=O)-R 1b , -CH 2 -C(=O)-methyl, -CH 2 -C(=O)-ethyl, -CH 2 -C(=O)-n-propyl, -CH 2 -C(=O)-isopropyl, -CH 2 -C(=O)-n-butyl, -CH 2 -C(=O)-isobutyl, -CH 2 -C(=O)-tert-butyl, -(CH 2 ) 2 -C(=O)-methyl, -CH(CH 3 )-C(=O)-methyl, -(CH 2 ) 2 -C(=O)-ethyl, -(CH 2 ) 2 -C(=O)-n-propyl, -(CH 2 ) 2 -C(=O)-isopropyl, -(CH 2 ) 2 -C(=O)-n-butyl, -(CH 2 ) 2 -C(=O)-isobutyl, -(CH 2 ) 2 -C(=O)-tert-butyl, -(CH 2 ) 3 -C(=O)-methyl, -(CH 2 ) 3 -C(=O)-ethyl, -(CH 2 ) 3 -C(=O)-n-propyl, -(CH 2 ) 3 -C(=O)-isopropyl, -(CH 2 ) 3 -C(=O)-n-butyl, -(CH 2 ) 3 -C(=O)-isobutyl, -(CH 2 ) 3 -C(=O)-tert-butyl, -(CH 2 ) 4 -C(=O)-methyl, -(CH 2 ) 4 -C(=O)-ethyl, -(CH 2 )4 -C(=O)-n-propyl, -(CH 2 ) 4 -C(=O)-isopropyl, -(CH 2 ) 4 -C(=O)-n-butyl, -(CH 2 ) 4 -C(=O)-isobutyl, -(CH 2 ) 4 -C(=O)-tert-butyl, -O-CH 2 -C(=O)-C 1-4 alkyl, -O-(CH 2 ) 2 -C(=O)-C 1-4 alkyl, -O-(CH 2 ) 3 -C(=O)-C 1-4 alkyl, -O-(CH 2 ) 4 -C(=O)-C 1-4 alkyl or -NHC(=O)-C 1-4 alkyl, wherein the -O-CH 2 -C(=O)-C 1-4 alkyl, -O-(CH 2 ) 2 -C(=O)-C 1-4 alkyl, -O-(CH 2 ) 3 -C(=O)-C 1-4 alkyl, -O-(CH 2 ) 4 -C(=O)-C 1-4 alkyl and -NHC(=O)-C 1-4 alkyl are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 R W substituents, wherein each R W , R 1 , R 1a and R 1b has the meaning as defined in the present invention.

[0019] In some embodiments of the present invention, Z as defined in the present invention is -C=O-R 1 , -CH 2 O-R 1a , -OC(=O)-R 1b , -CH 2 -C(=O)-methyl, -CH 2 -C(=O)-ethyl, -CH 2 -C(=O)-n-propyl, -CH 2-C(=O)-isopropyl, -CH 2 -C(=O)-n-butyl, -CH 2 -C(=O)-isobutyl, -CH 2 -C(=O)-tert-butyl, -(CH 2 ) 2 -C(=O)-methyl, -CH(CH 3 )-C(=O)-methyl, -(CH 2 ) 2 -C(=O)-ethyl, -(CH 2 ) 2 -C(=O)-n-propyl, -(CH 2 ) 2 -C(=O)-isopropyl, -(CH 2 ) 2 -C(=O)-n-butyl, -(CH 2 ) 2 -C(=O)-isobutyl, -(CH 2 ) 2 -C(=O)-tert-butyl, -(CH 2 ) 3 -C(=O)-methyl, -(CH 2 ) 3 -C(=O)-ethyl, -(CH 2 ) 3 -C(=O)-n-propyl, -(CH 2 ) 3 -C(=O)-isopropyl, -(CH 2 ) 3 -C(=O)-n-butyl, -(CH 2 ) 3 -C(=O)-isobutyl, -(CH 2 ) 3 -C(=O)-tert-butyl, -(CH 2 ) 4 -C(=O)-methyl, -(CH 2 ) 4 -C(=O)-ethyl, -(CH 2 ) 4 -C(=O)-n-propyl, -(CH 2 ) 4 -C(=O)-isopropyl, -(CH 2 ) 4 -C(=O)-n-butyl, -(CH 2 ) 4 -C(=O)-isobutyl, -(CH 2 ) 4-C(=O)-tert-butyl, -O-CH 2 -C(=O)-methyl, -O-CH 2 -C(=O)-ethyl, -O-CH 2 -C(=O)-n-propyl, -O-CH 2 -C(=O)-isopropyl, -O-CH 2 -C(=O)-n-butyl, -O-CH 2 -C(=O)-isobutyl, -O-CH 2 -C(=O)-tert-butyl, -O-(CH 2 ) 2 -C(=O)-methyl, -O-(CH 2 ) 2 -C(=O)-ethyl, -O-(CH 2 ) 2 -C(=O)-n-propyl, -O-(CH 2 ) 2 -C(=O)-isopropyl, -O-(CH 2 ) 2 -C(=O)-n-butyl, -O-(CH 2 ) 2 -C(=O)-isobutyl, -O-(CH 2 ) 2 -C(=O)-tert-butyl, -O-(CH 2 ) 3 -C(=O)-methyl, -O-(CH 2 ) 3 -C(=O)-ethyl, -O-(CH 2 ) 3 -C(=O)-n-propyl, -O-(CH 2 ) 3 -C(=O)-isopropyl, -O-(CH 2 ) 3 -C(=O)-n-butyl, -O-(CH 2 ) 3 -C(=O)-isobutyl, -O-(CH 2 ) 3 -C(=O)-tert-butyl, -O-(CH 2 ) 4 -C(=O)-methyl, -O-(CH 2 ) 4 -C(=O)-ethyl, -O-(CH 2 ) 4 -C(=O)-n-propyl, -O-(CH 2 ) 4-C(=O)-isopropyl, -O-(CH 2 ) 4 -C(=O)-n-butyl, -O-(CH 2 ) 4 -C(=O)-isobutyl, -O-(CH 2 ) 4 -C(=O)-tert-butyl, -NHC(=O)-methyl, -NHC(=O)-ethyl, -NHC(=O)-n-propyl, -NHC(=O)-isopropyl, -NHC(=O)-n-butyl or -NHC(=O)-tert-butyl, wherein said -O-CH 2 -C(=O)-methyl, -O-CH 2 -C(=O)-ethyl, -O-CH 2 -C(=O)-n-propyl, -O-CH 2 -C(=O)-isopropyl, -O-CH 2 -C(=O)-n-butyl, -O-CH 2 -C(=O)-isobutyl, -O-CH 2 -C(=O)-tert-butyl, -O-(CH 2 ) 2 -C(=O)-methyl, -O-(CH 2 ) 2 -C(=O)-ethyl, -O-(CH 2 ) 2 -C(=O)-n-propyl, -O-(CH 2 ) 2 -C(=O)-isopropyl, -O-(CH 2 ) 2 -C(=O)-n-butyl, -O-(CH 2 ) 2 -C(=O)-isobutyl, -O-(CH 2 ) 2 -C(=O)-tert-butyl, -O-(CH 2 ) 3 -C(=O)-methyl, -O-(CH 2 ) 3 -C(=O)-ethyl, -O-(CH 2 ) 3 -C(=O)-n-propyl, -O-(CH 2 ) 3 -C(=O)-isopropyl, -O-(CH 2 ) 3 -C(=O)-n-butyl, -O-(CH 2 ) 3 -C(=O)-isobutyl, -O-(CH2 ) 3 -C(=O)-tert-butyl, -O-(CH 2 ) 4 -C(=O)-methyl, -O-(CH 2 ) 4 -C(=O)-ethyl, -O-(CH 2 ) 4 -C(=O)-n-propyl, -O-(CH 2 ) 4 -C(=O)-isopropyl, -O-(CH 2 ) 4 -C(=O)-n-butyl, -O-(CH 2 ) 4 -C(=O)-isobutyl, -O-(CH 2 ) 4 -C(=O)-tert-butyl, -NHC(=O)-methyl, -NHC(=O)-ethyl, -NHC(=O)-n-propyl, -NHC(=O)-isopropyl, -NHC(=O)-n-butyl, and -NHC(=O)-tert-butyl are each independently optionally unsubstituted or substituted by 1, 2, 3, or 4 R W groups, where each R W , R 1 , R 1a , and R 1b has the meaning described in the present invention.

[0020] In some embodiments of the present invention, the R 1 described in the present invention is selected from ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 1-pentyloxy, vinyl, propenyl, piperidinyl, dihydropyridine, morpholinyl, thiomorpholinyl, piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O cyclopropyl, -O cyclobutyl, -O cyclopentyl, -O cyclohexyl, benzyloxy, phenylamino, -(CH 2 ) 2 -phenyl, -CH=CH-phenyl, -CH 2 OC(=O)-methyl, -CH 2 OC(=O)-ethyl, -CH 2 OC(=O)-n-propyl, -CH 2 OC(=O)-isopropyl, -CH 2 OC(=O)-tert-butyl, -OCH 2 -OC(=O)-phenyl, benzyl, phenyl, -CH 2 COOH, -(CH 2 )2 -COOH, -(CH 2 ) 4 -COOH, N,N-dimethylamino or N,N-diethylamino, wherein the methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 1-pentyloxy, vinyl, propenyl, piperidinyl, dihydropyridine, morpholinyl, thiomorpholinyl, piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, benzyloxy, phenylamino, -(CH 2 ) 2 -phenyl, -CH=CH-phenyl, -CH 2 OC(=O)-methyl, -CH 2 OC(=O)-ethyl, -CH 2 OC(=O)-n-propyl, -CH 2 OC(=O)-isopropyl, -CH 2 OC(=O)-tert-butyl, -OCH 2 -OC(=O)-phenyl and benzyl are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 R W1 substituents, and the phenyl is substituted by 1, 2, 3 or 4 R W2 substituents, wherein each R W2 has the meaning as defined in the present invention.

[0021] In some embodiments of the present invention, the R as defined in the present invention 1a is selected from benzyl, -C=(O)O-methyl, -C(=O)O-ethyl, -C(=O)O-n-propyl, -C(=O)O-isopropyl, -C(=O)O-n-butyl, -C(=O)O-tert-butyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)-n-propyl, -C(=O)-isopropyl, -C(=O)-n-butyl, -C(=O)-tert-butyl or -C(=O)O-benzyl, wherein the benzyl, -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-n-propyl, -C(=O)O-isopropyl, -C(=O)O-n-butyl, -C(=O)O-tert-butyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)-n-propyl, -C(=O)-isopropyl, -C(=O)-n-butyl, -C(=O)-tert-butyl and -C(=O)O-benzyl are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 R W3 substituents, wherein each R W3 has the meaning as defined in the present invention.

[0022] In some embodiments of the present invention, the R as defined in the present invention 1bSelected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl or phenyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and phenyl are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 R W4 substituents, wherein each R W4 has the meaning as described in the present invention.

[0023] In some embodiments of the present invention, the R W , R W1 , R W2 , R W3 and R W4 each independently selected from -OH, -F, -Cl, -Br, -I, =O, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy or 2-butoxy.

[0024] In some embodiments of the present invention, the compound described in the present invention has a compound with the structure shown in Formula II or Formula III, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound shown in Formula II or Formula III:

[0025]

[0026] In a second aspect of the present invention, the present invention provides a compound, the structure of which is selected from one of the following:

[0027]

[0028]

[0029]

[0030] In a third aspect of the present invention, the present invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises: the compound described in the first aspect or the second aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof.

[0031] According to an embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0032] In a fourth aspect of the present invention, there is provided the use of the compound according to the first or second aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition according to the third aspect, in inhibiting the expression of acetylcholinesterase.

[0033] It should be noted that the inhibition of the expression of acetylcholinesterase is carried out for non-therapeutic purposes, for example, to study the effect of the compound according to the present invention on inhibiting acetylcholinesterase in vitro cells.

[0034] In a fifth aspect of the present invention, there is provided the use of the compound according to the first or second aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition according to the third aspect, in the preparation of a drug, wherein the drug has at least one of the following uses: for the preparation of a drug for inhibiting the expression of acetylcholinesterase; for the preparation of a drug for preventing and / or treating Alzheimer's disease.

[0035] According to an embodiment of the present invention, the dosage form of the drug is selected from, but not limited to, injection, tablet, capsule or granule.

[0036] According to an embodiment of the present invention, the dosage form of the drug is selected from injection.

[0037] In a sixth aspect of the present invention, there is provided a method for inhibiting the expression of acetylcholinesterase, or for preventing and / or treating Alzheimer's disease, comprising the step of administering to a subject in need the compound according to the first or second aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition according to the third aspect.

[0038] Terms and Definitions

[0039] Unless otherwise specified, the definitions of groups and terms recited in the specification and claims of the present application, including their exemplary definitions, preferred definitions, definitions recited in tables, and definitions of specific compounds in the examples, etc., can be combined and combined with each other arbitrarily. The group definitions and compound structures after such combination and combination should fall within the scope described in the specification of the present application.

[0040] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art to which the claimed subject matter pertains. Unless otherwise specified, all patents, patent applications, and published materials cited herein in their entirety are incorporated herein by reference. If there are multiple definitions for a term herein, the definition in this chapter shall prevail.

[0041] Unless otherwise specified or there is an obvious conflict in the context, the articles "a", "one (kind)", and "the" used herein are intended to include "at least one" or "one or more". Therefore, these articles used herein refer to articles for one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, that is, there may be more than one component considered to be adopted or used in the implementation of the described embodiment.

[0042] It should be understood that the above summary and the following detailed description are exemplary and for explanatory purposes only, and do not limit the subject matter of the present invention in any way. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that unless clearly stated otherwise in the text, the singular forms used in this specification and claims include the plural forms of the things referred to. It should also be noted that unless otherwise specified, the use of "or" means "and / or". In addition, the terms "comprising" and other forms, such as "including", "containing", and "having" are not restrictive.

[0043] Definitions of standard chemical terms can be found in reference works (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise specified, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR, and UV / VIS spectroscopy and pharmacological methods. Unless a specific definition is provided, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and the treatment of patients. For example, the instructions of the manufacturer for the use of the kit can be utilized, or the reactions and purifications can be carried out in a manner known in the art or as described in the present invention. Generally, the above techniques and methods can be implemented according to the descriptions in a number of general and more specific documents cited and discussed in this specification, in a conventional manner well-known in the art. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0044] Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are replaced by specific substituents. Unless otherwise indicated, a substituted group can have one substituent replacing at each substitutable position of the group. When more than one position in the given structural formula can be replaced by one or more substituents selected from a specific group, then the substituents can replace at each substitutable position either the same or differently. When there are multiple substituents, the substituents can be the same or different. For example, "optionally substituted by R"2 "Substituted phenyl", wherein the hydrogen atoms on the phenyl can be substituted by one or more R 2 substituents, and when there are multiple R 2 substituents, said R 2 can be selected from the same or different groups.

[0045] As described in the present invention, the compounds of the present invention can optionally be substituted by one or more substituents, such as the compounds of the general formula above, or as the specific examples, subclasses, and a class of compounds included in the present invention in the examples. It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted". Generally, the term "optionally", whether before or after the term "substituted", means that one or more hydrogen atoms in the given structure are substituted by specific substituents. Unless otherwise indicated, an optional substituent group can have a substituent substituting at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, then the substituents can be the same or different at each position.

[0046] The terms "alkylamino" and "alkamino" can be used interchangeably, and they include "N-alkylamino" and "N,N-dialkylamino", wherein the hydrogen atoms in the amino group are independently substituted by one or two alkyl groups respectively. Among them, in some embodiments, the alkanamino is a lower alkylamino group formed by one or two C 1-12 alkyl groups connected to the nitrogen atom. In some other embodiments, the alkanamino is a lower alkylamino group formed by one or two C 1-6 alkyl groups connected to the nitrogen atom. In some other embodiments, the alkanamino is a lower alkylamino group formed by one or two C 1-4 alkyl groups connected to the nitrogen atom. In still some other embodiments, the alkanamino is a lower alkylamino group formed by one or two C 1-3 alkyl groups connected to the nitrogen atom. Suitable alkanamino groups can be monoalkylamino or dialkylamino, and examples of alkanamino include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, N-methyl N-ethylamino, N-ethyl N-n-propylamino, and so on.

[0047] The term "cycloalkyl" represents a monovalent or polyvalent saturated monocyclic system containing 3-6 carbon atoms. Further examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0048] The term "alkylene" refers to a saturated divalent or polyvalent hydrocarbon radical obtained by removing two or more hydrogen atoms from a saturated straight-chain or branched-chain hydrocarbon radical. Unless otherwise specified in detail, the alkylene radical contains 1-12 carbon atoms. In some embodiments, the alkylene radical contains 1-6 carbon atoms; in other embodiments, the alkylene radical contains 1-4 carbon atoms; in still other embodiments, the alkylene radical contains 1-3 carbon atoms; in still other embodiments, the alkylene radical contains 1-2 carbon atoms. Examples of alkylene include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylidene (-CH(CH 3 )CH 2 -), and so on.

[0049] The term "six-membered heterocyclic group" is a heterocyclic group composed of 6 atoms, referring to a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing 6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Six-membered heterocyclic groups include, but are not limited to, piperidyl, dihydropyridine, morpholinyl, thiomorpholinyl, piperazinyl, etc. In addition, it should be noted that unless otherwise explicitly indicated, in the description mode adopted in the present invention, "each... independently is" can be interchanged with "each... independently is", "each... is independently", and "each... independently is", and should be understood in a broad sense. It can either mean that among different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that among the same group, the specific options expressed between the same symbols do not affect each other.

[0050] In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group type or range. Specifically, the present invention includes each independent secondary combination of each member of these group types and ranges. For example, the term "C 1-6 alkyl" specifically refers to methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl independently disclosed.

[0051] When used alone or as part of other substituents, the term "alkyl" refers to a saturated straight-chain or branched-chain monovalent hydrocarbon radical having 1-6 carbon atoms, having 2-6 carbon atoms, or having 1-4 carbon atoms, or having 1-3 carbon atoms, wherein the alkyl can be independently and optionally substituted by one or more substituents described in the present invention, and the substituents include, but are not limited to, deuterium, amino, hydroxyl, cyano, F, Cl, Br, I, mercapto, nitro, oxo (=O), etc. Examples of alkyl include, but are not limited to, methyl (Me, -CH 3) Ethyl (Et, -CH 2 CH 3 ) n-Propyl (n-Pr, -CH 2 CH 2 CH 3 ) Isopropyl (i-Pr, -CH(CH 3 ) 2 ) n-Butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ) sec-Butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ) tert-Butyl (t-Bu, -C(CH 3 ) 3 ) n-Pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-Pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ) 3-Pentyl (-CH(CH 2 CH 3 ) 2 ) and so on. The terms "alkyl" and its prefix "alk-" are used herein to include both straight-chain and branched-chain saturated carbon chains.

[0052] When used alone or as part of another substituent, the term "alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon radical having from two to forty carbon atoms with at least one carbon-carbon sp2 double bond (e.g., C 2 -C 6 alkenyl, and for example C 2 -C 4 alkenyl), and includes groups having "cis" and "trans" orientations or "E" and "Z" orientations. Examples of alkenyl include, but are not limited to, vinyl, propenyl (-CH=CHCH 3 ), allyl (-CH 2 CH=CH 2 ).

[0053] In the present application, the terms "salt" or "pharmaceutically acceptable salt" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" pertains to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0054] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereoisomers, and conformational isomers.

[0055] Depending on the choice of starting materials and methods, the compounds of the present invention may exist in the form of one or a mixture of the possible isomers, for example as pure enantiomers, or as a mixture of isomers such as a racemic and diastereoisomeric mixture, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center(s) in the molecule. The prefixes D and L or (+) and (-) are symbols used to specify the rotation of plane-polarized light caused by the compound, where (-) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory.

[0056] When depicting the bonds to a chiral carbon in the formula of the present invention as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. The graphical representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62:114 - 120. Wedge and dashed bonds are used to denote the absolute configuration of a stereocenter.

[0057] The term "tautomer" refers to functional group isomers resulting from the rapid migration of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomers of a compound can exist in two or more interconvertible forms. Prototropic tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in an equilibrium form, and attempting to isolate a single tautomer usually results in a mixture whose physical and chemical properties are consistent with those of a mixture of compounds. The position of the equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0058] The term "solvate" refers to a compound or a salt thereof of the present invention that includes a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces, and when the solvent is water, it is a hydrate.

[0059] The term "prodrug" means a compound that can be converted into a biologically active compound of the present invention under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying the functional groups in the compound, and such modification can be removed by conventional operations or in vivo to obtain the parent compound. Prodrugs include compounds formed by connecting a hydroxyl group or an amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group, respectively.

[0060] In the present application, a "pharmaceutical composition" refers to a preparation of a compound of the present invention and a medium commonly accepted in the art for delivering a biologically active compound to a mammal (such as a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, promote the absorption of the active ingredient, and thus exert its biological activity.

[0061] In the present application, a "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is permitted by the relevant government regulatory authorities for use in humans or livestock.

[0062] The term "excipient" refers to a pharmaceutically inert ingredient. Non-limiting examples of the types of "excipients" include binders, disintegrants, lubricants, glidants, stabilizers, fillers and diluents, etc. Excipients can enhance the handling properties of pharmaceutical preparations, that is, make the preparations more suitable for direct compression by increasing fluidity and / or adhesiveness.

[0063] The term "treatment" refers to a therapeutic treatment. When referring to a specific disease or disorder, treatment means: (1) alleviating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade that causes or gives rise to the disorder or (b) one or more biological manifestations of the disorder, (3) improving one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing down the development of the disorder or one or more biological manifestations of the disorder.

[0064] The term "prevention" means reducing the risk of acquiring or developing a disease or disorder.

[0065] The term "patient" refers to any animal, preferably a mammal, that is about to receive or has received administration of the compound or composition according to an embodiment of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being preferred.

[0066] The term "therapeutically effective amount" refers to the amount of a compound that is sufficient to effectively treat a disease or disorder described herein when administered to a patient. The "therapeutically effective amount" will vary depending on the compound, the disorder and its severity, and the age of the patient to be treated, and can be adjusted by those skilled in the art as needed.

[0067] Additional aspects and advantages of the present invention will be given in part in the following description, will become apparent in part from the following description, or will be learned through the practice of the present invention.

[0068] The characteristics of the pharmaceutical composition described in the present invention include the salts of the compounds of formula (I), such as the salts of the compounds shown in formula (I), and pharmaceutically acceptable excipients. The salts or their pharmaceutical compositions described in the present invention can effectively inhibit acetylcholinesterase and are suitable for the treatment of Alzheimer's disease, especially for diseases or symptoms caused by acetylcholinesterase. Detailed Description of the Invention

[0069] The embodiments of the present invention will be described in detail below. The embodiments described below are exemplary and are only used to explain the present invention and should not be construed as limiting the present invention. For those techniques or conditions not specified in the embodiments, they shall be carried out according to the techniques or conditions described in the literature in the art or according to the product specifications. For reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0070] Example 1 Preparation Method of the Compound

[0071] 1. Preparation of Compound (1)

[0072]

[0073] Donepezil (1.00 g, 1 eq), lithium bis(trimethylsilyl)amide (1.50 eq) and tetrahydrofuran (12 ml) were added to a reaction flask, and the mixture was stirred at -70 °C for 0.5 h. Acetic anhydride (1.50 eq) was added to the reaction solution, and the mixture was stirred for 0.5 h, and then transferred to room temperature (20 °C - 30 °C) and reacted for 48 h; the reaction solution was extracted with saturated brine and water, the organic phase was concentrated under reduced pressure to obtain an oil, n-hexane was added for pulping, and the mixture was filtered under reduced pressure and dried in vacuo at 50 °C to obtain 0.34 g of a white solid, with a yield of 30.72% and a purity of 99.64%.

[0074] MS(ESI,pos.ion)m / z:422.5[M+H] + ;

[0075] 1H NMR(400MHz,CDCl 3 )δ7.30(d,J = 4.3Hz,4H),7.24(d,J = 4.2Hz,1H),6.96(s,1H),6.60(s,1H),3.87(d,J = 2.3Hz,6H),3.47(s,2H),3.24(s,2H),2.86(d,J = 11.5Hz,2H),2.34(s,3H),2.27(d,J = 7.1Hz,2H),1.92(s,2H),1.65(d,J = 12.6Hz,2H),1.49(s,1H),1.34 1.21(m,2H).

[0076] Preparation of Compound (2)

[0077]

[0078] Donepezil (2.00 g, 1 eq), lithium bis(trimethylsilyl)amide (1.50 eq) and tetrahydrofuran (20 mL) were added to a reaction flask, and the mixture was stirred at -20 °C for 0.5 h. Then, butyryl chloride (1.50 eq) was added, and the resulting reaction mixture was stirred for another 0.5 h and then transferred to room temperature (20 °C - 30 °C) for reaction for 24 h. The reaction solution was extracted with saturated brine and water respectively, and the organic phases were combined. The organic phase was concentrated under reduced pressure to obtain an oil. The obtained oil was separated and purified by column silica gel column (n - hexane / ethyl acetate (V / V) = 2 / 1) to obtain 1.06 g of a white solid, with a yield of 44.74% and a purity of 96.07%.

[0079] MS(ESI,pos.ion)m / z:450.5[M+H] + ;

[0080] 1 H NMR(599MHz,CDCl 3):δ 7.33 - 7.27 (m, 4H), 7.23 (dt, J = 6.0, 4.1 Hz, 1H), 6.96 (s, 1H), 6.58 (s, 1H), 3.87 (d, J = 3.4 Hz, 6H), 3.47 (s, 2H), 3.24 (s, 2H), 2.86 (d, J = 11.5 Hz, 2H), 2.58 (t, J = 7.4 Hz, 2H), 2.26 (d, J = 7.2 Hz, 2H), 1.91 (t, J = 10.9 Hz, 2H), 1.86 - 1.77 (m, 2H), 1.65 (d, J = 12.6 Hz, 2H), 1.49 (ddd, J = 11.2, 7.4, 3.8 Hz, 1H), 1.31 - 1.21 (m, 2H), 1.08 (t, J = 7.4 Hz, 3H).

[0081] Preparation of Compound (3)

[0082]

[0083] Donepezil (1.00 g, 1 eq), lithium bis(trimethylsilyl)amide (1.50 eq) and tetrahydrofuran (10 ml) were added to a reaction flask, and the mixture was stirred at -20 °C for 0.5 h. Then benzyl chloroformate (1.50 eq) was added, and the reaction was continued for 0.5 h. The reaction was then transferred to room temperature (20 °C - 30 °C) and reacted for 24 h. The reaction mixture was extracted with saturated brine and water, and the organic phase was concentrated under reduced pressure to obtain an oil. The obtained oil was separated and purified by silica gel column (n - hexane / ethyl acetate (V / V) = 2 / 1) to obtain 0.30 g of a white solid, with a yield of 21.90% and a purity of 98.37%.

[0084] MS(ESI, pos.ion) m / z: 514.3 [M + H] + ;

[0085] 1 H NMR(599 MHz, CDCl 3)δ 7.43 (d, J = 7.6 Hz, 3H), 7.35 (d, J = 6.9 Hz, 2H), 7.29 (d, J = 4.2 Hz, 3H), 7.25 (dd, J = 8.3, 4.0 Hz, 1H), 7.13 (s, 1H), 6.84 (s, 1H), 5.12 (dd, J = 47.8, 12.2 Hz, 2H), 4.08 (s, 2H), 3.97 (s, 3H), 3.90 (s, 3H), 3.64 (d, J = 16.8 Hz, 1H), 3.40 (dd, J = 20.7, 12.1 Hz, 2H), 2.89 (d, J = 16.8 Hz, 1H), 2.34 (d, J = 16.5 Hz, 2H), 2.08 (d, J = 9.5 Hz, 1H), 1.78 (d, J = 12.2 Hz, 2H), 1.63 (s, 2H), 1.50 (s, 1H), 1.27 (d, J = 18.2 Hz, 2H).

[0086] Preparation of Compound (5)

[0087]

[0088] Donepezil (2.00 g, 1 eq), lithium bis(trimethylsilyl)amide (1.50 eq) and tetrahydrofuran (20 mL) were added to a reaction flask, and the mixture was stirred at -20 °C for 0.5 h. Then valeryl chloride (1.50 eq) was added, and the resulting reaction mixture was stirred for another 0.5 h, and then transferred to room temperature (20 °C - 30 °C) for reaction for 24 h. The reaction solution was extracted with saturated brine and water respectively, and the organic phases were combined. The organic phase was concentrated under reduced pressure to obtain an oily substance. The obtained oily substance was separated and purified by column silica gel column (n - hexane / ethyl acetate (V / V) = 2 / 1) to obtain 0.78 g of a yellowish - white solid, with a yield of 32.37% and a purity of 95.39%.

[0089] MS(ESI, pos.ion) m / z: 464.3 [M + H] + ;

[0090] 1 H NMR(599 MHz, CDCl 3)δ 7.34 - 7.17 (m, 5H), 6.96 (s, 1H), 6.57 (s, 1H), 3.86 (d, J=1.5 Hz, 6H), 3.47 (s, 2H), 3.24 (s, 2H), 2.85 (d, J=11.2 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H), 2.26 (d, J=7.1 Hz, 2H), 1.91 (t, J=11.1 Hz, 2H), 1.84 - 1.73 (m, 2H), 1.65 (d, J=12.5 Hz, 2H), 1.49 (dq, J=14.5, 7.2 Hz, 3H), 1.33 - 1.20 (m, 2H), 1.00 (t, J=7.4 Hz, 3H).

[0091] 5. Synthesis of Compound (6)

[0092]

[0093] Donepezil (2.00 g, 1 eq), lithium bis(trimethylsilyl)amide (1.50 eq) and tetrahydrofuran (20 mL) were added to a reaction flask. The mixture was stirred at -20 °C for 0.5 h, then cyclohexanecarbonyl chloride (1.50 eq) was added. The resulting reaction mixture was stirred for another 0.5 h and then transferred to room temperature (20 °C - 30 °C) for reaction for 24 h. The reaction solution was extracted with saturated brine and water respectively, and the organic phases were combined. The organic phase was concentrated under reduced pressure to obtain an oily substance. The obtained oily substance was separated and purified by column silica gel column (n - hexane / ethyl acetate (V / V) = 2 / 1) to obtain 0.66 g of a yellowish - white solid, with a yield of 25.92% and a purity of 98.78%.

[0094] MS(ESI, pos.ion) m / z: 490.4 [M + H] + ;

[0095] 1 H NMR(400 MHz, CDCl 3 )δ 7.32 (d, J=4.3 Hz, 4H), 7.28 - 7.22 (m, 1H), 6.98 (s, 1H), 6.57 (s, 1H), 3.89 (d, J=3.2 Hz, 6H), 3.50 (s, 2H), 3.26 (s, 2H), 2.89 (d, J=11.4 Hz, 2H), 2.64 (ddd, J=11.2, 7.7, 3.6 Hz, 1H), 2.27 (d, J=7.1 Hz, 2H), 2.18 - 2.05 (m, 2H), 2.00 - 1.81 (m, 4H), 1.80 - 1.59 (m, 5H), 1.48 - 1.19 (m, 6H).

[0096] 6. Synthesis of Compound (7)

[0097]

[0098] Add donepezil (2.00 g, 1 eq), lithium bis(trimethylsilyl)amide (1.50 eq) and tetrahydrofuran (20 mL) into a reaction flask. Stir at -20 °C for 0.5 h, then add p-toluoyl chloride (1.50 eq). The resulting reaction mixture is stirred for another 0.5 h, and then transferred to room temperature (20 °C - 30 °C) for reaction for 24 h. The reaction solution is extracted with saturated brine and water respectively, and the organic phases are combined. The organic phase is concentrated under reduced pressure to obtain an oily substance. The obtained oily substance is separated and purified by a column silica gel column (n-hexane / ethyl acetate (V / V) = 2 / 1) to obtain 0.42 g of a yellowish-white solid, with a yield of 16.03% and a purity of 97.11%.

[0099] MS(ESI,pos.ion)m / z:498.3[M+H] + ;

[0100] 1 H NMR(400MHz,CDCl 3 )δ7.63(d,J=8.2Hz,2H),7.30 - 7.18(m,6H),7.11(d,J=8.1Hz,2H),6.91(s,1H),3.99(s,3H),3.92(s,3H),3.71(d,J=17.1Hz,1H),3.40(s,2H),3.05(d,J=17.1Hz,1H),2.80 - 2.66(m,2H),2.33(s,3H),2.16(qd,J=14.4,4.4Hz,2H),1.80(dd,J=12.4,5.6Hz,2H),1.56(d,J=7.1Hz,1H),1.45(d,J=10.0Hz,1H),1.28(d,J=16.6Hz,3H).

[0101] Synthesis of Compound (8)

[0102]

[0103] Add donepezil (2.00 g, 1 eq), lithium bis(trimethylsilyl)amide (1.50 eq) and tetrahydrofuran (20 mL) into a reaction flask, control the temperature at -20 °C and stir for 0.5 h, then add pivaloyl chloride (1.50 eq). The resulting reaction mixture is stirred for an additional 0.5 h, and then transferred to room temperature (20 °C - 30 °C) and reacted for 24 h. The reaction solution is extracted with saturated brine and water respectively, and the organic phases are combined. The combined organic phase is concentrated under reduced pressure to obtain an oily substance. The obtained oily substance is separated and purified by column silica gel column (n-hexane / ethyl acetate (V / V) = 2 / 1) to obtain 0.61 g of a yellowish-white solid, with a yield of 25.00% and a purity of 95.87%.

[0104] MS(ESI,pos.ion)m / z:464.4[M+H] + ;

[0105] 1 H NMR(400MHz,CDCl 3 )δ7.30(d,J=4.3Hz,4H),7.24(dd,J=8.9,4.6Hz,1H),6.96(s,1H),6.53(s,1H),3.86(d,J=5.9Hz,6H),3.47(s,2H),3.24(s,2H),2.86(d,J=11.5Hz,2H),2.25(d,J=7.1Hz,2H),1.91(t,J=10.9Hz,2H),1.65(d,J=12.4Hz,2H),1.41(s,9H),1.33 - 1.20(m,3H).

[0106] Synthesis of Compound (9)

[0107]

[0108] Add donepezil (2.00 g, 1 eq), lithium bis(trimethylsilyl)amide (1.50 eq) and tetrahydrofuran (20 mL) into a reaction flask, control the temperature at -20 °C and stir for 0.5 h, then add cinnamoyl chloride (1.50 eq). The resulting reaction mixture is stirred for an additional 0.5 h, and then transferred to room temperature (20 °C - 30 °C) and reacted for 24 h. The reaction solution is extracted with saturated brine and water respectively, and the organic phases are combined. The combined organic phase is concentrated under reduced pressure to obtain an oily substance. The obtained oily substance is separated and purified by column silica gel column (n-hexane / ethyl acetate (V / V) = 2 / 1) to obtain 0.90 g of a yellowish-white solid, with a yield of 33.58% and a purity of 93.55%.

[0109] MS(ESI,pos.ion)m / z:510.4[M+H] + ;

[0110] 11H NMR (400 MHz, CDCl 3 ) δ 7.64 (d, J = 15.7 Hz, 1H), 7.59 (dd, J = 6.3, 2.9 Hz, 2H), 7.47 (d, J = 15.7 Hz, 1H), 7.42 - 7.34 (m, 3H), 7.32 - 7.18 (m, 5H), 7.11 (s, 1H), 6.92 (s, 1H), 4.07 (d, J = 16.9 Hz, 1H), 3.98 (s, 3H), 3.87 (s, 3H), 3.42 (s, 2H), 2.87 (d, J = 17.0 Hz, 1H), 2.79 (t, J = 9.4 Hz, 2H), 2.44 (dd, J = 14.6, 4.6 Hz, 1H), 1.95 - 1.77 (m, 4H), 1.58 (t, J = 11.4 Hz, 2H), 1.40 - 1.24 (m, 3H).

[0111] 9. Synthesis of Compound (11)

[0112]

[0113] Donepezil (2.00 g, 1 eq), lithium bis(trimethylsilyl)amide (1.50 eq) and tetrahydrofuran (20 mL) were added to a reaction flask. The mixture was stirred at -20 °C for 0.5 h, then n-pentyl chloroformate (1.50 eq) was added. The resulting reaction mixture was stirred for another 0.5 h and then transferred to room temperature (20 °C - 30 °C) for reaction for 24 h. The reaction solution was extracted with saturated brine and water respectively, and the organic phases were combined. The organic phases were concentrated under reduced pressure to obtain an oily substance. The obtained oily substance was separated and purified by column silica gel column (n-hexane / ethyl acetate (V / V) = 2 / 1) to obtain 0.46 g of a yellow oily substance, with a yield of 17.69% and a purity of 97.33%.

[0114] MS (ESI, pos. ion) m / z: 494.1 [M + H] + ;

[0115] 1 1H NMR (400 MHz, CDCl 3)δ 7.28 (d, J = 7.5 Hz, 1H), 7.26 (d, J = 3.3 Hz, 2H), 7.24 - 7.17 (m, 1H), 7.13 (s, 1H), 6.87 (s, 1H), 4.04 (t, J = 6.7 Hz, 2H), 3.96 (s, 3H), 3.87 (s, 3H), 3.68 (d, J = 16.9 Hz, 1H), 3.44 (d, J = 9.0 Hz, 2H), 2.98 (d, J = 16.9 Hz, 1H), 2.85 - 2.73 (m, 2H), 2.25 (dd, J = 14.3, 4.7 Hz, 1H), 1.85 (dd, J = 24.6, 12.5 Hz, 2H), 1.72 (dd, J = 14.3, 6.1 Hz, 1H), 1.63 - 1.49 (m, 4H), 1.43 - 1.28 (m, 4H), 1.27 - 1.17 (m, 4H), 0.84 (t, J = 6.8 Hz, 3H).

[0116] Synthesis of Compound (13)

[0117]

[0118] Donepezil (2.00 g, 1 eq), lithium bis(trimethylsilyl)amide (1.50 eq) and tetrahydrofuran (20 mL) were added to a reaction flask, and the mixture was stirred at -20 °C for 0.5 h. Then, 4-fluorobenzoyl chloride (1.50 eq) was added, and the resulting reaction mixture was stirred for another 0.5 h and then transferred to room temperature (20 °C - 30 °C) for reaction for 24 h. The reaction solution was extracted with saturated brine and water respectively, and the organic phases were combined. The organic phase was concentrated under reduced pressure to obtain an oily substance, and the obtained oily substance was separated and purified by column silica gel column (n-hexane / ethyl acetate (V / V) = 2 / 1) to obtain 1.55 g of a yellow solid with a yield of 58.71% and a purity of 96.81%.

[0119] MS (ESI, pos. ion) m / z: 502.3 [M + H] + ;

[0120] 1 H NMR (400 MHz, CDCl 3)δ 7.82 (dd, J = 8.7, 5.4 Hz, 2H), 7.31 - 7.20 (m, 5H), 7.19 (s, 1H), 7.00 (t, J = 8.6 Hz, 2H), 6.92 (s, 1H), 4.00 (s, 3H), 3.92 (s, 3H), 3.73 (d, J = 17.1 Hz, 1H), 3.40 (s, 2H), 3.04 (d, J = 17.1 Hz, 1H), 2.74 (t, J = 10.3 Hz, 2H), 2.27 - 2.19 (m, 1H), 2.11 (dd, J = 14.3, 4.9 Hz, 1H), 1.78 (d, J = 10.6 Hz, 2H), 1.56 (d, J = 8.7 Hz, 1H), 1.43 (d, J = 9.9 Hz, 1H), 1.34 - 1.22 (m, 3H).

[0121] Synthesis of Compound (20)

[0122]

[0123] Donepezil (2.00 g, 1 eq), lithium bis(trimethylsilyl)amide (1.50 eq) and tetrahydrofuran (20 mL) were added to a reaction flask, and the mixture was stirred at -20 °C for 0.5 h. Then, chloroacetyl chloride (1.50 eq) was added, and the resulting reaction mixture was stirred for another 0.5 h and then transferred to room temperature (20 °C - 30 °C) for reaction for 24 h. The reaction solution was extracted with saturated brine and water respectively, and the organic phases were combined. The combined organic phase was concentrated under reduced pressure to obtain an oily substance. The obtained oily substance was separated and purified by column silica gel column (n - hexane / ethyl acetate (V / V) = 2 / 1) to obtain 0.61 g of a yellow oily substance with a yield of 24.21% and a purity of 96.49%.

[0124] MS (ESI, pos. ion) m / z: 480.5 [M + H] + ;

[0125] 1 H NMR (400 MHz, CDCl 3)δ 7.30 (d, J = 4.3 Hz, 4H), 7.27 - 7.21 (m, 1H), 6.95 (s, 1H), 6.69 (s, 1H), 4.86 (s, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.48 (s, 2H), 3.25 (s, 2H), 2.86 (d, J = 11.5 Hz, 2H), 2.27 (d, J = 7.1 Hz, 2H), 2.20 (s, 3H), 1.92 (t, J = 10.9 Hz, 2H), 1.64 (d, J = 12.3 Hz, 2H), 1.49 (ddd, J = 11.1, 7.3, 3.7 Hz, 1H), 1.28 (ddd, J = 14.1, 11.9, 3.2 Hz, 3H).

[0126] Synthesis of Compound (22)

[0127]

[0128] Donepezil (1.00 g, 1 eq), lithium bis(trimethylsilyl)amide (1.50 eq) and tetrahydrofuran (10 mL) were added to a reaction flask, and the mixture was stirred at -20 °C for 0.5 h. Then, p-chlorophenyl isocyanate (1.50 eq) was added, and the resulting reaction mixture was stirred for another 0.5 h and then transferred to room temperature (20 °C - 30 °C) for reaction for 24 h. The reaction solution was extracted with saturated brine and water respectively, and the organic phases were combined. The combined organic phase was concentrated under reduced pressure to obtain an oil. The obtained oil was separated and purified by column silica gel column (n-hexane / ethyl acetate (V / V) = 2 / 1) to obtain 0.15 g of a white solid, with a yield of 11.19% and a purity of 99.29%.

[0129] MS (ESI, pos. ion) m / z: 493.1 [M + H] + ;

[0130] 1 H NMR (599 MHz, CDCl 3)δ 7.40 (dt, J = 14.2, 4.8 Hz, 3H), 7.32 (d, J = 6.9 Hz, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 4.15 (d, J = 10.7 Hz, 1H), 4.10 (s, 2H), 3.96 (d, J = 5.4 Hz, 3H), 3.89 (s, 3H), 3.46 (t, J = 10.0 Hz, 2H), 3.06 (d, J = 17.2 Hz, 1H), 2.89 (d, J = 17.2 Hz, 1H), 2.50 (d, J = 12.7 Hz, 2H), 2.34 (s, 1H), 1.76 (s, 1H), 1.73 - 1.63 (m, 3H), 1.63 - 1.58 (m, 2H), 1.26 (dd, J = 63.1, 45.1 Hz, 2H), 0.96 (s, 9H).

[0131] Synthesis of Compound (26)

[0132]

[0133] Donepezil (1.00 g, 1 eq), lithium bis(trimethylsilyl)amide (1.50 eq) and tetrahydrofuran (10 mL) were added to a reaction flask, and the mixture was stirred at -20 °C for 0.5 h. Then p-chlorophenyl isocyanate (1.50 eq) was added, and the resulting reaction mixture was stirred for another 0.5 h and then transferred to room temperature (20 °C - 30 °C) for reaction for 18 h. The reaction solution was extracted with saturated brine and water respectively, and the organic phases were combined. The organic phase was concentrated under reduced pressure to obtain an oil. The obtained oil was separated and purified by a column of silica gel (n-hexane / ethyl acetate (V / V) = 2 / 1) to obtain 0.40 g of a white solid, with a yield of 27.78% and a purity of 97.71%.

[0134] MS (ESI, pos.ion) m / z: 533.3 [M + H] + ;

[0135] 1 H NMR (599 MHz, CDCl 3)δ 7.48 (d, J = 8.7 Hz, 2H), 7.42 - 7.37 (m, 3H), 7.34 (d, J = 6.8 Hz, 2H), 7.12 (s, 1H), 6.87 (s, 1H), 4.11 (dd, J = 28.0, 13.1 Hz, 2H), 3.98 (s, 3H), 3.89 (s, 3H), 3.52 (d, J = 11.6 Hz, 1H), 3.44 (d, J = 11.4 Hz, 1H), 2.96 (d, J = 17.6 Hz, 1H), 2.54 (s, 2H), 2.16 (d, J = 9.8 Hz, 3H), 2.03 (d, J = 13.7 Hz, 1H), 1.75 (s, 3H), 1.62 (s, 2H), 1.24 (s, 2H).

[0136] Synthesis of Compound (32)

[0137]

[0138] 1) Add 10 g of donepezil, 100 mL of methanol, 4.32 g of sodium ethoxide, and 5.49 g of hydroxylamine hydrochloride into a reaction flask, heat up to 65 °C and react until no raw materials are left as detected by TLC; concentrate the reaction solution under reduced pressure to obtain a yellow solid, add 100 mL of dichloromethane and 100 mL of 5% sodium bicarbonate solution for dilution, and extract. Separate the organic phase by liquid separation, and concentrate the organic phase under reduced pressure to obtain 10.8 g of white solid of donepezilone oxime.

[0139] 2) Add 2.00 g of the donepezilone oxime obtained in the above step 1 and 30 mL of tetrahydrofuran into a reaction flask, heat up to 45 °C until it dissolves clearly, then cool down to room temperature (20 - 30 °C), add sodium carbonate (2.00 eq) and valeryl chloride (1.50 eq), and react for 8 h. Extract the reaction solution with saturated brine and water, concentrate the organic phase under reduced pressure to obtain an oil. The obtained oil is separated and purified by column silica gel column (n - hexane / ethyl acetate (V / V) = 2 / 1) to obtain 0.32 g of white solid, with a yield of 13.22% and a purity of 97.18%.

[0140] MS (ESI, pos.ion) m / z: 479.4 [M + H] + ;

[0141] 1 H NMR (400 MHz, CDCl 3) δ 7.31 (t, J = 5.4 Hz, 5H), 6.76 (s, 1H), 3.90 (d, J = 2.8 Hz, 6H), 3.49 (d, J = 12.9 Hz, 3H), 3.13 (dd, J = 16.5, 7.2 Hz, 1H), 2.90 (dd, J = 21.5, 11.5 Hz, 2H), 2.68 (d, J = 16.5 Hz, 1H), 2.44 (t, J = 7.5 Hz, 2H), 1.96 (dd, J = 14.9, 7.4 Hz, 2H), 1.83 (dd, J = 23.1, 11.8 Hz, 3H), 1.77 - 1.67 (m, 2H), 1.59 (d, J = 11.3 Hz, 1H), 1.48 - 1.24 (m, 6H), 0.96 (t, J = 7.3 Hz, 3H).

[0142] Synthesis of Compound (33)

[0143]

[0144] Add 2.00 g of donepezil oxime and 30 mL of tetrahydrofuran to a reaction flask. Heat to 45 °C until dissolved clearly, then cool to room temperature (20 - 30 °C) and add sodium carbonate (2.00 eq) and p-methylbenzoyl chloride (1.50 eq) and react for 8 h. The reaction solution is extracted with saturated brine and water. The organic phase is concentrated under reduced pressure to obtain an oily substance. The obtained oily substance is separated and purified by a column silica gel column (n-hexane / ethyl acetate (V / V) = 2 / 1) to obtain 0.78 g of a white solid, with a yield of 30.00% and a purity of 98.80%.

[0145] MS(ESI, pos.ion) m / z: 513.3 [M + H] + ;

[0146] 1 H NMR(400 MHz, CDCl 3 ) δ 8.05 (d, J = 8.1 Hz, 2H), 7.77 (s, 1H), 7.60 - 7.51 (m, 2H), 7.45 - 7.36 (m, 3H), 6.82 (s, 1H), 4.00 (s, 2H), 3.92 (d, J = 5.7 Hz, 3H), 3.79 (s, 3H), 3.40 - 3.20 (m, 4H), 2.65 (ddd, J = 38.7, 23.5, 10.8 Hz, 3H), 2.44 (s, 3H), 2.05 (d, J = 3.9 Hz, 2H), 1.94 (d, J = 21.6 Hz, 1H), 1.91 - 1.72 (m, 4H), 1.62 (dt, J = 14.4, 7.2 Hz, 1H), 1.31 - 1.21 (m, 1H).

[0147] Example 2 In Vitro Liver Microsome Experiment

[0148] 1. Experimental Method

[0149] 1) Sample Preparation

[0150] 01 Solution Preparation: Dissolve the test compound or control compound using 10 mM DMSO, then take 5 μL and add 495 μL of 50% ACN / H 2 O Diluent Preparation (Conc.: 100 μM test compound or control compound, 10% DMSO, 45% ACN);

[0151] 02 Solution Preparation: Take 10 μL of the above-prepared 01 solution (100 μM test compound or control compound) and dilute it with 90 μL of buffer (Conc.: 10 μM test compound or control compound, 1% DMSO, 4.5% ACN);

[0152] 2) Prepare 96-well plates, named T0, T20, T60, NCF60 (additional ones can be added if necessary);

[0153] 3) Take 14 μL of liver microsome solution with a concentration of 20 mg / mL, dilute it with 486 μL of buffer to obtain a diluted liver microsome solution, and then incubate the above-prepared 02 sample solution and the diluted liver microsome solution at 37 °C for 10 min;

[0154] 4) Take 45 μL of the diluted liver microsome solution after incubation in step 3), add pre-cooled reaction termination solution (ACN) (150 μL / well), and add 5 μL of the test compound or positive control working solution as the T0 sample to the mixture. Stir well, seal and keep at 2 - 8 °C for analysis;

[0155] 5) Take 45 μL of the diluted liver microsome solution after incubation in step 3) and transfer it to the corresponding wells of the T60 and T20 plates and preheat. Add 5 μL of the test compound or positive control working solution at the required time point to initiate the reaction. The final reaction system contains 0.5 mg / mL of liver microsome (Conc.: 1 μM test compound or control compound, 0.1% DMSO, 0.45% ACN);

[0156] 6) Add pre-cooled reaction termination solution (150 μL / well) to terminate the reaction at 20 min and 60 min of the reaction respectively;

[0157] 7) Centrifuge at 4000 rpm for 5 min;

[0158] 8) Take another 96-well plate and add 150 μL of MeOH / H 2 O (MeOH / H 2O (volume ratio 1:1), then 30 μL of the centrifuged supernatant was taken and added to MeOH / H 2 O (MeOH / H 2 O (volume ratio 1:1)) and mixed well, then LC-MS was measured.

[0159] 2. Experimental results

[0160] The in vitro liver microsome test results of the compounds synthesized in the present invention are shown in Table 1, indicating that most of the compounds of the present invention can be metabolized into the prototype drug donepezil. Among them, compared with the existing compound (1), the ER values of the compounds (2), (5) and (6) of the present invention are all greater than that of compound (1), indicating that the metabolic rates of the compounds (2), (5) and (6) of the present invention are extremely fast; in addition, the T 1 / 2 of the compounds (2), (5) and (6) of the present invention are all lower than the T 1 / 2 of compound (1), indicating that after the compounds of the present invention enter the human body, they can be rapidly converted into the prototype drug donepezil through liver microsomal enzyme metabolism, avoiding the risk that the modified compounds are metabolized and excreted without being converted in the body, which is beneficial to controlling a stable blood drug concentration and improving bioavailability.

[0161] Table 1: Stability of compounds in human liver microsomes (in vitro)

[0162]

[0163] Note: Slow metabolism (ER < 0.3), moderate metabolism (ER 0.3 - 0.7), fast metabolism (ER > 0.7); / represents very fast metabolism, and the sample is metabolized completely at t0 detection after being added to liver microsomes, and the data are selected from human liver microsomes. Parecoxib sodium is used as a control.

[0164] Example 3 Determination of compound solubility

[0165] 1. Experimental method

[0166] Unless otherwise specified, the test sample ground into fine powder was weighed or the liquid sample was measured, and a certain amount of solvent was added at 25 ± 2 °C, and shaken strongly for 0.5 min every 5 min; the dissolution situation within 30 min was observed. If there were no visually visible solute particles or droplets, it was considered completely dissolved.

[0167] Among them, the judgment criteria are as follows:

[0168] Very soluble means that 1 g (mL) of solute can dissolve in less than 1 mL of solvent;

[0169] Freely soluble means that 1 g (mL) of solute can dissolve in 1 - less than 10 mL of solvent;

[0170] Dissolution means that 1 g (mL) of solute can dissolve in 10 to less than 30 mL of solvent;

[0171] Sparingly soluble means that 1 g (mL) of solute can dissolve in 30 to less than 100 mL of solvent;

[0172] Slightly soluble means that 1 g (mL) of solute can dissolve in 100 to less than 1000 mL of solvent;

[0173] Very slightly soluble means that 1 g (mL) of solute can dissolve in 1000 to less than 10000 mL of solvent;

[0174] Practically insoluble or insoluble means that 1 g (mL) cannot dissolve in 10000 mL of solvent.

[0175] 2. Experimental results

[0176] The solubility in water of the compounds synthesized in the present invention is shown in Table 2. It can be seen that, except for compound (22), the solubilities of the remaining compounds are lower than that of donepezil prototype. Among them, compound (6) and compound (8) are very slightly soluble, indicating that when the compounds of the present invention are made into drug dosage forms such as nanocrystals or microspheres and injected into the body, they can slowly release into the blood through extremely low solubility to achieve the purpose of long-acting effect, and then be rapidly metabolized by hepatic microsomes of the compound into the donepezil prototype drug, maintaining a stable blood drug concentration and high bioavailability, and ensuring the stability and safety of the drug.

[0177] Table 2: Solubility of compounds in water

[0178]

[0179] Note: Solubility test was carried out in pure water

[0180] In the description of this specification, the description with reference to terms such as "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0181] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula I: --- selected from a single bond or a double bond; Y is selected from -O- or =N-; Z is -C(=O)-R 1 , -CH 2 O-R 1a , -OC(=O)-R 1b , -C 1-4 alkylene -C(=O)-C 1-4 alkyl, -O-C 1-6 alkylene C(=O)-C 1-4 alkyl or -NHC(=O)-C 1-4 alkyl, wherein the -O-C 1-6 alkylene C(=O)-C 1-4 alkyl and -NHC(=O)-C 1-4 alkyl are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 R W substituents; R 1 selected from C 2-4 alkyl, C 1-6 alkyloxy, C 2-6 alkenyl, six-membered heterocyclic group, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, benzyloxy, phenylamino, -(CH 2 ) 2 -phenyl, -CH=CH-phenyl, -CH 2 -OC(=O)C 1-4 alkyl, -OCH 2 -OC(=O)-phenyl, benzyl, phenyl, -CH 2 COOH, -(CH 2 ) 2 -COOH, -(CH 2 ) 4 -COOH or C 1-5 alkylamino, wherein the C 1-6 alkyloxy, C 2-6 alkenyl, six-membered heterocyclic group, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, benzyloxy, phenylamino, -(CH 2 ) 2 -phenyl, -CH=CH-phenyl, -CH 2 -OC(=O)C 1-4 alkyl, -OCH 2 -OC(=O)-phenyl and benzyl are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 R W1 substituents, and the phenyl is substituted by 1, 2, 3 or 4 R W2 substituents; R 1a selected from benzyl, -C(=O)O-C 1-4 alkyl, -C(=O)-C 1-4 alkyl or -C(=O)O-benzyl, wherein the benzyl, -C(=O)O-C 1-4 alkyl, -C(=O)-C 1-4 alkyl and -C(=O)O-benzyl are each independently optionally unsubstituted or substituted with 1, 2, 3 or 4 R W3 substituents; R 1b selected from C 1-6 alkyl or phenyl, wherein said C 1-6 alkyl and phenyl are each independently optionally unsubstituted or substituted with 1, 2, 3 or 4 R W4 substituents; R W 、R W1 、R W2 、R W3 and R W4 are each independently selected from -OH, -F, -Cl, -Br, -I, =O, C 1-4 alkyl or C 1-4 alkoxy.

2. The compound according to claim 1, wherein, Z is -C(=O)-R 1 , -CH 2 O-R 1a , -OC(=O)-R 1b , -C 1-4 alkylene-C(=O)C 1-4 alkyl, -O-C 1-4 alkyleneC(=O)-C 1-4 alkyl or -NHC(=O)-C 1-4 alkyl, wherein the -O-C 1-4 alkyleneC(=O)-C 1-4 alkyl and -NHC(=O)-C 1-4 alkyl are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 R W substituents; or Z is -C(=O)-R 1 、-CH 2 O-R 1a 、-OC(=O)-R 1b 、-CH 2 -C(=O)-C 1-4 alkyl, -(CH 2 ) 2 -C(=O)-C 1-4 alkyl, -CH(CH 3 )-C(=O)-C 1-4 alkyl, -(CH 2 ) 3 -C(=O)-C 1-4 alkyl, -(CH 2 ) 4 -C(=O)-C 1-4 alkyl, -O-C 1-4 alkylene C(=O)-C 1-4 alkyl or -NHC(=O)-C 1-4 alkyl, wherein the -O-C 1-4 alkylene C(=O)-C 1-4 alkyl and -NHC(=O)-C 1-4 alkyl are each independently optionally unsubstituted or substituted with 1, 2, 3 or 4 R W substituents; or Z is -C(=O)-R 1 、-CH 2 O-R 1a 、-OC(=O)-R 1b 、-CH 2 -C(=O)-methyl, -CH 2 -C(=O)-ethyl, -CH 2 -C(=O)-n-propyl, -CH 2 -C(=O)-isopropyl, -CH 2 -C(=O)-n-butyl, -CH 2 -C(=O)-isobutyl, -CH 2 -C(=O)-tert-butyl, -(CH 2 ) 2 -C(=O)-methyl, -CH(CH 3 )-C(=O)-methyl, -(CH 2 ) 2 -C(=O)-ethyl, -(CH 2 ) 2 -C(=O)-n-propyl, -(CH 2 ) 2 -C(=O)-isopropyl, -(CH 2 ) 2 -C(=O)-n-butyl, -(CH 2 ) 2 -C(=O)-isobutyl, -(CH 2 ) 2 -C(=O)-tert-butyl, -(CH 2 ) 3 -C(=O)-methyl, -(CH 2 ) 3 -C(=O)-ethyl, -(CH 2 ) 3 -C(=O)-n-propyl, -(CH 2 ) 3 -C(=O)-isopropyl, -(CH 2 ) 3 -C(=O)-n-butyl, -(CH 2 ) 3 -C(=O)-isobutyl, -(CH 2 ) 3 -C(=O)-tert-butyl, -(CH 2 ) 4 -C(=O)-methyl, -(CH 2 ) 4 -C(=O)-ethyl, -(CH 2 ) 4 -C(=O)-n-propyl, -(CH 2 ) 4 -C(=O)-isopropyl, -(CH 2 ) 4 -C(=O)-n-butyl, -(CH 2 ) 4 -C(=O)-isobutyl, -(CH 2 ) 4 -C(=O)-tert-butyl, -O-C 1-4 alkylene C(=O)-C 1-4 alkyl or -NHC(=O)-C 1-4 alkyl, wherein said -O-C 1-4 alkylene C(=O)-C 1-4 alkyl and -NHC(=O)-C 1-4 alkyl are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 R W substituents; or Z is -C(=)O-R 1 、-CH 2 O-R 1a 、-OC(=O)-R 1b 、-CH 2 -C(=O)-methyl, -CH 2 -C(=O)-ethyl, -CH 2 -C(=O)-n-propyl, -CH 2 -C(=O)-isopropyl, -CH 2 -C(=O)-n-butyl, -CH 2 -C(=O)-isobutyl, -CH 2 -C(=O)-tert-butyl, -(CH 2 ) 2 -C(=O)-methyl, -CH(CH 3 )-C(=O)-methyl, -(CH 2 ) 2 -C(=O)-ethyl, -(CH 2 ) 2 -C(=O)-n-propyl, -(CH 2 ) 2 -C(=O)-isopropyl, -(CH 2 ) 2 -C(=O)-n-butyl, -(CH 2 ) 2 -C(=O)-isobutyl, -(CH 2 ) 2 -C(=O)-tert-butyl, -(CH 2 ) 3 -C(=O)-methyl, -(CH 2 ) 3 -C(=O)-ethyl, -(CH 2 ) 3 -C(=O)-n-propyl, -(CH 2 ) 3 -C(=O)-isopropyl, -(CH 2 ) 3 -C(=O)-n-butyl, -(CH 2 ) 3 -C(=O)-isobutyl, -(CH 2 ) 3 -C(=O)-tert-butyl, -(CH 2 ) 4 -C(=O)-methyl, -(CH 2 ) 4 -C(=O)-ethyl, -(CH 2 ) 4 -C(=O)-n-propyl, -(CH 2 ) 4 -C(=O)-isopropyl, -(CH 2 ) 4 -C(=O)-n-butyl, -(CH 2 ) 4 -C(=O)-isobutyl, -(CH 2 ) 4 -C(=O)-tert-butyl, -O-CH 2 -C(=O)-C 1-4 alkyl, -O-(CH 2 ) 2 -C(=O)-C 1-4 alkyl, -O-(CH 2 ) 3 -C(=O)-C 1-4 alkyl, -O-(CH 2 ) 4 -C(=O)-C 1-4 alkyl or -NHC(=O)-C 1-4 alkyl, wherein the -O-CH 2 -C(=O)-C 1-4 alkyl, -O-(CH 2 ) 2 -C(=O)-C 1-4 alkyl, -O-(CH 2 ) 3 -C(=O)-C 1-4 alkyl, -O-(CH 2 ) 4 -C(=O)-C 1-4 alkyl and -NHC(=O)-C 1-4 alkyl are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 R W substituents; or Z is -C=O-R 1 、-CH 2 O-R 1a 、-OC(=O)-R 1b 、-CH 2 -C(=O)-methyl, -CH 2 -C(=O)-ethyl, -CH 2 -C(=O)-n-propyl, -CH 2 -C(=O)-isopropyl, -CH 2 -C(=O)-n-butyl, -CH 2 -C(=O)-isobutyl, -CH 2 -C(=O)-tert-butyl, -(CH 2 ) 2 -C(=O)-methyl, -CH(CH 3 )-C(=O)-methyl, -(CH 2 ) 2 -C(=O)-ethyl, -(CH 2 ) 2 -C(=O)-n-propyl, -(CH 2 ) 2 -C(=O)-isopropyl, -(CH 2 ) 2 -C(=O)-n-butyl, -(CH 2 ) 2 -C(=O)-isobutyl, -(CH 2 ) 2 -C(=O)-tert-butyl, -(CH 2 ) 3 -C(=O)-methyl, -(CH 2 ) 3 -C(=O)-ethyl, -(CH 2 ) 3 -C(=O)-n-propyl, -(CH 2 ) 3 -C(=O)-isopropyl, -(CH 2 ) 3 -C(=O)-n-butyl, -(CH 2 ) 3 -C(=O)-isobutyl, -(CH 2 ) 3 -C(=O)-tert-butyl, -(CH 2 ) 4 -C(=O)-methyl, -(CH 2 ) 4 -C(=O)-ethyl, -(CH 2 ) 4 -C(=O)-n-propyl, -(CH 2 ) 4 -C(=O)-isopropyl, -(CH 2 ) 4 -C(=O)-n-butyl, -(CH 2 ) 4 -C(=O)-isobutyl, -(CH 2 ) 4 -C(=O)-tert-butyl, -O-CH 2 -C(=O)-methyl, -O-CH 2 -C(=O)-ethyl, -O-CH 2 -C(=O)-n-propyl, -O-CH 2 -C(=O)-isopropyl, -O-CH 2 -C(=O)-n-butyl, -O-CH 2 -C(=O)-isobutyl, -O-CH 2 -C(=O)-tert-butyl, -O-(CH 2 ) 2 -C(=O)-methyl, -O-(CH 2 ) 2 -C(=O)-ethyl, -O-(CH 2 ) 2 -C(=O)-n-propyl, -O-(CH 2 ) 2 -C(=O)-isopropyl, -O-(CH 2 ) 2 -C(=O)-n-butyl, -O-(CH 2 ) 2 -C(=O)-isobutyl, -O-(CH 2 ) 2 -C(=O)-tert-butyl, -O-(CH 2 ) 3 -C(=O)-methyl, -O-(CH 2 ) 3 -C(=O)-ethyl, -O-(CH 2 ) 3 -C(=O)-n-propyl, -O-(CH 2 ) 3 -C(=O)-isopropyl, -O-(CH 2 ) 3 -C(=O)-n-butyl, -O-(CH 2 ) 3 -C(=O)-isobutyl, -O-(CH 2 ) 3 -C(=O)-tert-butyl, -O-(CH 2 ) 4 -C(=O)-methyl, -O-(CH 2 ) 4 -C(=O)-ethyl, -O-(CH 2 ) 4 -C(=O)-n-propyl, -O-(CH 2 ) 4 -C(=O)-isopropyl, -O-(CH 2 ) 4 -C(=O)-n-butyl, -O-(CH 2 ) 4 -C(=O)-isobutyl, -O-(CH 2 ) 4 -C(=O)-tert-butyl, -NHC(=O)-methyl, -NHC(=O)-ethyl, -NHC(=O)-n-propyl, -NHC(=O)-isopropyl, -NHC(=O)-n-butyl or -NHC(=O)-tert-butyl, wherein the -O-CH 2 -C(=O)-methyl, -O-CH 2 -C(=O)-ethyl, -O-CH 2 -C(=O)-n-propyl, -O-CH 2 -C(=O)-isopropyl, -O-CH 2 -C(=O)-n-butyl, -O-CH 2 -C(=O)-isobutyl, -O-CH 2 -C(=O)-tert-butyl, -O-(CH 2 ) 2 -C(=O)-methyl, -O-(CH 2 ) 2 -C(=O)-ethyl, -O-(CH 2 ) 2 -C(=O)-n-propyl, -O-(CH 2 ) 2 -C(=O)-isopropyl, -O-(CH 2 ) 2 -C(=O)-n-butyl, -O-(CH 2 ) 2 -C(=O)-isobutyl, -O-(CH 2 ) 2 -C(=O)-tert-butyl, -O-(CH 2 ) 3 -C(=O)-methyl, -O-(CH 2 ) 3 -C(=O)-ethyl, -O-(CH 2 ) 3 -C(=O)-n-propyl, -O-(CH 2 ) 3 -C(=O)-isopropyl, -O-(CH 2 ) 3 -C(=O)-n-butyl, -O-(CH 2 ) 3 -C(=O)-isobutyl, -O-(CH 2 ) 3 -C(=O)-tert-butyl, -O-(CH 2 ) 4 -C(=O)-methyl, -O-(CH 2 ) 4 -C(=O)-ethyl, -O-(CH 2 ) 4 -C(=O)-n-propyl, -O-(CH 2 ) 4 -C(=O)-isopropyl, -O-(CH 2 ) 4 -C(=O)-n-butyl, -O-(CH 2 ) 4 -C(=O)-isobutyl, -O-(CH 2 ) 4 -C(=O)-tert-butyl, -NHC(=O)-methyl, -NHC(=O)-ethyl, -NHC(=O)-n-propyl, -NHC(=O)-isopropyl, -NHC(=O)-n-butyl, and -NHC(=O)-tert-butyl are each independently optionally unsubstituted or substituted with 1, 2, 3, or 4 R W substituents.

3. The compound according to claim 1 or 2, wherein, R 1 Selected from ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 1-pentyloxy, vinyl, allyl, piperidinyl, dihydropyridine, morpholinyl, thiomorpholinyl, piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, benzyloxy, phenylamino, -(CH 2 ) 2 -phenyl, -CH=CH-phenyl, -CH 2 OC(=O)-methyl, -CH 2 OC(=O)-ethyl, -CH 2 OC(=O)-n-propyl, -CH 2 OC(=O)-isopropyl, -CH 2 OC(=O)-tert-butyl, -OCH 2 -OC(=O)-phenyl, benzyl, phenyl, -CH 2 COOH, -(CH 2 ) 2 -COOH, -(CH 2 ) 4 -COOH, N,N-dimethylamino or N,N-diethylamino, wherein the methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 1-pentyloxy, vinyl, allyl, piperidinyl, dihydropyridine, morpholinyl, thiomorpholinyl, piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, benzyloxy, phenylamino, -(CH 2 ) 2 -phenyl, -CH=CH-phenyl, -CH 2 OC(=O)-methyl, -CH 2 OC(=O)-ethyl, -CH 2 OC(=O)-n-propyl, -CH 2 OC(=O)-isopropyl, -CH 2 OC(=O)-tert-butyl, -OCH 2 -OC(=O)-phenyl and benzyl are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 R W1 substituents, and the phenyl is substituted by 1, 2, 3 or 4 R W2 substituents.

4. The compound according to any one of claims 1-3, wherein, R 1a selected from benzyl, -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-n-propyl, -C(=O)O-i-propyl, -C(=O)O-n-butyl, -C(=O)O-t-butyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)-n-propyl, -C(=O)-i-propyl, -C(=O)-n-butyl, -C(=O)-t-butyl or -C(=O)O-benzyl, wherein the benzyl, -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-n-propyl, -C(=O)O-i-propyl, -C(=O)O-n-butyl, -C(=O)O-t-butyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)-n-propyl, -C(=O)-i-propyl, -C(=O)-n-butyl, -C(=O)-t-butyl and -C(=O)O-benzyl are each independently optionally unsubstituted or substituted with 1, 2, 3 or 4 R W3 substituents; R 1b selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl or phenyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and phenyl are each independently optionally unsubstituted or substituted with 1, 2, 3 or 4 R W4 substituents.

5. The compound according to any one of claims 1-4, wherein, R W 、R W1 、R W2 、R W3 and R W4 are each independently selected from -OH, -F, -Cl, -Br, -I, =O, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy or 2-butoxy.

6. The compound according to any one of claims 1-5, characterized in that, it is a compound represented by formula II or formula III, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula II or formula III:

7. A compound, the structure of which is selected from one of the following:

8. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises: the compound according to any one of claims 1-7, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof; Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

9. Use of the compound according to any one of claims 1-8, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition according to claim 7, in the preparation of a drug for inhibiting the expression of acetylcholinesterase or preventing and / or treating Alzheimer's disease.

10. The use according to claim 9, characterized in that, the dosage form of the drug is selected from injection, tablet, capsule or granule.

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