WO2012065527A1 - Compouds and uses as l-type calcium channel blocker and/or acetylcholinesterase inhibitor thereof - Google Patents

Abstract

Disclosed in this invention are compounds and the uses as L-type calcium channel blocker and/or acetylcholinesterase inhibitor thereof. The uses of said compounds in the manufactures of a medicament for the treatment of cardiovascular diseases, apoplexy or senile dementia are also disclosed in the present invention.

Description

 Compounds and their use as L-type calcium channel blockers or/and acetylcholinesterase inhibitors This application claims to be filed on November 15, 2010, at the Chinese Patent Office, Application No. 201010546303.5, entitled "Compounds and Their Acts" The priority of the Chinese Patent Application for the Application of L-Type Calcium Channel Blockers or/and Acetylcholinesterase Inhibitors is hereby incorporated by reference in its entirety. Technical field

 This invention relates to the field of chemical synthesis, and in particular to compounds and their use as L-type calcium channel blockers or/and acetylcholinesterase inhibitors.

Background technique

 Alzheimer's disease is a central nervous system degenerative disease characterized by chronic, progressive cognitive impairment and memory impairment. The main pathological features are senile plaques, neurofibrillary tangles and neuronal loss, which seriously affect patients. Cognition, memory, language function and personal life ability and emotional personality. At present, the more accepted pathology of Alzheimer's disease in the world is "the theory of cholinergic deficiency." It is said that the loss of choline acetate, a neurotransmitter in the brain of patients, is a key cause of Alzheimer's disease.

 Cholinesterase is a key enzyme in biological nerve conduction. In the cholinergic synapse, the enzyme can degrade acetylcholine, stop the excitatory effects of neurotransmitters on the postsynaptic membrane, and ensure the neural signal in the organism. The normal delivery. However, acetylcholinesterase can catalyze the cleavage reaction of acetylcholine, which leads to the loss of acetylcholine and the failure of nerve signaling, which affects the body's cognitive and memory functions. At present, acetylcholinesterase inhibitors are used to inhibit the activity of cholinesterase, delay the hydrolysis of acetylcholine, increase the level of acetylcholine in the synaptic cleft, and achieve the purpose of treating Alzheimer's disease.

Vascular dementia is an acquired intelligent damage syndrome caused by various cerebrovascular diseases. The clinical manifestations are intelligent decline in memory, calculation, attention and executive function. It is the second only after Alzheimer's disease. The most common cause of dementia. The researchers believe that a mechanism of injury is: Infarction, hypoxic hypoperfusion and hemorrhagic lesions lead to a decrease in brain tissue volume and delayed necrosis of neurons, which in turn leads to impaired acetylcholine nerves in the brain, reduced release of acetylcholine, and progressive memory impairment and cognitive impairment. Social and daily life, activity ability declined. Taking an acetylcholinesterase inhibitor can effectively improve a patient's cognitive function, executive function, and daily living ability.

 Another mechanism of damage in cerebral cortical neurons in patients with vascular dementia is due to increased intrapulmonary calcium influx, leading to decreased learning and memory function. If a calcium channel antagonist, such as nimodipine, enters the brain tissue, the receptor associated with the calcium channel reversibly binds to it, thereby inhibiting the influx of calcium ions into the nerve cells, thereby increasing tolerance to ischemia, dilating the cerebral blood vessels and Improve brain blood supply, protect neurons, and effectively improve cognitive function in patients with vascular dementia.

 Therefore, it is important to develop a compound which inhibits the activity of acetylcholinesterase and blocks the extracellular calcium from flowing into the cell through the calcium channel.

Summary of the invention

 The present invention is directed to the development of Alzheimer's disease and vascular dementia with increased calcium influx and reduced acetylcholine release, providing compounds and their use as L-type calcium channel blockers or/and acetylcholinesterase inhibitors. The compounds of the present invention have a significant inhibitory effect on L-type calcium channels and acetylcholinesterase.

 In order to achieve the above object, the present invention provides the following technical solutions:

The present invention provides a compound of the formula YLX, wherein Y is selected from the group consisting of a group of formula I, formula II or formula III,

 Formula I, formula II, III

Wherein, and independently selected from the group consisting of hydrogen, a halogen atom, a nitro group, an amino group, a trifluoromethyl group, an amino group, a d-c ₄ alkoxy group, a d-C ₄ alkane fluorenyl group, a dC ₈ alkyl group, a c ₂ -c ₈ chain Alkenyl or c ₂ -c ₈ alkynyl;

R ₂ and R ₃ may be independently selected from nitro, cyano or trifluoromethyl; Ar may be selected from an aryl or heteroaryl group, and the C _r C ₄ position of the aryl or heteroaryl group may be optionally a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, an amino group, a dC ₄ alkylthio group, dC ₈ alkyl, C ₂ -C ₈ alkenyl or/and C ₂ -C ₈ alkynyl substituted.

And may also be independently selected from -NR ₅ R ₆ , and the dC ₄ position of Ar is optionally substituted by -NR ₅ R ₆ , wherein R ₅ and R _{6 are} independently selected from hydrogen, dC ₈ alkyl, C ₂ -C ₈ chain Alkenyl or C ₂ -C ₈ alkynyl;

R ₂ and R ₃ may also be independently selected from -COOR ₇ or -CONR ₇ ; the dC ₄ position of Ar may be optionally substituted by -COOR ₇ , wherein R ₇ may be selected from (^-( ₈ alkyl, C ₂ -C ₈ Alkenyl or C ₂ -C ₈ alkynyl;

 In the formula of the compound provided by the present invention, X may be selected from a group having a structure such as any one of the formulae IV to X, and may be bonded to L through any one of R.

式 IV 式 VI

Formula IV

Wherein R may be selected from a direct bond, a hydrogen, a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, an amino group, a dC ₄ alkylthio group, a dC ₁₂ alkyl group, a C ₂ -C ₁₂ alkenyl group or a C ₂ - C ₁₂ alkynyl;

R may also be selected from -NR ₅ R ₆ or -COOR ₇ , wherein R ₅ and R ₆ may be independently selected from hydrogen, dC ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, R ₇ may be selected from dC ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl;

L may be selected from a direct bond, a Ci-Ci ₂ alkylene group, a C ₂ -C ₁₂ subchain group or a C ₂ -C ₁₂ alkynylene group. Preferably, in the compound provided by the present invention, R pR ₄ and Ar may be independently selected from dC ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, one or more of which - The CH ₂ - group may be optionally substituted by -0, -S -, -S0 ₂ - or / and -NR ₅ -, and R ₅ may be selected from hydrogen, dC ₈ alkyl, C ₂ -C ₈ alkenyl or c ₂ -c ₈ alkynyl.

Preferably, in the compound provided by the present invention, and R ₄ and Ar may be independently selected from the group consisting of (^ _-8 alkyl, C ₂ -C ₈ chain or C ₂ -C ₈ alkynyl, which may be optionally Substituted by one or more carbonyl oxygens or/and hydroxyl groups.

Preferably, in the compound provided by the present invention, R ₇ may be selected from dC ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, which may be optionally dC ₄ alkoxy or -NR ₅ R _{6 is} substituted, and R ₅ and R ₆ may be independently selected from hydrogen, dC ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl.

Preferably, in the compounds provided herein, R ₅ and R ₆ may be independently selected from dC ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, which may be optionally phenyl or Substituted phenyl substituents.

Preferably, in the compound provided by the present invention, L and R are independently selected from (^- ₁₂ alkylene, C ₂ -C ₁₂ alkenylene or C ₂ -C ₁₂ alkynylene, one or more of them) The -CH ₂ - group may be optionally -0-, -S-, -S0 ₂ -, cycloalkylene, arylene, heteroalicyclic, heteroarylene or/and -NR ₅ - Alternatively, R ₅ may be selected from hydrogen, dC ₈ alkyl, C ₂ -C ₈ chain or C ₂ -C ₈ alkynyl.

Preferably, L and R may also be independently selected from (^-( ₁₂ alkylene, C ₂ -C ₁₂ alkenylene or C ₂ -C ₁₂ alkynylene, which may optionally be one or more Carbonyloxy or / and hydroxy substituted.

 Preferably, the compound provided by the present invention, Y, may also be selected from:

Amlodipine nimodipine In the present invention, when X is a structure represented by Formula IV, and L is a direct bond, L is bonded to the benzene ring of X. Preferably, the compound provided by the present invention, when independently selected from 14 _{4 is} selected from C _r C ₄ alkyl, R ₂ and R _{3 are} independently selected from -COOR ₇ and L is a direct bond, X is preferably a structure as shown in Formula IV R ₇ is preferably selected from dC ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl.

In the present invention, when R ₂ and R _{3 are} independently selected from -COOR ₇ , R ₄ is a fluorenyl group or an amino group, and X is a structure represented by Formula IV, L is preferably bonded to the benzene ring of X, and R ₇ is preferably selected from C. _r C ₈ alkyl, C ₂ -C ₈ chain or C ₂ -C ₈ alkynyl.

In the present invention, when R ₂ and R _{3 are} independently selected from -COOR ₇ , R ₄ is a fluorenyl group or an amino group, and X is a structure represented by formula VII, L is preferably bonded to the benzene ring of X, and R ₇ is preferably selected from d. -Cg alkyl, C ₂ -C ₈ chain or C ₂ -C ₈ alkynyl.

In the present invention, when R ₂ and R _{3 are} independently selected from -COOR ₇ , R ₃ is -COOCH ₃ , R ₄ is a fluorenyl group, X is a structure represented by Formula VII, and Ar is a chlorophenyl group, L is preferably not Is -CH ₂ OCH ₂ -, and R ₇ is preferably from Ci-C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl.

Preferably, the compound provided by the present invention, R _{4 is} selected from C _r C ₄ alkyl, R ₂ and R _{3 are} independently selected from -COOR ₇ and X is as defined in formula VII, and Ar may be selected from phenyl, C _{The r} C ₄ position may be optionally a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, an amino group, -NR ₅ R ₆ , dC ₄ alkylthio group, -COOR ₇ , Ci-Cg alkyl group, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl substituted, R ₅ and R ₆ may be selected from hydrogen, dC ₈ alkyl, C ₂ -C ₈ chain or C ₂ -C ₈ alkynyl, R ₇ may be selected From dC ₈ alkyl, C ₂ -C ₈ chain or C ₂ -C ₈ alkynyl.

In the present invention, when both 1 and ₄ are a fluorenyl group, R ₃ is -COOCH ₃ and X is a structure represented by the formula IV, L is bonded to the benzene ring of X.

In the present invention, when both 1 and ₄ are fluorenyl groups, R ₃ is -COOCH ₃ and X is a structure represented by Formula IX, L is not bonded to the benzene ring of X.

Preferably, the compound provided by the present invention, and independently selected from C _r C ₄ alkyl, R ₃ may be -COOR ₇ , X is as defined in formula IV, formula VII, IX or X, and Ar is selected from phenyl or benzene. And oxadiazolyl, Its (^- ₄ position may be optionally substituted by a prime atom, a nitro group, a cyano group, a trifluoromethyl group, an amino group, -NR ₅ R ₆ , dC ₄ alkyl ketone group, -COOR ₇ , dC ₈ alkyl group, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl substituted, R ₅ and R ₆ may be selected from hydrogen, C C8 alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, R ₇ may be selected dC ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl.

In the present invention, alkyl means a saturated straight or branched hydrocarbon group, including mercapto, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl An alkylene group refers to a divalent alkyl group; an alkylthio group refers to a sulfur-substituted alkyl group; an alkenyl group refers to an unsaturated straight-chain or branched hydrocarbon group composed of at least one carbon-carbon double bond, Including 4-glycosyl, propylene, isopropylene, butene, isobutylene, tert-butene, n-pentene, n-hexene; alkenylene refers to divalent chain women; alkynyl refers to one or more An unsaturated linear or branched hydrocarbon group consisting of carbon-carbon bonds, including ethynyl, propyne, isopropyne, butyne, isobutyne, tert-butyne, pentyne, hexyne; Is a divalent alkynyl group; a cycloalkyl group means a cyclic alkyl group including a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group. A cycloalkylene group refers to a divalent cycloalkyl group; a cycloalkenyl group refers to a cyclic alkenyl group, including cyclopentyl, cyclohexenyl, cycloheptenyl, cyclooctenyl; alkoxy refers to Is an alkyl group bonded through an oxygen bond; an alkenyloxy group means an alkenyl group bonded through an oxygen bond; a substituted phenyl group means a phenyl group substituted by one or two or more substituents, wherein the substituent includes (^ - ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, dC ₆ alkoxy, C ₂ -C ₆ alkenoxy, phenoxy, benzyloxy, hydroxy, «, Oxyl hydroxyl, ureido, aminodecanoyl, aminodecanoyl, carbonyl, carbozoyL amino, hydroxyamino, nonanoylamino, decanoyl, decyl, cyano, cyanoamino, isocyano, isocyanate, diazo , azido, fluorenyl, triazide, nitrile, nitro, nitroso, isonitroso, nitrosylamino, imino, nitrosomino, oxo, dC ₆ alkylthio, Sulfonyl, sulfamoyl, oxysulfoxide, sulfhydryl, sulfinyl, sulfo, sulfonyl, thioalkoxy, thiocyano, isocyanato, thioindole Amido, halo, haloalkyl, chlorooxy, chlorooxy, perchloric acid, trifluoromethyl, iodosyl, iodoyl, phosphino, phosphinyl, diphosphoryl, phosphono, Sulfhydryl, selenoalkyl, disilyl, silaneoxy, silane, silylene, and carbocyclic and heterocyclic moieties; aryl refers to a cyclic aromatic hydrocarbon moiety having one or more closed loops Substituting, including phenyl, benzyl, naphthyl, anthryl, phenanthryl, biphenyl; arylene refers to divalent aryl; heteroaryl refers to cyclic aryl having one or more than two closed loops a moiety having at least one hetero atom or a hetero atom, such as sulfur, nitrogen or oxygen, including pyrrolyl, furyl, thiol, pyridyl, oxazolyl, thiazolyl, benzofuranyl, Benzothiazyl; heteroarylene refers to a divalent heteroaryl; heteroalicyclic represents a monocyclic or fused ring group having 5 to 9 ring atoms in the ring, one, two or The three ring atoms are heteroatoms selected from N, 0 or SO _m , where m is an integer from 0 to 2 and the remaining ring atoms are C. These rings may have one or more double bonds, but these rings do not have a fully conjugated π-electron system; unsubstituted heteroalicyclic groups include pyrrolidinyl, piperidino, piperazino, morpholino a thiomorpholino group, a homopiperazino group or the like; a heteroalicyclic group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or two or more, more preferably one or two. Or three, more preferably one or two, including lower alkyl, trihaloalkyl, halogen, hydroxy, lower alkoxy, fluorenyl, lower alkylthio, cyano, acyl, thioacyl, 0 - aminodecanoyl, oxime-aminodecanoyl, 0-thioaminodecanoyl, oxime-thioaminodecanoyl, C-amido, oxime-amido, nitro, oxime-sulfonylamino, S-sulfonyl Amino; preferably, the heteroalicyclic group is optionally substituted by one or two substituents including halogen, lower alkyl, trihaloalkyl, hydroxy, decyl, cyano, oxime-amido, mono- or di- Alkylamino, carboxy or oxime-sulfonylamino; heteroalicyclic refers to Monovalent heteroalicyclic; refers to a halo substituted with fluoro, chloro, bromo or iodo group.

 The compounds provided herein also comprise isomers of the compounds, pharmaceutically acceptable equivalents or mixtures of the two.

 Preferably, the isomers of the compounds provided herein are those which have the same number and type of atoms and which have the same molecular weight but differ in atomic arrangement and configuration. A mixture comprising one or more of stereoisomers, diastereomers, enantiomers, non-racemates, racemates, and the like.

Isoforms refer to compounds having the same number and type of atoms, the same molecular weight, but different atomic arrangements and configurations; stereoisomers refer to only the arrangement of atoms in space. The same isomer; the diastereomer refers to a stereoisomer that is not mirror image of each other; the diastereomer occurs in a compound having two or more asymmetric carbon atoms, such a compound 2 ⁿ optical isomers, where _n is the number of asymmetric carbon atoms; enantiomers refer to stereoisomers that are not mirror images of each other; racemates refer to the same aliquot A mixture of individual enantiomers; a non-racemate refers to a mixture of individual enantiomers containing different aliquots.

 Since the compounds of the invention may have one or more asymmetric carbon centers, they may exist as optical isomers or as racemic or non-racemic mixtures of optical isomers. Optical isomers can be obtained by resolution of the racemic mixture in a conventional manner. The process comprises treating the diastereomeric salt with an optically active acid or base and then isolating the mixture of diastereomers by crystallization, followed by dissociation of the optically active base from the salt. Suitable acids may include tartaric acid, dicarboxylic acid tartaric acid, dibenzoyl tartaric acid, dinonyl tartaric acid, and camphoric acid. A method of separating optical isomers involves the use of an optimally selective chiral column to maximize separation of the enantiomers. It is also possible to react a compound of the invention with an activated form of an optically active acid or a diol or an isocyanate to synthesize a covalent diastereomeric molecule, such as an ester, amide, acetal or ketal, and then use conventional A method such as chromatography, distillation, crystallization or sublimation can separate the synthetic diastereomers and then hydrolyze to release the enantiomerically pure compound. In some cases, since the compound can be a prodrug, it is not necessary to hydrolyze the optically active drug of the parent prior to administration to the patient. Similarly, the optically active compound of the present invention can be obtained using an optically active starting material.

 The compounds of the invention include individual optical isomers as well as racemic or/and non-racemic mixtures. In some non-racemic mixtures, the R configuration can be enriched, while in other non-racemic mixtures, the S configuration can be enriched.

 Preferably, the pharmaceutically acceptable equivalents of the compounds provided herein may comprise one or a mixture of two or more of a pharmaceutically acceptable salt, hydrate, solvate, metabolite, prodrug or isostere. .

Preferably, the compounds provided herein are pharmaceutically acceptable equivalents, pharmaceutically acceptable Accepted salts include the acid or base salts of the compounds provided herein. The pharmaceutically acceptable salt has the pharmaceutical activity of the compound and is suitable for both biological and practical applications. The compound provided by the present invention is in a pharmaceutically acceptable equivalent, and the pharmaceutically acceptable acid salt may comprise acetate, adipate, alginate, aspartate, benzoate, benzene. Acid salt, hydrogen sulfate, butyrate, citrate, camphorate, camphorate, cyclopentane propionate, digluconate, lauryl sulfate, ethyl sulphate, Fumarate, glucoheptanoate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrocyanate, hydroiodide, 2-hydroxyethionate, lactic acid Salt, maleate, sulphate, 2-toxin, nicotinate, oxalate, thiocyanate, decyl sulphate and undecanoate. Preferably, the compound provided by the present invention is in a pharmaceutically acceptable equivalent, and the pharmaceutically acceptable basic salt may comprise an ammonium salt, an alkali metal salt such as a sodium and potassium salt, an alkaline earth metal salt such as a calcium salt and a magnesium salt, and an organic compound. A salt formed by a base such as a dicyclohexylamine salt, an N-mercapto-D glucosamine salt, and a salt with an amino acid such as arginine and lysine. Preferably, the basic nitrogen-containing group can be quaternized by the following reagents, including lower alkyl halides such as sulfonium, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulphates Salts such as dithiol, diethyl, dibutyl and dipentyl sulfate; long chain compounds such as sulfhydryl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl The base compound is phenyl bromide.

 Preferably, the compounds provided herein are in pharmaceutically acceptable equivalents, and the prodrugs refer to derivatives of the compounds of the invention which require biotransformation, such as metabolism, prior to their pharmacological utility. Prodrugs are formulated from substances that improve chemical stability, improve patient acceptance and compliance, improve bioavailability, prolonged duration of action, improve organ selectivity, improve formulation, such as enhanced water solubility, or reduce side effects such as toxicity. Prodrugs can be prepared from the compounds of the invention by conventional methods, see BURGER'S MEDICINAL CHEMISTRY AND DRUG CHEMISTRY, 5th Edition, Vol. 1, pp. 172-178, 949-982 (1995).

In the present invention, an isostere refers to an element, a functional group, a substituent, a molecule or an ion having different molecular formulas but exhibiting similar or identical physical properties. For example, tetrazole is a carboxylic acid Isosteres because they have properties similar to carboxylic acids, even though they have different molecular formulas. Typically, two equal rows of molecules have similar or identical sizes and shapes. Ideally, the equal rows of molecules will be isomorphic and capable of crystallizing together. Other physical properties of the isostere molecule generally include boiling point, density, viscosity, and thermal conductivity. However, because the outer orbits can be hybridized differently, some properties may differ: dipole moment, polarity, polarization, size and shape. The electronic isosteres include bioisosteres. In addition to physical similarities, bioisosteres share certain biological properties. Typically, bioisosteres interact with the same recognition sites or broadly produce similar biological effects.

 In the present invention, an effective amount refers to an amount necessary to produce an intended effect, such as: regulating calcium homeostasis, treating a disease involving calcium homeostasis, treating cardiovascular disease, stroke or dementia or inhibiting Acetylcholinesterase or L-type calcium channel.

 In the present invention, a metabolite refers to a substance produced by metabolism or by a metabolic process.

 Preferably, the compound provided by the present invention is specifically:

 Compound 1: 3,5-Dimercapto-4-(3-(diaminoaminodecanoyloxy)phenyl)-2,6-dimercapto-1,4-dihydropyridine-3,5-di Carboxylic ester

 Compound 2: 3-isopropyl-5-(2-decyloxyethyl)-4-(3-(diaminoaminodecanoyloxy)phenyl)-2,6-dimercapto-1,4 -dihydropyridine-3,5-dicarboxylate

Compound 3: 3,5-dimercapto-4-(3-nitro-4-(diindenylnonanoyloxy)phenyl)-2,6-didecyl -1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 4: 5-isopropyl-3-indolyl-2-(4-(diamidinoindolyloxy)phenyl)-6-fluorenyl-4-(3-nitrophenyl)-1, 4-dihydropyridine-3,5-dicarboxylate;

 Compound 5: 5-isopropyl-3-indolyl-2-(4-(diaminoaminodecanoyloxy)phenyl)-6-fluorenyl-4-(1-indolyl-5-nitro- 1H-imidazol-2-yl)-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 6: 3-ethyl-5-mercapto-2-((2-((5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl) Amino)ethoxy)indenyl)-4-(2-chlorophenyl)-6-yl-1 4-dihydropyridine-3,5-dicarboxylate;

Compound 7: 3-ethyl-5-mercapto-4-(2-chlorophenyl)-2-((2-(4-(diaminoaminodecanoyloxy))benzyl) Amino)ethoxy)indenyl)-6-mercapto-1 4-dihydropyridine-3,5-dicarboxylate;

 Compound 8: 3-(5-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)pentanyl)-5-mercapto-2,6-diindolyl-4 -(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

Compound 9: 3-(5-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)pentanyl)-5-mercapto-2,6-dimercapto-4 -(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 10: 3-(2-((1-(3-(Diaminoaminocarbonyl)phenyl)ethyl)(indenyl)amino)ethyl)-indenyl-2,6-didecyl -4-(3-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate;

Compound 11: 3-(2-((4-(Diylaminodecanoyloxy)benzyl)(fluorenyl)amino)ethyl)-5-fluorenyl-2,6-dimercapto-4-( 3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate; 0?N,

 Compound 12: 3-(4-(4-(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)piperazin-1-yl)phenethyl)-indenyl-2, 6-Dimercapto-4-(3-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 13: 3-(3-(4-(3-(Diaminoaminodecanoyloxy)benzyl)piperazin-1-yl)propyl)-; -mercapto-2,6-diindenyl- 4-(3-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 14: 3-mercapto-5-(2-(indolyl-(2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)amino)ethyl) - 2,6-diamidino-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

Compound 15: 3-(2-(Diamino)-2-(3-(4-indole-ethyl-decylaminodecanoyloxy)phenyl]indolyl-2,6-diindolyl-4 -(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 16: 3-(2-(6-(Diaminoaminodecanoyloxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-5-indenyl-2, 6-Dimercapto-4-(3-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 17: 3-mercapto-5-(1-(2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)piperidin-4-yl)-2, 6-Dimercapto-4-(3-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate;

Compound 18: 3-(2-(2-(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)ethoxy)ethyl)-5-indenyl-2 , 6-diamidino-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 19: 3-(2-(6-(Diaminoaminodecanoyloxy)-2-mercapto-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-5- Mercapto-2,6-diamidino-4-trinitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 20: 3-((6-(Diaminoaminodecanoyloxy)-2-indolyl-1,2,3,4-tetrahydroisoquinolin-1-yl)indolyl-5-indenyl —2,6-dimercapto- 4-(3-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 21: 3-mercapto-5-(1-(3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperidin-4-yl)-2, 6-Dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

化合物 22: 3-曱基 -5-((5-((6-氯 -1,2,3,4-四氢吖啶 -9-基)氨基)戊基)氨基曱 酰基) -2,6-二曱基 -4-(3-硝基苯基) -1,4-二氢吡啶 -3-羧酸酯；

Compound 22: 3-mercapto-5-((5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)aminodecanoyl)-2,6 - Dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;

 Compound 23: 3-mercapto-2,6-dimercapto-4-(3-nitrophenyl)-5-((1-(2-((1,2,3,4-tetrahydroacridine)) -9-yl)amino)ethyl)piperidin-4-ylaminodecanoyl)-1,4-dihydropyridine-3-carboxylate;

 Compound 24: 3-mercapto-5-(5-((1,2,3,4-tetrahydroacridin-9-yl)amino)-2,6-diindol-4-(3-nitrate Phenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 25: 3-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-5-indenyl-2,6-didecyl- 4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

Compound 26: -(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-5-indolyl-4-(2-chloro Phenyl)-2,6-dimercapto-1,4-dihydropyridine-3 5-dicarboxylate;

Compound 27: 3-(10-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)indolyl)-5-indenyl-2,6-didecyl- 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

Compound 28: 3-(2-((2-(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)thio)ethyl)-indenyl- 2,6-diamidino-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 29: 3-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-5-ethyl-2,6-didecyl- 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

Compound 30: 5-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-3-indolyl-2-((2-amino-ethyl) Oxy)indenyl)-4-(2-chlorophenyl-6-mercapto-1,4-dihydropyridine-3,5-dicarboxylate;

Compound 31: 3-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-5-isopropyl-2,6-di Mercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 32: 3-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-5-indolyl-4-(benzo[c] [l,2,5]oxadiazol-4-yl)-2,6-dimercapto-1 4-dihydropyridine-3,5-dicarboxylate;

 Compound 33: 3-(1-(4-(Diaminoaminodecanoyloxy)benzyl)piperidin-4-yl)-5-indolyl-2,6-diindenyl-4-(3-nitrate Phenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 34: 3-(3-(4-(Diaminoaminodecanoyloxy)benzylamino)propyl)-5-indolyl-2,6-dimercapto-4-(3-nitrophenyl) - 1 ,4-dihydropyridine-3,5-dicarboxylate;

Compound 35: (E)-3-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-5-indenyl- 4-(2 -(3-tert-butoxy-3-oxoprop-1-en-1-yl)phenyl)-2,6-dimercapto-1,4-dihydropyridine-3,5-dicarboxylic acid ester;

 Compound 36: 3-(4-(2-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)cyclohexyl)-5-indenyl-2, 6-Dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 37: 3-mercapto-5-((1-(2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)piperidin-4-yl) fluorenyl) -2,6-dimercapto-4-(3-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate;

Compound 38: 3-(4-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)but-2-yn-1-yl)-5-indenyl-2 , 6-diamidino-4-(3-nitrophenyl)-1 4-dihydropyridine-3,5-dicarboxylate;

Compound 39: 3-(6-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)-2-indolylheptan-2-yl)-5-indenyl-2, 6-Dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 40: 3-ethyl-5-mercapto-2-((2-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)ethoxy) fluorenyl)- 4-(2-chlorophenyl)-6-mercapto-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 41: 3-ethyl-5-mercapto-2-((2-(3-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)propylamino) ethoxylate曱) mercapto)-4- 2-chlorophenyl)-6-mercapto-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 42: 3-ethyl-5-mercapto-2-((2-(2-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)ethylamino) ethoxylate 4-(2-chlorophenyl-6-mercapto-1,4-dihydropyridine-3,5-dicarboxylate;

Compound 43: 3-ethyl-5-mercapto 2-((2-(di-((3,5,6-tridecylpyrazin-2-yl)indolyl)amino)) Ethoxy)indenyl)-4-(2-chlorophenyl-6-mercapto-1,4-dihydropyridine-3,5-dicarboxylate;

Compound ^44: 3-Yue-5- (1 - ((3,5,6-Yue pyrazine - ² - yl) Yue-yl) piperidin-4-yl) - ^2,6 Yue group - 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 45: 3-mercapto-5-(2-(1-((3,5,6-tridecyl-2-yl)indolyl)piperidin-4-yl)ethyl)-2,6- Dimercapto- 4-(3-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 46: 3-mercapto-5-(1-((3,5,6-tridecylpyrazin-2-yl)indolyl)piperidin-4-yl)indolyl-2,6-diindole 4--4-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate;

Compound 47: 3-ethyl-5-mercapto-4-(2-chlorophenyl)-6-mercapto-2-((2-((3,5,6-tridecylpyrazine-2-) Ethylamino)ethoxy)indenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 48: 3-ethyl-5-mercapto-4-(2-chlorophenyl)-6-mercapto-2-((2-(2-(indolyl-((3,5,6-tri) Mercaptopyrazin-2-yl)decylamino)ethylamino)ethoxy)indenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 49: 3-mercapto-5-(1-(2-(indolyl((3,5,6-trimethylpiperazin-2-yl)indolyl)amino)ethyl)piperidin-4- -2,6-diamidino-4-trinitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 50: 3,5-Dimercapto-4-(2-chloro-4-(5-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)pentyloxy) Phenyl)-2,6-dimercapto-1 4-dihydropyridine-3,5-dicarboxylate;

Compound 51 : 3-mercapto-5-(5-(1,2,3,4,5,6,7,8-octahydroacridin-9-ylamino)pentyl)-2,6-didecyl 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 52: 3-ethyl-5-mercapto-4-(2-chlorophenyl)-2-((2-(1-(4-indole-ethyl-decylaminodecanoyloxy)phenyl) Ethylamino)ethoxymethyl)-6-fluorenyl-1,4-dihydropyridine-3,5-dicarboxylate;

化合物 53 : 3-曱基 -5-(5-(5,6,7,8-四氢喹啉 -2(1H)-酮 -5-基氨基)戊基) -2,6- 二曱基—4-(3-硝基苯基 -1,4-二氢吡啶 -3,5-二羧酸酯；

Compound 53 : 3-mercapto-5-(5-(5,6,7,8-tetrahydroquinolin-2(1H)-one-5-ylamino)pentyl)-2,6-didecyl 4-(3-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate;

 Compound 54: 3-mercapto-5-(1-(2-(1,2,3,4-tetrahydroacridin-9-ylamino)ethyl)piperidin-4-yl)-4-(2) , 3-dichlorophenyl)-2,6-dimercapto-1,4-dihydropyridine-3,5-dicarboxylate.

本发明还提供了该化合物作为 L-型钙通道阻滞剂或 /和乙酰胆碱酯酶抑 制剂的应用。

The invention also provides the use of the compound as an L-type calcium channel blocker or/and an acetylcholinesterase inhibitor.

 The invention also provides the use of the compound for the manufacture of a medicament for modulating calcium homeostasis, treating cardiovascular disease, stroke or dementia. Calcium homeostasis refers to the intrinsic balance of intracellular calcium; cardiovascular disease refers to heart, blood vessel or circulatory diseases; dementia refers to a more serious mental disorder, the patient's brain development is basically mature, intelligent It is also normal, but in the future, it will cause serious damage to the brain due to various harmful factors, causing serious mental retardation. Treatment refers to: prevention of diseases in animals susceptible to diseases, disorders or diseases but not yet diagnosed already. The occurrence of a disorder or condition, or the inhibition of a disease, disorder, or condition, that is, preventing its development, relieving a disease, disorder, or condition, that is, causing the disease, disorder, or condition to subside.

 Preferably, the compound provided by the present invention is used in the preparation of a drug for dementia, and the dementia is Alzheimer's disease or vascular dementia.

 The invention also provides a pharmaceutical composition prepared according to the compound, the pharmaceutical composition comprising a compound provided by the invention, further comprising a pharmaceutically acceptable carrier.

 Preferably, the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable material, composition or vehicle, which may be a liquid or solid filler, diluent, excipient or soluble capsule forming material, carrying or transporting the target compound from An organ or part of the body to another organ or another part of the body.

Preferably, the pharmaceutically acceptable carrier comprises a saccharide, a starch, a cellulose and a derivative thereof, a powdered tragacanth, malt, gelatin, talc, an excipient, an oil, a glycol, a polyol, an ester. , agar, buffer, alginic acid, non-pyrogenic water, isotonic saline, Ringer's solution, ethanol, pH buffer, polyester, polycarbonate, polyanhydride, and others compatible in the composition to be used Non-toxic substances. Preferably, in a pharmaceutically acceptable carrier, the saccharide may comprise lactose, glucose and sucrose; the starch may comprise corn starch, potato starch; the cellulose and its derivatives comprise sodium carboxymethyl cellulose, ethyl cellulose and acetic acid Cellulose; the excipient may comprise cocoa butter, a wax for suppositories; The oil may comprise peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil; the glycol may comprise propylene glycol; the polyol may comprise glycerin, sorbitol, mannitol, polyethylene glycol; Ethyl oleate, ethyl laurate; buffer contains magnesium hydroxide, aluminum hydroxide.

 The detection of the L-type calcium channel block activity of the compound provided by the present invention shows that the inhibition rate of the compound at 100 nmol/L for the L-type calcium channel is 8.71-35.77%, and the compound of the compound at 1000 nmol/L is L. The inhibition rate of the -type calcium channel is 26.43-83.54%; the detection of the acetylcholinesterase inhibitory activity of the compound provided by the present invention shows that when the inhibition rate of acetylcholinesterase activity is 50%, the amount of the compound is 16-1470. Nmol/L, it can be seen that the compound can effectively block the L-type calcium channel and has obvious inhibitory effect on acetylcholinesterase; therefore, according to the pathogenesis, the compound and the pharmaceutical composition containing the same have cardiovascular diseases and strokes. Alzheimer's disease has an improving effect and has a therapeutic effect on Alzheimer's disease or vascular dementia. detailed description

 The present invention discloses the use of the compound and the compound as an L-type calcium channel blocker or an inhibitor of acetylcholinesterase activity, and those skilled in the art can learn from the contents of the present article and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention. The method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.

 The invention will be further illustrated by the following examples: Example 1 Preparation of the compound provided by the invention 1

The preparation process is as follows:

Accurately weigh 3.0 g of about 24.6 mmol of 3-hydroxybenzaldehyde, dissolve it in 100 mL of acetone, stir to dissolve, add 6.8 g, which is equivalent to 50 mmol of K ₂ C0 ₃ solid powder, stir vigorously, then slowly add dropwise 2.75 g is 25.6 mmol of hydrazine, hydrazine-dimercaptochloro amide, with a small amount of bubbles. After the reaction is stable, the reactor is transferred to a 60 ° C oil bath and heated to reflux. TLC is detected. After 21 h, the reaction is stopped, cooled, filtered, and the residue is discarded. The filtrate is evaporated to dryness and then diluted with saturated NaHC0 ₃ solution. After extraction with ethyl acetate, the organic extract was collected, washed with water, dried over anhydrous sodium sulfate, filtered, evaporated, A gradient of 5:1 to 3:1 was eluted to give 1.5 g of 3-(N,N-diaminoaminononanoyloxy)phenylfurfural as a colorless oily compound. ESI-MS: [M + H] ⁺ = 194.1.

 0.5 g of about 2.6 mmol of 3-(indole, indole-dioxaaminononanoyloxy) benzofural prepared above, together with 0.6 g of about 5.2 mmol of decyl acetoacetate and 0.4 g of about 5.2 mmol of acetic acid Ammonium was added to the reaction system, 40 mL of sterol was added, and the mixture was heated to 80 ° C. After TLC detection, the reaction was stopped after 18 h, cooled, and the organic layer was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under pressure to obtain a yellow solid, which was purified by silica gel column chromatography, eluting with a gradient of petroleum ether and ethyl acetate in a ratio of 3: 1-1:1 to obtain the compound 1 provided by the present invention. It was a yellow solid, 0.5 g, yield 50%.

 The compound 1 provided by the present invention was tested and the results were as follows:

 ESI-MS: [M + Na]+ = 411.1 ; [M - H]" = 387.2;

ifiNMR (500 MHz, CDC1 ₃ ) δ 2.30 (6H, s), 2.99 (3H, s), 3.08 (3H, s), 3.66 (6H, s), 5.01 (1H, s), 5.83 (1H, s) , 6.89 (1H, ddd, J = 1.0 Hz, 2.4 Hz, 8.0 Hz), 6.96 (1H, m), 7.07 (1H, dd, J = 1.2 Hz, 6.6 Hz), 7.18 (1H, m). Example 2 Preparation of Compound 2 Provided by the Invention

 The preparation process is as follows:

Accurately weigh 2.0 g of isopropyl acetoacetate, dissolve it in 15 mL of absolute ethanol, add 1.6 g of ammonium acetate of about 20.83 mmol, heat reflux at 90 °C in oil bath, detect by TLC, stop reaction after 24 h, low temperature The reaction solution was evaporated to dryness under reduced pressure to give compound Si 2.0 g, yield 100%. ESI-MS: [M + H] ⁺ = 144.1.

Weigh 300 mg of about 0.90 mmol of acetoacetate-2-methoxyethyl ester, add 0.2 mL of acetic anhydride under ice bath, stir for 30 min, add 35 μΙ of concentrated gram acid, and gradually increase the color of the system. , slowly add 365 mg of about 0.91 mmol of 3-(anthracene, fluorenyl-nonylaminononanoyloxy) benzofural, stir at room temperature overnight, stop the reaction, and pour the reaction system into a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was extracted with EtOAc. EtOAc (EtOAc m. Elution with a gradient of 5: 1-4:1 gave compound S ₂ 330 mg, yield 50.1%, ESI-MS: [M + H] ⁺ = 336.1.

330 mg of about 0.96 mmol of S _{2 was} dissolved in 10 mL of absolute ethanol, 200 mg of about 1.41 mmol of compound Si was added, heated to reflux, detected by TLC, and the reaction was stopped after 12 h, and cooled. After evaporating the solvent, the residue was subjected to silica gel column chromatography, eluting with a gradient of petroleum ether and ethyl acetate at a ratio of 4: 1-3:1 to give the compound 2, 180 mg of the present invention in a yield of 40.3%.

 The compound 2 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + NH ₄ ] ⁺ = 478.0; [M - H]" = 459.0.

IfiNMR (500 MHz, CDC1 ₃ ) δ 1.12 (3Η, d, / = 6.3 Hz), 1.26 (3H, d, / = 6.3 Hz), 2.31 (6H, d, J= 3.4 Hz), 2.98 (3H, s ), 3.07 (3H, s), 3.36 (3H, s), 3.55 (2H, t, J= 4.9 Hz), 4.17 (2H, m), 5.02 (1H, m), 5.65 (1H, d, J= 16.2 Hz), 6.89 (1H, ddd, J= 1.1 Hz, 2.3 Hz, 3.4 Hz), 6.98 (1H, t, J= 1.9 Hz), 7.12 (1H, d, J= 7.8 Hz), 7.17 (1H, Td, /= 2.0, 7·8 Ηζ).

Example 3 Preparation of Compounds Provided by the Invention 3

 The preparation process is as follows:

Accurately weigh 0.5 g of 2.99 mmol of 3-nitro-4-hydroxybenzaldehyde, dissolve it in 5 mL of anhydrous pyridine solution, stir to dissolve, and then slowly add 0.38 g of about 3.55 mol of hydrazine, Ν- Dimethyl chloroformamide, a small amount of bubbles are generated. After the reaction is stable, it is allowed to stand at room temperature. After TLC detection, the reaction is stopped after 14 hours. Solids are precipitated. After filtration, the residue is filtered. The filtrate is diluted with ethyl acetate and then added dropwise. 1 mol/L hydrochloric acid was used to adjust the pH value. 7. The organic layer was extracted, washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give a white solid. The white solid obtained above was purified by silica gel column chromatography. The elution of petroleum ether and acetone in a volume ratio of 2:1 was eluted to give a white solid powder S ₃ 420 mg, yield 60%, ESI-MS: [M + H] + = 239.1.

Accurately weigh 420 mg, or 1.76 mmol, of the white solid powder S ₃ obtained above, ie 3-nitro-4-(N,N-diaminoaminodecanoyloxy)benzaldehyde, 520 mg or 4.0 mmol of acetyl Ethyl acetate, 1.3 g is 16.8 mmol of ammonium acetate and 200 mg of 0.88 mmol of phase transfer catalyst TEBA, and added 10 mL of distilled water, heated at 90 °C, detected by TLC, stopped after 18 h, cooled, ethyl acetate extracted organic layer, washed Drying with anhydrous sodium sulfate, filtration, and concentration under reduced pressure to give a yellow solid, which was purified by silica gel column chromatography, using a gradient of petroleum ether and ethyl acetate of 4: 1-3:1. Elution, the compound 3 provided by the present invention was obtained as a yellow solid powder, 400 mg, yield 52.4%.

 The compound 3 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + NH ₄ ] ⁺ = 451.1; [M - H] - = 432.1.

ifiNMR (300 MHz, CDC1 ₃ ) 52.20 (6H, s), 3.02 (3H, s), 3.12 (3H, s), 3.64 (6H, s), 5.01 (1H, s), 6.02 (1H, s), 7.13 (1H, d, J = 8.4 Hz), 7.56 (1H, dd, / = 2.2 Hz, 8.4 Hz), 7.93 (1H, d, J = 2.2 Hz). Example 4 Preparation of Compound 4 Provided by the Invention

 The preparation process is as follows:

Accurately weigh 5 g of 36.8 mmol of 4-hydroxyacetophenone, dissolve it in 30 mL of DMF solution, slowly add NaH powder under ice bath, and generate a large amount of gas. After the reaction is stable, add 13.2 g to the system. 146.7 mmol of dinonyl carbonate, the reaction started at room temperature, accompanied by a large amount of foam, TLC detection, the reaction was stopped after 24 h, the reaction solution was poured into ice water to quench the reaction, and the reaction solution was adjusted with a 1 mol/L hydrochloric acid solution. The pH value is 2, the organic layer is extracted with ethyl acetate, washed with water, anhydrous sulfuric acid The sodium was dried, filtered and concentrated, and then purified by silica gel column chromatography, eluting with a gradient of petroleum ether and ethyl acetate at a ratio of 5: 1-4:1 to obtain a compound S ₄ 1.3 g, yield 18.3 %. ESI-MS: [M - H]- = 193.1.

Accurately weigh 1.3 g or 6.7 mmol of the compound S ₅ prepared above, dissolve it in 50 mL of acetone, stir to dissolve, add 3.0 g of a solid powder of K ₂ C0 _{3 of} about 21.7 mmol, stir vigorously, then slowly add 0.8 g. Approximately 7.3 mmol of hydrazine, hydrazine-dimercaptochloro amide, a small amount of bubbles are generated. After the reaction is stable, the reactor is transferred to a 60 ° C oil bath and heated to reflux. TLC detection, 12 h after the reaction is stopped, cooling, The reaction system was filtered, the residue was filtered off, and the filtrate was evaporated to dryness, then purified by silica gel column chromatography, eluting with a gradient of petroleum ether and ethyl acetate at a ratio of 6: 1-5:1 to give a colorless oily compound. S ₅ 880 mg, yield 51.7 %, ESI-MS: [M + H] + = 266.1.

Accurately weigh 0.4 g, or 1.56 mmol, of the compound S ₅ prepared above, dissolved in 20 mL of benzene, add 0.25 g of about 1.65 mol of trinitrophenylfurfural and a catalytic amount of piperidine 0.1 mL, glacial acetic acid 0.2 mL , refluxing, TLC detection, 12 h to stop the reaction, after cooling, the reaction solution was directly subjected to silica gel column chromatography, eluting with a gradient of petroleum ether and ethyl acetate in a volume ratio of 6: 1-4:1. Compound S ₆ 410 mg, yield 66.1%, ESI-MS: [M+H]+ = 399.1.

410 mg, ie 1.03 mmol of the compound S ₇ obtained above, was dissolved in 20 mL of absolute ethanol, and 260 mg of compound Si prepared by adding about 1.8 mmol was added, refluxed, detected by TLC, and the reaction was stopped after 40 h, and cooled. The solvent is evaporated to dryness at a low temperature, and subjected to silica gel column chromatography, eluting with a gradient of petroleum ether and ethyl acetate at a volume ratio of 4: 1-2:1 to obtain a compound 4, 0.2 g of the present invention. The rate is 26.7%.

 The compound 4 provided by the present invention was tested and the results were as follows:

ESI-MS [M+NH ₄ ] ⁺ = 540.9; [M - H]" = 521.9.

ifiNMR (500 MHz, CDC1 ₃ ) δ 1.13 (2Η, ά, J = 6.3 Hz), 1.27 (3Η, m), 2.36 (3H, s), 3.02 (3H, s), 3.11 (3H, s), 3.40 (3H, s), 4.99 (1H, m), 5.20 (1H, ά, J = 11.9 Hz), 5.88 (1H, d, J = 15.6 Hz), 7.17 (2H, m), 7.32 (2H, m) , 7.42 (1H, t, J = 7.9 Hz), 7.75 (1H, d, J = 7.7 Hz), 8.03 (1H, m), 8.25 (1H, t, J Example 5 Preparation of Compound 5 Provided by the Invention

 The preparation process is as follows:

Accurately weigh 0.5 g of 3.5 mmol of 1,2-didecyl-5-nitro-1H-imidazole, add to the reaction flask, add 0.8 g of about 7.2 mmol of selenium dioxide, evacuate, and protect with nitrogen. Under 140. After reacting for 5 min, the system was cooled, the reaction was stopped, and the mixture was diluted with water. The organic layer was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Elution with a gradient of petroleum ether to ethyl acetate in a gradient of 8: 1-6:1 gave compound S ₇ 120 mg, yield 22.1%, ESI-MS: [M + H] ⁺ = 156.1.

0.2 g of about 0.77 mmol of the compound S ₅ obtained above is dissolved in 20 mL of benzene, 120 mg of the compound S _{7 of} about 0.77 mol, a catalytic amount of piperidine 0.05 mL, and 0.1 mL of glacial acetic acid are added. After refluxing, TLC detection, the reaction was stopped after 12 h, and the reaction solution was directly subjected to silica gel column chromatography, and eluted with a gradient of petroleum ether and ethyl acetate in a volume ratio of 3:1-2:1. Compound S ₈ 220 mg, yield 71.1%, ESI-MS: [M + H] ⁺ = 403.1.

220 mg of about 0.55 mmol of the above prepared S _{8 was} dissolved in 20 mL of absolute ethanol, and 150 mg of about 1.05 mmol of the compound obtained above was added to reflux, and the reaction was stopped by TLC. After 48 h, the reaction was stopped, and the reaction solution was cooled. Evaporation at low temperature, directly by silica gel column chromatography, using an elution system containing 1% triethylamine. The eluent was washed with a gradient of petroleum ether and ethyl acetate in a volume ratio of 3: 1-2:1. The compound obtained by the present invention was obtained in the form of 5, 60 mg in a yield of 20.8%.

The compound 5 provided by the present invention was tested and the results were as follows: ESI-MS: [M + H] ⁺ = 527.9; [M - H]" = 525.9.

ifiNMR (500 MHz, CDC1 ₃ ) δ 1.19 (3H, m), 1.28 (3H, m), 2.36 (3H, ά, J = 3.1 Hz), 3.01 (3H, s), 3.11 (3H, s), 3.30 (3H, s), 4.23 (3H, s), 5.05 (1H, m), 5.18 (1H, s), 6.11 (1H, s), 7.14 (2H, m), 7.29 (2H, m), 7.99 ( 1H, s). Example 6 Preparation of Compound 6 Provided by the Invention

 The preparation process is as follows:

Accurately weigh 17.1 g, 0.1 mol of 4-chloro-2-aminobenzoic acid and 9.8 g of 0.1 mol of cyclohexanone, place in an ice bath, slowly add 90 mL of phosphorus oxychloride solution, and then slowly slow down the reaction system. Move into the oil bath, slowly heat to reflux, stop the reaction after 2 h, dilute the solvent of phosphorus oxychloride, dilute the remaining reactant with ethyl acetate, slowly add potassium carbonate solution slowly, adjust the pH of the reaction solution to more than 8, separate organic The layer is washed with water, dried with anhydrous sodium sulfate, filtered and concentrated to obtain a dark viscous material, which is added with an appropriate amount of acetone, dissolved in a refrigerator, and crystallized in a refrigerator to obtain a compound S ₉ 11.0 g, yield 43.8 %. , ESI-MS: [M + H]+ = 252.0.

1 g of about 3.9 mmol of the above-prepared S ₉ , ie 6,9-dichloro-1,2,3,4-tetrahydroacridine and 0.4 g of about 3.9 mmol of 5-amino-n-pentanol and 100 g Mg is about 0.67 mmol catalytic amount of Nal, then accurately weigh 2 g of phenol into the system, vacuum, under nitrogen protection, slowly warm to 180 °C, 2 h, then stop the reaction, cooling, the reaction solution through dichlorin After dilute the alkane, the residue was purified by silica gel column chromatography. The volume ratio of dichloromethane to decyl alcohol was 15:1, and the compound S _{1 ()} 0.85 g was eluted. 47.2 % , ESI-MS: [M + H] ⁺ = 319.1.

1.3 g of about 4.08 mmol of the above prepared S _{1 () was} dissolved in 20 mL of anhydrous dichloromethane, and 32.6 g of about 10.0 mmol of PPh and 42.6 g of about 7.95 mmol of CBr _{4 were added} to the reaction system. Stir at room temperature overnight, TLC detection, after the reaction is completed, the reaction is stopped, a part of the precipitate is formed, the filter residue is filtered, the reaction liquid is collected, and the organic layer is extracted with water, washed with water, dried with anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The yellow oil was purified by silica gel column chromatography eluting with 1% triethylamine. The volume ratio of petroleum ether to ethyl acetate in the eluent was 3:1 to obtain S 900 mg, yield 73.5 % , ESI-MS: [Μ + Η]+ = 381.1.

Accurately weigh 380 mg of 1 mmol of compound S _u and 449 mg of 1.1 mmol of amlodipine in 10 mL of acetonitrile, followed by 414 mg of approximately 3 mmol of potassium carbonate. The mixed reaction was allowed to react under reflux overnight, and after cooling to room temperature, the potassium carbonate was filtered off, the filtrate was washed with CH ₂ C _{2 2} , and the solvent was removed by rotary evaporation, and the residue was purified by column chromatography to afford compound 6 of the present invention. , 356 mg, yield 50%.

 The compound 6 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 709;

ifiNMR (CDC1 ₃ , 500 MHz) δ 7.89 (1H, s), 7.87 (1H, s), 7.58 (1H, s), 7.36 (1H, dd, / = 1.5, 7.5 Hz), 7.27 (1H, dd, J = 2.5 Hz, 8.5 Hz), 7.22 (1H, dd, / = 1.5 Hz, 8.5 Hz), 7.11 (1H, dt, / = 1.5 Hz, 7.5 Hz), 7.03 (1H, dt, J = 2.0 Hz, 7.5 Hz), 5.40 (1H, s), 4.78 (1H, d, J = 16.5 Hz), 4.69 (1H, d, J = 16.5 Hz), 4.02-4.06 (2H, m), 3.88-4.01 (1H, m), 3.64 (2H, dt, J = 1.5 Hz, 5.5 Hz), 3.62 (3H, s), 3.48 (2H, t, J = 7.0 Hz), 3.01-3.05 (2H, m), 2.85 (2H, i, J = 5.5 Hz), 2.65-2.68 (4H. m), 2.34 (3H, s), 1.88-1.93 (4H. m), 1.65-1.71 (2H. m), 1.52-1.57 (2H. m) , 1.41-1.47 (2H. m), 1.17 (3H, t, «7= 7.5 Hz). Example 7 Preparation of Compound 7 Provided by the Invention

The preparation process is as follows:

Accurately weigh 1 g of 8.06 mmol of 4-hydroxyphenylhydranol, dissolve it in 100 mL of acetone, stir to dissolve, add 5.56 g of about 40 mmol of K ₂ C0 ₃ solid powder, stir vigorously, then slowly add 0.9 g. About 8.06 mmol of hydrazine, hydrazine-dimercaptochloro hydrazide, a small amount of bubbles are generated. After the reaction is stable, the reactor is transferred to a 60 ° C oil bath and heated to reflux. TLC detection, after 18 h, the reaction is completed and then stopped. the reaction was cooled, the reaction system was filtered, the filter cake was discarded, the filtrate was collected and evaporated to dryness, diluted with saturated NaHC0 ₃ solution was added, and the organic phase was extracted with ethyl acetate and the organic extract was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure The colorless oily compound S ₁₂ 1.4 g was obtained, yield 93.1%, ESI-MS: [M - H]" = 194.1, without further separation, directly involved in the next reaction.

1.4 g of about 7.2 mmol of the product S ₁₂ prepared above was dissolved in 50 mL of chloroform, and a solution of thionyl chloride in chloroform was added dropwise in an ice bath, which was about ll mmol/L, and the addition was completed, and the temperature was slowly raised to room temperature. After TLC, the reaction was completed. After 4 h, the reaction was completed, the reaction was stopped, the organic solvent was evaporated, diluted with an appropriate amount of purified water, and the organic layer was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give oil SB. 1.4 g, yield 93.3 %, ESI-MS: [Μ + Η]+ = 214.1.

Accurately weigh 500 mg, 2.34 mmol of compound S ₁₃ , dissolved in acetonitrile, and add 1.0 g of about 2.53 mmol of amlodipine, ((, 3-ethyl-5-mercapto-2-((2-) Aminoethoxy)indenyl)-4-(2-chlorophenyl)-6-indenyl 1,4-dihydropyridine 3,5-dicarboxylate, 1.04 g of about 7.59 mmol of potassium carbonate powder and 35 mg is about 0.23 mmol catalytic amount of Nal, the reaction system is transferred to an 80 °C oil bath for reflux, TLC tracking monitoring, 16 h after the reaction is completed, the reaction is stopped, the organic solvent is evaporated, and the reaction is carried out. The liquid was purified by silica gel column chromatography, eluting with a gradient of 1% triethylamine, eluting with a gradient of petroleum ether and ethyl acetate in a gradient of 2: 1-1:1. The compound provided by the invention 7, 750 mg, yield 54.1%.

 The compound 7 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 586.1 [M - H]" = 584.1.

ifiNMR (500 MHz, CDC1 ₃ ) δΐ.17 (3Η, s), 1.23 (3Η, s), 2.29 (3H, s), 2.86 (2H, m), 3.00 (3H, s), 3.09 (3H, s ), 3.64 (2H, m), 3.71 (2H, t, J = 7.0 Hz), 3.83 (2H, s), 4.03 (2H, m), 4.68 (1H, ά, J = 16.5 Hz), 4.77 (1H , ά, J = 16.5 Hz), 5.40 (1H, s), 7.03 (1H, m), 7.08 (2H, m), 7.12 (1H, td, /= 1.4 Hz, 7.5 Hz), 7.22 (1H, dd , J = 1.3 Hz, 8.0 Hz), 7.30 (2H, m), 7.36 (1H, dd, J = 1.7 Hz, 7.8 Hz), 7.57 (1H, s). Example 8 Preparation of Compound 8 Provided by the Invention

 The preparation process is as follows:

Accurately weigh 650 mg of approximately 2.0 mmol of 5-(oxacarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid, Dissolved in lO mL DMF, stirred and dissolved, added 900 mg of about 2.3 mmol of the above prepared S _u and 160 mg of about 1.1 mmol of K ₂ C0 ₃ powder, placed in a 50 ° C oil bath for reaction, TLC detection, After 5 h, the reaction was stopped, the reaction system was cooled, the reaction system was filtered, the residue was filtered, and the filtrate was diluted with water. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography, using an elution system containing 1% triethylamine, eluting with a gradient of petroleum ether and ethyl acetate in a volume ratio of 3: 1-2:1 to obtain the compound provided by the present invention. 8, a yellow solid, 990 mg, yield 61.8%. The compound 8 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 633.1; [M - H] - = 631.1.

ifiNMR (500 MHz, CDC1 ₃ ) 51.15 (2H, m), 1.66 (4H, m), 1.91 (4H, m), 2.35 (6H, s), 2.66 (2H, s), 3.04 (2H, s), 3.40 (2H, s), 3.63 (3H, s), 4.01 (2H, m), 4.05 (1H, m), 5.09 (1H, s), 5.97 (1H, s), 7.28 (1H, dd, J= 2.0 Hz, 9.1 Hz), 7.32 (1H, t, J= 8.0 Hz), 7.60 (1H, m), 7.88 (1H, d, J= 9.1 Hz), 7.92 (1H, d, J= 2.0 Hz), 7.95 (1H, m), 8.11 (1H, t, «7= 2.0 Hz). Example 9 Preparation of Compound 9 Provided by the Invention

 The preparation process is as follows:

Accurately weigh 6.6 g of 57 mmol of acetoacetate, 5.0 g of 28.7 mmol of 2,3-dichlorobenzaldehyde, 2.0 g of 57 mmol of ammonia in a single-necked flask, and add 40 mL of sterol. The mixture was heated to reflux under a nitrogen atmosphere, and allowed to react overnight. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was purified by column chromatography to yield compound S ₁₄ 8.9 g, yield: 84 %, ESI-MS: [M + H] ⁺ = 370.

1.03 g of about 2.8 mmol of the compound S ₁₄ prepared above was dissolved in 15 mL of a methanol solution, and 260 mg of about 1.14 mmol of TEBAc and 40% of NaOH 2.5 mL were added.

70. The mixture was stirred under reflux with C. After reacting overnight, the sterol was removed by rotary evaporation, diluted with water, and the pH was adjusted to 2-3 with 2 mol/L hydrochloric acid. The solid precipitated from the reaction system was filtered to give the product S ₁₅ 200 mg. Yield 20%, ESI-MS: [M-H]+ = 354.

75 mg of approximately 0.21 mmol of the above-prepared S ₁₅ , 80 mg, approximately 0.21 mmol of compound S _u , 55 mg of approximately 0.4 mmol K ₂ CO ₃ in a single-necked flask, 5 mL of DMF, nitrogen Heat to 50 under protection. C, the reaction is 2 h, and the temperature is lowered to 30. After the reaction was completed, the reaction mixture was stirred and purified by column chromatography. Purification afforded the compound of the present invention 9, 46 mg in a yield of 35%.

 The compound 9 provided by the present invention was tested and the results were as follows:

 ESI-MS: 656 [M + H]+.

ifiNMR (500 MHz, CDC1 ₃ ) 51.15 (2H, m), 1.66 (4H, m), 1.91 (4H, m), 2.35 (6H, s), 2.66 (2H, s), 3.04 (2H, s), 3.40 (2H, s), 3.63 (3H, s), 4.01 (2H, m), 4.05 (1H, m), 5.09 (1H, s), 5.97 (1H, s), 7.01 (1H, t, J= 7.8 Hz), 7.15 (1H, dd, J= 7.8 Hz, 1.5 Hz), 7.27 (1H, m), 7.29 (1H, m), 7.88 (1H, d, J= 9.0 Hz), 7.92 (1H, d , J= 1·8 Ηζ). Example 10 Preparation of Compound 10 Provided by the Invention

 The preparation process is as follows:

Accurately weigh 5 g of 36.8 mmol of 3-hydroxyacetophenone, dissolve it in 60 mL of pyridine, stir to dissolve, slowly add 7.9 g of about 73.5 mol of hydrazine, hydrazine-dimercaptochloro amide, with a small amount of bubbles. Generated, after the reaction is stable, heat to 50 °C, TLC detection, stop reaction after 12 h, cooling, ice A 3 mol/L hydrochloric acid solution was added to the system under the bath to neutralize the excess pyridine, and then the organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated. Purified by a gradient of 4: 1-3:1 with a mixture of petroleum ether and ethyl acetate to give a colorless oily compound S ₁₆ 7.3 g, yield 94.8 %, ESI-MS: [M + H] + = 208.1.

1.0 g of about 4.8 mmol of the above-prepared S _{16 was} dissolved in 21 mL of decyl alcohol solution, and dissolved by stirring in an ice bath. After 10 min, 65 mg of about 1.7 mmol of NaBH ₄ solid powder was slowly added in portions, and the reaction started to be large. The bubble is generated, the reaction system is gradually raised to room temperature, detected by TLC, the reaction is stopped after 3 h, the solvent is evaporated under reduced pressure at a low temperature, and the residue is diluted with water, and the organic layer is extracted with dichloromethane. sulfate, filtered, and concentrated under reduced pressure to give a colorless oil S ₁₇ 900 mg, yield 90%, ESI-MS: [ M + Na] + = 232.1.

900 mg of about 4.3 mmol of the above-prepared S _{17 was} dissolved in chloroform, and a chloroform solution containing 1.6 g of about 14.4 mmol of thionyl chloride was added dropwise in an ice bath, and the addition was completed, and the reaction was slowly raised to room temperature. TLC tracking and monitoring, 12 h after the reaction to be complete, the reaction was stopped, the organic solvent was distilled off, the residue reaction was diluted with saturated sodium bicarbonate solution, the organic layer was extracted with ethyl acetate, washed with water, dried, filtered, and concentrated to give an oil which was S ₁₈ 910 Mg, yield 93.8 %, ESI-MS: [M + H] + = 228.1.

600 mg of about 2.64 mmol of the above-prepared S _{18 was} dissolved in 20 mL of acetonitrile, and 0.6 g of about 7.9 mmol of N-mercaptoethanolamine and 420 mg of about 3.0 mmol of potassium carbonate powder were added thereto. The reaction system was transferred to a 80 ° C oil bath for reflux, and TLC was followed up. After 12 h, the reaction was completed, the reaction was stopped, the organic solvent was evaporated, and the reaction product was purified by silica gel column chromatography using ethyl acetate and triethylamine. Elution with a gradient of 100:0-100:1 gave a colorless oily compound S ₁₉ 380 mg, yield 51.3 %, ESI-MS: [M + H]+ = 267.1.

Accurately weigh 0.16 g, ie 0.5 mmol, of 5-(oxacarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid In DMF, 0.16 g of about 1.0 mmol of DCC was added, 160 mg of about 1 mmol of catalytic DMAP and 130 mg of about 0.49 mmol of S _{19 were} applied, and the reaction system was transferred to 80 ° C under nitrogen. Bath reaction, TLC tracking monitoring, 24 h After the reaction is complete, the reaction is stopped, the reaction system is cooled, the reaction system is filtered, the residue is filtered, the filtrate is diluted with water, and the organic layer is extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography, using an elution system containing 1% triethylamine, eluting the eluent to a volume ratio of petroleum ether to ethyl acetate of 1: 3-0: 1 to elute, and obtaining the provided by the present invention Compound 10 is a yellow oily compound, 65 mg, yield 22%.

 The compound 10 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 581.1; [M - H] - = 579.1.

ifiNMR (500 MHz, CDC1 ₃ ) δ 1.26 (3H, m), 2.04 (2H, s), 2.18 (3H, d, J= 4.9 Hz), 2.33 (3H, s), 2.36 (3H, s), 3.00 (3H, s), 3.09 (3H, s), 3.58 (1H, d, J = 2.1 Hz),

3.62 (3H, s), 4.10 (2H, m), 5.11 (1H, ά, J = 1.6 Hz), 5.73 (1H, s), 6.98 (1H, d), 7.03 (1H, d, J= 7.7 Hz ), 7.12 (lH,t, J= 4.0 Hz), 7.32 (1H, td, J= 1.7 Hz, 8.0 Hz),

7.63 (1H, dd, / = 6.4 Hz, 7.6 Hz), 7.98 (1H, m), 8.09 (1H, dd, J = 2.0 Hz, 4.0 Hz). Example 11 Preparation of the Compound Provided by the Invention 11

 The preparation process is as follows:

0.4 g of about 1.8 mmol of S _{13 was} dissolved in acetonitrile, 0.21 g of about 2.7 mmol of N-mercaptoethanolamine and 560 mg of about 4.0 mmol of potassium carbonate powder were added, and the system was transferred to 80. C oil Reflux in the bath, TLC tracking and monitoring, after 16 h, the reaction was completed, the reaction was stopped, the organic solvent was evaporated, diluted with an appropriate amount of pure water, and the organic layer was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was subjected to chromatography on silica gel column chromatography, eluting with a gradient of ethyl acetate and triethylamine in a ratio of 100:0 to 100:1 to afford compound S ₂ as colorless oil. 200 mg, yield 44.0%, ESI-MS: [M + H] ⁺ = 253.1.

Accurately weigh 0.17 g, 0.51 mmol of 5-(oxacarbonyl)-2,6-diamidino-4-(3-nitrophenyl)-1,4-dihydropyridine-3-acid In 10 mL of DMF, 0.17 g of about 1.0 mmol of DCC, 20 mg of about 0.16 mmol of catalytic DMAP and 130 mg of about 0.51 mmol of S ₂ prepared above were added. Vacuuming, under nitrogen protection, the system was transferred to a 80 °C oil bath for reaction, TLC tracking and monitoring, after 14 h, the reaction was completed, the reaction was stopped, the reaction system was cooled, the reaction system was filtered, the filtrate was discarded, and the filtrate was diluted with water. The organic layer was extracted with ethyl acetate. EtOAc (EtOAc m. The elution of the ether to ethyl acetate was carried out in a gradient of 3: 1-1 : 1 to give Compound 11 as a yellow oily compound, 125 mg, yield 43.

 The compound 11 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 566.9; [M - H]" = 564.9.

ifiNMR (500 MHz, CDC1 ₃ ) δ 2.19 (3Η, s), 2.26 (3Η, s), 2.34 (3H, s), 2.62 (2H, t, J= 6.0 Hz), 3.01 (3H, s), 3.10 (3H, s), 3.47 (2H, m), 3.63 (3H, s), 4.16 (2H _: m), 5.12 (1H, s), 6.16 (1H, s), 7.01 (2H, m), 7.24 ( 2H, m), 7.32 (1H, t, J= 8.0 Hz) _: 7.64 (1H, dt, J= 1.3 Hz, 7.7 Hz), 7.97 (1H, ddd, J= 1.1 Hz, 2.3 Hz, 8.2 Hz), 8.09 (1H, t, «7= 2.0 Hz). Example 12 Preparation of Compound 12 Provided by the Invention

The preparation process is as follows:

准确称取 1.05 g 即 74 mmol的对氨基苯乙醇和 6.61 g 即 37 mmol的盐 酸氮芥于正丁醇中搅拌回流反应 24h,降至室温后，加水稀释，以 15 % NaOH 调节 pH值至 10左右， 用二氯曱烷萃取有机相， 萃取液用无水 Na₂S0₄干燥 后， 浓缩、 硅胶柱分离纯化， 采用二氯曱烷与曱醇的体积比为 5: 1~1 : 1 的洗 脱液进行洗脱， 得到化合物 S₂₁ 5.8 g, 收率为 76 %。

Accurately weigh 1.05 g of 74 mmol of p-aminophenylethanol and 6.61 g of 37 mmol of hydrochloric acid mustard in n-butanol and reflux for 24 h. After cooling to room temperature, dilute with water and adjust the pH to 10 with 15 % NaOH. The organic phase is extracted with dichlorosilane. The extract is dried with anhydrous Na ₂ SO ₄ , concentrated and purified by silica gel column. The volume ratio of dichlorosilane to decyl alcohol is 5:1~1:1. The eluate was eluted to give Compound S ₂₁ 5.8 g in a yield of 76 %.

Accurately weigh 1.20 g, ie 5.8 mmol of the above prepared S ₂₁ and 1.46 g, ie 5.8 mmol of S ₉ , ie 6,9-dichloro-1,2,3,4-tetrahydroacridine in n-pentanol After refluxing for 16 h, the mixture was concentrated to room temperature, and then concentrated and purified by silica gel column eluting with eluting with petroleum ether and ethyl acetate at a volume ratio of 1:1 to obtain compound S ₂₂ 230 mg, yield 9.4 % .

Accurately weigh 42 mg, 0.1 mmol of S ₂₂ dissolved in 5 mL of dichlorosilane, add 125 mg of about 0.4 mmol of tetrabromocarbonate and 125 mg of 0.5 mmol of triphenylphosphine, and stir at room temperature for 18 h. The mixture was concentrated and purified on a silica gel column. eluting with 1% triethylamine, eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain compound S ₂₃ 34 mg , yield 71 %.

Weigh 34 mg of approximately 0.07 mmol of S ₂₃ , 24 mg of approximately 0.07 mmol of 4-(3-nitro-phenyl)-2,6-diamidino-1,4-dihydropyridine-3,5 - Monodecyl dicarboxylate and 9.7 mg of about 0.07 mmol of potassium carbonate dissolved in 4 mL of DMF, 50. The reaction was stirred for 12 h under C, 20 mL of water was added, and the organic phase was extracted twice with 20 mL of ethyl acetate. The organic phase was combined, dried, concentrated and purified by silica gel column. The ratio of petroleum ether to ethyl acetate was 2:1. The elution system is eluted to obtain the present invention. Compound 12, 50 mg, yield 97%.

 The compound 12 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 736.1 ; [M - H] - = 734·1.

ifiNMR (500 MHz, CDC1 ₃ ) δ 8.12 (d, J = 9.0 Hz, 1H), 8.08 (t, J = 2.0 Hz, 1H), 7.98-8.00 (m, 2H), 7.55 (dt, J= 1.3, 7.7 Hz, 1H), 7.32-7.38 (m, 2H), 7.10 (d J= 8.6 Hz, 2H), 6.92 (d, J= 8.6 Hz, 2H), 5.84 (s, 1H), 5.10 (s, 1H ), 4.26 (t, J = 7.1 Hz, 2H), 3.67 (s, 3H), 3.46 (bs, 4H), 3.35 (bs, 4H), 3.12 (t, J= 6.5 Hz, 2H), 2.95-2.97 (m, 2H), 2.84-2.88 (m, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 1.85-1.96 (m, 4H). Example 13 Preparation of Compound 13 Provided by the Invention

 The preparation process is as follows:

Accurately weigh 2 g of 16 mmol of 3-hydroxyphenylhydranol, dissolve in 150 mL of acetone, stir to dissolve, add 8.3 g of about 60 mmol of K ₂ C0 ₃ solid powder, stir vigorously, slowly add 1.8 g about For 16 mmol of hydrazine, hydrazine-dimercaptochloro amide, a small amount of bubbles were generated, and after the reaction was stabilized, the reactor was moved to 60. The reaction was heated and refluxed in a C oil bath, and the reaction was stopped by TLC. After 12 h, the reaction was stopped, cooled, and the residue was filtered, and the filtrate was evaporated to dryness, diluted with saturated NaHC0 ₃ and acetic acid. Ethyl acetate was extracted organically, and the extract was washed with water, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the compound S ₂₄ 3.1 g (yield 99.8 %, ESI-MS: [M - H]" = 194.1, the next step is not carried out without separation.

3.1 g of about 16 mmol of the above-prepared compound S _{24 was} dissolved in chloroform, and 2.8 g of chloroform solution of 2.8 g of thionyl chloride was added dropwise in an ice bath, and the reaction was slowly increased to room temperature after the dropwise addition, TLC tracking monitoring, 12 h after the reaction was complete, the reaction was stopped, the organic solvent was evaporated, diluted with saturated sodium bicarbonate solution, the organic layer was extracted with ethyl acetate, washed with water, dried, filtered, and concentrated to give a pale yellow oil S ₂₅ 2.2 g, yield 88.0%, ESI-MS: [M + H]+ = 214.0.

1.0 g of about 4.4 mmol of compound S _{25 was} dissolved in acetonitrile, 2.0 g of about 23.2 mmol of anhydrous piperazine and 1.6 g of about 11.6 mmol of potassium carbonate powder were added, and the reaction system was transferred to an oil bath of 80 ° C. The reflux reaction was monitored by TLC. After 12 h, the reaction was completed. The reaction was stopped. The reaction was cooled and filtered. The filtrate was evaporated to dryness. The compound S ₂₆ 1.04 g was obtained as a colorless oil, yield: 87.7 %, ESI-MS: [M + H] ⁺ = 264.1.

160 mg of about 0.61 mmol of compound S _{26 was} dissolved in acetonitrile, 160 mg of about 1.16 mmol of tribromopropanol and 200 mg of about 1.5 mmol of potassium carbonate powder were added, and the system was transferred to an oil bath of 80 ° C. The reaction was refluxed, and the reaction was monitored by TLC. After 12 h, the reaction was complete, the reaction was stopped, the reaction was cooled, and the reaction system was filtered. The filtrate was evaporated to dryness and purified directly on silica gel column chromatography eluting with ethyl acetate as eluent. Colorless oily compound S ₂₇ 70 mg, yield 40%, ESI-MS: [M + H] ⁺ = 322.2.

Dissolving 0.1 g of about 0.3 mmol of 5-(oxacarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3-in acid in DMF Add 0.1 g of about 0.5 mmol of DCC, 12 mg of about 0.1 mmol of catalytic DMAP and 70 mg of about 0.22 mmol of S ₂₇ , evacuate, and transfer the reaction system to 80 ° C oil bath under nitrogen protection. Medium reaction, TLC tracking monitoring, after 15 h, the reaction is complete, stop the reaction, cool, filter, discard the residue, collect the filtrate and dilute with water, extract with ethyl acetate The organic phase is washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated, evaporated, and purified by silica gel column chromatography, eluting with a gradient of petroleum ether and ethyl acetate in a gradient of 10: 1-1:1. The compound 13 and 80 mg of the present invention are yellow oily compounds in a yield of 50.8%.

 The compound 13 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 636.2; [M - H]" = 634.2.

ifiNMR (500 MHz, CDC1 ₃ ) δ 1.75 (2Η, m), 2.41-2.45 (4Η, m), 2.30 (2H, t), 2.32 (6H, s), 2.61-2.67 (4H, m), 3.00 ( 3H, s), 3.09 (3H, S), 3.48 (2H, s), 3.63 (3H, s), 4.08 (2H, m), 5.07 (1H, s), 6.63 (1H, s), 6.99 (1H , dd, J = 1.5 Hz, 3.0 Hz), 7.08 (1H, d, J = 2.0 Hz), 7.13 (1H, d, J = 7.7 Hz), 7.28 (1H, t, J = 7.8 Hz), 7.36 ( 1H, t, J= 7.9 Hz), 7.62 (1H, d, J= 7.7 Hz), 7.98 (1H, ddd, /= 1.0 Hz, 2.3 Hz, 8.2 Hz), 8.09 (1H, t, /= 2.0 Hz ). Example 14 Preparation of Compound 14 Provided by the Invention

 The preparation process is as follows:

Accurately weigh 7.0 g of 51 mmol of anthranilic acid and 6.0 g of 61 mmol of cyclohexanone in an ice bath, slowly add 25 mL of phosphorus oxychloride, and after the addition, transfer the reaction system. In an oil bath of 110 °C, stir and reflux for 3 h, then reduce to room temperature, slowly pour into about 200 mL of ice water, adjust the pH to about 9 with 1 mol/L NaOH, and extract the organic phase 3 times with ethyl acetate. The combined extracts were concentrated, purified by silica gel column chromatography, eluting with eluting system containing 1% triethylamine. The volume ratio of petroleum ether to ethyl acetate in the eluent was 20:1 to obtain compound S ₂₈ 3 g , the yield was 27%. Take 1.0 g of approximately 4.6 mmol of S ₂₈ and 280 mg of approximately 4.6 mmol of B The alcoholamine was stirred and refluxed in n-pentanol for 18 hours. After the temperature was lowered to room temperature, about 5 times by volume of ethyl acetate was added to precipitate a large amount of an off-white solid, which was filtered and dried to give a solid S ₂₉ 1.2 g, yield 93%.

After accurately weighing 0.96 g or 4.0 mmol of S ₂₉ in 18 mL of DMF, 3.92 g of about 11.9 mmol of carbon tetrabromide and 3.14 g of triphenylphosphine of about 11.9 mmol were added, and the reaction was stirred at room temperature for 18 h. Diluted with 0.01 mol/L of dilute hydrochloric acid, the impurities were extracted with ethyl acetate, and the aqueous acid layer was collected. The pH was adjusted to about 9 with 1 mol/L NaOH, and extracted twice with dichloromethane. The combined extracts were dried, concentrated, and separated and purified by silica gel column eluted with an eluent containing 1% triethylamine, eluent petroleum ether and ethyl acetate in a volume ratio of 5: 1, to obtain S _3. 650 mg, yield 54%.

650 mg of about 2.1 mmol of S ₃ o, 481 mg of about 6.3 mmol of 2-mercaptoethanol and 885 mg of about 6.3 mmol of potassium carbonate dissolved in 10 mL of acetonitrile, and stirred at room temperature for 12 h. After suction filtration, the filtrate was dried, concentrated, and purified by silica gel column. eluted with a washing system containing 1% triethylamine. The volume ratio of petroleum ether to ethyl acetate in the eluent was 1:1~1:3. Elution was carried out to obtain Compound S ₃₁ 330 mg in a yield of 52%.

330 mg of about 1.1 mmol of compound S _{31 was} dissolved in 5 mL of dichloromethane, and 902 mg of about 2.7 mmol of carbon tetrabromide and 723 mg of about 2.7 mmol of triphenylphosphine were added, and the reaction was stirred at room temperature for 18 h. . Further, it was diluted with 0.01 mol/L of dilute hydrochloric acid, and the impurities were extracted with ethyl acetate. The aqueous acid layer was taken, and the pH was adjusted to about 9 with 1 mol/L NaOH, and extracted twice with dichloromethane. The combined extracts were dried, concentrated and purified by silica gel column eluting with eluting with 1% triethylamine. The volume ratio of petroleum ether to ethyl acetate in the eluent was 5:1 to obtain compound S ₃₂ 230 mg, yield 58%.

230 mg of approximately 0.64 mmol of S ₃₂ , 212 mg of approximately 0.64 mmol of 5-(oxacarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4-di Hydropyridine-3-carboxylic acid and 88 mg of approximately 0.64 mmol of potassium carbonate were dissolved in 10 mL of DMF, 50. The reaction was stirred at C for 12 h. Add 50 mL of water, extract the organic phase three times with 50 mL of ethyl acetate, combine the extracts, dry, concentrate, and separate and purify on silica gel column. Elution with an elution system containing 1% triethylamine in a volume ratio of petroleum ether to ethyl acetate of 1:2 gave the compound 14, 250 mg of the present invention in a yield of 64%.

 The compound 14 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 614.2; [M - H] - = 612.1.

IfiNMR (500 MHz, DMSO- ₆ ) δ 9.00 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.96 (t, J = 2.0 Hz, 1H), 7.91-7.93 (m, 1H), 7.69 (dd, J= 8.5, 0.9 Hz, 1H), 7.59-7.60 (m, 1H), 7.45-7.50 (m, 2H), 7.28 (s, 1H), 5.21 (t, J= 5.3 Hz, 1H) , 5.01 (s, 1H), 4.02-4.12 (m, 2H), 3.46 (s, 3H), 3.43-3.45 (m, 2H), 2.87 (t, J = 6.3 Hz, 2H), 2.59-2.63 (m , 4H), 253-2.56 (m, 2H), 2.28 (s, 3H), 2.26 (s, 3H), 2.19 (s, 3H), 1.75-1.80 (m, 4H). Example 15 Preparation of Compound 15 Provided by the Invention

 The preparation process is as follows:

Accurately weigh 10 g of 7.4 mmol of 3-hydroxyacetophenone, dissolve it in 180 mL of acetone solution, stir to dissolve, add 10.3 g of 7.6 mmol of potassium carbonate powder, and slowly add 8.9 g of about 7.5 mmol. N-fluorenyl, hydrazine-ethyl chloroformamide, a small amount of bubbles are generated. After the reaction is stable, reflux at 60 °C, TLC detection, stop reaction after 12 h, cool, filter, evaporate the filtrate, add saturated NaHC0 ₃ solution diluted, and the organic phase was extracted with ethyl acetate, the extract was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give an oil, to give a colorless oily compound S ₃₃ 17.1 g, yield 90%, ESI-MS: [M + H]+ = 222.1. 12 mg of about 2.3 mmol of the above-prepared compound S _{33 was} dissolved in glacial acetic acid, and slowly added dropwise about 2.3 mmol of bromine water 120 μΐ, reacted at room temperature, detected by TLC, and stopped after 3 h, and diluted with water in the system. and sodium hydrogen carbonate was added under ice-cooling to adjust the pH greater than 7, the organic layer was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil S ₃₄ 600 mg, 87.2% yield , ESI-MS: [M + H]+ = 284.0.

Accurately weigh 760 mg or 2.3 mmol of 5-(oxacarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid in 10 mL DMF, stirred to dissolve, ₂ C0 ₃ powder was added 600 mg of S ₃₄ is about 2.0 mmol and 1.15 mmol of about 160 mg K, the reaction was placed in an oil bath at 50 ° C, TLC detection, 5 h after the reaction was stopped The mixture is cooled, filtered, and the filtrate is diluted with water. The organic layer is washed with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrated extract is purified by silica gel column chromatography eluting with eluent The volume ratio of petroleum ether to ethyl acetate was 2:1 to obtain a yellow solid compound S ₃₅ 876 mg, yield 87.6%, ESI-MS: [M + H] ⁺ = 538.K

876 mg of about 1.6 mmol of compound S _{35 was} dissolved in 20 mL of sterol solution, and dissolved by stirring in an ice bath. After 10 min, NaB 120 mg of a solid powder of about 3.2 mmol was slowly added thereto in succession. The bubble is generated, the system is gradually raised to room temperature, the reaction is detected by TLC, the reaction is stopped after 5 h, the solvent is evaporated under reduced pressure at low temperature, diluted with water, extracted with ethyl acetate, washed with organic layer, dried over anhydrous sodium sulfate, filtered and decompressed. Concentration gave a colorless oil S ₃₆ 800 mg, yield 92.0%, ESI-MS: [M+Na]+ = 562.1

500 mg of about 1.45 mmol of S _{36 was} dissolved in chloroform. 220 μ of a solution of 2.90 mmol of thionyl chloride in chloroform was added dropwise in an ice bath. After the addition was completed, the solution was slowly warmed to room temperature, TLC tracking monitoring, 12 After the completion of the reaction, the reaction was stopped, and the saturated sodium bicarbonate solution was slowly added to the system under ice-cooling. The organic phase was extracted with chloroform, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to give an oil, S ₃₇ 440 mg. Rate 55.0 %, ESI-MS: [M + H] + = 572.1.

440 mg of approximately 0.77 mmol of S _{37 was} dissolved in acetonitrile and 124 mg was added to approximately 1.8 mmol. Diammonium hydrochloride and 539 mg of potassium carbonate powder of about 3.9 mmol, the reaction system was transferred to an 80 °C oil bath for reflux, TLC tracking monitoring, after 12 h, after the reaction was completed, the reaction was stopped, cooled, filtered, and the residue was filtered. The collected filtrate was evaporated to dryness, and purified by silica gel column chromatography, eluting with an eluent of 3:1 by volume ratio of dichloromethane to decyl alcohol to obtain the compound of the present invention, 15, 300 mg. The rate is 67.2%.

 The compound 15 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 581.1; [M - H] - = 579.1.

ifiNMR (500 MHz, CDC1 ₃ ) δ 1.22 (3H, m), 2.19 (3H, s), 2.31 (3H, s), 2.39 (3H, s) 3.07 (3H, s), 2.99 (3H, s), 3.57 (2H, m), 3.65 (3H, s), 4.29 (IH, m), 4.51 (IH, d, J = 6.8 Hz), 4.92 (IH, d, J = 11.7 Hz), 5.48(1H, s ), 5.84(1H, s), 7.06(1H, m), 7.28(1H, m), 7.32(1H, m), 7.42 (IH, m), 7.52 (IH, m), 7.94 (IH, m) , 7.99 (IH, t, J= 1.2), 8.06 (IH, t, «7= 1.9 Hz). Example 16 Preparation of Compound 16 Provided by the Invention

The preparation process is as follows:

At 0. At pH C, 0.92 mL of approximately 7.2 mmol of ethyl chlorohydrazide was added dropwise to 10 mL of CH ₂ C1 containing 1.0 g of about 6.6 mmol of m-methoxyphenethylamine and 1.1 g of about 8 mmol of potassium carbonate. _{2 In the} solution, stir for 1 h. After the reaction is completed, the reaction mixture is diluted with 50 mL of water, and the aqueous phase is extracted with CH ₂ C1 ₂ , and the combined organic phases are combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated The product was isolated and purified by column chromatography to yield compound S ₃₈ 1.4 g, yield 81%. ESI-MS: [M + H] ⁺ = 266.

Accurately weigh 500 mg of 1.89 mmol of S ₃₈ dissolved in 2.5 mL of P0C1 ₃ and heat to 80 ° C for 4 h. After cooling, the reaction mixture was slowly poured into ice water, and the aqueous phase was alkalized by potassium carbonate. extracted with ethyl acetate, the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent removed by rotary evaporation, the residue was purified by column chromatography to give compound S ₃₉ 260 mg, 56% yield. ESI-MS: [M + H]+ = 248.

Accurately weigh 380 mg of about 1.54 mmol of S ₃₉ , dissolve it in 3 mL of acetic acid, add 20 mg of Pt0 ₂ , stir for 3 h at room temperature, filter off the catalyst, wash with methanol, remove the solvent by rotary evaporation, and remove Retentate was added water and extracted with ethyl acetate and basified with solid potassium carbonate, the combined organic phases were washed with water, brine, dried over anhydrous sodium sulfate, filtered and the solvent was removed by rotary evaporation, the residue was purified by column chromatography to give compound S ₄ . 330 mg, yield 86%. ESI-MS: [M + H] ⁺ = 250.

In a nitrogen atmosphere, in an 18 mL solution containing 1.0 mol of BBr ₃ and 18 mmol of dichloromethane, the mixture was slowly added dropwise to -78 ° C and contained 2.5 g of about 10 mmol of compound S ₄ . In the 30 mL of dichloromethane solution, after the addition is completed, gradually increase to room temperature, react for 3 h, add 10 mL of water to quench the reaction, neutralize to a weak alkaline with a saturated solution of NaHC0 ₃ , and use CH ₂ C1 _{2 for the} aqueous phase. The combined organic phases were washed with water, brine, dried over anhydrous sodium sulfate, filtered and the solvent was removed by rotary evaporation to give compound S ₄₁ 800 mg, without purification, was used directly in the next step. ESI-MS: [M + H] ⁺ = 236.

Accurately weigh 1.4 g of about 6.4 mmol of Boc ₂ 0 into a THF solution containing 1.0 g of about 4.3 mmol of S ₄₁ , stir at room temperature for 1 h, remove the solvent by rotary evaporation, and remove the residue by column chromatography. Compound S ₄₂ 1.15 g. ESI-MS: [M + H] ⁺ = 336.

0.47 mL of approximately 5.07 mmol of hydrazine, hydrazine-dimercaptochloro hydrazide was added dropwise to an 8 mL DMF solution containing 1.15 g of approximately 3.44 mmol of Compound S ₄₂ and 700 mg of approximately 5.07 mmol of potassium carbonate at room temperature. Stir at room temperature overnight. After the reaction is completed, 20 mL of water is added, and the aqueous phase is extracted with ethyl acetate. The organic phase is combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The compound S ₄₃ 1.2 g was obtained by isolation and purification, and the yield was 92%. ESI-MS: [M + H] ⁺ = 407.

At -78. Under C, LiAlH ₄ was slowly added to a solution of 1.2 g of about 3 mmol of compound S ₄₃ in 20 mL of THF. The reaction system was stirred at the same temperature for 20 min, stirred at 0 ° C for 20 min, and then added to the reaction solution. 0.6 mL of water, 3 mL of 15 ^Q / 々 NaOH solution, 0.9 mL of water, anhydrous magnesium sulfate, filtered, discarding the residue, collecting the filtrate, removing the solvent by rotary evaporation, and separating the residue by column chromatography to obtain the compound S ₄₄ 717 mg , the yield was 73%. ESI-MS: [M + H] ⁺ = 365.

At 0. C, slowly add 314 mg of 1.2 mmol of PPh _{3 in} batches to contain 220 mg Approximately 0.6 mmol of compound S ₄₄ and 400 mg of a solution of 1.2 mmol of CBr ₄ in 10 mL of dichloromethane were allowed to warm to room temperature and allowed to react overnight at room temperature. The reaction was quenched with water, the aqueous phase was extracted with dichloromethane Yue alkoxy, combined organic phases were washed with water, brine, dried over anhydrous sodium sulfate, filtered and the solvent removed by rotary evaporation, the residue was purified by column chromatography to give compound S ₄₅ 101 mg The yield was 39%.

55 mg of about 0.13 mmol of compound S ₄₅ and 43 mg of about 0.13 mmol of 5-(oxacarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4- Dihydropyridine-3-carboxylic acid was dissolved in 3 mL of DMF and 35 mg of approximately 0.25 mmol of potassium carbonate was added. The resulting mixture was at 50. After the reaction was carried out for 3 h, cooled to rt, EtOAc (EtOAc) (EtOAc m. The compound S ₄₆ 83 mg was obtained by column chromatography to give a yield of 94%. ESI-MS: [M + H]+ = 679.

 For the preparation of the hydrochloride salt

 The compound 16 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 579.

ifiNMR (CDC1 ₃ , 500 MHz): 8.10-8.11 (IH, m), 7.97-7.99 (IH, m), 7.62-7.65 (IH, m), 7.34-7.39 (IH, m), 6.94-6.97 (IH , m), 6.86-6.89 (IH, m), 6.84 (IH, s), 5.84 (IH, s), 5.10 (IH, d, / = 3.0Hz), 4.18-4.40 (3H, m), 3.94- 4.06 (IH, m), 3.65 (3H, ά, J = 4.5Hz), 3.19-3.24 (IH, m), 3.05 (6H, ά, J = 40.5 Hz), 2.83-2.90 (IH, m), 2.72 -2.79 (IH, m), 2.35 (6H, ά, J = 7.0 Hz), 2.01-2.21 (2H. m). Example 17 Preparation of Compound 17 Provided by the Invention

准确称取 2.0 g 即 6.6 mmol的化合物 S₃₀, 1.3 g 即 13.2 mmol的 4-羟基 哌¹¹定， 493 mg 即 3.3 mmol的換化钠和 908 mg 即 6.6 mmol的碳酸钾溶于于 30 mL丙酮中， 于室温下搅拌反应 18h。 抽滤， 收集滤液干燥、 浓缩、 硅胶 柱分离纯化， 采用含有 1 %三乙胺的洗脱体系进行洗脱， 洗脱液中石油醚与 乙酸乙酯的体积比为 3:1 , 得到 S₄₇ 1.9 g, 收率为 89 %。 The preparation process is as follows:

Accurately weigh 2.0 g, ie 6.6 mmol of compound S _30, 1.3 g 4- hydroxypiperidine set ¹¹ i.e. 13.2 mmol, 493 mg sodium i.e., 3.3 mmol of transducer i.e., 6.6 mmol and 908 mg of potassium carbonate were dissolved in 30 mL of acetone The reaction was stirred at room temperature for 18 h. After suction filtration, the collected filtrate was dried, concentrated, and purified by silica gel column eluting with eluting system containing 1% triethylamine. The volume ratio of petroleum ether to ethyl acetate in the eluent was 3:1, and S ₄₇ 1.9 was obtained. g, yield 89%.

Weigh 2.0 g of 5.8 mmol of 5-(oxacarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid, dissolved in In a mixed solution of 16 mL of dichlorodecane and 4 mL of DMF, it was stirred in an ice bath, and 1.0 g of about 8.4 mmol of thionyl chloride was slowly added dropwise, and the mixture was reacted for 2 hours in an ice bath. Then 9 mL of a solution of 1.9 g of about 5.8 mmol of compound S ₄₂ in dichloromethane was added and the reaction was continued for 3 h. Then, the pH of the reaction solution is adjusted to about 9 by adding saturated NaHC0 ₃ , and the organic phase is extracted twice with dichloromethane, and the dichloromethane extract is combined, dried with anhydrous NaSO ₄ , concentrated, and purified by silica gel column. The elution system of % triethylamine was eluted, and the volume ratio of petroleum ether to ethyl acetate in the eluate was 1:1, and the compound 17 of the present invention, 2.8 g, was obtained in a yield of 74%.

 The compound 17 provided by the present invention was tested and the results were as follows:

 ESI-MS: [M + H]+ = 640.0; [M - H]" = 638.0.

ifiNMR (500 MHz, CDC1 ₃ ) δ 8.14 (t, J = 2.0 Hz, 1H), 7.99-8.03 (m, 2H), 7.95-7.96 (m, 1H), 7.65 (dt, J= 1.3, 7.7 Hz, 1H), 7.56 (t, J= 7.1 Hz, 1H), 7.38 (t, J= 7.9 Hz, 1H), 7.33-7.35 (m, 1H), 5.91 (s, 1H), 5.12 (s, 1H), 4.81 (bs, 1H), 3.67 (s, 3H), 3.57-3.58 (m, 2H), 3.09 (bs, 2H), 2.76 (bs, 2H), 2.68-2.74 (bs, 2H), 2.55-2.57 ( m, 4H), 2.40 (s, 3H), 2.36 (s, 3H), 1.93-1.95 (m, 4H), 1.76-1.80 (m, 4H). Example 18 Preparation of Compound 18 Provided by the Invention

 The preparation process is as follows:

准确称取 1.0 g 即 4.0 mmol的 化合物 S₉, 即 6,9-二氯 -1,2,3,4-四氢吖啶 和 420 mg 即 4.0 mmol的二甘醇胺溶于 5 mL正戊醇中搅拌回流， 反应 16h, 降至室温后， 加入约 25 mL的乙酸乙酯， 析出大量灰白色固体， 抽滤、 干燥， 制得化合物 S₄₈ 1.2 g, 收率为 86 %。

Accurately weigh 1.0 g of 4.0 mmol of compound S ₉ , ie 6,9-dichloro-1,2,3,4-tetrahydroacridine and 420 mg of 4.0 mmol of diglycolamine dissolved in 5 mL of n-pentane The alcohol was stirred and refluxed for 16 h. After the mixture was cooled to room temperature, about 25 mL of ethyl acetate was added to precipitate a large white solid, which was filtered and dried to yield compound S ₄₈ 1.2 g, yield 86%.

Accurately weigh 1.0 g of 3.1 mmol of compound S ₄₈ dissolved in 3 mL of DMF, placed in an ice bath, add 0.3 mL of phosphorus tribromide dropwise, and move to room temperature for 8 h. Add 50 mL of water to dilute, adjust the pH of the reaction solution to about 9 with potassium carbonate solution, extract the organic phase twice with ethyl acetate, combine the extracts, dry, concentrate, and separate and purify on silica gel column, using 1% triethylamine. The elution system was eluted. The volume ratio of petroleum ether to ethyl acetate in the eluate was 3:1, and the compound S ₄₉ 620 mg was obtained in a yield of 52%.

Accurately weigh 620 mg or 1.6 mmol of S ₄₉ , 539 mg or 1.6 mmol of 5-(oxacarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4-di Hydropyridine-3-carboxylic acid and 224 mg, 1.6 mmol of potassium carbonate, were dissolved in 8 mL of DMF at 50. Stir at C and react for 12 h. Dilute with 50 mL of water, extract 3 times with 50 mL of ethyl acetate, combine the organic extracts, dry, concentrate, and purify on silica gel column. Elute system with 1% triethylamine elute. The volume ratio of ether to ethyl acetate was 1:1, and the compound of the present invention, 18,410 mg, was obtained in a yield of 40%.

The compound 18 provided by the present invention was tested and the results were as follows: ESI-MS: [M + H] ⁺ = 634.8; [M - H]" = 632.9.

IfiNMR (500 MHz, CDC1 ₃ ) δ 8.11 (t, J = 1.9 Hz, 1H), 7.92-7.94 (m, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.86 (d, 9.0 Hz, 1H) ), 7.62 (dt, J= 1.3, 7.7 Hz, 1H), 7.31 (t, /= 7.9 Hz, 1H), 7.25-7.28 (m, 1H), 5.94 (s, 1H), 5.11 (s, 1H) , 4.48 (bs, 1H), 4.20-4.28 (m, 2H), 3.67-3.70 (m, 2H), 3.54-3.59 (m, 7H), 3.03 (t, J = 6.2 Hz, 2H) 2.65-2.71 ( m, 2H), 2.35 (s, 6H), 1.86-1.91 (m, 4H). Example 19 Preparation of Compound 19 Provided by the Invention

 The preparation process is as follows:

Accurately weigh 710 mg or 3.0 mmol of the crude product S ₄₁ prepared above, dissolved in 8 mL of HCOOH, mixed with 8 mL of 37% concentrated HCHO, heated to 80 °C for 3 h, cooled and saturated with NaHC0 ₃ The solution is slowly neutralized to a weakly basic phase, and the aqueous phase is extracted with ethyl acetate. The organic phase is combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated. S ₅₀ 508 mg. ESI-MS: [M + H] ⁺ = 250.

0.36 mL of approximately 3.9 mmol of hydrazine, hydrazine-dimercaptochloro hydrazide was added dropwise to 330 mg of about 1.33 mmol of compound S ₅ at room temperature. And a solution of 1.1 g of about 8 mmol of potassium carbonate in 5 mL of DMF was stirred overnight. After the reaction was completed, 15 mL of water was added, the aqueous phase was extracted with ethyl acetate, and the organic phase was combined and washed with water and brine. Dry with sodium sulfate, filter, and dissolve by rotary evaporation The residue was purified by column chromatography to give Compound S ₅₁ 374 mg (yield: 88%). ESI-MS: [M + H] ⁺ = 321.

LiAlH ₄ was slowly added to a solution of about 0.94 mmol of compound S ₅₁ in 5 mL of THF at -20 ° C. After stirring at this temperature for 30 min, 0.2 mL of water was added to the reaction solution in a concentration of 15 % NaOH aqueous solution 0.4 mL, water 0.5 mL, a small amount of anhydrous magnesium citrate, filtered, and the solvent was removed by rotary evaporation. The residue was purified by column chromatography to yield compound S ₅₂ 165 mg, yield 63%. ESI-MS: [M + H] ⁺ = 279.

At 0. 283 mg of about 1.08 mmol of PPh ₃ was slowly added in portions to a solution containing 150 mg of about 0.54 mmol of compound S ₅₂ and 357 mg of about 1.08 mmol of CBr ₄ in 10 mL of dichloromethane, and naturally rose to Allow to react at room temperature overnight at room temperature. The reaction was quenched with water, the aqueous phase was extracted with CH ₂ C1 ₂ and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the solvent was removed by rotary evaporation, the residue was purified by column chromatography to give compound S ₅₃ 106 Mg, yield 58%. ESI-MS: [M + H] ⁺ = 341.

53 mg of about 0.16 mmol of compound S ₅₃ and 52 mg of about 0.16 mmol of 5-(oxacarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4- Dihydropyridine-3-carboxylic acid was dissolved in 3 mL of DMF and 43 mg of approximately 0.32 mmol of potassium carbonate was added. At 50. After the reaction was carried out for 3 h, cooled to rt, EtOAc (EtOAc) (EtOAc m. Separation and purification by column chromatography gave the compound 19, 88 mg of the present invention in a yield of 96%.

 The compound 19 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 593.

ifiNMR (CDC1 ₃ , 500 MHz): 8.10 (1H, t, J = 2.0 Hz), 7.98 (1H, ddd, J= 1.5, 2.5, 8.5 Hz), 7.64 (1H, άά, J = 1.5, 8.0 Hz) , 7.36 (1H, dt, / = 1.5, 8.0 Hz), 6.88 (1H, dd, /= 2.5, 9.5 Hz), 6.83 (2H, dt, /= 2.5, 8.0 Hz), 5.91 (1H, d, J = 9.0 Hz), 5.11 (1H, ά, J = 9.0Hz), 4.19-4.31 (1H, m), 4.02-4.11 (1H, m), 3.65 (3H, s), 3.50-3.58 (1H, m) , 3.04 (6H, d, J= 39 Hz), 2.80-2.86 (1H, m), 2.67-2.75 (2H, m), 2.41 (3H, d, J = 33.5 Hz), 2.35 (3H, s), 2.33 (3H, s), 2.08-2.15 (1H. m), 1.95-2.02 (1H. m), 1.70-1.74 (1H. m). Example 20 Preparation of Compound 20 Provided by the Invention

 The preparation process is as follows:

Accurately weigh 2.4 g or 15.9 mmol of m-methoxy phenethylamine, dissolve it in 12 mL of 48% HBr solution, heat under reflux for 5 h, cool to room temperature, and vortex off the solvent to obtain compound S ₅₄ 3.2 g. The yield was 93% and was used directly in the next step without purification. ESI-MS: [M + H] ⁺ = 138.

0.3 g of about 2 mmol of benzyloxyacetaldehyde was added dropwise to 0.31 g of a solution of about 2 mmol of compound S ₅₄ in 10 mL of methanol at room temperature, and stirred under reflux for 2 d. Solvent was removed by rotary evaporation, the residue was separated and purified by column chromatography to give compound S ₅₅ 328 mg, 61% yield. ESI-MS: [M + H] ⁺ = 270.

Mix 1.5 g of HCOOH solution of about 5.58 mmol of compound S ₅₅ with 16 mL of 37% HCHO solution, heat to 80 °C for 3 h, cool and slowly neutralize to weakly alkaline with NaHC0 ₃ saturated solution. The aqueous phase is extracted with ethyl acetate. The organic phase is combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. Compound S ₅₆ 570 mg was obtained in a yield of 36%. ESI-MS: [M + H] ⁺ = 284. 0.28 mL of approximately 3.0 mmol of hydrazine, hydrazine-dihydrazinyl chloroamide was added dropwise to 570 mg of approximately 2 mmol of compound S ₅₆ and 1.38 g of approximately 10 mmol of potassium carbonate in 12 mL of DMF. Stir at room temperature overnight. After the reaction is completed, 20 mL of water is added, and the aqueous phase is extracted with ethyl acetate. The organic phase is combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The compound S ₅₇ 529 mg was obtained in a yield of 75%. ESI-MS: [M + H] ⁺ = 355.

529 mg of about 1.5 mmol of compound S _{57 was} dissolved in 15 mL of ethanol, 265 mg of Pd/C was added, and hydrogen was stirred for 3 d at room temperature. The catalyst was filtered off, the reaction solution was washed with methanol, and the solvent was removed by rotary evaporation. The compound S ₅₈ 250 mg was obtained by column chromatography to give a yield of 63%. ESI-MS: [M + H] ⁺ = 265.

Under nitrogen protection, 28 mg of about 0.106 mmol of compound S ₅₈ , 41 mg of about 0.123 mmol of 5-(oxacarbonyl)-2,6-dimercapto-4-(3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid, 46 mg of about 0.223 mmol of DCC and 14 mg of about 0.115 mmol of DMAP in a single-necked flask, adding 3 mL of DMF, heating to 80 °C, reaction After the reaction was completed, 10 mL of water was added, and the aqueous layer was extracted with ethyl acetate. Separation and purification by column chromatography gave the compound 20, 63 mg of the present invention in a yield of 57%.

 The compound 20 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 579.

ifiNMR (CDC1 ₃ , 500 MHz) δ 8.09 (1H, t, J = 2.0 Hz), 7.97-8.00 (1H, m), 7.64 (1H, dt, J = 1.5, 7.5 Hz), 7.37 (1H, d, J = 8.0 Hz), 7.12 (1H, d, J = 8.0 Hz), 6.82-6.90 (2H, m), 5.73 (1H, s), 5.08 (1H, ά, J = 6.5Hz), 4.45-4.50 ( 1H, m), 4.29-4.38 (1H, m), 3.68-3.74 (1H, m), 3.65 (3H, s), 3.03-3.12 (1H, m), 3.09 (6H, d, J = 6.5 Hz) , 2.74-2.83 (2H, m), 2.60-2.71 (1H, m), 2.45 (3H, ά, J = 3.5 Hz), 2.34 (3H, d, J= 2.0 Hz), 2.21 (3H, d, / = 23 Hz). Example 21 Preparation of Compound 21 Provided by the Invention

 The preparation process is as follows:

 S61

Accurately weigh 3.0 g of about 13.8 mmol of S ₂₈ and 1.2 g of about 16.5 mmol of 3-aminopropanol, dissolve in 10 mL of n-pentanol and reflux for 18 h. After cooling to room temperature, add about 30 mL of acetic acid. Ethyl acetate, a large amount of an off-white solid was precipitated, suction filtered and dried to give a solid compound S ₅₉ 2.4 g, yield 68%.

After 2.4 g of about 9.4 mmol of the compound S ₅₉ prepared above was dissolved in 20 mL of DMF, 6.1 g of about 18.8 mmol of carbon tetrabromide and 4.9 g of about 18.8 mmol of triphenylphosphine were added at room temperature. Stir and react for 18 h. Further, diluted with 0.01 mol/L of dilute hydrochloric acid, the impurities were extracted with ethyl acetate, and an aqueous acid layer was taken. The pH of the reaction mixture was adjusted to about 9 with potassium carbonate, and then extracted three times with dichloromethane. The combined extracts were dried, concentrated and purified by silica gel column eluting with eluting with 0.5% triethylamine. The volume ratio of petroleum ether to ethyl acetate in the eluent was 5:1 to obtain S ₆ . 2.5 g, yield 84%.

Accurately weigh 2.5 g of approximately 7.9 mmol of compound S ₆₀ , 1.6 g of approximately 1.57 mmol of 4-hydroxypiperidine, 590 mg of approximately 3.9 mmol of sodium for replacement and 1.1 g of approximately 7.9 mmol of potassium carbonate. Dissolved in 30 mL of acetone, stirred at room temperature, and reacted for 18 h. After suction filtration, the collected filtrate was dried, concentrated, and purified by silica gel column, eluting with an elution system containing 1% triethylamine. The volume ratio of dichloromethane to decyl alcohol in the eluent was 5:1 to obtain a compound. S ₆₁ 2.6 g, yield 97%.

1.2 g of about 3.5 mmol of 5-(oxacarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4-dihydrogen Pyridine-3-carboxylic acid, dissolved in a mixed solution of 8 mL of dichlorosilane and 2 mL of DMF, stirred in an ice bath, slowly added 625 mg of 5.2 mmol of thionyl chloride, and an ice bath reaction 2 h. Then, a solution containing 1.0 g of about 3.0 mmol of S ₆₁ in 7 mL of dichloromethane was added and the reaction was continued for 3 h. Then add saturated NaHC0 _{3 to} adjust the pH of the reaction solution to about 9, and extract the organic phase twice with dichloromethane. The extract is combined with dichloromethane, dried, concentrated, purified by silica gel column, using 1% triethylamine. The elution system was eluted, and the volume ratio of petroleum ether to ethyl acetate in the eluate was 1:4, and the compound 21 provided in the present invention was obtained as an oil, 1.5 g, yield 78%.

 The compound 21 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 654.1; [M - H] - = 652.2.

IfiNMR (500 MHz, CDC1 ₃ ) δ 8.12 (t, J = 2.0 Hz, IH), 7.98-8.03 (m, 2H), 7.92 (d, J = 8.4 Hz, IH), 7.63 (dt, J= 1.3, 7.7 Hz, IH), 7.54-7.57 (m, IH), 7.32-7.37 (m, 2H), 6.09 (s, IH), 5.11 (s, IH), 4.80 (bs, IH), 3.66 (s, 3H ), 3.59 (t, J = 6.3 Hz, 2H), 3.06-3.08 (m, 2H), 2.75-2.76 (m, 2H), 2.48 (t, J = 6.3 Hz, 2H), 2.38 (s, 3H) , 2.36 (s, 3H), 1.92-1.96 (m, 6H), 1.82-1.85 (m, 4H), 1.69-1.75 (m, 4H). Example 22 Preparation of Compound 22 Provided by the Invention

 The preparation process is as follows:

准确称取 1.07 g约为 4.26 mmol的化合物 S₉, 即 6,9-二氯 -1,2,3,4-四氢吖 啶和 1.74 g约为 17 mmol的 1,5-二氨基正戊烷， 溶于 5 mL正戊醇溶液中， 加热到 160-165 °C, 使其在回流状态下反应过夜， 冷却至室温， 加入 20 mL DCM稀释反应液，有机层依次用 2 mol/L的 NaOH 2次、水、饱和食盐水洗， 无水硫酸钠干燥，过滤浓缩，所得残留物经硅胶柱层析分离纯化得化合物 S₆₂ 1.24 g, 收率为 92 %。 ESI-MS: [M + H]+ = 318。

Accurately weigh 1.07 g of about 4.26 mmol of compound S ₉ , ie 6,9-dichloro-1,2,3,4-tetrahydroacridine and 1.74 g of about 17 mmol of 1,5-diamino-n-pentane Alkane, dissolved in 5 mL of n-pentanol solution, heated to 160-165 °C, allowed to react under reflux overnight, cooled to room temperature, diluted with 20 mL of DCM, the organic layer was sequentially used 2 mol / L NaOH 2 times, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated, the resulting residue was purified by silica gel column chromatography to give compound S ₆₂ 1.24 g, 92% yield. ESI-MS: [M + H]+ = 318.

Accurately weigh 252 mg or 0.76 mmol of 5-(oxacarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid, 34 Mg 0.25 mmol of HOBt and 145 mg of 0.76 mmol of EDCI were dissolved in 8 mL of DMF. After stirring at room temperature for 5 min, 2 mL of DMF solution containing 200 mg of about 0.63 mmol of compound S ₆₆ was added dropwise at room temperature. Stir overnight. Water was added diluted aqueous phase extracted with ethyl acetate, the organic phases were combined, successively washed with ₂₀ H and brine, dried over anhydrous sodium sulfate, filtered and the solvent removed by rotary evaporation, the residue was purified by flash column chromatography The compound 22, 333 mg of the present invention was obtained in a yield of 84%.

 The compound 22 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 632.

ifiNMR (CDC1 ₃ , 500 MHz) δ 8.38 (1H, d, / = 1.5 Hz), 8.25 (1H, d, / = 9.0 Hz), 8.08 (1H, s), 7.92 (1H, dd, / = 2.0, 8.0 Hz), 7.64 (1H, ά, J = 7.5 Hz), 7.37 (1H, t, J= 8.0 Hz), 7.33 (1H, dd, J= 2.0, 9.0 Hz), 7.22 (1H, s), 6.56 (1H, s), 5.89 (1H, t, J = 6.0 Hz), 4.95 (1H, s), 3.83-3.88 (2H, m), 3.60 (3H, s), 3.21-3.26 (4H, m), 2.64-2.69 (2H, m), 2.39 (3H, s), 2.25 (3H, s), 1.78-1.89 (8H. m), 1.45-1.54 (2H, m). Example 23 Preparation of Compound 23 Provided by the Invention

The preparation process is as follows:

0. 0.56 mL of approximately 7.2 mmol of MsCl was added dropwise to 20 mL of DCM solution containing 1.17 g of approximately 3.6 mmol of compound S ₄₇ and 1.56 mL of approximately 10.8 mmol of TEA, and stirred at room temperature for 1 h. After the reaction is completed, 20 mL of water is added, and the aqueous phase is extracted with DCM. The combined organic phase is combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated. Compound S ₆₃ 1.15 g, yield 79%. ESI-MS: [M + H] ⁺ = 404.

403 mg of approximately 6.2 mmol of NaN _{3 was} added portionwise to 20 mL of a DMF solution containing 500 mg of approximately 1.24 mmol of compound S ₆₃ at room temperature and heated to 80. C reacted overnight. After the reaction is completed, water is added, and the aqueous phase is extracted with ethyl acetate. The organic phase is combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. ₆₄ 300 mg, yield 70%. ESI-MS: 351 [M + H]+.

300 mg of about 0.86 mmol of compound S _{64 was} dissolved in 10 mL of methanol, 30 mg of Pd/C was added, hydrogenation was carried out overnight at room temperature, the catalyst was filtered off, the methanol was washed, and the solvent was removed by rotary evaporation. The compound S ₆₅ 235 mg was obtained by fractionation and purification, and the yield was 85%. ESI-MS: [M + H] ⁺ = 325.

Accurately weigh 243 mg of about 0.73 mmol of 5-(oxacarbonyl)- 2,6-dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid , 33 mg is about 0.24 mmol of HOBt and 139 mg is about 0.73 mmol of EDCI, dissolved in 8 mL of DMF, stirred at room temperature for 5 min, then added dropwise. 198 mg of about 0.61 mmol of compound S ₆₅ in 2 mL of DMF, and the mixture was stirred at room temperature overnight. Diluted with water, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed successively with 3⁄40 and brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The compound provided by the invention 23, 272 mg, yield 70%.

 The compound 23 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 639.

IfiNMR (CDC1 ₃ , 500 MHz) δ 8.14 (1H, t, J = 2.0 Hz), 8.05 (1H, ddd, J = 1.5, 2.5, 8.0 Hz), 7.99 (1H, d, J = 8.5 Hz), 7.94 (1H, d, J = 8.0 Hz), 7.65 (1H, dt, J = 1.5, 7.5 Hz), 7.55 (2H, td, J= 1.5, 8.0 Hz), 7.43 (1H, t, J= 8.0 Hz) , 7.33 (1H, td, J = 1.5, 7.5 Hz), 5.94 (1H, s), 5.28 (1H, d, J = 8.0Hz), 4.92 (1H, s), 3.79-3.86 (1H, m), 3.65 (3H, s), 3.55 (2H, t, J = 6.0 Hz), 3.08 (2H, t, J = 6.0 Hz), 2.72 (2H, t, J = 6.0 Hz), 2.61-2.70 (2H, m ), 2.54 (2H, t, J = 6.0 Hz), 2.34 (3H, s), 2.24 (3H, s), 2.13-2.23 (2H, m), 1.85-1.95 (6H, m), 1.75-1.85 ( 1H, m), 1.58-1.74 (1H, m). Example 24 Preparation of Compound 24 Provided by the Invention

 The preparation process is as follows:

Weigh 2.2 g of about 10.0 mmol of S ₂₈ and 1.0 g of about 10.0 mmol of 5-aminopentanol, dissolve it in 10 mL of n-pentanol, and reflux for 18 h. After cooling to room temperature, the reaction solution is concentrated. Separation and purification on a silica gel column, elution with an elution system containing 1% triethylamine, dichloride in the eluent The volume ratio of decane to decyl alcohol was 50:1, and S ₆₆ 2.5 g was obtained, and the yield was 88%.

Accurately weigh 3.5 g, 10.6 mmol of 5-(oxacarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid In a mixed solution of 20 mL of dichloromethane and 5 mL of DMF, the mixture was stirred in an ice bath, and 1.26 g of 10.6 mmol of thionyl chloride was slowly added dropwise, and the mixture was reacted for 2 hours in an ice bath. Then 10 mL of a solution containing 2.5 g of about 8.8 mmol of S ₆₆ in dichloromethane was added and the reaction was continued for 3 h. Add saturated NaHC0 _{3 to} adjust the pH of the reaction solution to about 9, extract twice with dichloromethane, combine with dichloromethane extract, dry NaS0 ₄ dry, concentrate, silica gel column separation and purification, using 1% triethyl The elution system of the amine was eluted, and the volume ratio of petroleum ether to ethyl acetate in the eluate was 1:1 to obtain a yellow solid product, that is, the compound 24, 2.9 g of the present invention was obtained in a yield of 55%.

 The compound 24 provided by the present invention was tested and the results were as follows:

 ESI-MS: [M + H]+ = 599.0; [M - H]" = 597.0.

IfiNMR (500 MHz, CDC1 ₃ ) δ 8.11 (t, J = 2.0 Hz, 1H), 7.90-7.96 (m, 3H), 7.61 (dt, J = 1.3, 7.7 Hz, 1H), 7.54-7.57 (m, 1H), 7.30-7.37 (m, 2H), 5.98 (s, 1H), 5.09 (s, 1H), 3.98-4.13 (m, 2H), 3.93 (bs, 1H), 3.63 (s, 3H), 3.41 -3.43 (m, 2H), 3.06-3.07 (m, 2H), 2.70-2.72 (m, 2H), 2.35 (s, 6H), 1.92-1.93 (m, 4H), 1.62-1.67 (m, 4H) , 1.32-1.36 (m, 2H). Example 25 Preparation of Compound 25 Provided by the Invention

 The preparation process is as follows:

准确称取 1.42 g即 10 mmol的 2,2,6-三曱基 -4H-1,3-二噁英 -4-酮和 0.82 mL约为 12 mmol的 2-羟基乙腈， 溶于 10 mL二曱苯中， 加热到 140-145。C, 回流反应 l h, 冷却至室温， 旋转蒸发除去溶剂， 残留物经快速柱层析分离纯 化得化合物 S₆₇ 1.4 g, 收率为 90 %。 ESI-MS: [M + H]⁺ = 156。

Accurately weigh 1.42 g of 10 mmol of 2,2,6-trimethyl-4H-1,3-dioxin-4-one and 0.82 mL of approximately 12 mmol of 2-hydroxyacetonitrile in 10 mL of two In toluene, heat to 140-145. The reaction mixture was refluxed for 1 h, cooled to room temperature, and the solvent was evaporated, and the residue was purified by flash column chromatography to yield compound S ₆₇ 1.4 g. ESI-MS: [M + H] ⁺ = 156.

Accurately weigh 2.3 g of 15 mmol of compound S ₆₇ , 2.27 g of 15 mmol of o-nitrophenylfurfural, 1.73 g of 15 mmol of 3-aminocrotonate, placed under a nitrogen atmosphere, in a single-necked flask After adding 50 mL of isopropanol, heating under reflux, overnight, and after completion of the reaction, the solvent was removed by rotary evaporation, and the residue was purified by column chromatography to yield compound S ₆₈ 5.0 g, yield 87%. ESI-MS: [M + H] ⁺ = 386.

5.0 g of about 13 mmol of the compound S ₆₈ prepared above was dissolved in 50 mL of ethanol, and 601 mg of about 14.3 mmol of LiOH-H ₂ 0 was added at room temperature. After stirring for 2 h, the ethanol in the reaction system was rotated. After evaporation, water was added and the pH was adjusted to 4-5 with 2 mol/L hydrochloric acid, and then the solid precipitated in the system was filtered to give compound S ₆₉ 2.3 g, yield 53%. ESI-MS: [M + H] ⁺ = 333.

Accurately weigh 332 mg or 1 mmol of compound S ₆₉ , 318 mg of 1 mmol of compound S ₁₀ , 412 mg of 2 mmol of DCC and 122 mg of 1 mmol of DMAP in a single-necked flask, under nitrogen, add DMF lO mL, heated to 80. After the reaction was completed, the reaction was completed. EtOAc was evaporated. Separation and purification by column chromatography gave the compound 25, 436 mg of the present invention in a yield of 69%.

 The compound 25 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 633.

IfiNMR (CDC1 ₃ , 500 MHz) δ 7.97 (IH, ά, J = 1.0 Hz), 7.91 (IH, d, J = 9.0 Hz), 7.64 (IH, dd, /= 1.5, 8.0 Hz), 7.50 (IH , dd, J = 1.0, 8.0 Hz), 7.42 (IH, td, J = 1.0, 8.0 Hz), 7.29 (IH, dd, J = 2.0, 9.0 Hz), 7.17 (IH, td, J= 1.5, 8.0 Hz), 5.91 (IH, s), 5.77 (IH, s), 4.10-4.20 (IH, m), 4.05-4.12 (IH, m), 3.92-3.97 (IH, m), 3.56 (3H, s) , 3.47 (2H, t, J = 6.5 Hz), 3.03-3.08 (2H, m), 2.63-2.67 (2H, m), 2.34 (3H, s), 2.31 (3H, s), 1.90-1.93 (4H, m), 1.59-1.64 (4H, m), 1.25-1.30 (2H, m). Example 26 Preparation of Compound 26 Provided by the Invention

 The preparation process is as follows:

Accurately weigh 2.3 g of 15 mmol of compound S ₆₇ , 2.1 g of 15 mmol of o-chlorobenzaldehyde, and 1.73 g of 15 mmol of 3-aminocrotonate in a single-necked flask under nitrogen protection. 50 mL of ethanol was added, and the mixture was heated to reflux, and the reaction was completed overnight. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was purified by column chromatography to afford compound S ₇ . 4.2 g, yield 75%. ESI-MS: [M + H] ⁺ = 375.

4.2 g of approximately 11.2 mmol of compound S _{7 will be obtained} . Dissolve in 50 mL of ethanol solution, add 518 mg of 12.3 mmol of LiOH-H ₂ 0 at room temperature, stir for 2 h, then remove the ethanol in the reaction system by rotary evaporation, add water, adjust with 2 mol/L hydrochloric acid. The pH of the reaction mixture was adjusted to 4-5, and the solid which precipitated from the system was filtered to obtain 2.8 g of Compound S ₇₁ in a yield of 78%. ESI-MS: [M + H] ⁺ = 322.

321 mg of approximately 1 mmol of compound S _{7 was} weighed out. 318 mg of about 1 mmol of compound Sio, 412 mg of about 2 mmol of DCC and 122 mg of about 1 mmol of DMAP were placed in a single-necked flask, and under nitrogen, DMF 10 mL was added and heated to 80. C, reaction overnight, reaction finished After the whole, 20 mL of water was added, and the aqueous phase was extracted with ethyl acetate. The organic phase was combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The compound of the present invention, 26, 538 mg, yielded 87%.

 The compound 26 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 622.

IfiNMR (CDC1 ₃ , 500 MHz) δ 7.94 (1H, d, / = 1.5 Hz), 7.88 (1H, d, / = 9.0 Hz), 7.36 (1H, dd, J= 1.5, 7.5 Hz), 7.29 (1H , dd, J= 2.0, 9.0 Hz), 7.17 (1H, dd, J = 1.5, 8.5 Hz), 7.08 (1H, td, J= 1.0, 7.5 Hz), 6.96 (1H, td, J= 1.5, 8.5 Hz), 5.75 (1H, s), 5.37 (1H, s), 3.98-4.10 (3H, m), 3.60 (3H, s), 3.43 (2H, t, / = 2.0 Hz), 3.03-3.08 (2H , m), 2.62-2.67 (2H, m), 2.31 (3H, s), 2.30 (3H, s), 1.90-1.93 (4H, m), 1.58-1.66 (4H, m), 1.24-1.30 (2H , m). Example 27 Preparation of Compound 27 Provided by the Invention

 The preparation process is as follows:

Accurately weigh 502 mg, ie 2.0 mmol, of compound S ₉ , ie 6,9-dichloro-1,2,3,4-tetrahydroacridine and 346 mg of about 2.0 mmol of 10-aminosterol, dissolved in 4 mL n-pentanol was stirred at reflux, the reaction 18 h, after cooled to room temperature, diluted with saturated NaHCO ₃ solution, extracted three times with dichloro Yue alkoxy, extracts were combined, dried over anhydrous NaS0 _4, concentrated and purified by silica gel column separation, Elution was carried out using an elution system containing 1% triethylamine, and the volume ratio of petroleum ether to ethyl acetate in the eluate was 2:1 to obtain a compound S ₇₂ 400 mg in a yield of 52%.

Weigh 376 mg of about 1.1 mmol of 5-(oxacarbonyl)-2,6-dimercapto-4-(3-nitrobenzene -1,4-dihydropyridine-3-carboxylic acid, dissolved in a mixture of 4 mL of dichloromethane and 1 mL of DMF, stirred in an ice bath, slowly added dropwise 184 mg of about 1.5 mmol Dichlorosulfoxide, ice bath reaction for 2 h. Then add 4 mL of 400 mg of approximately 1.0 mmol of S ₇₂ dichloromethane solution and continue the ice bath for 3 h. Add saturated NaHC0 _{3 to} adjust the pH of the reaction solution to about 9, dichloromethane extraction twice, combined with dichlorodecane extract, anhydrous NaS0 ₄ dry, concentrated, silica gel column separation and purification, using 1% triethyl The elution system of the amine was eluted, and the volume ratio of petroleum ether to ethyl acetate in the eluate was 2:1, and the compound 27, 420 mg of the present invention was obtained in a yield of 58%.

 The compound 27 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 702.8; [M - H]" = 700.9.

ifiNMR (500 MHz, CDC1 ₃ ) δ 8.11 (t, J = 2.0 Hz, 1H), 7.97-8.00 (m, 1H),

7.89- 7.92 (m, 2H), 7.63 (dt, J= 1.4, 7.8 Hz, 1H), 7.36 (t, J= 7.9 Hz, 1H),

7.26-7.28 (m, 1H), 5.99 (s, 1H), 5.10 (s, 1H), 3.97-4.08 (m, 2H), 3.65 (s, 3H), 3.46-3.50 (m, 2H), 3.03 ( Bs, 2H), 2.67 (bs, 2H), 2.36 (s, 3H), 2.35 (s, 3H),

 1.90- 1.93 (m, 4H), 1.55-1.67 (m, 4H), 1.36-1.39 (m, 2H), 1.19-1.24 (m, 10H). Example 28 Preparation of Compounds Provided by the Invention 28

 The preparation process is as follows:

Accurately weigh 502 mg, ie 2.0 mmol, of compound S ₉ , ie 6,9-dichloro-1,2,3,4-tetrahydroacridine and 242 mg of approximately 2.0 mmol of 2-(2-aminoethyl) Sulfuric acid, dissolved in 4 mL of n-pentanol, stirred and refluxed, reacted for 18 h, and after being cooled to room temperature, about 12 mL of ethyl acetate was added to precipitate a large amount of white. The solid was suction filtered and dried to give a solid compound S ₇₃ 625 mg.

Weigh 365 mg of about 1.1 mmol of 5-(oxacarbonyl)-2,6-diamidino-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid, dissolved In a mixed solution of 4 mL of dichloromethane and 1 mL of DMF, the mixture was stirred in an ice bath, and 179 mg of about 1.5 mmol of thionyl chloride was slowly added dropwise, and the mixture was reacted for 2 hours in an ice bath. Then, 4 mL of a solution of 336 mg of about 1.0 mmol of S ₇₃ in dichloromethane was added and the reaction was continued for 3 h. Then, the pH of the reaction solution was adjusted to about 9 by adding saturated NaHC0 ₃ , and extracted twice with dichloromethane, and the dichloromethane extract was combined, dried over anhydrous NaSO ₄ , concentrated and purified by silica gel column. The elution system of ethylamine was eluted, and the volume ratio of petroleum ether to ethyl acetate in the eluate was 2:1, and the compound 28, 620 mg of the present invention was obtained in a yield of 95%.

 The compound 28 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 650.8; [M - H]" = 648.8.

IfiNMR (500 MHz, CDC1 ₃ ) δ 8.11 (t, J = 2.0 Hz, 1H), 7.96-7.98 (m, 1H), 7.89-7.91 (m, 2H), 7.62 (dt, J= 1.4, 7.7 Hz, 1H), 7.35 (t, J= 7.9 Hz, 1H), 7.29 (dd, J= 2.2, 9.0 Hz 1H), 6.10 (s, 1H), 5.09 (s, 1H), 4.56 (bs, 1H), 4.16 -4.25 (m, 2H), 3.62-3.65 (m, 5H), 3.03-3.04 (m, 2H), 2.78 (t, J = 6.2 Hz, 2H), 2.73 (dt, J = 1.6, 6.8 Hz, 4H ), 2.36 (s, 3H), 2.35 (s, 3H), 1.90-1.92 (m, 4H). Example 29 Preparation of Compound 29 Provided by the Invention

 The preparation process is as follows:

将 2.3 g约为 15 mmol的化合物 S₆₇, 2.27 g约为 15 mmol的间硝基苯曱 醛， 1.94 g约为 15 mmol的 3-氨基巴豆酸乙酯置于单颈瓶中，在氮气保护下， 加入异丙醇 50 mL, 加热至回流反应过夜， 反应完全后， 旋转蒸发除去溶剂， 残留物经柱层析分离纯化得到化合物 S₇₄ 5.7 g, 收率为 95 %。 ESI-MS: [M + H]⁺ = 400。

2.3 g of approximately 15 mmol of compound S ₆₇ , 2.27 g of approximately 15 mmol of m-nitrophenylfurfural, 1.94 g of approximately 15 mmol of ethyl 3-aminocrotonate in a single-necked flask, protected with nitrogen Next, 50 mL of isopropyl alcohol was added, and the mixture was heated to reflux overnight. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was purified by column chromatography to yield 5.7 g of Compound S ₇₄ in a yield of 95 %. ESI-MS: [M + H] ⁺ = 400.

5.7 g of about 14.3 mmol of compound S _{74 was} dissolved in 50 mL of ethanol, and 661 mg of about 15.7 mmol of LiOH-H ₂ 0 was added at room temperature. After stirring for 1 h, the ethanol in the reaction system was removed by rotary evaporation, and water was added. The pH of the reaction mixture was adjusted to 4-5 with 2 mol/L hydrochloric acid, and the solid precipitated in the system was filtered to give the compound S ₇₅ 4.49 g, yield 91%. ESI-MS: [M + H] ⁺ = 347.

346 mg of approximately 1 mmol of compound S ₇₅ , 318 mg of approximately 1 mmol of compound S ₁₀ , 412 mg of approximately 2 mmol of DCC and 122 mg of approximately 1 mmol of DMAP in a single-necked flask, protected with nitrogen Next, add DMF lO mL and heat to 80. After the reaction was completed, the reaction was completed. After the reaction was completed, 20 mL of water was added, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The compound 29, 380 mg of the present invention was obtained by chromatography to give a yield of 59%.

 The compound 29 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 647.

IfiNMR (CDC1 ₃ , 500 MHz) δ 8.12 (1H, t, J = 2.0 Hz), 7.95 (1H, ddd, J = 1.0 _: 2.5, 8.0 Hz), 7.90 (1H, d, J = 2.5 Hz), 7.88 (1H, d, J = 9.0 Hz), 7.61 (1H, dt, J = 1.0, 7.5 Hz), 7.33 (1H, t, J = 8.0 Hz), 7.28 (1H, dd, J= 2.5, 9.0 Hz) , 5.88 (1H, s), 5.09 (1H, s), 3.98-4.12 (4H, m), 3.92-3.97 (1H, m), 3.42 (2H, , J = 7.0 Hz), 3.01-3.06 (2H, m), 2.64-2.68 (2H, m), 2.35 (6H, s), 1.90-1.93 (4H, m), 1.57-1.67 (4H, m), 1.28-1.37 (2H, m), 1.21 (3H, t, J = 7.0 Hz). Example 30 Preparation of Compound 30 Provided by the Invention

The preparation process is as follows:

0.3 mL of glacial acetic acid was added to a 15 mL aqueous ammonia solution containing 10 g of about 65 mmol of compound S ₆₇ and stirred at room temperature for 2 h, then the solid precipitated in the system was filtered to give the product S ₇₇ 1.93 g, yield 19 % ESI -MS: [M + H]+ = 155

Under nitrogen protection, a solution of 7.26 g of approximately 38 mmol of N-(2-hydroxyethyl)phthalic acid in THF was added dropwise to a solution of -10 C, containing 2.28 g of approximately 57 mmol. NaH in 15 mL of THF was added and stirred at -10 C for 30 min. Further, 15 mL of a THF solution containing 4.2 mL of about 36.2 mmol of decyl chloroacetoacetate was slowly added dropwise to the above system. After the dropwise addition, the reaction system was naturally warmed to room temperature and stirred overnight. The reaction was quenched by the addition of 4 mL of ethanol. The reaction mixture was poured into 100 mL of 1 mol/L of glacial hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The organic phase was combined and washed with saturated sodium hydrogen carbonate and water. , dried over anhydrous sodium sulfate, filtered and the solvent was removed by rotary evaporation, the residue was purified by column chromatography to give compound S ₇₆ 5.93 g, yield 54% ESI-MS: [M + H] + = 306

Under nitrogen protection, 3.81 g of approximately 12.5 mmol of compound S ₇₇ 1.76 g is approximately 12.5 Ethyl o-chlorobenzaldehyde, 1.93 g of about 12.5 mmol of compound S _{76 was} placed in a single-necked flask, 50 mL of isopropanol was added, and heated to reflux. The reaction was completed overnight. After completion of the reaction, the solvent was removed by rotary evaporation. Separation and purification by column chromatography gave Compound S ₇₈ 3.53 g, yield 50%. ESI-MS: [M + H] ⁺ = 564.

Weigh 210 mg of about 0.37 mmol of compound S ₇₈ dissolved in 5 mL of ethanol, add 17 mg of about 0.51 mmol of LiOH aqueous solution at room temperature, stir for 2 h, then remove the ethanol in the reaction system by rotary evaporation. Diluted with water, adjusted to pH 4-5 with 2 mol/L hydrochloric acid, and the solid precipitated from the system was filtered to give Compound S ₇₉ 130 mg. ESI-MS: [M + H] ⁺ = 511.

Under nitrogen protection, weigh 130 mg of about 0.255 mmol of compound S ₇₉ , 81 mg of about 0.255 mmol of compound S _{1 ()} , 105 mg of about 0.51 mmol of DCC and 31 mg of about 0.255 mmol of DMAP. In a flask, add 5 mL of DMF and heat to 80. After the reaction was completed, the reaction was completed, the mixture was diluted with water (20 mL), and the aqueous layer was evaporated, evaporated, evaporated, evaporated, evaporated. Separation and purification by column chromatography gave Compound S ₈₀ 60 mg. ESI-MS: [M + H] ⁺ = 811.

60 mg of about 0.074 mmol of the compound S _{80 was} dissolved in 0.77 mL of a guanamine aqueous solution containing 8.94 mmol of decylamine and a concentration of 40%, and stirred at room temperature overnight. The mixture is diluted with water, and the aqueous phase is extracted with ethyl acetate. The organic phase is combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to remove solvent. 30, 39 mg, yield 78%.

 The compound 30 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 681.

IfiNMR (CD ₃ OD, 500 MHz) δ 8.30 (1H, d, J = 9.5 Hz), 7.79 (1H, d, J = 2.5 Hz), 7.53 (1H, dd, J= 2.5, 9.0 Hz), 7.37 ( 1H, dd, J= 2.0, 8.0 Hz), 7.16 (1H, dd, J = 1.0, 8.0Hz), 7.13 (1H, td, / = 1.0, 7.5 Hz), 7.00 (1H, td, J = 2.0, 7.5 Hz), 5.35 (1H, s), 4.74 (1H, d, / = 13.5 Hz), 4.64 (1H, d, / = 13.5 Hz), 3.97-4.08 (2H, m), 3.77-3.82 (4H, m), 3.57 (3H, s), 3.22 (2H, t, J = 5.0 Hz), 2.98-3.03 (2H, m), 2.65-2.70 (2H, m), 2.36 (3H, s), 1.92-1.98 (4H, m), 1.72-1.79 (2H, m), 1.60-1.66 (2H, m), 1.22-1.33 (2H, m ).

Example 31 Preparation of a Compound Provided by the Invention 31

 The preparation process is as follows:

 S82 S10

Under nitrogen protection, 2.3 g of approximately 15 mmol of compound S ₆₇ , 2.27 g of approximately 15 mmol of m-nitrophenylfurfural, 2.15 g of approximately 15 mmol of compound S _l is isopropyl 3-aminocrotonate The mixture was placed in a single-necked flask, 50 mL of isopropanol was added, and the mixture was heated to reflux. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was purified by column chromatography to yield compound S ₈₁ 5.9 g, yield 95 %. . ESI-MS: [M + H] ⁺ = 414.

Weigh 6.05 g of about 14.6 mmol of compound S ₈₁ dissolved in 50 mL of ethanol, add 674 mg of about 16 mmol of LiOH aqueous solution at room temperature, stir for 1 h, then remove the ethanol in the reaction system and add it. The mixture was diluted with water, and the pH of the reaction mixture was adjusted to 4-5 with 2 mol/L hydrochloric acid. The solid precipitated from the system was filtered to give the compound S ₈₂ 5.1 g, yield 97%. ESI-MS: [M + H] ⁺ = 361.

Under nitrogen protection, weigh 360 mg of about 1 mmol of compound S ₈₂ , 318 mg, about 1 mmol of Sio, 412 mg of about 2 mmol of DCC and 122 mg of about 1 mmol of DMAP. In a single-necked flask, add 10 mL of DMF and heat to 80. C reaction overnight, complete reaction After adding 20 mL of water, the aqueous phase is extracted with ethyl acetate. The organic phase is combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The compound provided by the invention 31, 430 mg, yielded 65%.

 The compound 31 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 661.

IfiNMR (CDC1 ₃ , 500 MHz) δ 8.13 (IH, t, J = 2.0 Hz), 7.95 (IH, ddd, J = 1.0, 2.0, 8.5 Hz), 7.90 (IH, d, J = 2.0 Hz), 7.87 (IH, d, J = 9.5 Hz), 7.62 (IH, dt, J = 1.0, 7.0 Hz), 7.32 (IH, t, J= 8.0 Hz), 7.28 (IH, dd, J= 2.0, 9.0 Hz) , 5.89 (IH, s), 5.07 (IH, s), 4.92-4.97 (IH, m), 3.97-4.10 (2H, m), 3.90-3.98 (IH, m), 3.42 (2H, t, J = 7.0 Hz), 3.01-3.06 (2H, m), 2.64-2.68 (2H, m), 2.35 (6H, s), 1.90-1.93 (4H, m), 1.58-1.65 (4H, m), 1.30-1.36 (2H, m), 1.23 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 6.5 Hz).

Example 32 Preparation of Compounds Provided by the Invention 32

 The preparation process is as follows:

Under nitrogen protection, weigh 542 mg of approximately 3.5 mmol of compound S ₆₇ , 518 mg of approximately 3.5 mmol of benzo[c][l,2,5]oxadiazol-4-furfural, 402 mg approximately 3.5 mmol of 3-aminocrotonate was placed in a single-necked flask, 10 mL of isopropanol was added, heated to reflux, and allowed to react overnight. After completion of the reaction, the solvent was removed by rotary evaporation, and the residue was purified by column chromatography. S ₈₃ 1.3 g, The yield was 97%. ESI-MS: [M + H]+ = 383.

1.3 g of about 3.4 mmol of compound S _{83 was} dissolved in 15 mL of ethanol, and added to an aqueous solution containing 157 mg of about 3.7 mmol of LiOH at room temperature. After stirring for 1 h, the ethanol in the reaction system was distilled off and water was added. After dilution, the pH of the reaction mixture was adjusted to 4-5 with 2 mol/L hydrochloric acid, and the solid precipitated from the system was filtered to give Compound S ₈₄ 0.99 g, yield 88%. ESI-MS: [M + H] ⁺ = 330.

Under nitrogen, 329 mg of approximately 1 mmol of compound S ₈₄ , 3 18 mg of approximately 1 mmol of compound S _{1 ()} , 412 mg of approximately 2 mmol of DCC and 122 mg of approximately 1 mmol of DMAP were placed In a single-necked flask, add DMF lO mL and heat to 80. After the reaction was completed, the reaction was completed. After the reaction was completed, 20 mL of water was added, and the aqueous phase was extracted with ethyl acetate. The organic phase was combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. Chromatographic separation and purification gave the compound 32, 354 mg of the present invention in a yield of 56%.

 The compound 32 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 630.

ifiNMR (CDC1 ₃ , 500 MHz) δ 7.92 (1H, s), 7.89 (1H, ά, J = 9.0 Hz), 7.55-7.58 (1H, m), 7.29 (1H, dd, J = 2.5, 9.0 Hz) , 7.23-7.25 (2H, m), 6.01 (1H, s), 5.51 (1H, s), 3.94-4.03 (3H, m), 3.56 (3H, s), 3.40-3.45 (2H, m), 3.03 -3.07 (2H, m), 2.63-2.68 (2H, m), 2.33 (6H, s), 1.90- 1.93 (4H, m), 1.47-1.63 (4H, m), 1.23-1.28 (2H, m) .

Example 33 Preparation of the Compound Provided by the Invention 33

The preparation process is as follows:

Accurately weigh 500 mg of about 2.4 mmol of compound S ₁₃ in acetonitrile, add 250 mg of about 2.5 mmol of 4-hydroxypiperidine, 40 mg of about 0.24 mmol of catalytic amount of sodium iodide and 1.0 g of about 7.5 mmol of potassium carbonate powder, the reaction system was transferred to an 80 °C oil bath for reflux, TLC tracking and monitoring, after 14 h, the reaction was complete, the reaction was stopped, cooled, filtered, and the residue was filtered, and the filtrate was evaporated to dryness. language purified with ethyl acetate and triethylamine in a volume ratio of 100: 0-100: 1 gradient, to give a colorless oily compound S ₈₅ 550 mg, 81.2% yield. ESI-MS: [M + H] ⁺ = 279.1

Dissolving 0.7 g of about 2.1 mmol of 5-(oxacarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3-in acid in DMF 0.7 g of about 4.3 mmol of DCC, 40 mg of about 0.32 mmol of catalytic DMAP and 0.55 g of about 2.0 mmol of compound S _{85 were added} , and the reaction system was transferred to 80 ° C under nitrogen. The reaction was started in the bath, monitored by TLC, and the reaction was completed after 15 h. The reaction was stopped, cooled, filtered, and the residue was filtered. The filtrate was diluted with water. The organic layer was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. The mixture was concentrated and purified by silica gel column chromatography, eluting with an elution system containing 1% triethylamine. The volume ratio of petroleum ether to ethyl acetate in the eluent was 1: 1 - 1 : 1 , The color oily product, i.e., the compound 33, 310 mg provided in the present invention, yielded 26.3%.

 The compound 33 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 593.2; [M - H]" = 591.2.

ifiNMR (500 MHz, CDC1 ₃ ) δ 1.67 (4Η, m), 2.27 (3Η, s), 2.34 (3H, s), 2.61 (4H, m), 3.03 (3H, s), 3.08 (3H, s), 3.47 (2H, s), 3.65 (3H, s), 4.78 (1H, m), 5.08 (1H, s), 5.88 ( 1H, s), 7.05 (2H, dd, J = 2.0 Hz, 6.6 Hz), 7.27 (2H, d, J = 8.5 Hz), 7.36 (lH,t, / = 3.0 Hz), 7.63 (1H, dt, J = 1.3 Hz, 7.7 Hz), 7.98 (1H, ddd, J = 1.0 Hz, 2.2 Hz, 3.3 Hz), 8.09 (lH, t, J = 2.0 Hz). Example 34 Preparation of Compound 34 Provided by the Invention

 The preparation process is as follows:

 S88

1.5 g of about 7.04 mmol of compound S _{13 was} weighed and dissolved in acetonitrile, 1.0 g of about 14.08 mmol of propanolamine, 104 mg of about 0.69 mmol of catalytic sodium iodide and 3.0 g of about 21.73 mmol were added. Potassium carbonate powder, the reaction system was transferred to an 80 °C oil bath for reflux, TLC tracking and monitoring, after 15 h, the reaction was completed, the reaction was stopped, cooled, filtered, and the residue was filtered, and the filtrate was evaporated to dryness, and purified by silica gel column chromatography. Using a gradient of ethyl acetate and triethylamine in a ratio of 100:0 to 100:1 to give a colorless oily compound S ₈₆ 720 mg, yield of 40.6 %. ESI-MS: [M + H]+ = 253.1.

720 mg of about 2.6 mmol of S _{86 was} dissolved in dichloromethane, and an ice bath was added. 2.8 g of about 13 mmol of BOC ₂ 0 was slowly added. The system was slowly warmed to room temperature for reaction, TLC was monitored, and the reaction was carried out for 12 h. Completely, stop the reaction, distill off the organic solvent, and purify by silica gel column chromatography, eluting with an elution system containing 1% triethylamine. The volume ratio of petroleum ether to ethyl acetate in the eluent is 4: 1- 0: 1 , a colorless oily compound S ₈₇ 1.0 g was obtained, yield 99.8 %. ESI-MS: [M + Na] ⁺ = 375.K 1.0 g of about 3.0 mmol of 5-(oxacarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3-acid is dissolved in DMF , adding 1.0 g of DCC of about 6.1 mmol, 50 mg is about

0.4 mmol of DMAP and 1.0 g of about 2.8 mmol of Compound S _87, evacuated under nitrogen, to 80 ° C into the reaction system in an oil bath, the reaction was started, tracking and monitoring TLC until complete reaction after 14 h, stopped The reaction mixture is cooled, filtered, and the residue is filtered. The filtrate is diluted with water. The organic layer is extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel column chromatography with petroleum ether and acetic acid The ethyl ester was eluted in a gradient of 2: 1-1:1 to give a colorless oily compound S ₈₈ 1.6 g with a yield of 86.1 %. ESI-MS: [M - H]" = 665.2.

Weigh 1.6 g of about 2.4 mmol of compound S ₈₈ dissolved in 20 mL of dichlorosilane, ice bath, slowly add 4.0 mL of about 12.2 mmol of trifluoroacetic acid, slowly increase the system to room temperature, TLC tracking monitoring, 12 After h, the reaction was stopped, and the mixture was diluted with saturated sodium bicarbonate solution in an ice bath. The pH of the aqueous layer was more than 7. The organic layer was extracted, washed with saturated NaCl, washed with water, dried over anhydrous sodium sulfate twice, filtered and filtered. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography eluting with eluting with 1% triethylamine. The volume ratio of petroleum ether to ethyl acetate in the eluent was 1:1-0:

1. A yellow oily product was obtained, i.e., the compound provided in the present invention was 34, 1.2 g, and the yield was 92.3%.

 The compound 34 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 567.2; [M - H]" = 565.2.

ifiNMR (500 MHz, CDC1 ₃ ) δ 1.58 (1Η, s), 1.79 (2H, m), 2.03 (3H, s), 2.34 (3H, s), 2.61 (2H, m), 3.02 (3H, s) , 3.11 (3H, S), 3.63 (3H, s), 3.72 (2H, s), 4.15 (2H, m), 5.07 (1H, s), 6.30 (1H, s), 7.02 (2H, dd, J = 2.0, 6.6), 7.25 (2H, dd, J= 2.Q. 6.6), 7.35 (lH,t, J = 8.0), 7.63 (1H, dt, J = 1.3, 7.7), 7.97 (1H, ddd , J = 1.0, 2.3, 8.0), 8.07 (1H, d, /= 2.0 Example 35 Preparation of Compound 35 Provided by the Invention

The preparation process is as follows:

在 -5 °C下， 将含有 77 mg约为 0.58 mmol的邻苯二曱醛和 228 mg约为 0.5 mmol的叔丁氧羰基曱基三苯基溴化磷的 DCM溶液 8 mL緩慢滴加到含有 100 mg约为 2.5 mmol氢氧化钠的 2 mL水溶液中。 搅拌 1 h后， 分液， 分出 有机层， 收集水相用 CH₂C1₂萃取， 合并有机相， 经饱和食盐水洗涤， 无水硫 酸钠干燥， 过滤， 旋转蒸发除去溶剂， 残留物经柱层析分离纯化得到化合物 S₈₉ 60 mg, 收率为 52 %。 ESI-MS: [M + H]+ = 233。

8 mL of DCM solution containing 77 mg of about 0.58 mmol of phthalaldehyde and 228 mg of about 0.5 mmol of t-butoxycarbonyldecyltriphenylphosphonium bromide was slowly added dropwise at -5 °C. Contains 100 mg of approximately 2.5 mmol of sodium hydroxide in 2 mL of water. After stirring for 1 h, separated, the organic layer was separated, the water was collected CH ₂ C1 _2. The combined organic phase phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and solvent was removed by rotary evaporation, the residue was purified by column Purification by chromatography gave Compound S ₈₉ 60 mg, yield 52%. ESI-MS: [M + H]+ = 233.

Under nitrogen protection, 666 mg of about 4.3 mmol of compound S ₆₇ , 1.0 g of about 4.3 mmol of compound S ₈₉ , and 496 mg of about 4.3 mmol of 3-aminocrotonate were placed in a single-necked flask. ethanol was added 20 mL, heated to reflux overnight. after completion of the reaction, the solvent was removed by rotary evaporation, the residue was purified by column chromatography to give compound S _9. 1.29 g , yield was 65%. ESI-MS: [M + H] ⁺ = 467.

1.29 g of about 2.77 mmol of compound S _{9 will be obtained} . Dissolve in 15 mL of ethanol, add 126 mg of about 3.01 mmol of LiOH aqueous solution at room temperature, stir for 1 h, then remove the ethanol in the reaction system, add water and adjust the pH of the reaction solution with 2 mol/L hydrochloric acid. The solid which precipitated in the system was filtered to give the compound S ₉₁ 980 mg in a yield of 86%. ESI-MS: [M + H] ⁺ = 414.

Under nitrogen protection, weigh 413 mg of approximately 1 mmol of compound S ₉₁ , 318 mg of approximately 1 mmol of Sio, 412 mg of approximately 2 mmol of DCC and 122 mg of approximately 1 mmol of DMAP. In a single-necked flask, add 10 mL of DMF and heat to 80. C, reaction overnight, to be reacted After completion, 20 mL of water was added, and the aqueous phase was extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The compound provided by the present invention 35, 357 mg, yield was 50%.

 The compound 35 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 714.

_3⁄4 NMR (CDC1 ₃ , 300 MHz): 8.43 (1H, d, J = 15.9 Hz), 7.93 (1H, d, / = 2.4 Hz), 7.89 (1H, d, J = 8.7 Hz), 7.39 (2H, Ddd, J = 1.2, 3.0, 7.2 Hz), 7.28 (1H, dd, J = 2.1, 8.7 Hz), 7.22 (1H, td, J = 1.5, 7.5 Hz), 7.04 (1H, dt, J = 1.5, 7.5 Hz), 6.24 (1H, d, J= 15.6 Hz), 5.88 (1H, s), 5.32 (1H, s), 4.08-4.17 (1H, m), 3.92-4.01 (2H, m), 3.51 ( 3H, s), 3.41 (2H, t, / = 6.0 Hz), 3.01-3.08 (2H, m), 2.62-2.68 (2H, m), 2.34 (3H, s), 2.31 (3H, s), 1.88 -1.93 (4H, m), 1.51-1.60 (4H, m), 1.53 (9H, s), 1.19-1.30 (2H, m).

Example 36 Preparation of Compounds Provided by the Invention 36

The preparation process is as follows:

Accurately weigh 502 mg of approximately 2.0 mmol of compound S ₉ , ie 6,9-dichloro-1,2,3,4-tetrahydroacridine and 286 mg of approximately 2.0 mmol of 4-(2-aminoethyl) ) cyclohexyl dissolved in 3 mL of n-pentanol was stirred at reflux, the reaction 18 h, after cooled to room temperature, diluted with saturated NaHCO ₃ solution, extracted three times with dichloro Yue alkoxy, extracts were combined, dried over anhydrous NaS0 _4, The mixture was concentrated and purified by silica gel column eluting with 1% triethylamine. The volume ratio of petroleum ether to ethyl acetate in the eluent was 2:1, and the compound S ₉₂ 553 mg was obtained. 77%.

Weigh 564 mg of approximately 1.7 mmol of 5-(oxacarbonyl)-2,6-diamidino-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid, dissolved In a mixed solution of 4 mL of dichlorodecane and 1 mL of DMF, Stir in an ice bath, slowly add 276 mg of about 2.3 mmol of thionyl chloride, react for 2 h in an ice bath, then add 4 mL of chloroformane containing 553 mg of about 1.5 mmol of compound S ₉₂ to continue the ice. Bath reaction for 3 h. Then, the pH of the reaction solution was adjusted to about 9 by adding saturated NaHC0 ₃ , extracted twice with dichloromethane, and the dichloromethane extract was combined, dried over anhydrous NaSO ₄ , concentrated and purified by silica gel column, using 1% The elution system of ethylamine was eluted, and the volume ratio of petroleum ether to ethyl acetate in the eluate was 3:1, and the compound 36, 53 mg of the present invention was obtained in a yield of 5%.

 The compound 36 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 673.2; [M - H] - = 671 ·2.

IfiNMR (500 MHz, CDC1 ₃ ) δ 8.11 (t, J = 2.0 Hz, IH), 7.98-8.00 (m, IH), 7.89-7.93 (m, 2H), 7.61 (dt, J = 1.3, 7.7 Hz, IH), 7.36 (t, J = 7.9 Hz, IH), 7.28-7.29 (m, IH), 6.01 (s, IH), 5.05 (s, IH), 4.58-4.64 (m, IH), 4.31 (s , IH), 3.63 (s, 3H), 3.52-3.55 (m, 2H), 3.05 (bs, 2H), 2.65 (bs, 2H), 2.36 (s, 3H), 2.35 (s, 3H), 1.91- 1.92 (m, 6H), 1.70-1.79 (m, 6H), 1.55-1.60 (m, 3H).

Example 37 Preparation of Compounds Provided by the Invention 37

 The preparation process is as follows:

准确称取 3.3 g 约为 10.9 mmol的化合物 S₃。， 832 mg 约为 7.2 mmol的 4-哌 曱醇， 543 mg 约为 3.6 mmol的換化钠和 998 mg 约为 7.2 mmol的碳 酸钾分散于 10 mL丙酮中， 于室温下搅拌反应 18 h。 抽滤， 弃滤渣， 收集滤 液干燥、 浓缩、 硅胶柱分离纯化， 采用含有 1 %三乙胺的洗脱体系进行洗脱， 洗脱液中石油醚与乙酸乙酯的体积比为 1:2,得到化合物 S₉₃ 1.7 g, 收率为 68 %。 称取 664 mg 约为 2.0 mmol 的 5- (曱氧羰基) -2,6-二曱基 -4-(3-硝基苯 基)— 1 ,4-二氢吡啶 -3-羧酸， 溶于 4 mL二氯曱烷和 1 mL DMF的混合溶液中， 置于冰浴中搅拌，緩慢滴加 280 mg 约为 2.4 mmol的二氯亚砜，冰浴反应 2 h。 然后加入含有 678 mg 约为 2.0 mmol化合物 S₉₆的二氯曱烷 2 mL, 继续冰浴 反应 3 h。 再加入饱和 NaHC0₃调节反应液 pH值至 8左右， 二氯曱烷萃取 2 次， 合并有机相， 无水 NaS0₄干燥、 浓缩、 硅胶柱分离纯化， 采用含有 1 % 三乙胺的洗脱体系进行洗脱， 洗脱液中石油醚与乙酸乙酯的体积比为 1: 1 , 得到本发明提供的化合物 37, 871 mg, 收率为 67 %。

Accurately weigh 3.3 g of approximately 10.9 mmol of compound S ₃ . 832 mg of about 7.2 mmol of 4-pipetanol, 543 mg of about 3.6 mmol of sodium for change and 998 mg of potassium 7.2 mmol of about 7.2 mmol were dispersed in 10 mL of acetone, and the reaction was stirred at room temperature for 18 h. After suction filtration, the filter residue was discarded, and the filtrate was collected, dried, concentrated, purified by silica gel column, eluted with an elution system containing 1% triethylamine, and the volume ratio of petroleum ether to ethyl acetate in the eluent was 1:2. Compound S ₉₃ 1.7 g, yield 68%. Weigh 664 mg of approximately 2.0 mmol of 5-(oxacarbonyl)-2,6-diamidino-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid, dissolved In a mixed solution of 4 mL of dichlorodecane and 1 mL of DMF, it was stirred in an ice bath, and 280 mg of about 2.4 mmol of thionyl chloride was slowly added dropwise, and the mixture was reacted for 2 h in an ice bath. Then 2 mL of chloranidine containing 678 mg of about 2.0 mmol of compound S _{96 was added and} the reaction was continued for 3 h. Then add saturated NaHC0 _{3 to} adjust the pH of the reaction solution to about 8, dichloromethane extraction twice, combine the organic phase, dry NaS0 ₄ dry, concentrate, silica gel column separation and purification, using an elution system containing 1% triethylamine Elution was carried out, and the volume ratio of petroleum ether to ethyl acetate in the eluate was 1:1, and the compound 37, 871 mg of the present invention was obtained in a yield of 67%.

 The compound 37 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 654.2; [M - H]" = 652.2.

ifiNMR (500 MHz, CDC1 ₃ ) δ 8.14 (t, J = 2.0 Hz, 1H), 7.99-8.03 (m, 3H),

7.64 (dt, J= 1.3, 7.7 Hz, 1H), 7.56 (t, J= 7.7 Hz, 1H), 7.37 (t, J= 7.9 Hz, 1H), 7.32-7.35 (m, 1H), 6.02 (s , 1H), 5.37 (bs, 1H), 5.11 (s, 1H), 3.87-4.02 (m, 2H),

3.65 (s, 3H), 3.58 (bs, 2H), 3.09-3.11 (m, 2H), 2.84-2.90 (m, 2H), 2.72-2.74 (m, 2H), 2.57 (t, J = 5.7 Hz, 2H), 2.40 (s, 3H), 2.36 (s, 3H), 1.97-2.06 (m, 3H), 1.90-1.92 (m, 4H), 1.66-1.70 (m, 4H).

Example 38 Preparation of Compounds Provided by the Invention 38

 The preparation process is as follows:

在 0。C下， 称取 21 g约为 110 mmol的 TsCl分批加到 60 mL含有 8.6 g 约为 100 mmol丁炔二醇和 16 mL约为 200 mmol吡啶的 DCM中， 室温下搅 拌 2h。加入 50 mL水， 水相用 DCM萃取， 合并有机相， 经饱和食盐水洗涤， 无水硫酸钠干燥， 过滤， 旋转蒸发除去溶剂， 残留物经柱层析分离纯化得到 化合物 S₉₄ 1.93 g, 收率为 8 %。 ESI-MS: [M + H]+ = 241。

At 0. C, weigh 21 g of about 110 mmol of TsCl in batches and add 60 mL to contain 8.6 g. Approximately 100 mmol of butynediol and 16 mL of DCM of approximately 200 mmol of pyridine were stirred at room temperature for 2 h. After adding 50 mL of water, the aqueous phase is extracted with DCM, and the organic layer is combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to remove the solvent. The residue was purified by column chromatography to give compound S ₉₄ 1.93 g. The rate is 8%. ESI-MS: [M + H]+ = 241.

1.93 g of about 8 mmol of compound S _{94 was} dissolved in 15 mL of aqueous ammonia and stirred at room temperature overnight. The solvent was removed by rotary evaporation to give the compound S ₉₅ 1.9 g.

Will contain 1.2 g of about 5 mmol of compound S ₉ , ie 6,9-dichloro-1,2,3,4-tetrahydroacridine, 1.9 g of about 8 mmol of compound S ₉₅ and 2.1 mL of about 15 60 mL of n-pentanol solution of mmol TEA was heated to 160-165 °C, allowed to react under reflux overnight, cooled to room temperature, and most of the solvent was removed by rotary evaporation. The residue was neutralized to a weak base with saturated sodium hydrogen carbonate solution. Sex. The organic phase was combined extracts were alkoxy extracted with dichloro Yue, washed with water, brine, dried over anhydrous sodium sulfate, filtered, concentrated and the resulting residue was purified by column chromatography on silica gel column chromatography to give compounds S ₉₆ 133 mg. ESI-MS: [M + H] ⁺ = 301.

Under nitrogen protection, weigh 120 mg of about 0.4 mmol of compound S ₉₆ , 133 mg of about 0.4 mmol of 5-(oxacarbonyl)-2,6-dimercapto-4-(3-nitrophenyl) -1,4-Dihydropyridine-3-carboxylic acid, 165 mg, 0.8 mmol of DCC and 49 mg of 0.4 mmol of DMAP were placed in a single-necked flask, and 5 mL of DMF was added and heated to 80. After the reaction was completed, the reaction was completed. After the reaction was completed, 10 mL of water was added, and the aqueous phase was extracted with ethyl acetate. The organic phase was combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. Chromatographic separation and purification gave the compound 38, 60 mg of the present invention in a yield of 24%.

 The compound 38 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 615.

_3⁄4 NMR (CDC1 ₃ , 500 MHz) δ 8.14 (1H, t, J = 2.0 Hz), 7.99 (1H, d, J = 2.0 Hz), 7.96 (1H, ddd, / = 1.0, 2.5, 8.5 Hz), 7.90 (1H, d, J = 8.5 Hz), 7.59 (1H, dt, J = 1.5, 8.0 Hz), 7.31-7.35 (2H, m), 6.09 (1H, s), 5.07 (1H, s), 4.66 (1H, dt, J = 2.0, 16 Hz), 4.55 (1H, dt, J= 2.0, 16 Hz), 4.23 (2H, s), 3.64 (3H, s), 3.10 (2H, t, / = 5.5 Hz), 2.77 (2H, t, J = 5.5 Hz), 2.39 (3H, s), 2.25 (3H, s), 1.88-1.94 (4H, m). Example 39 Preparation of Compound 39 Provided by the Invention

 The preparation process is as follows:

Take S ₉ 1.0 g, about 4.0 mmol and 2-mercapto-6-amino-2-heptanol 693 mg, about 4.8 mmol in n-pentanol and reflux for 18 h, after cooling to room temperature, column chromatography, elution was performed with elution systems containing 1% triethylamine, petroleum ether: ethyl acetate = 5: 1 to 2: 1, to obtain a solid S ₉₇ 510 mg, 35% yield.

Accurately weigh out 5-(oxacarbonyl)-2,6-diamidino-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 332 mg, about 1 mmol, Dissolved in 10 mL DMF, stirred and dissolved, added S ₉₇ 360 mg, about 1 mmol, DCC 412 mg, about 2 mmol, DMAP 122 mg, about 1 mmol, and reacted at 80 °C overnight. After cooling, 20 mL of water was added, and ethyl acetate was extracted 20 mL x 3 times, dried, column chromatography, dichloromethane: decyl alcohol = 100:1 to 70:1 to give solid 203 mg, yield 30%.

 The compound 39 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 675.2; [MH]" = 673.2.

ifiNMR (500 MHz, CDC1 ₃ ) δ 0.96 (3H, s), 1.32 (6H, m), 1.67 (7H, m), 1.90 (4H, br, s), 2.27 (3H, d, J = 7.0 Hz) , 2.33 (3H, d, J = 1.5 Hz), 2.64 (2H, d, J = 5 Hz), 3.05 (2H, br, s), 3.61 (3H, ά, J = 9 Hz), 3.70 (2H, Br, s), 5.02 (1H, ά, J = 3 Hz), 7.27 (2H, m), 7.57 (IH, m), 7.79 (IH, d, J= 9.5 Hz), 7.93 (2H, m), 8.09 (IH, t, /=2Hz).

Example 40 Preparation 40

 The preparation process is as follows:

Accurately weigh 408 mg of amlodipine, about 1 mmol, S ₉ 251 mg, about 1 mmol, 1.0 g of phenol, about 10.6 mmol, Nal 52 mg, about 0.35 mmol, heated to 180 °C for 1.5 h. . Cooling to room temperature, column chromatography, dichloromethane: decyl alcohol = 120:1 - 60:1 afforded product 180 mg, yield 28.8%.

 The compound 40 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 624.1; [M - H] - = 622.1.

ifiNMR (500 MHz, CDC1 ₃ ) δ 1.18 (3H, t, J=7 Hz), 1.91 (4H, t, J= 2.5 Hz), 2.31 (3H, s), 2.68 (2H, s), 3.08 (2H , s), 3.61 (3H, s), 3.86 (2H, d, J= 5.5 Hz), 3.94 (2H, d, J= 5.5 Hz), 4.05 (2H, m), 4.79 (2H, t, J= 15 Hz), 5.42 (IH, s), 7.03 (2H, m), 7.11 (IH, m), 7.22 (IH, m), 7.33 (IH, m), 7.37 (IH, m), 7.87 (IH, ά, J = 2 Hz), 8.03 (IH, d, J = 9Hz).

Example 41 Preparation of Compounds Provided by the Invention 41

The preparation process is as follows:

取 S₉1.26 g, 约为 5 mmol和丙醇胺 1.88 g, 约为 25 mmol于 15 mL正戊 醇中搅拌回流反应 23h, 降至室温后， 柱层析， 二氯曱烷： 曱醇 =40:1~20:1, 得固体 S₉₈1.15 g, 收率为 79%。

Take S ₉ 1.26 g, about 5 mmol and 1.85 g of propanolamine, about 25 mmol in 15 mL of n-pentanol, stir and reflux for 23 h, after cooling to room temperature, column chromatography, dichlorodecane: decyl alcohol = 40:1~20:1, the solid S ₉₈ 1.15 g, the yield was 79%.

Accurately weigh 1.33 g of carbon tetrabromide, about 4 mmol, S ₉₈ 580 mg, about 2.0 mmol dissolved in 15 mL of dichloromethane, and add 1.05 g of triphenylphosphine at 0 ° C, about 4 mmol. The reaction was stirred at room temperature for 18 h. 15 mL of water, 15 mL x 3 times of dichloromethane extraction, drying, column chromatography, dichloromethane: decyl alcohol = 100:1 to 20:1, yielding S ₉₉ 827 mg, yield 90%.

Accurately weigh amlodipine 827 mg, about 2.35 mmol, S ₉₉ 479 mg, about 1.17 mmol, dissolved in 15 mL of acetonitrile, and force K ₂ C0 ₃ 484 mg, about 3.51 mmol, and reflux overnight. Cooling to room temperature, filtration, column chromatography, methylene chloride: decyl alcohol = 100:1 to 60:1, yielded product 210mg, yield 26%.

 The compound 41 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 681.2; [M - H] - = 679.2.

ifiNMR (500 MHz, CDC1 ₃ ) δ 1.17 (3H, t, /= 7.5 Hz), 1.88 (4H, m), 2.31 (3H, s), 2.68 (2H, br, s), 2.88 (2H, m) , 2.91 (2H, m); 3.04 (2H, br, s), 3.61 (3H, s), 3.63 (2H, m), 3.69 (2H, m), 4.04 (2H, m), 4.74 (2H, m ), 5.40 (IH, s), 7.03 (IH, t, J= 7.5 Hz), 7.08 (IH, t, J= 7.5 Hz), 7.23 (3H, m), 7.34 (IH, d, J= 7.5 Hz) ), 7.93 (2H, d, /=9.5 Hz).

Example 42 Preparation of Compound 42 Provided by the Invention The preparation process is as follows:

Accurately weigh 1.33 g of carbon tetrabromide, about 4 mmol, S ₁₀ 552 mg, about 2.0 mmol dissolved in 15 mL of dichloromethane, and add 1.05 g of triphenylphosphine at 0 °C, about 4 mmol. The reaction was stirred at room temperature for 18 h. Was added 15 mL of water, extracted with dichloro alkoxy Yue 15 mL x 3, dried, column chromatography, dichloro-alkoxy Yue: Yue alcohol = 100: 1 to 20: 1, to obtain S _3. 630 mg, yield 93.2%.

Accurately weigh amlodipine 408 mg, about 1 mmol, and S ₃ . 630 mg, approximately 2 mmol, dissolved in 10 mL of acetonitrile, added to K ₂ C0 ₃ 405 mg, approximately 3 mmol, refluxed overnight. Cool to room temperature, filter, column chromatography, dichloromethane: decyl alcohol = 100:1 to 40:1 to give product 280 mg, yield 42%.

 The compound 42 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 667.1; [M - H] - = 665.2.

ifiNMR (500 MHz, CDC1 ₃ ) δ 1.16 (3H, t, / = 7.5 Hz), 1.90 (4H, m), 2.31 (3H, s), 2.72 (2H, br, s), 2.93 (4H, m) , 3.02 (2H, m); 3.55 (2H, m), 3.61 (3H, s), 3.70 (2H, m), 4.04 (2H, m), 4.75 (2H, m), 5.41 (IH, s), 7.01 (IH, m), 7.08 (IH, m), 7.11 (IH, m), 7.23 (IH, m), 7.27 (IH, m), 7.35 (IH, m), 7.92 (IH, s), 7.94 (IH, d, J = 9.5 Hz).

Example 43 Preparation of the Compound Provided by the Invention 43

 The preparation process is as follows:

准确称取 2,3,5,6-四曱基吡嗪 4 g, 约为 29 mmol, NBS 5.36 g, 约为 30.2 mmol, 过氧化苯曱酰 12 mg, 约为 0.05 mmol溶于 20 m四氯化碳中， 搅拌回 流反应 10h。冷却至室温，柱层析，石油醚： 乙酸乙酯 = 20: 1~10: 1 ,得到 2- (溴 曱基) -3,5,6-三曱基吡嗪 5.3 g, 收率为 85 %

Accurately weigh 2 g of 2,3,5,6-tetradecylpyrazine, about 29 mmol, NBS 5.36 g, about 30.2 mmol, benzoyl peroxide 12 mg, about 0.05 mmol dissolved in 20 m four In the carbon chloride, the mixture was stirred and refluxed for 10 hours. Cool to room temperature, column chromatography, petroleum ether: ethyl acetate = 20: 1 to 10: 1 to give 2-(bromomethyl) -3,5,6-tridecylpyrazine 5.3 g, yield 85 %

Accurately weigh amlodipine 408 mg, about 1 mmol, 2-(bromoindolyl)-3,5,6-trimercaptopyrazine 321 mg, about 1.5 mmol, dissolved in 10 mL of acetonitrile, added to K ₂ C0 ₃ 405 mg, ca. 3 mmol, refluxed overnight. Cool to room temperature, filter, column chromatography, dichloromethane: decyl alcohol = 100: 1~50: 1 , product 283 mg, yield 56%

 The compound 43 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 677.2; [M - H]" = 675.3

ifiNMR (500 MHz, CDC1 ₃ ) δ 1.18 (3Η, t, J= 7.0 Hz), 2.27 (3H, s), 2.39 (6H _: s), 2.47 (12H, s), 2.82 (2H, t, J = 5 Hz), 3.63 (3H, s), 3.75 (2H, m), 3.88 (4H, s), 4.05 (2H, m), 4.60 (2H, m), 5.41 (1H, s), 7.01 (1H, d, J = 6 Hz), 7.12 (1H, t, J = 7.5 Hz), 7.22 (1H, d, J = 8 Hz), 7.38 (1H, d, J = 6 Hz), 7.55 (1H, s) .

Example 44 Preparation of Compounds Provided by the Invention 44

The preparation process is as follows:

Accurately weigh 2-(bromopurinyl)-3,5,6-trimercaptopyrazine 214 mg, about 1 mmol, 4-hydroxypiperidine 101 mg, about 1 mmol, dissolved in 10 mL of acetonitrile. K ₂ C0 ₃ 405 mg, approximately 3 mmol, was added and refluxed overnight. After cooling to room temperature, the solvent acetonitrile was evaporated under reduced pressure, diluted with 15 mL of water, and 15 mL x 3 times of dichloromethane was evaporated, and then dichloromethane was evaporated under reduced pressure to give crude product ₍₁ ). 186 mg, yield 79%

Accurately weigh out 258 mg of 5-(曱oxycarbonyl)-2,6-diamidino-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid, about 0.78 mmol, Dissolve in 10 mL DMF, stir to dissolve, add S ₁₀ o 183 mg, It is about 0.78 mmol, DCC 321 mg, about 1.56 mmol, DMAP 95 mg, about 0.78 mmol, and reacts overnight at 80 °C. After cooling, 20 mL of water was added, and 20 mL x 3 times of ethyl acetate was extracted, dried, and then purified by column chromatography, methylene chloride: decyl alcohol = 150:1 to 50:1 to give solid 269 mg, yield 63%.

 The compound 44 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 550.2; [M - Η]- = 548·2.

ifiNMR (300 MHz, CDC1 ₃ ) δ 1.69 (4H, m), 2.26 (4H, m), 2.35 (6H, s), 2.48 (6H, s), 2.56 (3H, s), 3.56 (2H, s) , 3.65 (3H, s), 4.75 (1H, t, J= 7 Hz), 5.08 (1H, s) 5.76 (1H, s), 7.37 (1H, t, J= 13 Hz), 7.63 (1H, d , J = 12.5 Hz), 8.00 (1H, d, J = 14 Hz), 8.10 (1H, d, «7= 2.5 Hz).

EXAMPLE 45 Preparation of Compounds Provided by the Invention 45

The preparation process is as follows:

Accurately weigh 2-(bromoindolyl)-3,5,6-trimercaptopyrazine 214 mg, about 1 mmol, 4-hydroxyethylpiperidine 129 mg, about 1 mmol, dissolved in 10 mL acetonitrile Medium, K ₂ C0 ₃ 405 mg, approximately 3 mmol, refluxed overnight. Cool to room temperature, dilute the solvent acetonitrile under reduced pressure, dilute with 15 mL of water, extract 15 mL x 3 times with dichloromethane, dry, and distill off dichloromethane under reduced pressure to give crude S _{1 (1 1} 210 mg. The rate is 80%.

Accurately weigh out 5-(oxacarbonyl)-2,6-diamidino-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 332 mg, about 1 mmol, Dissolved in 10 mL DMF, stirred and dissolved, added S ₁₀₁ 210 mg, about 0.8 mmol, DCC 412 mg, about 2 mmol, DMAP 122 mg, about 1 mmol, and reacted at 80 °C overnight. After cooling, 20 mL of water was added, and 20 mL x 3 times of ethyl acetate was extracted, dried, and column chromatography, dichloromethane: decyl alcohol = 150:1 to 40:1 to give solid 375 mg, yield 65%.

The compound 45 provided by the present invention was tested and the results were as follows: ifiNMR (500 MHz, CDC1 ₃ ) δ 1.51 (7H, m), 1.98 (2H, br, s), 2.35 (3H, s) 2.37 (3H, s), 2.48 (6H, s), 2.56 (3H, s ), 2.78 (2H, br, s), 3.54 (2H, br, s), 3.65 (3H _: s), 4.07 (2H, m), 5.08 (1H, s), 5.72 (1H, s), 7.36 ( 1H, t, J = 7.5 Hz), 7.60 (1H, m) 7.99 (1H, m), 8.09 (1H, t, J = 2.5 Hz).

Example 46 Preparation of Compounds Provided by the Invention 46

准确称取 2- (溴曱基) -3,5,6-三曱基吡嗪 214 mg, 约为 1 mmol, 4-羟曱基 哌啶 115 mg, 约为 1 mmol, 溶于 10 mL乙腈中， 力口入 K₂C0₃ 405 mg, 约为 3 mmol, 回流过夜。 冷却至室温， 减压蒸除溶剂乙腈， 加 15 mL水稀释， 二 氯曱烷萃取 15 mL x 3次， 干燥， 减压蒸除二氯曱烷， 得到粗品 S₁₍)₂ 224 mg, 收率 90 %。 The preparation process is as follows:

Accurately weigh 2-(bromopurinyl)-3,5,6-trimercaptopyrazine 214 mg, about 1 mmol, 4-hydroxymercaptopiperidine 115 mg, about 1 mmol, dissolved in 10 mL acetonitrile Medium, K ₂ C0 ₃ 405 mg, approximately 3 mmol, refluxed overnight. Cool to room temperature, dilute the solvent acetonitrile under reduced pressure, add 15 mL of water, dilute chloroform to extract 15 mL x 3 times, dry, distill off dichloromethane under reduced pressure to give crude S _{1 (} ) ₂ 224 mg. The rate is 90%.

Accurately weigh out 298 mg of 5-(曱oxycarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate, about 0.9 mmol, Dissolved in 10 mL DMF, stirred and dissolved, added S ₁₀₂ 224 mg, about 0.9 mmol, DCC 371 mg, about 1.8 mmol, DMAP 110 mg, about 0.9 mmol, and reacted at 80 °C overnight. After cooling, 20 mL of water was added, and ethyl acetate was extracted 20 mL x 3 times, dried, column chromatography, dichloromethane: decyl alcohol = 150:1 to 40:1 to give solid 382 mg, yield 68%.

 The compound 46 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 564.2; [M - H]" = 562.2.

ifiNMR (300 MHz, CDC1 ₃ ) δ 1.55 (5Η, m), 2.03 (2Η, m), 2.35 (3H, s), 2.37 (3H, s), 2.48 (6H, s), 2.56 (3H, s) , 2.79 (2H, br, s), 3.58 (2H, br, s), 3.65 (3H, s), 3.87 (2H, m), 5.08 (1H, s), 5.78 (1H, s), 7.35 (1H , t, J = 13 Hz), 7.62 (1H, d, J = 12 Hz), 8.00 (1H, m), 8.08 (1H, t, J = 3 Hz). Example 47 Preparation of Compound 47 Provided by the Invention

 The preparation process is as follows:

 Accurately weigh (3,5,6-tridecylpyrazin-2-yl) decyl alcohol 25 mg, about 0.146 mmol, thionyl chloride 97 mg, about 0.822 mmol, dissolved in 3 mL of dichlorodecane Medium, stir overnight. The solvent and the remaining thionyl chloride were evaporated under reduced pressure, and 10 mL of a saturated aqueous solution of sodium hydrogencarbonate was added, and 10 mL x 3 times of dichloromethane was combined, the organic layer was combined, dried, and the solvent was evaporated under reduced pressure to give 2-(chloropurine) Base) -3,5,6-tridecylpyrazine crude 30 mg.

Accurately weigh amlodipine 67 mg, about 0.164 mmol, 2-(chloroindolyl)-3,5,6-trimethylpyrrolidazole 30 mg, about 0.164 mmol, dissolved in 10 mL of acetonitrile. K ₂ C0 ₃ 23 mg, ca. 0.164 mmol, stirred at room temperature overnight. Filtration, column chromatography, dichloromethane: decyl alcohol = 100: 1 to 50: 1 , product 20 mg, yield 15%.

 The compound 47 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 543.3.

ifiNMR (500 MHz, CDC1 ₃ ) δ 1.18 (3H, t, J = 7.5 Hz), 2.50 (12H, m), 3.41 (2H, br, s), 3.60 (3H, s), 4.00 (4H, m) , 4.80 (2H, m), 5.40 (1H, s), 7.02 (1H, m), 7.11 (1H, m), 7.22 (1H, d, J= 7 Hz), 7.42 (1H, d, J= 6 Hz), 8.20 (1H, s).

Example 48 Preparation of Compounds Provided by the Invention 48

The preparation process is as follows:

 Accurately weigh 1.88 mg of aminoethanol 1.88 mg, about 25 mmol, 11.8 g of thionyl chloride, about 0.1 mmol, dissolved in 25 mL of toluene, and stirred overnight. The solvent and the remaining thionyl chloride were evaporated under reduced pressure, and the crude material was crystallised from isopropyl alcohol.

Accurately weigh out 330 mg of 2-chloro-N-mercaptoethane hydrochloride, about 2.6 mmol, 2-(bromoindolyl)-3,5,6-trimercaptopyrazine 556 mg, about 2.6 mmol It was dissolved in 10 mL of acetonitrile, and K ₂ C0 ₃ 359 mg was added, which was about 2.6 mmol, and stirred at room temperature overnight. Filtration, column chromatography, dichloromethane: decyl alcohol = 100: 1-50: 1 , yielded product S _{1 () 3} 261 mg, yield 44.2 %.

Accurately weigh amlodipine 140 mg, about 0.344 mmol, Si ₀₃ 65 mg, about 0.286 mmol, dissolved in 5 mL acetonitrile, add K ₂ C0 ₃ 79 mg, about 0.572 mmol, Nal 21 mg, about 0.143 mmol, stirred under reflux overnight. Cool to room temperature, filter, column chromatography, dichloromethane: decyl alcohol = 80: 1 to 30: 1 to give product 20 mg, yield 12%.

 The compound 48 provided by the present invention was tested and the results were as follows:

 ESI-MS: [M + H]+ = 600.2; [M - H]" = 598.3.

ifiNMR (500 MHz, CDC1 ₃ ) δ 1.22 (4Η, m), 2.41 (6Η, s), 2.49 (3H, s), 2.55 (3H, s), 2.85 (3H, s), 3.06 (6H, m) , 3.60 (3H, s), 4.05 (4H, m), 5.41 (1H, s), 7.01 (1H, m), 7.12 (1H, m), 7.21 (1H, m), 7.41 (1H, m).

Example 49 Preparation of Compounds Provided by the Invention 49

The preparation process is as follows:

Accurately weigh 40 mg of 4-hydroxypiperidine, about 0.396 mmol, Si ₀₃ 74 mg, about 0.326 mmol, dissolved in 5 mL of acetonitrile, and weighed into K ₂ C0 ₃ 90 mg, about 0.652 mmol, Nal 24 Mg, about 0.163 mmol, stirred under reflux overnight. Cooling to room temperature, filtration, thin layer chromatography, methylene chloride: decyl alcohol = 100: 1-50:1 to give product S ₁₀₄ 658 mg, yield 5.43 %.

Accurately weigh out 5-(曱oxycarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 113 mg, about 0.34 mmol, Dissolved in 10 mL DMF, stirred and dissolved, added S _{1 (M} 83 mg, about 0.284 mmol, DCC 117 mg, about 0.568 mmol, DMAP 35 mg, about 0.284 mmol, 80 ° C overnight. Cool, add 20 mL of water, ethyl acetate extraction 20 mL x 3 times, drying, column chromatography, dichloromethane: decyl alcohol = 80:1 to 40:1 to give a solid 40 mg, yield 23%.

 The compound 49 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 607.2; [M - H]" = 605.3.

ifiNMR (500 MHz, CDC1 ₃ ) δ 1.99 (8Η, m), 2.35 (3Η, s), 2.39 (6H, s), 2.49 (3H, s), 2.53 (3H, s), 2.77 (6H, m) , 2.82 (3H, s), 3.67 (3H, s), 3.81 (1H, m), 4.87 (1H, br, s), 5.12 (1H, s), 5.70 (1H, s), 7.42 (1H, m ), 7.67 (1H, d, / = 7 Hz), 7.99 (1H, s), 8.12 (1H, t, /= 2 Hz).

Example 50 Preparation of a Compound Provided by the Invention 50

The preparation process is as follows:

 Accurately weigh 10 g of 3-chloro-4-cyanophenol, about 65 mmol, dissolved in 150 mL of anhydrous tetrahydrofuran, and add 160 mL of 1 mol/L DIB AH in cyclohexane solution at -78 °C. It was about 160 mmol, slowly added to room temperature after the addition, and stirred overnight. Cool to 0 °C, add 1 mol / L hydrochloric acid 60 mL to quench the reaction, add 180 mL of water to dilute, filter, extract 100 mL of ethyl acetate 3 times, combine the organic layer, dry, pressurize the solvent to obtain a solid 8.3 g, yield 82%.

Accurately weigh 1 g of 2-chloro-4-hydroxybenzaldehyde, about 6.4 mmol, dissolved in 1 mL of ethylene glycol, add 50 mg of p-benzoic acid, about 0.26 mmol, and stir at 100 ° C for 2 h. Cooled to room temperature, diluted with ethyl acetate 10 mL, the organic layer was washed with water, dried, the solvent was distilled off under reduced pressure to obtain a crude product S _105, quantitatively.

Accurately weigh S _{1 () 5} 2 g, about 10 mmol, S _l0 2.65 g, about 8.33 mmol, triphenylphosphine 2.88 g, about 11.0 mmol dissolved in 40% DEAD benzene solution 1.91 g, about It was 11.0 mmol and stirred at room temperature overnight. Diluted with 10 mL of water, extracted with ethyl acetate 10 mL X 3 times, drying, column chromatography, dichloro-alkoxy Yue: Yue alcohol = 100: 1 to 50: 1, to give the product S ₁₀₆ 3.78 g, yield 63%.

Accurately weigh S _{1 () 6} 500 mg, about 1 mmol, dissolved in 8 mL 1,4-dioxane, stir and dissolve, add 8 mL of 2 mol / L hydrochloric acid aqueous solution, react at 40-50 ° C for 5 h . After cooling, 20 mL of water and 20 mL of dichloromethane were added for 3 times, dried, and column chromatography, methylene chloride: decyl alcohol = 80:1 to 40:1 to give solid S ₁₀₇ 314 mg, yield 69%.

Accurately weigh S ₁₀₇ 1 g, about 2.2 mmol, 2-amino-2-butenoate 253 mg, about 2.2 mmol, acetoxyacetate 255 mg, ca. 2.2 mmol, dissolved in 10 mL isopropanol and stirred at reflux overnight. Cooling to room temperature, column chromatography, dichloromethane: decyl alcohol = 150: 1 to 60: 1 , yielding a solid, 0.97 g, yield 68%.

 The compound 50 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 652.2; [M - H] - = 650.2.

ifiNMR (400 MHz, CDC1 ₃ ) δ 1.46 (2H, m), 1.67 (2H, m), 1.83 (4H, s), 2.23 (6H, s), 2.59 (2H, s), 2.96 (2H, s) , 3.45 (2H, t, J = 6.8 Hz), 3.54 (6H, s), 3.82 (2H, t, J = 6 Hz), 5.23 (1H, s), 5.68 (1H, s), 6.57 (1H, d, J = 8.4 Hz), 6.68 (1H, d, J = 2 Hz), 7.18 (3H, m), 7.83 (2H, d, J = 9.2 Hz).

Example 51 Preparation of a Compound Provided by the Invention 51

 The preparation process is as follows:

Accurately weigh SIOS 796 mg, about 4 mmol, dissolved in 30 mL of ethanol, add Pt ₂ 0 91 mg, 0.4 mmol, 1 mol/L hydrochloric acid 0.1 mol, and hydrogenate at room temperature for 2 h. Filtration and evaporation of the filtrate under reduced pressure gave a solid residue S ₁₀₉ 860 mg. The solid residue was dissolved in P0C1 ₃ and refluxed for 3 h. Cooled to room temperature, evaporated under reduced pressure to remove excess P0C1 _3, diluted with ethyl acetate, washed with water, dried, ethyl acetate was distilled under reduced pressure to give S _u. Crude 830 mg.

Accurately weigh S _u . 740 mg, about 3.35 mmol, 1.38 g of 5-amino-1-pentanol, about 13.4 mmol, 3.5 g of phenol, Nal 132 mg, about 0.88, mixed and heated to 180 ° C for 2 h. Cool to room temperature and dilute with 10 mL of dichloromethane. Column chromatography, dichloromethane: decyl alcohol = 60: 1 to 20: 1 , 980 mg of product was obtained, yield 98%.

Accurately weigh 5-(曱oxycarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 346 mg, about 1.04 mmol, dissolved in 10 mL of DMF, stirred and dissolved, and forced into S _u . 300 mg, about 1.04 mmol, DCC 428 mg, about 2.08 mmol, DMAP 127 mg, about 1.04 mmol, 80. C reacted overnight. After cooling, 20 mL of water was added, and ethyl acetate was extracted 20 mL x 3 times, dried, and then purified by column chromatography, methylene chloride: decyl alcohol = 80:1 to 20:1 to give solid 467 mg, yield 86%.

 The compound 51 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 603.2; [M - H] - = 601 ·2.

ifiNMR (400 MHz, DMSO- ₆ ) δ 1.17 (2H, m), 1.36 (2H, m), 1.48 (2H, m), 1.68 (8H, m), 2.28 (6H, s), 2.45 (4H, m ), 2.62 (4H, m), 3.02 (2H, m), 3.55 (3H, s), 3.88 (1H, m), 3.98 (1H, m), 4.38 (1H, br, s), 4.97 (1H, s), 7.52 (1H, t, J = 8.6 Hz), 7.60 (1H, d, J = 8.6 Hz), 7.98 (2H, m), 9.08 (1H, s).

Example 52 Preparation of Compounds Provided by the Invention 52

 The preparation process is as follows:

Accurately weigh amlodipine 250 mg, about 0.63 mmol, dissolved in 10 mL of acetonitrile, stir to dissolve, add S ₁₁₂ 130 mg, and stir at about 0.76 mmol at room temperature overnight. Column chromatography, ethyl acetate: petroleum ether = 4:1 to 1:1 to give a solid, 60 mg, yield 20%.

 The compound 52 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 614.2; [M - H] - = 612.3.

ifiNMR (500 MHz, DMSO- ₆ ) δ 1.10 (6H, m), 1.26 (6H, m), 2.28 (3H, s), 2.88 (2H, br, s), 3.00 (2H, br, s), 3.46 (2H, m), 3.50 (3H, s), 3.73 (1H, m), 3.96 (2H, m), 4.51 (1H, d, /= 14.5 Hz), 4.60 (1H, d, /= 14.5 Hz) , 5.30 (1H, s), 7.02 (2H, d, J = 8 Hz), 7.11 (1H, m), 7.21 (1H, t, J = 7.5 Hz), 7.26 (1H, m), 7.34 (3H, m), 8.62 (1H, d, J = 11 Hz). Example 53 Preparation of Compound 53 Provided by the Invention

 The preparation process is as follows:

Accurately weigh 2.4 g of 3-amino-2-cyclohexenone, about 20 mmol dissolved in 2.37 g of decanoic acid ester, and react for about 28 mmol with stirring at 190 °C for 3 h. After cooling to room temperature, 6 mL of dichloromethane was added, filtered, and the filter cake was washed with 2 mL of dichloromethane and dried to give a solid S ₁₁₃ 916 mg.

Accurately weigh S ₁₁₃ 163 mg, about 1.0 mmol, 5-amino-1-pentanol 124 mg, about 1.2 mmol, 4 drops of acetic acid, dissolved in 8 mL of hydrazine, refluxed for 24 h. Concentrate, add 3 mL of decyl alcohol to dissolve, add 100 mg of sodium borohydride, about 2.6 mmol, and stir at room temperature for 24 h. Column chromatography, dichloromethane: decyl alcohol = 5:1 gave a solid S ₁₁₅ 216 mg.

Accurately weigh out 664 mg of 5-(indolylcarbonyl)-2,6-dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid, about 2 mmol, Dissolve in 10 mL DMF, stir to dissolve, add S ₁₁₅ 216 mg, about 0.86 mmol, dichlorin 238 mg, about 2 mmol, stir for 5 h under ice bath. Diluted with 20 mL of water, extracted with 20 mL of ethyl acetate (3×××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××

 The compound 53 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 565.4.

IfiNMR (400 MHz, MeOD) δ 1.29 (2H, m), 1.58 (4H, m), 1.88 (4H, m), 2.31 (3H, s), 2.34 (3H, s), 2.70 (4H, m), 3.62 (3H, s), 3.88 (IH, br, s), 4.02 (IH, m), 4.10 (IH, m), 5.06 (IH, s), 5.49 (IH, s), 6.38 (IH, d, J = 9.2 Hz), 7.46 (IH, d, J = 8 Hz), 7.59 (2H, m), 7.99 (IH, m), 8.09 (IH, s). Example 54 Preparation of Compound 54 Provided by the Invention

 The preparation process is as follows:

Accurately weigh S ₁₅ 2.13 g, about 6 mmol, dissolved in 10 mL DMF, stir to dissolve, add S ₄₇ 1.6 mg, about 5 mmol, chlorite 857 mg, about 7.2 mmol, 0 °C After reacting for 5 h, 20 mL of water was added, and ethyl acetate was extracted 20 mL X 3 times, dried, column chromatography, ethyl acetate: petroleum ether = 2:1 to 1:2 to give a solid 1.77 g, yield 54.4%.

 The compound 54 provided by the present invention was tested and the results were as follows:

ESI-MS: [M + H] ⁺ = 664.3.

ifiNMR (400 MHz, CDC1 ₃ ) δ 1.65 (2H, m), 1.97 (6H, m), 2.18 (2H, m), 2.31 (3H, s), 2.36 (3H, s), 2.58 (2H, t, J = 4.8 Hz), 2.82 (4H, m), 3.10 (2H, s), 3.57 (2H, s), 3.66 (3H, s), 4.13 (1H, m), 4.76 (1H, t, J= 4.4 Hz), 5.32 (1H, br, s), 5.48 (1H, s), 5.95 (1H, s), 7.10 (1H, t, J= 7.6 Hz), 7.26 (1H, m), 7.37 (2H, m ), 7.58 (1H, t, J = 7.2 Hz), 7.94 (1H, d, J = 8.4 Hz), 8.05 (1H, d, J = 8.8 Hz). Detection of L-type Ca ²⁺ channel blocking activity of the compound of Example 55

 According to the patch clamp technique, the calcium current of the rat dorsal root ganglion cells was measured according to the following method, thereby determining the inhibitory activity of the compound provided by the present invention on the L-type calcium ion channel.

 Dorsal root ganglion cell culture:

Reagents: D-MEM/F- 12 Medium, Gibco; fetal bovine serum ie FBS, Gibco; collagenase, Sigma; poly-L-lysine, Sigma; trypsin, Invitrogen; trypsin inhibitor, Sigma; Dorsal root ganglion cell culture medium: 90% D-MEM/F-12, 10% FBS, P/S 100U/mL; Digestive juice, freshly prepared before experiment: 5 mL D-MEM/F-12, 5 mg collagen Enzyme, 2.5 mg trypsin.

 Instruments: Multiclamp 700B Amplifier, Molecular Devices, USA; DigiData 1440 A/DD/A Converter, MDC, USA; PclamplO Software, Molecular Devices, USA; Inverted Microscope, Nikon Ti-S, Japan; Programmable Micropipette DMZ- Universal Puller, Germany; Programmable straw maker, DMZ-Universal Puller, Germany.

Preparation of rat dorsal root ganglion cells: Two rats, 140 g of Wister rats were decapitated under pentobarbital anesthesia, and the lumbar L4-L6 dorsal root ganglia were quickly separated from the ridge. In PBS; the connective tissue and septum on the ganglion are removed, and the ganglion is cut into several pieces and placed in the digestive juice at 37. C, 5 % C0 ₂ treatment for 25-30 min, add trypsin inhibitor to terminate digestion; centrifuge the digested cell suspension at 1000 rpm for 2 min, remove the supernatant and add the culture solution, mix After the hook treatment, centrifuge again at 1000 rpm for 2 min, remove the supernatant and add the culture solution; transfer the cells to a culture sub-zone coated with 35 mm 25 g/mL poly-L-lysine, culture 2 h, get the dorsal root ganglion cells for patch clamp experiments.

 10 mmol, 100 mmol of the compound 1, the compound 8-11, the compound 17, the compound 19, and the compound 23 prepared in Example 1, Example 8-11, and Example 17, 19, respectively, were weighed and dissolved at room temperature. A solution of 100 mmol/L and 1000 mmol/L was prepared at a concentration of 100% DMSO. The above DMSO solution was then diluted at a ratio of 1:1000 to give the final test solution.

 The patch clamp test solution is divided into an extracellular solution and a custom solution, and the ratios are shown in Table 1 and Table 2.

 Table 1 Ratio of extracellular solution

 Cell bud solution mmol/L

 CsCl 139

BaCl ₂ 5.0

 Hydroxyethylpiperazineethanesulfonic acid (HEPES) 10

MgCl ₂ 1.0 Glucose 10

 Tetraethylammonium chloride (TEA) 30

 4-aminopyrine (4-AP) 5

 Tetrodotoxin 0.002

 pH 7.4 was adjusted with CsOH, and the osmotic pressure was 305-310 milliosmoles.

 Table 2 straw solution ratio

 The pH was adjusted to 7.3 with CsOH and the osmotic pressure was 290-295 milliosmoles. The pipette solution is divided into several portions and stored at -20 °C before use.

Patch Clamp Test: The test was performed at room temperature using a whole cell patch clamp technique, controlled by a Multiclamp 700B amplifier, a DigiData 1440 A/DD/A converter, a 1 kHz filter, using Pclamp 10 software. The cells tested were continuously passed through a perfusion system - a biological fast solution converter, RSC-160, and a bath solution of 1-2 mL/min. This process was performed under an inverted microscope and the perfusion point was manually inserted. Pull the borosilicate glass capillary (BF150-86-10, Sutter Instrument Co.) using a programmable micropipette maker. The pipette end resistance is 2 - 4 ΜΩ. The voltage control sequence, from a holding potential of -60 mV, reaches O mV over 300 ms and then back to -60 mV over 60 ms. This voltage control sequence is repeated every 10 s during the test. During the initial recording, when the peak current reaches a steady state, ie < 5 % change, 5-10 recording points, the test compound is added at a low concentration until the peak current reaches the stable 5 recording points again, and if the peak current has not changed, wait 5 min. Add a high concentration of compound test if necessary. Two cells were tested per compound. Data analysis and curve fitting were performed using Clampfit (V10.2, Molecular Devices), Excel 2003 (Microsoft) and SigmaPlot. Test compound inhibition rate. Calculated as follows:

 [ (blank current - residual current after compound addition) / blank current] xl 00 %

 The inhibitory effects of 100 nmol/L and 1 μηιοΙ/L compounds are shown in Table 3:

Table 3 The compounds provided by the present invention have an L-type Ca ²⁺ channel blocking activity

Example 56 Detection of Acetylcholinesterase Inhibitory Activity of Compounds

 Rat brain homogenate was used as an enzyme source for acetylcholinesterase.

 Experimental reagents and consumables: Buffer: lO x PBS, 0.1 mol/L, pH 7.4, purchased from invitrogen;

Triton X-100, purchased from Biyuntian; substrate, Ach-S-CL, sigma: ready-to-use, each time PBS is used to prepare 0.1 mol/L stock solution; color developer, DTNB, sigma: with PBS Formulated as a 0.005 mol/L stock solution; Stop solution, 3 % SDS: Prepare a 3 % SDS solution in PBS. 96-well transparent plate, corning; pipetting gun, pipette tip. Vistar rats were purchased from Qinglongshan Farm in Nanjing, Jiangsu Province. Experimental equipment: Homogenizer and Tecan M200 microplate reader.

Experimental steps: Preparation of brain homogenate: Two rats, completely remove the whole brain, wash the whole brain with ice-cold PBS until the adhered blood is cleaned, cut the whole brain into pieces on an ice pack, and dispense into 8 5 mL EP tubes. In each tube, 2 mL of lOxPBS containing 0.5% Triton was added, and the mixture was homogenized by a homogenizer to obtain a suspension at 12000 rpm, 4. C Centrifuge for 10 min, carefully pipet the supernatants of each tube, mix them into another new pre-cooled EP tube, store the supernatant at 50 minutes per tube, and store at -20 °C for later use.

 Compound working fluid configuration: The compound of 0.01 mol/L stock solution was diluted with DMSO to a working concentration of lOOx, from high to low of 1000, 250, 62.5, 15.625, 3.9063, 0.9766, 0.2441, respectively, four times in sequence. Compared to the dilution, a total of seven concentration gradients, unit: mol / L.

 Dilution of brain homogenate working solution: Enzyme working solution is obtained by diluting the brain homogenate supernatant with PBS in a ratio of 1:100.

 Preparation of substrate working solution: The substrate of 0.1 mol/L stock solution was diluted to 4 mmol/L with PBS, and the working solution was reserved.

 Procedure: Take 96-well plates, add 48 PBS to each well; add 2 - series concentration gradient of the working solution of the compound to each well, and add 2 μ DMSO directly to the positive control group and the negative control group; add 50 cerebral stalks per well. Working fluid, use a plate shaker to mix the hooks, seal each well with membrane, and incubate at 37 °C for 48 h; add 50 μΐ 0.005 mol/L color solution to each well; add 50 L substrate working solution per well The negative control group was directly added with 50 L of 10×PBS, mixed by a plate shaker, and allowed to stand at 37 ° C for 1 h; the absorbance at 412 nm of each well was measured on a Tecan M200 microplate reader.

 Data Processing: Calculate the average of all drug-administered and control groups. The formula for calculating the inhibition rate is as follows:

^Mean group average 0D value - negative control average 0D value,

 Inhibition rate: ^ (I ) X 100%

^ The average 0D value of the positive control - the average 0D value of the negative control is used to find the logarithm of the base 10 of the dosing concentration. The logarithmic value is the abscissa and the inhibition rate is the ordinate. The figure is drawn in origin6.0 and a piece is fitted. Pharmacological dose-effect relationship S-shaped curve, find the corresponding 50% Table 4 results of detection of acetylcholinesterase inhibitory activity of compounds

Example 57 Detection of Acetylcholinesterase Inhibitory Activity of Compounds

 Materials and Instruments: AmplexR Red Acetylcholine/ Acetylcholinesterase Assay Kit, A12217, invitrogen; 96-well blackboard, Costar #3925; Infinite M200 enzyme-labeled detector, Tecan.

 Kit stock solution configuration:

An Amplex Red reagent, Component A, 200μ DMSO, Component B, -20 °C protected from light; 5 x buffer, Component E diluted to lx with deionized water according to the required volume, ie 1 X Reaction Buffer;—Hrp, Component C, 1 mL 1 Reaction Buffer, -20 after dispensing. C storage; 5 μΐ^ 3.3 % of 13⁄40 ₂ , Component D, added to 234.1 deionized water to obtain 20 mmol/L H ₂ 0 ₂ working solution, ready for use; Choline Oxidase, add 600 μ 1 Reaction Buffer, store at -20 °C after dispensing; 5 mg Ach-cl, Componentg, add 275 deionized water in proportion to 100 mmol/L Ach application solution, now known as ready-to-use; One AchE, add 600 μΐ 1 Reaction Buffer, -20 after dispensing. C save.

 Compound configuration: According to the sample quality and molecular weight, the compound was configured into a 0.01 mol/L stock solution in DMSO. The concentration of 100× compound was prepared: First, the compound stock solution was firstly set to 1000 μηιοΙ/L, 200 μηιοΙ/L, 40 μηιοΙ with DMSO. /L, 8 μηιοΙ/L, 1.6 μηιοΙ/L, 0.32 μηιοΙ/L, concentration gradient of 0.064 μηιοΙ/L.

 4 Configuration of AchE application solution: Dilute the AchE stock solution with 1 X Reaction Buffer according to the actual required volume in a ratio of 1:250.

 2 Configuration of working fluid: According to the actual required volume, each stock solution is mixed according to the ratio of 200 μL Amplex Red reagent : 100 Horseradish peroxidas: 100 Choline Oxidase: lO L Ach : 9590 μΐ 1 Reaction Buffer to obtain 2 working liquid.

Operation procedure: Add 48 reaction buffers to each well of the designed 96-well blackboard. Add a solution of 100 x compound concentration to the above compound in the wells of each well. 2 duplicate wells; positive control wells were added 2 DMSO + 48 μL 1 Reaction Buffer, positive test wells were directly added to 100 μL of 20 mM H ₂ 0 ₂ working solution, and negative control wells were added 2 μΐ DMSO + 98 μΕ 1 Reaction Buffer, each Two wells were set in the wells; compound assay wells and positive control wells were added with 50 μl χ AchE application solution per well, all wells were added with 2 χ working solution per well, mixed, and the enzymatic reaction was initiated. The total reaction system was 200. L, the final concentration of the compound thus obtained is 10 μηιοΙ/L, 2 μηιοΙ/L, 0.4 μηιοΙ/L, 0.08 μηιοΙ/L, 0.016 μηιοΙ/L, 0.0032 μηιοΙ/L, 0.00064 μηιοΙ/L; Incubation at room temperature 30-45 Min.

 Fluorescence detection: Under the Infinite M200 enzyme-labeled detector, the fluorescence value of each well at the excitation wavelength of 540 nm and the emission wavelength of 590 nm was measured.

Data processing: Calculate the average of all drug-administered and control groups and calculate the inhibition rate as follows: The average OD value of the drug group - negative control level: l ^ OD value

 Inhibition rate = Ci ) χ ιοο%

The average 0D value of the positive control - the average 0D value of the negative control was used to find the logarithm of the base of the dosing concentration. The logarithmic value was plotted on the abscissa and the inhibition rate was plotted on the ordinate. The original 6.0 was drawn and a pharmacological fit was fitted. The dose-effect relationship is determined by the sigmoid curve, and the drug concentration corresponding to the 50% inhibition rate is obtained, that is, the IC _{5 which} inhibits the activity of the compound for acetylcholinesterase. value. The results of the detection of the compound for acetylcholinesterase inhibitory activity are shown in Table 5.

Table 5 Results of detection of acetylcholinesterase inhibitory activity of compounds The compounds provided by the present invention inhibit active IC _5Q (nmol/L) Compound 6 600

 Compound 8 140

 Compound 9 24

 Compound 14 390

 Compound 17 17

 Compound 18 280

 Compound 21 16

 Compound 22 65

 Compound 23 22

 Compound 24 790

 Compound 25 350

 Compound 26 450

 Compound 27 300

 Compound 28 230

Compound 29 190 Compound 30 170

 Compound 31 400

 Compound 32 140

 Compound 35 560

 Compound 36 110

 Compound 37 72

 Compound 38 1100

 Compound 39 418

 Compound 40 437

 Compound 41 70

 Compound 42 64

 Compound 50 995

 Compound 51 617

 Compound 54 168

 Tacrine 370

 The above description is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art can also make several improvements and retouchings without departing from the principles of the present invention. It should be considered as the scope of protection of the present invention.

Claims

Rights request A compound of the formula Y-L-X, characterized in that Y is selected from the group consisting of a group of formula I, formula II or formula III,

Wherein, and independently selected from the group consisting of hydrogen, a halogen atom, a nitro group, an amino group, a trifluoromethyl group, an amino group, a d-c ₄ alkoxy group, a d-C ₄ alkane fluorenyl group, a dC ₈ alkyl group, a c ₂ -c ₈ chain Alkenyl or c ₂ -c ₈ alkynyl; R ₂ and R _{3 are} independently selected from nitro, cyano or trifluoromethyl; Ar is selected from aryl or heteroaryl, and the C _r C ₄ position of the aryl or heteroaryl is optionally substituted by halogen atom, nitro group, cyano group, trifluoromethyl group, amino group, dC ₄ alkylthio group, dC _8- alkyl, C ₂ -C ₈ alkenyl or / and C ₂ -C ₈ alkynyl substituted; And independently selected from -NR ₅ R ₆ , the C _r C ₄ position of Ar is optionally substituted by -NR ₅ R ₆ , and R ₅ and R _{6 are} independently selected from hydrogen, dC ₈ alkyl, C ₂ -C ₈ chain Alkenyl or C ₂ -C ₈ alkynyl; R ₂ and R ₃ are also independently selected from -COOR ₇ or -CONR ₇ , the dC ₄ position of Ar is optionally substituted by -COOR ₇ and R _{7 is} selected from dC ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl;  X is selected from the group represented by any one of Formula IV to Formula X, and is bonded to L through any one of R,

Wherein R is selected from a direct bond, hydrogen, a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, an amino group, a Ci-C ₄ alkylthio group, a dC ₁₂ alkyl group, a C ₂ -C ₁₂ alkenyl group or a C ₂ group _; -C ₁₂ alkynyl; R is further selected from -NR ₅ R ₆ or -COOR ₇ , and R ₅ and R _{6 are} independently selected from hydrogen, dC ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, and R _{7 is} selected from C _r C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl; L is selected from a direct bond, a C Ci2 alkylene group, a C ₂ -C ₁₂ alkenylene group or a C ₂ -C ₁₂ alkynylene group. The compound according to claim 1, wherein, and Ar are independently selected from dC ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, one or more of which are - The CH ₂ - group is optionally substituted by -0, -S -, -S0 ₂ - or / and -NR ₅ -, and R _{5 is} selected from hydrogen, C _r C ₈ alkyl, C ₂ -C ₈ alkenyl Or C ₂ -C ₈ alkynyl. 3. The compound of claim 1, wherein Ar is independently selected from and and C _r C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group, optionally substituted with one Or two or more carbonyl oxygen or / and hydroxyl substituted. 4. The compound of claim 1, wherein, R ₇ is selected from C _r C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group, an optionally substituted C _r C ₄ alkoxy or -NR ₅ R ₆ substituted, R ₅ and R _{6 are} independently selected from hydrogen, C C8 alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. Either ₍₈ alkynyl ^ - 5. The compound of claim 1, wherein, R ₅ and R _{6 are} independently selected from C _r C ₈ alkyl, C ₂ -C ₈ alkenyl or (¾ It is optionally replaced by a phenyl or phenyl substituent. The compound according to claim 1, wherein L and R are selected from (^-( ₁₂ alkylene, C ₂ -Ci ₂ alkenylene or C ₂ -C ₁₂ alkynylene, one of Or two or more -CH ₂ - groups may be optionally -0-, -S-, -S0 ₂ -, cycloalkylene, arylene, heteroalicyclic, heteroarylene or/and- NR ₅ -substitution, R _{5 is} selected from hydrogen, dC ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The compound according to claim 1, wherein L and R are selected from (^-( ₁₂ -alkylene, C ₂ -Ci ₂ sub-chain or C ₂ -C ₁₂ alkynylene) It is optionally substituted by one or two or more carbonyl oxygen or/and a hydroxyl group. 8. The compound of claim 1, wherein RPR _{4 is} independently selected from C _R C ₄ alkyl, R ₂ and R _{3 are} independently selected from -COOR ₇ , L is a direct bond, and X is represented by Formula IV. Structure, R _{7 is} selected from dC ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The compound according to claim 1, wherein R ₄ is C _R C ₄ alkyl, R ₂ and R _{3 are} independently selected from -COOR ₇ , X is a structure represented by formula VII, and Ar is dC ₄ A substituted phenyl group, R _{7 is} selected from the group consisting of Ci-C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The compound according to claim 1, wherein RPR _{4 is} independently selected from C _R C ₄ alkyl, R ₃ is -COOR ₇ , X is a structure represented by formula IV, VII, IX or X, and Ar is dC in which phenyl substituted or benzo-oxadiazolyl _4, R ₇ is selected from C _r C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group.  The compound according to any one of claims 1 to 10, which comprises an isomer thereof, a pharmaceutically acceptable equivalent or a mixture thereof.  The compound according to any one of claims 1 to 11, which is specifically:  3,5-Dimercapto-4-(3-(diaminoaminodecanoyloxy)phenyl)-2,6-dimercapto-1,4-dihydropyridine-3,5-dicarboxylate ; 3-isopropyl- _{5- (2} -methoxyethyl)-4-(3-(diaminoaminodecanoyloxy)phenyl)-2,6-diamidino-1,4-dihydro Pyridine-3,5-dicarboxylate;  3,5-Dimercapto-4-(3-nitro-4-(diamidinoindolyloxy)phenyl)-2,6-diamidino-1,4-dihydropyridine-3,5 - a dicarboxylic acid ester; 5-isopropyl-3-indenyl- _2- (4-(diaminoaminodecanoyloxy)phenyl)-6-fluorenyl-4-(3-nitrophenyl)-1,4-di Hydropyridine-3,5-dicarboxylate; 5-Isopropyl-3-indolyl- _2- (4-(diaminoaminodecanoyloxy)phenyl)-6-indolyl-4-(1-indolyl-5-nitro-1H-imidazole -2-yl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-ethyl-5-mercapto-2-((2-((5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)amino) Ethoxy)indenyl)-4-(2-chlorophenyl)-6-mercapto-1,4-dihydropyridine-3,5-dicarboxylate; 3-ethyl-5-indolyl-4-(2-chlorophenyl)-2-((2-(4-(diaminoaminocarbonyl)benzylamino)ethoxylate () fluorenyl)- ₆ -fluorenyl-1,4-dihydropyridine-3,5-dicarboxylate;  3-(5-(6-Chloro-1,2,3,4-tetrahydroacridin-9-ylamino)pentanyl)-5-mercapto-2,6-dimercapto-4-(3 -nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-(5-(6-Chloro-1,2,3,4-tetrahydroacridin-9-ylamino)pentanyl)-5-mercapto-2,6-dimercapto-4-(2) , 3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-(2-((1-(3-(Diaminoaminocarbonyl)phenyl)ethyl)(indenyl)amino)ethyl)-5-indenyl-2,6-diinyl- 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate; _{3- (2} - ₍₍ diylaminodecanoyloxy)benzyl)(fluorenyl)amino)ethyl)-5-fluorenyl-2,6-dimercapto-4-(3-nitro Phenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-(4-(4-(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)piperazin-1-yl)phenethyl)-5-mercapto-2,6 - Dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-(3-(4-(3-(Diaminoaminodecanoyloxy)benzyl)piperazin-1-yl)propyl)-5-indolyl-2,6-dimercapto-4-( 3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-mercapto-5-(2-(indolyl-(2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)amino)ethyl)-2,6 - Dimercapto- 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-(2-(Diamino)-2-(3-(4-N-ethyl-decylaminodecanoyloxy)phenyl))-5-indenyl-2,6-diindenyl- 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-(2-(6-(Diaminoaminodecanoyloxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-5-indenyl-2,6- Mercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-mercapto-5-(1-(2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)piperidin-4-yl)-2,6-di Mercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-(2-(2-(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)ethoxy)ethyl)-5-indenyl-2,6- Dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate; 3-(2-(6-(Diaminoaminodecanoyloxy)-2-mercapto-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-5-indenyl- 2,6-diamidino-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate; 3-((6-(Dioxaaminodecanoyloxy)-2-mercapto-1,2,3,4-tetrahydroisoquinolin-1-yl)indolyl)-5-indenyl-2, 6-Dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-mercapto-5-(1-(3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperidin-4-yl)-2,6-di Mercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-mercapto-5-((5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)aminodecanoyl)-2,6-diindole 4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;  3-mercapto-2,6-dimercapto-4-(3-nitrophenyl)-5-((1-(2-((1,2,3,4-tetrahydroacridin-9-) (amino)ethyl)piperidin-4-yl)aminodecanoyl)-1,4-dihydropyridine-3-carboxylate;  3-mercapto-5-(5-((1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-2,6-diamidino-4-(3-nitro Phenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-5-indolyl-2,6-diindenyl-4-( 2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-5-indolyl-4-(2-chlorophenyl)-2 , 6-dimercapto-1,4-dihydropyridine-3,5-dicarboxylate;  3-(10-((6-Chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)indolyl)-5-indolyl-2,6-dimercapto-4-( 3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-(2-((2-(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)thio)ethyl)-5-indenyl-2 , 6-dimercapto- 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-5-ethyl-2,6-dimercapto-4-( 3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  5-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-3-indolyl-2-((2-aminoethoxy) Mercapto) 4-(2-chlorophenyl)-6-mercapto-1,4-dihydropyridine-3,5-dicarboxylate;  3-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-5-isopropyl-2,6-didecyl-4- (3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate; 3-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-5-indolyl-4-(benzo[c][l, 2,5] evil (oxazol-4-yl)-2,6-dimercapto-1,4-dihydropyridine-3,5-dicarboxylate;  3-(1-(4-(Diaminoaminodecanoyloxy)benzyl)piperidin-4-yl)-5-indolyl-2,6-dimercapto-4-(3-nitrophenyl) - 1 ,4-dihydropyridine-3,5-dicarboxylate;  3-(3-(4-(Diaminoaminodecanoyloxy)benzylamino)propyl)-5-indolyl-2,6-diamidino-4-(3-nitrophenyl)-1 , 4-dihydropyridine-3,5-dicarboxylate;  (E)-3-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-5-indolyl-4-(2-(3) -tert-butoxy-3-methoxypropenyl small)phenyl)-2,6-dimercapto-1,4-dihydropyridine-3,5-dicarboxylate;  3-(4-(2-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)cyclohexyl)-5-fluorenyl-2,6-di Mercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-mercapto-5-((1-(2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)piperidin-4-yl)indolyl) -2 , 6-dimercapto- 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-(4-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)but-2-yn-1-yl)-5-indenyl-2,6- Dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-(6-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)-2-indolylheptan-2-yl)-5-indenyl-2,6-di Mercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-ethyl-5-mercapto-2-((2-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)ethoxy)indolyl)-4-( 2-chlorophenyl)-6-mercapto-1,4-dihydropyridine-3,5-dicarboxylate;  3-ethyl-5-mercapto-2-((2-(3-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)propylamino)ethoxy) oxime 4-(2-chlorophenyl)-6-mercapto-1,4-dihydropyridine-3,5-dicarboxylate;  3-ethyl-5-mercapto-2-((2-(2-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)ethylamino)ethoxy) oxime 4-(2-chlorophenyl)-6-mercapto-1,4-dihydropyridine-3,5-dicarboxylate; ³ -ethyl- ⁵ -fluorenyl ² -(( ² - (di-(( ³ , ⁵ , ⁶ -tridecylpyrazine- ² -yl)indolyl)amino)ethoxy)indolyl) -4 -(2-chlorophenyl)-6-mercapto-1,4-dihydropyridine-3,5-dicarboxylate; 3-mercapto-5-(1-((3,5,6-tridecylpyrazin-2-yl)indolyl)piperidin-4-yl)-2,6-diindol-4-( 3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate; 3-mercapto-5-(2-(1-((3,5,6-tridecyl-2-yl)indolyl)piperidin-4-yl)ethyl)-2,6-didecyl 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-mercapto-5-(1-((3,5,6-tridecylpyrazin-2-yl)indolyl)piperidin-4-yl)indolyl-2,6-dimercapto-4 -(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-ethyl-5-fluorenyl- 4-(2-chlorophenyl)-6-mercapto-2-((2-((3,5,6-tridecylpyrazin-2-yl)indole) Amino)ethoxy)indenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-ethyl-5-mercapto-4-(2-chlorophenyl)-6-mercapto-2-((2-(2-(indenyl)((3,5,6-tridecyl)p ratio Pyridaz-2-yl)mercapto)amino)ethylamino)ethoxy)indolyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-Hydrazino-5-(1-(2-(indolyl((3,5,6-tridecylpiperazin-2-yl)indolyl)amino)ethyl)piperidin-4-yl) - 2,6-diamidino-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3,5-Dimercapto-4-(2-chloro-4-(5-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)pentyloxy)phenyl) -2,6-dimercapto-1,4-dihydropyridine-3,5-dicarboxylate;  3-mercapto-5-(5-(1,2,3,4,5,6,7,8-octahydroacridin-9ylamino)pentyl)-2,6-dimercapto-4- (3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-ethyl-5-mercapto-4-(2-chlorophenyl)-2-((2-(1-(4-indole-ethyl-decylaminodecanoyloxy)phenyl)ethylamino) Ethoxy)indenyl)-6-mercapto-1,4-dihydropyridine-3,5-dicarboxylate;  3-mercapto-5-(5-(5,6,7,8-tetrahydroquinolin-2(1H)-one-5-ylamino)pentyl)-2,6-dimercapto-4- (3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;  3-mercapto-5-(1-(2-(1,2,3,4-tetrahydroacridin-9-ylamino)ethyl)piperidin-4-yl)-4-(2,3- Dichlorophenyl)-2,6-dimercapto-1,4-dihydropyridine-3,5-dicarboxylate.  13. Use of a compound according to any one of claims 1 to 12 as an L-type calcium channel blocker or / and an acetylcholinesterase inhibitor.  14. Use of a compound according to any one of claims 1 to 12 for the manufacture of a medicament for modulating calcium homeostasis, treating cardiovascular disease, stroke or dementia. 15. The use according to claim 14, wherein the dementia comprises Alzheimer's disease or Vascular dementia.  16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12.