WO2013152704A1 - 5-amino-1,4-dihydro-1,8-naphthyridine derivative and pharmaceutical composition and use thereof - Google Patents

Abstract

Disclosed in the present invention is a class of 5-amino-1,4-dihydro-1,8-naphthyridine derivatives and the pharmaceutical composition and use thereof. The class of 5-amino-1,4-dihydro-1,8-naphthyridine derivatives of the present invention is compounds capable of both inhibition of the activity of acetylcholinesterase and retardation of the flow of extracellular calcium into cells through calcium channels, with double activity, important potential treatment value and wide applicability in preparing drugs for treating cardiovascular diseases, cerebrovascular diseases or alzheimer's disease.

Description

 5-J^-l,4-dihydro-1,8-naphthyridine derivative and its pharmaceutical composition and use The present application claims to be submitted to the Chinese Patent Office on April 10, 2012, the application number is 201210104212.5, and the invention name is The priority of the Chinese patent application of "5-amino-1,4-dihydro-1,8-naphthyridine derivatives and their pharmaceutical compositions and uses" is incorporated herein by reference. Technical field

 The present invention relates to the field of medicinal chemistry, and in particular to a class of 5-amino-1,4-dihydro-1,8-naphthyridines or pharmaceutically acceptable salts thereof and the same or a pharmaceutically acceptable salt thereof A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof as an L-type calcium channel blocker or/and an acetylcholinesterase inhibitor The application, in particular, is for the preparation of a medicament for the treatment of cardiovascular diseases, cerebrovascular diseases or dementia. 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 loss." The theory is 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 that nerve signals are in vivo. The normal delivery. However, acetylcholinesterase can catalyze the cleavage reaction of acetylcholine, which leads to the loss of acetylcholine and the failure of neural signal transmission, thus affecting the cognitive and memory functions of the body. At present, acetylcholinesterase inhibitors are often 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, computational power, attention and executive function, which is second only to The second most common cause of dementia in Alzheimer's disease. The researchers believe that a mechanism of injury is: cerebral infarction, hypoxic hypoperfusion and hemorrhagic lesions, resulting in decreased brain tissue volume, delayed neuronal necrosis, and thus acetylcholine nerve damage in the brain, acetylcholine translation Reduced discharge, gradual emergence of memory impairment, cognitive impairment, social and daily life, decreased mobility. 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 calcium influx in the brain, 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.

 At present, there is no compound which can inhibit the activity of acetylcholinesterase and block the extracellular calcium ions from flowing into cells through calcium channels. Therefore, it is important to develop such compounds. Summary of the invention

 The object of the present invention is to provide a compound and a pharmaceutical composition capable of inhibiting acetylcholinesterase activity and blocking extracellular calcium ions from flowing into cells through a calcium channel and as an L-type calcium channel blocker or/and acetylcholine Application of esterase inhibitors.

 In order to solve the above technical problems, the technical solution provided by the present invention is:

 a class of salts as shown in formula I,

Wherein R is selected from aryl or heteroaryl, and the aryl or heteroaryl ring is optionally bonded to a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, an aryl group, a heteroaryl group, or a d -doalkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ chain or C ₂ -C; fe group substituted, wherein the substituents at two positions may be combined to form an aliphatic ring or a heterocyclic ring , an aromatic ring or a heteroaryl ring, the d-Cu)alkyl group, C ₃ -C ₈ The optionally -CH ₂ - in the cycloalkyl, C ₂ -C ₈ chain or C ₂ -C ₈ alkynyl group may be one or more of -0-, -S-, -S0 ₂ -, -C ( O)- or / and -NR ⁶ - substitution, hydrogen at any position in the d-do alkyl group, C ₃ -C ₈ cycloalkyl group, C ₂ -C ₈ chain group or C ₂ -C ₈ alkynyl group Can be substituted by one or more halogen atoms, an aryl group, a nitro group, a heteroalicyclic group, a hydroxyl group, -NR ⁸ R ⁹ ;

X is selected from -0-, -NR ⁷ -;

R ⁸ and R ^{9 are} independently selected from hydrogen, dC ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, or R ⁸ and R ⁹ are taken together to form a heteroalicyclic group of 5 to 9 ring atoms;

R ⁶ and R ^{7 are} independently selected from the group consisting of hydrogen, -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl;

R ^{1 is} selected from the group consisting of hydrogen, hydroxy, aryl, heteroaryl, C Cs alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, said C _r The optional -CH ₂ - in the C ₈ alkyl group, the C ₃ -C ₈ cycloalkyl group, the C ₂ -C ₈ alkenyl group or the C ₂ -C ₈ alkynyl group may be one or more -0-, -S _{-, -S0 2 -, -C (} O) - and / or -NR ⁶ - substitution, the C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group in any position may be substituted with one or more of the hydrogen atoms of halogen, atmosphere, nitro, aryl, heteroaryl, -NR ⁸ R ⁹ substituents;

R ^{2 is} selected from the group consisting of hydrogen, a halogen atom, a nitro group, an amino group, a hydroxyl group, a trihaloalkyl group, a dC ₈ alkyl group, a C ₃ -C ₈ cycloalkyl group, a C ₂ -C ₈ alkenyl group or a C ₂ -C ₈ alkyne. group, a C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl optionally -CH ₂ - may be substituted with one or more _{-0-, -S -, -S0 2 -} , -C (O) - and / or -NR ⁶ - substitution, the C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C Any hydrogen in the ₈ -alkenyl or C ₂ -C ₈ alkynyl group may be substituted by one or more halogen atoms, an aryl group, a nitro group, -NR ⁸ R ⁹ ;

R ³ is selected from hydrogen, C _r C ₈ alkyl or C ₃ -C ₈ cycloalkyl group, a C _r C ₈ alkyl or C ₃ -C ₈ cycloalkyl group optionally substituted -CH ₂ - may be substituted with one or more _{-0-, -S -, -S0 2 -} , -C (O) - and / or -NR ⁶ - substitution, the C _r C ₈ alkyl or C ₃ -C ₈ cycloalkyl group Any position of hydrogen may be substituted by one or more atomic atoms, an aryl group, a nitro group, -NR ⁸ R ⁹ ;

R ⁴ and R ^{5 are} independently selected from -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ chain or C ₂ -C ₈ alkynyl, said dC ₈ alkyl, c ₃ - The optional -CH ₂ - in the c ₈ cycloalkyl, c ₂ -c ₈ alkenyl or c ₂ -c ₈ alkynyl group may be one or more of -0-, -S-, -S0 ₂ -, - C(O)- or / and -NR ⁶ - substitution, anywhere in the C Cs alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group Hydrogen Substituted by one or more halogen atoms, an aryl group, a nitro group, an aryl group, a heteroaryl group, -NR ⁸ R ⁹ . Preferably, among the above compounds,

R is selected from a C ₆ -C ₁₂ aryl group or a C ₃ -C ₁₂ heteroaryl group, the aryl or heteroaryl group optionally having a halogen atom, an amino group, a nitro group, a cyano group, a C ₆ -C ₁₂ aryl, C ₃ -C ₁₂ heteroaryl, CC ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ chain or C ₂ -C ₈ alkynyl, optionally two The substituents at the position may be taken together to form an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaryl ring, the C _r C ₈ alkyl group, a C ₃ -C ₈ cycloalkyl group, a C ₂ -C ₈ chain group or a C ₂ group. The optional -CH ₂ - in the -C ₈ alkynyl group may be replaced by one or more of -0 -, -S -, -S0 ₂ -, -C(O)- or / and -NR ⁶ -, said dC Hydrogen at any position in the _8- alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group may be substituted by one or more prime atoms, cyano, hydroxy, -NR ⁸ R ⁹ substitution;

X is selected from -0-, -NR ⁷ -;

R ⁸ and R ^{9 are} independently selected from hydrogen, dC ₈ alkyl, C ₃ -C ₈ cycloalkyl, or R ⁸ and R ^{9 taken} together to form a heteroalicyclic group of 5 to 9 ring atoms;

R ⁶ and R ^{7 are} independently selected from the group consisting of hydrogen, C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl;

R ^{1 is} selected from dC ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ chain or C ₂ -C ₈ alkynyl, said dC ₈ alkyl, C ₃ -C ₈ cycloalkyl The optional -CH ₂ - in the C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group may be one or more of -0-, -S-, -C(O)- or/and-NR ⁶ - Substitution, the hydrogen at any position in the -C ₈ alkyl group, C ₃ -C ₈ cycloalkyl group, C ₂ -C ₈ alkenyl group or C ₂ -C ₈ alkynyl group may be substituted by one or more halogen atoms , an aryl group, a nitro group, a C ₆ -C ₁₂ aryl group, a C ₃ -C ₁₂ heteroaryl group, a -NR ⁸ R ⁹ substituent;

R ^{2 is} selected from! _3⁄4 atomic atom, C Cs alkyl group, C ₃ -C ₈ cycloalkyl group, C ₂ -C ₈ alkenyl group or C ₂ -C ₈ alkynyl group, the dC ₈ alkyl group, c ₃ -c ₈ cycloalkyl group optionally c ₂ -c ₈ alkenyl or c ₂ -c ₈ alkynyl -CH ₂ - may be substituted by one or more -0-, -S- and / or -NR ⁶ - substitution, the C _The hydrogen at any position in the _r C ₈ alkyl group, the C ₃ -C ₈ cycloalkyl group, the C ₂ -C ₈ chain group or the C ₂ -C ₈ alkynyl group may be one or more halogen atoms, a cyano group, -NR ⁸ R ⁹ substitution;

R ^{3 is} selected from hydrogen, C _r C ₈ alkyl or C ₃ -C ₈ cycloalkyl, and the optional -CH ₂ - in the dC ₈ alkyl or C ₃ -C ₈ cycloalkyl may be one or more a -0-, -S -, -C (O ) - and / or -NR ⁶ - substitution, the C _r C ₈ alkyl or C ₃ -C ₈ cycloalkyl group at any position in the hydrogen may be substituted with one or Substituted by a plurality of prime atoms; R ⁴ and R ^{5 are} independently selected from -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₂ -C ₄ chain or C ₂ -C ₄ alkynyl, said dC ₄ Any of an alkyl group, a c ₃ -c ₄ cycloalkyl group, a c ₂ -c ₄ alkenyl group or a c ₂ -c ₄ alkynyl group The -CH ₂ - may be replaced by one or more of -0, -S -, -S0 ₂ -, -C(0)- or / and -NR ⁶ -, the d-C4 alkyl group, C ₃ - The hydrogen at any position in the C ₄ cycloalkyl group, the C ₂ -C ₄ alkenyl group or the C ₂ -C ₄ alkynyl group may be one or more atomic atoms, an aryl group, a nitro group, a C ₆ -C ₁₂ aryl group, C ₃ -C ₁₂ heteroaryl, -NR ⁸ R ⁹ substituted.

 More preferably, among the above compounds,

R is selected from a C ₆ -C ₁₂ aryl group or a C ₃ -C ₁₂ heteroaryl group, and the ring of the aryl or heteroaryl group is optionally bonded to a halogen atom, a nitro group, an aryl group, a —C ₈ alkyl group, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl substituted, wherein the substituents at two optional positions may be taken together to form an aliphatic ring, a heterocyclic ring, an aromatic ring or a hetero an aromatic ring, a C _r C ₈ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group of -CH ₂ - may be substituted with one or more -0-, -S-, -so ₂ -, -c(o)- or / and -NR ⁶ - substitution, the dC ₈ alkyl group, C ₃ -C ₈ cycloalkyl group, C ₂ -C ₈ Any hydrogen in the alkenyl or C ₂ -C ₈ alkynyl group may be substituted by one or more halogen atoms, an aryl group, -NR ⁸ R ⁹ ;

X is selected from -0-, -NR ⁷ -;

R ⁸ and R ^{9 are} independently selected from hydrogen, C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl, or R ⁸ and R ^{9 taken} together to form a heteroalicyclic group of 5 to 9 ring atoms;

R ^{6 is} selected from the group consisting of hydrogen, C Cs alkyl, C ₃ -C ₈ cycloalkyl;

R ^{7 is} selected from the group consisting of hydrogen, C _r C ₈ alkyl;

R ^{1 is} selected from dC ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, said C Cs alkyl, C ₃ -C ₈ cycloalkyl The optional -CH ₂ - in the C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group may be one or more of -0-, -S-, -C(O)- or/and-NR ⁶ - Substitution, the hydrogen at any position in the -C ₈ alkyl group, the C ₃ -C ₈ cycloalkyl group, the C ₂ -C ₈ alkenyl group or the 0 ₂ -0 ₈ alkynyl group may be substituted by one or more halogen atoms , an aryl group, a C ₆ -C ₁₂ aryl group, (3⁄4-0 ₁₂ heteroaryl, -NR ⁸ R ⁹ substituted;

R ² is selected from C _r C ₈ alkyl or C ₃ -C ₈ cycloalkyl group, a C _r C ₈ alkyl or C ₃ -C ₈ cycloalkyl group optionally substituted -CH ₂ - may be substituted with one or more a -0-, -S- and / or -NR ⁶ - substitution, the C _r C ₈ alkyl or C ₃ -C ₈ cycloalkyl group at any position in the hydrogen may be substituted with one or more prime atoms, -NR ⁸ R ⁹ substituted; R ^{3 is} selected from hydrogen, C _r C ₈ alkyl;

R ⁴ and R ^{5 are} independently selected from -C ₄ alkyl, C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl, said C C4 alkyl, C ₂ -C ₄ chain or C ₂ - The optional -CH ₂ - in the C ₄ alkynyl group may be substituted by one or more of -0-, -S-, -S0 ₂ - or / and -C(O)-, the d-C4 alkyl group, c _{Of 2} -c ₄ alkenyl or c ₂ -c ₄ alkynyl Hydrogen can be replaced by one or more prime atoms at any position.

 More preferably, among the above compounds,

R is selected from phenyl or C ₃ -C ₆ heteroaryl, the phenyl or heteroaryl group optionally substituted on the ring positions by a halogen atom, a nitro group atmosphere, C _r C ₈ alkyl, C ₂ -C ₈ -alkenyl or C ₂ -C ₈ alkynyl group substituted, wherein two adjacent substituents may be bonded together to form an aliphatic ring, a heterocyclic, aromatic ring or a heteroaromatic ring, a C _r C ₈ alkyl, C ₂ - The optional -CH ₂ - in the C ₈ chain or C ₂ -C ₈ alkynyl group is one or more of -0-, -S -, -S0 ₂ -, -C(O)- or / and -NR ⁶ - substitution, the C _r C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group in any position may be substituted with one or more of the hydrogen atoms of halogen, atmosphere group, -NR ⁸ R ⁹ substitution;

 X is -0-;

R ⁸ and R ^{9 are} independently selected from hydrogen, C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl, or R ⁸ and R ^{9 taken} together to form a heteroalicyclic group of 5 to 9 ring atoms;

R ^{6 is} selected from the group consisting of hydrogen, C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl;

R ^{1 is} selected from dC ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, said C Cs alkyl, C ₃ -C ₈ cycloalkyl , optionally substituted C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group of -CH ₂ - may be substituted by one or more -0-, -S- and / or -NR ⁶ - replacing, the dC Hydrogen at any position in the _8- alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or c ₂ -c ₈ alkynyl group may be substituted by one or more atomic atoms, an aryl group, -NR ⁸ R ⁹ substitution;

R ^{2 is} selected from the group consisting of a trihaloalkyl group and a dC ₈ alkyl group;

R ^{3 is} selected from the group consisting of hydrogen and dC ₄ alkyl;

R ⁴ and R ^{5 are} independently selected from -C ₄ alkyl, and optionally -CH ₂ - in said C _r C ₄ alkyl may be one or more -0-, -S-, -S0 ₂ - or And -C(O)-substituted, the hydrogen at any position in the -C ₄ alkyl group may be substituted by one or more ! 3⁄4 atom atoms.

 More preferably, among the above compounds,

R is selected from a phenyl group or a C ₃ -C ₆ heteroaryl group, and the optional position on the ring of the phenyl or heteroaryl group is substituted by a halogen atom, a nitro group, an aryl group, a C _r C ₆ alkyl group, the C The optional -CH ₂ - in the _r C ₆ alkyl group is replaced by one or more of -0, -S -, -C(O)- or / and -NR ⁶ -, in the C _r C ₆ alkyl group Any position of hydrogen may be substituted by one or more halogen atoms, an aryl group, -NR ⁸ R ⁹ ;

 X is -0-;

R ⁸ and R ^{9 are} independently selected from hydrogen, C _r C ₈ alkyl, C ₃ -C ₆ cycloalkyl, or R ⁸ and R ⁹ together To form a heteroalicyclic group of 5 to 9 ring atoms;

R ^{6 is} selected from the group consisting of hydrogen, C _r C ₈ alkyl, C ₃ -C ₆ cycloalkyl;

R ^{1 is} selected from dC ₈ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl, said C Cs alkyl, C ₃ -C ₆ cycloalkyl And optionally in the C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl group -CH ₂ - may be one or more of -0-, -S-, -C(O)- or/and-NR ⁶ -substitution, hydrogen at any position in the -C ₈ alkyl group, C ₃ -C ₆ cycloalkyl group, C ₂ -C ₄ alkenyl group or C ₂ -C ₄ alkynyl group may be one or more prime atoms , cyano group, -NR ⁸ R ⁹ substituted;

R ^{2 is} selected from the group consisting of trihalofluorenyl, dC ₆ alkyl;

R ^{3 is} selected from the group consisting of hydrogen, decyl, and ethyl;

R ⁴ and R ^{5 are} independently selected from C _r C ₄ alkyl.

 Unless otherwise stated, the following terms used in the claims and the specification have the meanings discussed below:

 The method for expressing the number of carbon atoms of a group mentioned in the present application, for example, d-Cu), means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. until 10 carbon atoms are contained. Atom; alkyl refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched hydrocarbon groups, including, but not limited to, mercapto, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, An n-pentyl group, an n-hexyl group, etc.; an alkylene group means a divalent alkyl group;

 Alkenyl refers to an unsaturated straight or branched chain hydrocarbon group composed of at least one carbon-carbon double bond, including, but not limited to, ethylene, propylene, isopropylene, butylene, isobutylene, t-butene, n-pentene , isopentenyl, n-hexene, etc.;

 Alkenylene refers to a divalent alkenyl group;

 An alkynyl group refers to an unsaturated straight or branched chain hydrocarbon group consisting of one or two carbon-carbon porphins, including but not limited to ethynyl, propyne, isopropyne, butyne, isobutyne, Tert-butyne, pentyne, hexyne;

 Alkynylene refers to a divalent alkynyl group;

A cycloalkyl group refers to a monocyclic or fused ring that is all carbon (the fused ring means that each ring in the system shares an adjacent pair of carbon atoms with other rings in the system), one or more of which Without a fully linked pi-electron system, examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexene, cyclohexadiene, Cycloheptane, cyclooctane, Cycloheptadiene and cycloheptatriene;

 Alkoxy means an alkyl or cycloalkyl group bonded through an oxygen bond;

 Aryloxy represents -O-aryl and -0-heteroaryl, including but not limited to phenoxy, pyridyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, etc. and derivatives thereof ;

Substituted phenyl refers to a phenyl group substituted by one or more substituents, wherein the substituent includes, without limitation, C _r C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkyne , dC ₆ alkoxy, C ₂ -C ₆ alkenyloxy, phenoxy, benzyloxy, hydroxy, silk, peroxyhydroxy, ureido, aminodecanoyl, aminodecanoyl, carbonyl, amino, hydroxyamino , decanoylamino, decanoyl, fluorenyl, cyano, arylamino, isomeric, isocyanato, diazo, azide, decyl, triazide, nitrile, nitro, sub Nitro, isonitroso, nitrosylamino, imino, nitrosomino, oxo, dC ₆ alkylthio, sulfoamino, amyl acyl, oxythio, sulfhydryl, sulfinyl, sulfo, Sulfonyl, thioalkoxy, thiocyanato, isocyanothio, thiodecanoylamino, halo, haloalkyl, chlorooxy, chlorooxy, perchloric acid, trifluoromethyl, sub Iodoyl, iodosyl, phosphino, phosphinyl, diphosphoryl, phosphono, fluorenyl, selenoalkyl, ethylsilyl, nonylsilyl, hydrazine Alkyl, alkylene Yue silane, and carbocyclic and heterocyclic moieties;

 "Aryl" means a cyclic aromatic moiety having one or more ring closures, including, but not limited to, phenyl, benzyl, naphthyl, anthracenyl, phenanthryl, biphenyl, and the like; aryl may be substituted Or substituted; when substituted, preferably one or more, more preferably one, two or three, the substituents are independently selected from (not limited to) halogen atoms, nitro groups, aryl groups, trihalides Alkyl, acyl, heteroalicyclic, alkyl, cycloalkyl, alkenyl, alkynyl, mono or dialkylamino, hydroxy, decyl, alkoxy, alkylthio, etc.

"Heteroaryl" means a monocyclic or fused ring radical of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, 0 or S, the remaining ring atoms being C, In addition, it has a fully conjugated π-electron system; the unsubstituted heteroaryl group includes, without limitation, pyrrole, furan, and ρ-plug. Points, imidazole, pyrazole ¹ set, oxazole, isoxazole, [rho] plug oxazolyl, pyrazole, pyrimidine set ^{1, [rho]} morpholine Kui, Kui isopropyl morpholine, purine, carbazole, benzofuran, benzothiophene, benzo Oxadiazole or the like; the heteroaryl group may be substituted or unsubstituted, and the substituent is preferably one or more, more preferably one, two or three, independently selected from (not limited to) a halogen atom, a nitrate Base, aryl, trihaloalkyl, acyl, heteroalicyclic, alkyl, cycloalkyl, alkenyl, alkynyl, amino, mono or dialkylamino, hydroxy, thiol, Alkoxy group, alkylthio group, etc.;

 A heteroalicyclic group means a monocyclic or fused ring group having 5 to 9 ring atoms in the ring, wherein one, two or three ring atoms are selected from N, 0 or S(0) m hetero atoms, wherein m is an integer from 0 to 2, and the remaining ring atoms are C. These rings may have zero, one or more double bonds, but these rings do not have a fully conjugated π-electron system; unsubstituted heteroalicyclic groups are not limited Sexually includes pyrrolidinyl, piperidino, piperazino, morpholino, thiomorpholino, homopiperazino, etc.; heteroalicyclic can be substituted or unsubstituted, when When substituted, the substituent is preferably one or two or more, more preferably one or two or three, still more preferably one or two, and includes, without limitation, a lower alkyl group, a trihaloalkyl group, a halogen, Hydroxy, alkoxy, decyl, alkylthio, cyano, acyl, thioacyl, 0-aminodecanoyl, fluorenyl-aminodecanoyl, 0-thioaminodecanoyl, fluorenyl-thioaminodecanoyl, C -amido, oxime-amido, nitro, oxime-sulfonylamino, S-asamido; preferred , the heteroalicyclic group is optionally substituted by one or two substituents, and the substituents include, without limitation, halogen, lower alkyl, trihaloalkyl, hydroxy, decyl, aryl, oxime-amido, mono- or di- An alkylamino group, a carboxyl group or a hydrazine-sulfonylamino group;

 Atom refers to fluorine, chlorine, bromine or a breaking group;

The trihaloalkyl group represents a -CX ₃ group, wherein X is a halogen atom as defined above;

 An aliphatic ring represents a cyclic group of 3 to 9 carbon atoms, and the ring may have zero or one or more double bonds, but these rings do not have a fully conjugated π-electron system; the aliphatic ring may be substituted or not Substituted, the substituent is preferably one or two or more, more preferably one or two or three, and still more preferably one or two, independently selected from (not limited to) a halogen atom, a nitro group, a cyano group, Trihaloalkyl, acyl, heteroalicyclic, alkyl, cycloalkyl, alkenyl, alkynyl, amino, mono or dialkylamino, hydroxy, decyl, alkoxy, alkylthio, and the like.

A heterocyclic ring means a hetero atom having 5 to 9 ring atoms in the ring, wherein one, two or three ring atoms are selected from Ν, 0 or S(0)m, wherein m is an integer from 0 to 2, and the remaining rings The atom is C, and the rings may have zero, one or more double bonds, but these rings do not have a fully conjugated π-electron system; the unsubstituted heterocyclic ring includes, without limitation, pyrrolidine, piperidine, piperazine, Morpholine, thiomorpholine, homopiperazine, etc.; the heterocyclic ring 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, it is one or two, and includes, without limitation, a lower alkyl group, a trihaloalkyl group, a halogen group, a hydroxyl group, an alkoxy group, Mercapto, alkylthio, cyano, acyl, thioacyl, 0-aminodecanoyl, N-aminodecanoyl, 0-thioaminodecanoyl, N-thioaminodecanoyl, C-amido, N- Amido, nitro, N-sulfonylamino, S-sulfonylamino; preferably, the heterocyclic ring is optionally substituted by one or two substituents, and the substituents include, without limitation, halogen, lower alkyl, trihalide An alkyl group, a hydroxyl group, a decyl group, a cyano group, an N-acylamino group, a mono or dialkylamino group, a carboxyl group or an N-sulfonylamino group;

 The aromatic ring means a cyclic aromatic hydrocarbon moiety having one or more ring closures, including, but not limited to, benzene, naphthalene, anthracene, phenanthrene, etc.; the aromatic ring may be substituted or unsubstituted; preferably one or more when substituted More preferably, one, two or three, the substituents are independently selected from (not limited to) halogen atoms, nitro groups, cyano groups, trihaloalkyl groups, acyl groups, heteroalicyclic groups, alkyl groups, naphthenes Alkyl, alkenyl, alkynyl, mono or dialkylamino, hydroxy, decyl, alkoxy, alkylthio, etc.;

A heteroaryl ring means a monocyclic or fused ring group representing 5 to 12 ring atoms, containing one, two, three or four ring heteroatoms selected from N, 0 or S, the remaining ring atoms being C, in addition A fully conjugated π-electron system; the unsubstituted heteroaryl ring includes, without limitation, pyrrole, furan, ρ plug. Points, imidazole, pyrazole, oxazole, isoxazole, plug oxazolyl, pyrazole, pyrimidine set ^1, [rho] morpholine Kui, Kui iso ^[rho] morpholine, purine, carbazole, benzofuran, benzothiophene, benzo oxadiazole The azole or the like; the heteroaromatic ring may be substituted or unsubstituted, and the substituent is preferably one or more, more preferably one, two or three, independently selected from (not limited to) a halogen atom, a nitro group, Alkyl, trihaloalkyl, acyl, heteroalicyclic, alkyl, cycloalkyl, alkenyl, alkynyl, amino, mono or dialkylamino, hydroxy, decyl, alkoxy, alkylthio, etc. .

 The compounds provided herein also comprise a pharmaceutically acceptable equivalent of the compound or a mixture of two or more.

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

 Preferably, the compounds provided herein are in a pharmaceutically acceptable equivalent, and the pharmaceutically acceptable salts comprise the acid or base salts of the compounds provided herein. The pharmaceutically acceptable salts have the pharmaceutical activity of the compound and are desirable in both biological and practical applications.

The compounds provided herein are in a pharmaceutically acceptable equivalent, a pharmaceutically acceptable acid Salts include, without limitation, acetates, sulfates, phosphates, citrates, propionates, adipates, succinates, tartrates, alginates, aspartates, benzoic acid Salt, terpene phthalate, sulfonate, benzoate, hydrogen sulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, digluconate Salt, lauryl sulphate, ethyl sulphate, fumarate, glucoheptanoate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide , hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, sulfonate, 2-naphthyl, nicotinate, oxalate, thiocyanate, toluene Trans-acid salt 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 and 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, but not limited to, chlorides, bromides, and iodides of lower alkylates such as mercapto, ethyl, propyl, and butyl; Alkyl sulfates such as disulfonyl, diethyl, dibutyl and dipentyl sulfates; long chain compounds such as sulfhydryl, lauryl, myristyl and stearyl chlorides, bromides and iodides An aralkyl compound such as phenyl bromide.

 Preferably, the compounds provided herein are in a pharmaceutically acceptable equivalent, the prodrugs being derivatives of the compounds of the invention which require biological transformation, 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 formulations 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, isosteres refer to elements, functional groups, substituents, molecules or ions having different molecular formulas but exhibiting similar or identical physical properties. For example, tetrazole is an isostere of a carboxylic acid because it has properties similar to those of a carboxylic acid, even though they have different molecular formulas. Typically, two equal rows of molecules have similar or identical sizes and shapes. Ideally, the isosteric molecules will be isomorphic and capable of crystallizing together. Other physical properties of isostere molecules 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. Isosteres including biological isles Things. Biological isosteres share certain biological properties in addition to physical similarities. Typically, bioisosteres interact with the same recognition sites or broadly produce similar biological effects.

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

 The present invention provides the use of a 1,4-dihydro-1,8-naphthyridine derivative for the preparation of a calcium ion channel inhibitor drug and an acetylcholinesterase inhibitor drug.

 The present invention also provides the use of a 1,4-dihydro-1,8-naphthyridine derivative for the preparation of a medicament for regulating calcium homeostasis, treating cardiovascular diseases, cerebrovascular diseases or treating dementia.

 Among them, the dementia is preferably Alzheimer's disease or vascular dementia.

In the examples of the present invention, the inventors examined the L-type Ca ²⁺ channel blocking activity of the 1,4-dihydro-1,8-naphthyridine derivative by using a patch clamp technique and a high content screening analyzer. The experimental results show that the 1,4-dihydro-1,8-naphthyridine derivative has a strong blocking activity on the L-type Ca ²⁺ channel, and its activity is better than the positive control drugs Nifedipine and Nimodipine.

 In the examples of the present invention, the inventors examined the inhibitory activity of the 1,4-dihydro-1,8-naphthyridine derivative on acetylcholinesterase. The experimental results show that the 1,4-dihydro-1,8-naphthyridine derivative can inhibit the activity of acetylcholinesterase.

 Based on the above experimental results, the compound of the present invention is a compound which inhibits the activity of acetylcholinesterase and blocks the extracellular calcium from flowing into the cell through the calcium channel, and has a dual activity.

According to the preparation and effect examples of the present invention and the knowledge in the art, it can be inferred that when the substituent R in the formula of the present invention is an aryl group or a heteroaryl group, the aryl group or the heteroaryl group is bonded to a halogen atom at any position. Substituents such as a hydroxyl group, a cyano group, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group are substituted or ring-formed, and the obtained compounds are identical or similar in effect, and the preparation method is simple and easy. Here, any position on the alkyl group, the cycloalkyl group, the alkenyl group or the alkynyl group may be substituted by a substituent or any -CH ₂ - may be substituted.

Based on the preparation and effect examples of the present invention and the knowledge in the art, it can be inferred that the substituent R ^{1 in the} formula of the present invention is hydrogen, hydroxy, aryl, heteroaryl, -C ₈ alkyl, C ₃ -C ₈ a cycloalkyl group, a C ₂ -C ₈ alkenyl group or a C ₂ -C ₈ alkynyl group, a -C ₈ alkyl group, a C ₃ -C ₈ cycloalkyl group, a C ₂ -C ₈ alkenyl group or a C ₂ -C Any position on the ₈ alkynyl group is substituted by a substituent or any -CH ₂ - thereof is substituted, and the obtained compounds are identical or similar in effect, and the preparation method is simple and easy. Based on the preparation and effect examples of the present invention and the knowledge in the art, it can be inferred that the substituent R ^{2 in the} formula of the present invention is hydrogen, a halogen atom, a nitro group, an amino group, a hydroxyl group, a trihaloalkyl group, a -C ₈ alkyl group. , C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkene Any position on the group or C ₂ -C ₈ alkynyl group is substituted by a substituent or any -CH ₂ - thereof is substituted, and the obtained compounds are identical or similar in effect, and the preparation method is simple and easy.

According to the preparation and effect examples of the present invention and the knowledge in the art, it can be inferred that the substituent R ^{3 in the} formula of the present invention is hydrogen, dC ₈ alkyl or C ₃ -C ₈ cycloalkyl, dC ₈ alkyl or Any position on the C ₃ -C ₈ cycloalkyl group is substituted by a substituent or any -CH ₂ - thereof is substituted, and the obtained compounds are identical or similar in effect, and the preparation method is simple and easy.

According to the preparation and effect examples of the present invention and the knowledge in the art, it can be inferred that when the substituent X in the formula of the present invention is -0- or -NR ⁷ -, the obtained compounds are identical or similar in effect, and are prepared. The method is simple and easy. Wherein R ⁷ is hydrogen, aryl, heteroaryl, -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl.

 The present invention also provides a pharmaceutical composition comprising a 1,4-dihydro-1,8-naphthyridine derivative, a pharmaceutically acceptable equivalent or a mixture thereof, and a pharmaceutically acceptable carrier.

 The compounds of the general formula of the present invention can be synthesized by the following routes:

 NH HCI NC^ /\

detailed description

The present invention discloses 5-amino-1,4-dihydro-1,8-naphthyridine derivatives and pharmaceutical compositions and uses thereof, and those skilled in the art can learn from the contents of the present invention and appropriately improve the process parameters. Special need It is to be noted that all such alternatives and modifications will be apparent to those skilled in the art and are considered to be included in the 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.

 In order to make those skilled in the art better understand the technical solutions of the present invention, the present invention will be further described in detail below with reference to specific embodiments.

 Made in the embodiment of the invention

Compound 1 : 5-Amino-7-ethyl-2,6-dimercapto-4-(3-nitrophenyl)-1,4-2H-1,8-naphthyridine-3-carboxylic acid decyl ester , as shown in S1.

Compound 2: 5-Amino-7-ethyl-4-(3-decyloxyphenyl)-2,6-dimercapto-1,4-2H-1,8-naphthyridine-3-carboxylic acid Ester, as shown by S2

Compound 3: 5-Amino-7-ethyl-4-(2,3-dichlorophenyl)-2,6-dimercapto-1,4-2H-1,8-naphthyridine-3-carboxylic acid hydrazine Ester, as shown by S3.

 S4

 Compound 4: 5-Amino-4-(3-nitrophenyl)-2-indolyl-6-ethyl-7-propyl-1,4-2H-1,8-naphthyridine-3-carboxylic acid Oxime ester, such as S4

 S5

 Compound 5: ethyl 5-amino-7-ethyl-2,6-dimercapto-4-(3-chlorophenyl)-1,4-2Η-1,8-naphthyridin-3-carboxylate, As shown in S5.

 Compound 6: 5-Amino-6-ethyl-2-mercapto-4-(4-fluorophenyl)-7-propyl-1,4-2H-1,8-naphthyridine-3-carboxylic acid Ester, as shown in S6.

Compound 7: 5-amino-4-(2-chlorophenyl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridine-3-carboxylic acid isopropyl ester , as shown in S7.

 Compound 8: 5-amino-4-(2-fluorophenyl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridin-3-carboxylic acid isopropyl ester , as shown in S8.

 Compound 9: 5-Amino-4-(3-nitrophenyl)-6-ethyl-2-indolyl-7-propyl-1,4-2H-1,8-naphthyridine-3-carboxylic acid Isopropyl ester, as shown by S9.

 S10

 Compound 10: 5-amino-4-(2-chlorophenyl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridin-3-carboxylate , as S10

Compound 11 : 5-amino-4-(2-chlorophenyl)-7-ethyl-2,6-dimercapto-1,4-2H-1, 8-naphthyridin-3-carboxylic acid-2- Ethoxylated ethyl ester, as indicated by S11.

 Compound 12: 5-Amino-4-(2-fluorophenyl)-6-ethyl-2-indolyl-7-propyl-1,4-2H-1,8-naphthyridin-3-carboxylic acid Propyl ester, such as S

 Compound 13: 5-amino-4-(3-nitrophenyl)-6-ethyl-2-indolyl-7-propyl-1,4-2H-1,8-naphthyridine-3-carboxylic acid -2,2,2-trifluoroethyl

 Compound 14: 5-amino-4-(2-fluorophenyl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridin-3-carboxylic acid-2, 2,2-trifluoroethyl ester, such as S14

Compound 15 : 5-amino-4-(2,3,4,5,6-pentafluorophenyl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthalene Pyridine-3-carboxylic acid-ethyl ester, as indicated by S15.

 S16

 Compound 16: 5-amino-4-(2-decyloxyphenyl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridine-3-carboxylic acid- Ethyl ester, such as S 1

 Compound 17: 5-Amino-4-(3-fluorophenyl)-2,6-diethyl-7-propyl-1,4-2H-1,8-naphthyridin-3-carboxylic acid-decyl ester , as shown in S17.

 Compound 18: 5-Amino-4-(2-chlorophenyl)-2-trifluoromethyl-6-indolyl-7-ethyl-1,4-2Η-1,8-naphthyridin-3-carboxylate Acid -

 S19

Compound 19: 5-Amino-4-(3-trifluorodecylphenyl)-7-ethyl-2,6-dimercapto-1,4-2Η-1,8-naphthyridine-3-carboxylic acid - Ethyl ester, as indicated by S19.

 Compound 20: 5-amino-4-(3-fluorophenyl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridin-3-carboxylic acid-propargyl Ester, such as S20

Compound 21: 5-amino-4-phenyl-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridin-3-carboxylic acid-cyclopropenyl ester, such as S21

 S22

 Compound 22: 5-Amino-4-phenyl-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridine-3-carboxylic acid

- Cyanoethyl ester, as shown in S22.

Compound 23: 5-amino-4-(pyrimidin-5-yl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridine-3-carboxylic acid-isopropyl Ester, as shown in S23

Example 1: Synthesis of Compound S1

 S1 Step 1 Synthesis of raw material A

 Mix 6.64 g (10.06 mmol) of malononitrile and 4.63 g of absolute ethanol (10.06 mmol), stir in a reaction flask at room temperature, and add a solution of hydrochloric acid in an ice bath.

(10.39 mmol), warmed to room temperature, stirred and chilled overnight, filtered, washed and dried to give A ( 12.1 g), yield 80.4%, ESI-MS: 113.1 [M+H] ⁺ „ Step 2 Synthesis of Compound CI

Ethyl acetoacetate (13.0 g, 0.1 mol) was mixed with acetic anhydride (7.5 g, 0.073 mol), sulfuric acid (0.8 mL) was added with stirring in an ice bath, and 3-nitrobenzaldehyde (16.1 g, 0.11) was added. Mol), the solid slowly dissolved, after stirring for 1 h, TLC monitored the end of the reaction, adding 95% ethanol lOOmL, stirring and hooking, refrigerator refrigeration for 1 h, filtration, solid drying to obtain product CI 20.1g yield 80.7%. ESI-MS: 250.2 [M+H] ⁺ .

 Step 3 Synthesis of intermediate D1

A (2.2 g, 0.015 mol), ammonium acetate (3.3 g, 0.043 mol) and 10 mL of sterol were added to the reaction flask, stirred, refluxed for 30 min, C1 (3.5 g, 0.014 mol) was added, and reflux was continued for 30 min. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc) ESI- MS: 313.4 [MH]" ₀

Step 4 The intermediate D1 (HOmg, 0.35 mmol) was dissolved in 10 mL of 1,2-dichloroethane, and 3-pentanone (90.35 mg, 1.05 mmol) and A1C1 ₃ (85 mg 0.63 mmol) were added thereto under nitrogen. After microwave (MW=200W) reaction for 30min, after TLC monitoring the reaction of the raw materials, stop heating, cool to room temperature, pour into THF:H ₂ 0 = 1 : 1 solution (15 mL), add 10% NaOH with stirring. The mixture was extracted with chloroform (15 mL EtOAc). : 1 ), the product S1 was obtained as a yellow solid 58.6 mg, yield 40%. ESI- MS [M+H] ⁺ =383.1„

 3⁄4 NMR (400HZ CDC13): δΐ .20 (3Η, m), 1.94(3Η, s), 2.71(2Η, m), 2.51(3Η, s), 3.62 (3Η, s), 5.44 (2H, s), 7.56(1H, t, J=8.0), 7.76(1H, d, J=2.0), 8.05(1H, dd, J=1.2, 8.0), 8.38 (1H, s).

Implementation 2: Synthesis of Compound S2

Step 1 Synthesis of Compound C2

3-decyloxybenzaldehyde (27. 2 g, 0.2 mol), ethyl acetoacetate ( 26.1 g, 0.2 mol), catalytic amount of piperidine (0.85 g, 0.01 mol), acetic acid (0.6 g, 0.01 mol) and Add 100 mL of toluene to the reaction flask for 4 h. After TLC detection, dilute the reaction solution with ethyl acetate, add appropriate amount of water, extract, wash the organic phase with saturated NaHC0 ₃ solution, wash with saturated NaCl solution, 50×3, organic The layer of sewage Na ₂ S0 _{4 was} dried to obtain an oily product C2 39.7 g yield 80%. ESI-MS: 249.2 [M+H] ⁺ .

Step 2 Synthesis of intermediate D2 Add A (2.2 g, 0.015 mol), ammonium acetate (3.3 g, 0.043 mol) and 10 mL of sterol to the reaction flask, stir, reflux for 30 min, add C2 ( 3.47 g, 0.014 mol), and continue to reflux for 30 min. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc:EtOAc: ESI- MS: 312.4 [MH]" „

 Step 3

Intermediate D2 (HOmg, 0.35 mmol) was dissolved in 10 mL of 1,2-dichloroethane, and 3-pentanone (90 mg, 1.05 mmol) and A1C1 ₃ (85 mg 0.63 mmol) were added thereto under nitrogen. After heating and refluxing, TLC was used to monitor the completion of the reaction, the heating was stopped, and after cooling to room temperature, poured into THF:H ₂ 0 = 1 :1 solution (15 mL), and 10% aqueous NaOH solution was added dropwise to pH>7 with stirring. The mixture was extracted with chloroform (15 mL, EtOAc) (EtOAc (EtOAc) Product S2 yellow solid 59.2 mg, yield 44%. ESI- MS

[M+H] ⁺ =382.1.

3⁄4 NMR (400Hz CDC1 ₃ ): 1.21 (6H, m), 1.90 (3H, m), 2.33 (3H, s),

2.68(2H, m), 3.69 (3H, s), 4.06 (2H, m), 5.18 (1H, s), 6.73 (lH,dd, J=l .6,8.0), 6.86 (1H, t, J =8.0), 7.02 (1H, s), 7.14 (1H, t, J=8.0).

Implementation 3: Synthesis of Compound S3

Step 1 Synthesis of Compound C3

Mixing acetoacetate (13.0 g, 0.1 mol) with acetic anhydride (7.5 g, 0.073 mol), Sulfuric acid (0.8 mL) was added under stirring in an ice bath, then 2, 3-dichlorobenzaldehyde (18.9 g, 0.11 mol) was added, and the solid was slowly dissolved. After stirring for 1 h, the reaction was terminated by TLC, and 100 mL of ethanol was added. Stir well, refrigerator for 1h, filter, solid drying to obtain product C3 23.5g yield 86.1%. ESI-MS: 274.2 [M+H] ⁺ .

 Step 2 Synthesis of intermediate D3

 Add A (2.2 g, 0.015 mol), ammonium acetate (3.3 g, 0.043 mol) and 10 mL of sterol to the reaction flask, stir, reflux for 30 min, add C3 (2.7 g, 0.01 mol), and continue to reflux for 30 min. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc) ESI- MS: 337.2 [M-H]"„

 Step 3

Intermediate D3 (120 mg, 0.35 mmol) was dissolved in 10 mL of 1,2-dichloroethane, and 3-pentanone (90 mg, 1.05 mmol) and A1C1 ₃ (85 mg 0.63 mmol) were added thereto under nitrogen. After heating and refluxing, TLC was used to monitor the completion of the reaction, the heating was stopped, and after cooling to room temperature, poured into THF:H ₂ 0 = 1 :1 solution (15 mL), and 10% aqueous NaOH solution was added dropwise to pH>7 with stirring. The mixture was extracted with chloroform (15 mL, EtOAc), EtOAc (EtOAc m. Product S3, yellow solid 36.8 mg, yield 25.9%. ESI- MS

[M+H] ⁺ = 406.0.

toMR (400Hz, CDC1 ₃ ): 1.21 (3H, m), 1.97(3H, s), 2.46 (3H, s),

 2.66(2H, m), 3.64 (3H, s), 4.51 (2H, s), 5.15 (1H, s), 7.11 (1H, t, J=8.0), 7.28 (1H, dd, J=1.6, 8.0 ), 7.40 (1H, dd, J=1.6, 8.0).

Implementation 4: Synthesis of Compound S4

The intermediate Dl (100 mg, 0.32 mmol) was dissolved in 10 mL of 1,2-dichloroethane, 4-heptanone (75mg, 0.64mmol) and A1C1 ₃ (85mg 0.63mmol) were added, and the reaction was refluxed under nitrogen. After the reaction of TLC was monitored, the heating was stopped. After cooling to room temperature, it was poured into THF:H ₂ 0 = 1 : 1 solution (15 mL), stirring force under stirring. 10% NaOH aqueous solution to pH>7, the mixture is extracted with dichloromethane (15 mL x 3 ), combined organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, silica gel column chromatography Ester = 5 : 1 ~ 3: 1 ), the product S4 was obtained as a yellow solid, 17.4 mg, yield 13%. ESI- MS

[M+H] ⁺ = 411.3.

ifiNMR (400Hz CDC1 ₃ ): 1.02 (3H, t, J=7.2), 1.09 (3H, t, J=7.2), 1.65 (2H m), 2.44 (3H, s), 2.59 (2H, m), 2.65 (2H, m), 3.69 (3H, s), 4.48 (2H, s), 5.15(1H, s), 7.44 (1H, t, J=8.0), 7.67 (1H, d, J=2.0), 8.06 (1H, dd, J= 1.2, 8.0), 8.21 (1H, d, J=2.0).

Implementation 5: Synthesis of Compound S5

Step 1 Synthesis of Compound C5

3-chlorobenzaldehyde (3.0 g, 0.02 mol), ethyl acetoacetate (2.8 g, 0.02 mol), piperidine 8d, acetic acid 0.5 mL) and 15 mL of toluene were added to the reaction flask for reflux overnight, TLC monitoring After the reaction was completed, 5 mL of water was added, and ethyl acetate (20 mL, EtOAc) was evaporated. ESI-MS: 253.2 [M+H] ⁺ .

Step 2 Synthesis of intermediate D5 Add A (2.9 g, 0.019 mol), ammonium acetate (4.5 g, 0.058 mol), C5 (4.9 g, 0.019 mol) and 150 mL of sterol to the reaction flask, stir, reflux for 45 min, TLC detection, complete reaction, vacuum The residue was concentrated to give purified crystals eluted elut elut elut elut elut elut elut elut elut elut ESI-MS: 316.2 [MH] -.

 Step 4

Intermediate D5 (220 mg, 0.69 mmol) was dissolved in 30 mL of 1,2-dichloroethane, and 4,4-didecylcyclohexanone (120 mg, 1.38 mmol) and A1C1 ₃ (190 mg 1.43 mmol) were added thereto. Under the protection of nitrogen, the reaction was heated to reflux, overnight. After the reaction of TLC was monitored, the reaction was stopped. After cooling to room temperature, pour into THF:H ₂ 0 = 1:1 solution (15 mL), and add 10 with stirring. NaOH aqueous solution to pH>7, the mixture was extracted with dichloromethane (15 mL EtOAc), EtOAc (EtOAc) =3:1), product S5 yellow oil 124.3 mg was isolated, yield 46.6%. ESI-MS [M+H] ⁺ = 386.2.

3⁄4 NMR (400 Hz DMSO-d ₆ ): 1.10 (3H, m), 1.19 (3H, m), 1.89 (3H, s), 2.54 (2H, m), 2.30 (3H, s), 3.98 (2H, m) , 5.04 (1H, s), 5.41 (2H, m), 7.12 (1H, m), 7.19 (2H, t, J=2), 7.42 (1H, s).

Step 1 Synthesis of Compound C6

Ethyl acetoacetate (6.5 g, 0.05 mol) was mixed with acetic anhydride (3.8 g, 0.036 mol), sulfuric acid (0.4 mL) was added with stirring in an ice bath, and 4-fluorobenzaldehyde (6.2 g, 0.05 mol) was added. ), the solid slowly dissolves, after stirring for 1 h, TLC monitors the end of the reaction, and a small amount of water is added to quench the reaction. After adding 50 mL of dichloromethane, the organic layer was separated, the organic layer was washed with water, dried, concentrated, and purified by column chromatography (ethyl ether: ethyl acetate = 10:1) to yield product C6 lO. ESI-MS: 237.2 [M+H] ⁺ .

 Step 2 Synthesis of intermediate D6

 Add A (2.2 g, 0.015 mol), ammonium acetate (3.3 g, 0.043 mol), C6 (3.5 g, 0.014 mol) and 40 mL of sterol to the reaction flask, stir, reflux for 30 min, TLC detection, complete reaction, Concentration in vacuo, EtOAc (EtOAc:EtOAc) ESI-MS: 313.4 [M-H] -.

 Step 3

Intermediate D6 (220 mg, 0.69 mmol) was dissolved in 10 mL of 1,2-dichloroethane, and 3-pentanone (120 mg, 1.38 mmol) and A1C1 ₃ (190 mg 1.43 mmol) were added thereto under nitrogen. After reflux reaction, TLC was used to monitor the completion of the reaction, the heating was stopped, and after cooling to room temperature, poured into THF:H ₂ 0 = 1 :1 solution (15 mL), and 10% aqueous NaOH solution was added dropwise to pH>7, the mixture was stirred. The mixture was extracted with chloroform (15 mL EtOAc) (EtOAc:EtOAc:EtOAc The product S6 was obtained as a yellow solid 124.3 mg, yield 46.6%. ESI-MS: 398.2 [M+H] ⁺ .

 3⁄4 NMR (400 Hz DMSO-d6): 0.95 (6H, m), 1.18 (3H, m), 1.68 (2H, m), 2.29 (3H, s), 2.48 (4H, m), 3.97 (2H, m), 5.02 (1H, s), 5.32 (2H, s), 7.00 (2H, m), 7.33 (2H, m), 9.13 (1H, s).

Example 7: Synthesis of Compound S7

 Step 1 Synthesis of Compound C7

2-Chlorophenylfurfural (2.8 g, 0.02 mol), isopropyl acetoacetate ( 2.88 g, 0.02 mol), catalytic amount of piperidine 0.5 mL, acetic acid 0.5 mL, and toluene 20 mL were added to the reaction flask and heated to reflux. TLC was used to monitor the reaction. The mixture was combined with ethyl acetate (20 mL 3 ), and the organic phase was combined. The organic phase was washed with saturated NaHS0 ₃ and NaCI, dried over anhydrous sodium sulfate and evaporated. : ethyl acetate = 10:1), 4.8 g of product C7 pale yellow oil was isolated, yield 91%. ESI-MS: 267.1 [M+H] ⁺ .

 Step 2 Synthesis of intermediate D7

 Add A (2.7 g, 0.018 mol), ammonium acetate (4.2 g, 0.054 mol) and 20 mL of sterol to the reaction flask, stir, reflux for 30 min, add C7 (4.8 g, 0.018 mol), and continue to reflux for 30 min. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc) ESI-MS: 330.1 [M-H] -.

 Step 3

Intermediate D7 (331 mg, 1 mmol) was dissolved in 10 mL of 1,2-dichloroethane, and 3-pentanone (129 mg, 1.5 mmol) and A1C1 ₃ (200 mg, 1.5 mmol) were added thereto under nitrogen After heating and refluxing, the reaction was stopped overnight. After the TLC was monitored, the reaction was stopped. After cooling to room temperature, poured into THF:H ₂ 0 = 1:1 solution (15 mL), and 10% aqueous NaOH solution was added dropwise to pH> with stirring. 7. The mixture was extracted with chloroform (15 mL EtOAc). EtOAc (EtOAc) = 3:1), product S7 yellow solid 188.1 mg was isolated, yield 47%. ESI-MS

[M+H] ⁺ =400.0.

ifiNMR (CDC1 ₃ , 400 MHz): 7.27-7.55 (4H, m), 6.86 (1H, s), 5.43 (1H s), 4.87 (1H, m), 4.10 (2H, s), 2.65-2.78 (2H , m), 2.36(3H, s), 1.95(3H, s), 1.15-1.42 (6H, m), 1.00-1.09 (3H, m).

 Step 1 Synthesis of Compound C8

2-fluorobenzaldehyde ( 1.24 g, 0.01 mol), isopropyl acetoacetate ( 1.44 g, 0.01 mol ), catalytic amount of piperidine 0.25 mL, acetic acid 0.25 mL and toluene 20 mL were added to the reaction flask and heated to reflux. TLC was used to monitor the reaction. Water was added to 10 mL, ethyl acetate (20 mL 3 ), and the organic phase was combined. The organic phase was washed successively with saturated NaHS0 ₃ and EtOAc. : Ethyl acetate = 10:1). The product C8 was obtained as a pale yellow oil (yield: 54%). ESI-MS: 267.1 [M+H] ⁺ .

 Step 2 Synthesis of intermediate D8

Add A (0.83 g, 5.6m mol), ammonium acetate (1.3 g, 16.8m mol) and 15mL sterol to the reaction flask, stir, reflux reaction for 30 min, force into C8 (1.4 g, 5.6m mol), The mixture was refluxed for 30 min, EtOAc (EtOAc) eluted. ESI-MS: 314.1 [Μ-Η; Γ. Intermediate D8 (261 mg, 0.83 mmol) was dissolved in 10 mL of 1,2-dichloroethane, and 3-pentanone (107 mg, 1.25 mmol) and A1C1 ₃ (166 mg, 1.25 mmol) were added thereto under nitrogen After heating and refluxing, the reaction was stopped overnight. After the reaction of the material was completed by TLC, the heating was stopped. After cooling to room temperature, it was poured into THF:H ₂ 0 = 1 :1 solution (15 mL), and the mixture was stirred under stirring. 10% NaOH aqueous solution to pH>7, the mixture is extracted with dichloromethane (15 mL χ 3 ), the organic phase is combined, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated. Ester = 3: 1), the product S8 was obtained as a yellow solid 153 mg, yield 48%. ESI-MS [M+H]+= 384.3.

ifiNMR (CDC1 ₃ , 400 MHz): 7.74 (1H, s), 6.90-7.40 (4H, m), 5.33 (1H, s), 4.91-4.96 (1H, m), 4.14 (2H, s), 2.60- 2.68 (2H, m), 2.48(3H, s), 1.96(3H, s), 1.26 (3H, d, J =6.4 Hz), 1.18 (3H, d, J =7.6 Hz), 1.02 (3H, d , J = 6.4 Hz). Example 9: Synthesis of Compound S9

Step 1 Synthesis of Compound C9

3-nitrophenylfurfural (1.51 g, 0.01 mol), isopropyl acetoacetate (1.44 g, 0.01 mol), catalytic amount of piperidine 0.25 mL, acetic acid 0.25 mL, and toluene 20 mL were added to the reaction flask and heated to reflux. The reaction was carried out, and the reaction was completed by TLC. Water (10 mL), ethyl acetate (20 mL 3), and the organic phase was combined, and the organic phase was washed successively with saturated NaHS0 ₃ 2.77 g, yield: quantitative. ESI-MS: 278.1 [M+H] ⁺ .

Step 2 Synthesis of Intermediate D9 Add A ( 1.49 g, 10 mmol ), ammonium acetate ( 2.31 g, 30 mmol) and 15 mL of decyl alcohol to the reaction flask, stir, reflux for 30 min, add C9 ( 2.77 g, 10 m mol ), and continue to reflux for 30 min. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc) ESI-MS: 341.1 [Μ-Η; Τ.

 Step 3

Intermediate D9 (342 mg, 1 mmol) was dissolved in 10 mL of 1,2-dichloroethane, to which was added 4-heptanone 0.6 mL and A1C1 ₃ (200 mg, 1. 5 mmol). The reaction was refluxed overnight. After the reaction of the material was completed by TLC, the heating was stopped. After cooling to room temperature, it was poured into THF:H ₂ 0 = 1 :1 solution (15 mL), and 10% aqueous NaOH solution was added dropwise to pH>7 with stirring. The mixture was extracted with chloroform (15 mL, EtOAc), EtOAc (EtOAc m. Product S9 yellow solid 198 mg, yield 45%. ESI-MS [M+H]+=439.3.

ifiNMR (CDC1 ₃ , 400 MHz): 8.24 (1H, s), 8.04 (1H, d, J = 8.0 Hz), 7.67 (1H, d, J = 7.6 Hz), 7.42 (1H, t, J =8.0 Hz) ), 7.05 (1H, s), 5.15 (1H, s),

 5.00-5.06 (1H, m), 4.11 (2H, s), 2.30-2.53 (4H, m), 2.42 (3H, s), 1.65-1.71 (2R m), 1.31 (3H, d, J =6.0 Hz ), 1.20 (3H, d, J = 6.4 Hz), 1.09 (3H, t, J = 7.6 Hz), 1.02 (3H, t, J = 7.2 Hz).

 Sio

Step 1 Synthesis of Compound C10 2-Chlorophenylfurfural (2.8 g, 0.02 mol), allyl acetoacetate (2.84 g, 0.02 mol), catalytic amount of piperidine 0.5 ml, acetic acid 0.5 ml and toluene 20 ml were added to the reaction flask and heated to reflux. After the TLC was monitored, the reaction was completed, water (10 mL), ethyl acetate (20 mL, EtOAc), EtOAc (EtOAc) 5.28g, Yield: Quantitative.

 Step 2 Synthesis of intermediate D10

 Add A ( 1.49 g, 10 mmol ), ammonium acetate ( 2.31 g, 30 mmol) and 15 ml of decyl alcohol to the reaction flask, stir, reflux for 30 min, add C10 ( 2.64 g, 10 m mol ), and continue to reflux for 30 min. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc:EtOAc: ESI-MS: 328.1 [M-H] -.

 Step 3

Intermediate D10 (329 mg, 1 mmol) was dissolved in 10 mL of 1,2-dichloroethane, and 1 mL of 3-pentanone and A1C1 ₃ (200 mg, 1. 5 mmol) were added thereto, and heated under reflux with nitrogen. After the reaction was completed overnight, the reaction of the starting material was stopped by TLC, the heating was stopped, and after cooling to room temperature, poured into a THF:H ₂ 0 = 1 : 1 solution (15 mL), and a 10% aqueous NaOH solution was added dropwise to a pH of >7, the mixture was stirred. The product was extracted with chloroform (15 mL, EtOAc), EtOAc (EtOAc m. S10 yellow solid 303 mg, yield 76% ESI-MS [M+H]+= 398.2.

ifiNMR (CDC1 ₃ , 400 MHz): 7.50 (IH, d, J = 7.6 Hz), 7.27 (IH, d, J = 7.6

Hz), 7.17 (IH, t, J = 7.6 Hz), 7.09 (IH, t, J = 7.6 Hz), 6.70 (IH, s), 5.86-5.93 (IH, m), 5.47 (IH, s), 5.13 (IH, s), 5.08-5.12 (IH, m), 4.57-4.60 (2H, m), 4.50 (2H, s), 2.58-2.72 (2H, m), 2.46 (3H, s), 1.96 ( 3H, s), 1.20 (3H, t, J = 7.6 Hz). Example 11: Synthesis of Compound S11

 Step 1 Synthesis of Compound CI 1

2-Chlorophenylfurfural (2.8 g, 0.02 mol), acetoacetoxyacetate (3.2 g, 0.02 mol), catalytic amount of piperidine 0.5 ml, acetic acid 0.5 ml and toluene 20 ml were added to the reaction flask for heating. The reaction was refluxed, the end of the reaction monitored by TLC, water was added 10mL, extracted with ethyl acetate (20 mL 3), the combined organic phases, the organic phase was washed with saturated NaHS0 _3, NaCl, dried over anhydrous sodium sulfate, and concentrated to give the product as a pale yellow oil C11 5.1 g, yield: quantitative. ESI-MS: 283.1 tM+H]+.

 Step 2 Synthesis of intermediate D5

 Add A (2.69g, 18.1 mmol), ammonium acetate (4.19 g, 54.3 mmol) and 15 ml of decyl alcohol to the reaction flask, stir, reflux for 30 min, add C11 (5.1 g, 18.1 m mol), continue reflux for 30 min, TLC The reaction was completed, and the mixture was evaporated. EtOAcjjjjjjj ESI- MS: 348.1 [M-H]

 Step 3

Intermediate D11 (280 mg, 0.81 mmol) was dissolved in 10 mL of 1,2-dichloroethane, and 1 mL of 3-pentanone and A1C1 ₃ (160 mg, 1.2 mmol) were added thereto, and the reaction was heated under reflux with nitrogen. After TLC monitors the completion of the reaction, the heating is stopped. After cooling to room temperature, it is poured into THF:H ₂ 0 = 1:1 solution (15 mL), and the force is dropped under stirring. 10% NaOH aqueous solution to pH>7, the mixture is extracted with dichloromethane (15 mL×3), EtOAcjjjjjjjjjjjj =3:1), The product S11 was isolated as a yellow solid 223 mg, yield 66%. ESI-MS [M+H]+= 416.2. ifiNMR (CDC1 ₃ , 400 MHz): 7.50 (1H, d, J = 7.6 Hz), 7.27 (1H, d, J = 7.6 Hz), 7.17 (1H, t, J = 7.6 Hz), 7.09 (1H, t , J = 7.6 Hz), 6.70 (1H, s), 5.46 (1H, s), 4.51 (2H, s), 4.15-4.28 (2H, m), 3.55-3.67 (2H, m), 3.33 (3H, s), 2.48-2.59 (2H, m), 2.45 (3H, s), 1.96 (3H, s), 1.20 (3H, t, J = 7.6 Hz).

 Example 12: Synthesis of Compound S12

 Step 1 Synthesis of Compound C12

 2-fluorobenzoic acid (0.62 g, 5 mmol), allyl acetoacetate (0.71 g, 5 mmol), catalytic amount of piperidine 0.25 ml, acetic acid 0.25 ml and decylbenzene 10 ml were added to the reaction flask and heated to reflux, TLC After the completion of the reaction, 10 mL of water was added, and ethyl acetate (10 mL 3 ) was added. The organic phase was combined, and the organic phase was washed successively with saturated NaHS03, Rate: Quantitative. ESI-MS: 249.1 tM+H]+.

 Step 2 Synthesis of intermediate D12

 Add A (1.2 g, 8.1 mmol), ammonium acetate (1.77 g, 24.3 mmol) and 20 ml of decyl alcohol to the reaction flask, stir, reflux for 30 min, add C12 ( 2.64 g, 10 m mol ), and continue reflux for 30 min. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc. ESI-MS: 312.1 [Μ-Η; Γ.

Step 3 Intermediate D12 (313 mg, 1 mmol) was dissolved in 10 mL of 1,2-dichloroethane, to which was added 4-heptanone 1 mL and A1C1 ₃ (200 mg, 1. 5 mmol). After refluxing the reaction overnight, the reaction was stopped after TLC was monitored. After the reaction was completed, the mixture was cooled to room temperature, poured into a THF:H ₂ 0 = 1:1 solution (15 mL), and a 10% aqueous NaOH solution was added dropwise to a pH of >7. The mixture was extracted with chloroform (15 mL, EtOAc), EtOAc (EtOAc m. Product S12 yellow solid 213 mg, yield 52%. ESI-MS [M+H]+= 410.3.

ifiNMR (CDC1 ₃ , 400 MHz): 7.39 (IH, t, J = 6.8 Hz), 7.11-7.16 (IH, m), 6.69-7.10 (2H, m), 6.76 (IH, s), 5.83-5.93 ( IH, m), 5.38 (IH, s), 5.14-5.17 (IH, m), 5.12 (IH, s), 4.51-4.58 (2H, m), 4.37 (2H, s), 2.50-2.58 (3H, m), 2.47 (3H, s), 2.28-2.38 (IH, m), 1.60-1.72 (2H, m), 1.09 (3H, t, J = 7.2 Hz), 1.02 (3H, t, J = 7.2 Hz ).

 13: Synthesis of compound S13

Step 1 Synthesis of Compound B13

 2,2,6-trimethyl-1,3-dioxin-4-one (7.1 g, 0.05 mol) and 2,2,2-trifluoroethanol (10 g, O.lmol) were dissolved in diterpene In benzene (60 mL), the mixture was heated to 90 ° C, and the reaction was stirred overnight. After the reaction was completed, it was cooled to room temperature and used directly for the next step.

 Step 2 Synthesis of Compound C13

3-Nitrophenylfurfural (2.5 g, 16.7 mmol), acetoacetic acid-2,2,2-trifluoroethyl ester (about 16.7 mmol), catalytic amount of piperidine 0.5 ml, acetic acid 0.5 ml and toluene 20 ml The reaction mixture was added to a reaction flask to the temperature of 90 ° C, and the reaction was completed by TLC. Water (10 mL), ethyl acetate (30 mL 3), and the organic phase was combined, and the organic phase was washed successively with saturated NaHS03, Concentration, silica gel column chromatography ( petroleum ether: ethyl acetate = 10:1). ESI-MS: 318.1 [M+H] ⁺ .

 Step 3 Synthesis of intermediate D13

 Add A (0.47 g, 3.15 mmol), ammonium acetate (0.73 g, 9.45 mmol) and 20 ml of decyl alcohol to the reaction flask, stir, reflux for 30 min, add C13 (1.0 g, 3.15m mol), continue reflux for 30 min. , TLC, the reaction was completed, and the residue was evaporated. EtOAcjjjjjjjj ESI-MS: 381.1 [Μ-Η;

 Step 4

Intermediate D13 (357 mg, 0.93 mmol) was dissolved in 10 mL of 1,2-dichloroethane, to which was added 4-heptanone 1 mL and A1C1 ₃ (186 mg, 1. 4 mmol). After the reaction was continued overnight, the reaction was stopped after TLC was monitored. After the mixture was cooled to room temperature, it was poured into THF:H ₂ 0 = 1 :1 solution (15 mL), and the mixture was stirred under stirring. 10% NaOH aqueous solution to pH>7, the mixture is extracted with dichloromethane (15 mL x 3 ), combined organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, silica gel column chromatography Ester = 3: 1), 267 mg of product S13 yellow solid was isolated, yield 60%. ESI-MS [M+H]+ = 479.3.

ifiNMR (CDC1 ₃ , 400 MHz): 8.18 (1H, s), 8.06 (1H, d, J = 8.4 Hz), 7.68 (1H, d, J = 7.6 Hz), 7.44 (1H, d, J =8.0 Hz) ), 6.99 (1H, s), 5.12 (1H, s),

4.40-4.52 (2H, m), 4.09 (2H, s), 2.50-2.63 (3H, m), 2.44 (3H, s), 2.32-2.40 (1H, m), 1.66-1.73 (2H, m), 1.09 (3H, t, J = 7.6 Hz), 1.03 (3H, t, J = 7.6 Hz). Example 14: Synthesis of Compound S14

Step 1 Synthesis of Compound C14

2-Fluorobenzoic acid (2.07 g, 16.7 mmol), acetoacetic acid-2,2,2-trifluoroethyl ester (about 16.7 mmol), catalytic amount of piperidine 0.5 mL, acetic acid 0.5 mL, and toluene 20 mL were added. The reaction was carried out to a temperature of 90 ° C, and the reaction was completed by TLC. Water was added to 10 mL, ethyl acetate (30 mL 3 ), and the organic phase was combined. The organic phase was washed sequentially with saturated NaHS0 ₃ Silica gel column chromatography (petroleum ether: ethyl acetate = 10:1). ESI-MS: 291.1 [M+H] ⁺ .

 Step 2 Synthesis of intermediate D14

 Add A (0.48g, 3.2mmol), ammonium acetate (0.74g, 9.6mmol) and 20mL sterol to the reaction flask, stir, reflux for 30min, add C14 (0.93 g, 3.2m mol), continue reflux for 30 min. , TLC, the reaction was completed, EtOAc (EtOAc:EtOAc:EtOAc: ESI-MS: 354.1 [Μ-Η;

 Step 3

Intermediate D14 (264 mg, 0.74 mmol) was dissolved in 10 mL of 1,2-dichloroethane, and then 3-pentanone lOmL and A1C1 ₃ (148 mg, 1.11 mmol) were added thereto, and heated under nitrogen. The reaction was refluxed overnight. After the reaction of the material was completed by TLC, the heating was stopped, and after cooling to room temperature, it was poured into THF:H ₂ 0 = 1 :1 solution (15 mL), and the mixture was stirred under stirring. 10% NaOH aqueous solution to pH>7, the mixture is extracted with dichloromethane (15 mL x 3 ), the organic phase is combined, washed with brine, dried over anhydrous sodium sulfate, and evaporated. Ester = 3: 1), 152 mg of product S14 as a yellow solid was isolated, yield 49%. ESI-MS [M+H]+ = 424.2.

ifiNMR (CDC1 ₃ , 400 MHz): 7.37 (1H, td, Jj =7.6 Hz, J ₂ =2.0 Hz), 7.13-7.19 (1H, m), 6.97-7.08 (2H, m), 6.94 (1H, s ), 5.34 (1H, s), 4.36-4.43 (2H, m), 4.35 (2H, s), 2.59-2.70 (2H, m), 2.48 (3H, s), 1.98 (3H, s), 1.20 ( 3H, t, J = 7.6 Hz).

Example 15: Synthesis of Compound S15

Pentafluorobenzaldehyde (500 mg, 2.55 mmol), ethyl acetoacetate (431 mg, 3.32 mmol), intermediate A (383 mg, 2.55 mmol) and acetic acid (256 mg, 3.32 mmol) in a round bottom flask The mixture was dissolved in 30 mL of decyl alcohol, stirred under reflux for 5 h, cooled to room temperature, concentrated under vacuum, silica gel column chromatography ( petroleum ether: ethyl acetate = 3:1). Body D15, 102 mg, yield 11%. ESI-MS (m/z): 374.0 [M+H] ⁺ , 396.6 [M+Na] ⁺ .

 Step 2

Intermediate D15 (80 mg, 0.214 mmol) was placed in a tube, dissolved in 3 mL of 1,2-dichloroethane, and 3-pentanone (110 mg, 1.287 mmol) and trichloride were added thereto. Aluminum (85.5 mg, 0.643 mmol) was placed in a micro-reactor for reaction, temperature Τ = 100 ° C, time t = 3 h. After TLC was monitored, the reaction was stopped, cooled to room temperature, and poured. In THF:H ₂ 0 = 1: 1 solution (10 mL), stir the 10% aqueous NaOH solution to pH>7, and extract the mixture with dichloromethane (10 mL x 3 ), combine the organic phase, and saturate the salt. The mixture was washed with water, dried over anhydrous sodium sulfate, and evaporated to silica gel chromatography (ethyl ether: ethyl acetate = 3:1). ESI-MS (m/z): 442 [M+H] ⁺ .

3⁄4 NMR (400 MHz, DMSO-d ₆ ): δ 9.54 (1H, s), 5.55 (1H, s), 4.99 (2H, s), 3.94 (2H, m), 2.54 (2H, m), 2.31 (3H , s), 1.90 (3H, s), 1.11 (6H, t, J = 7.2 Hz). Example 16: Synthesis of Compound S16

 S16

step 1

 2-decyloxybenzaldehyde (6.8 g, 0.05 mmol) was weighed and dissolved in toluene (20 mL), to which was added piperidine (3.1 mL), ethyl acetoacetate (8.4 g, 0.06 mmol) and acetic acid ( 6.2 mL), heated to reflux overnight, concentrated in vacuo, EtOAc (EtOAc)EtOAc. Chromatography (petroleum ether: ethyl acetate = 10:1) gave product C16 as a yellow oil, 8.6 g, yield 68.7%.

 Step 2

 A (2.2 g, 14.6 mmol), ammonium acetate (3.3 g, 42.8 mmol) and 20 mL of sterol were added to the reaction flask, stirred, refluxed for 30 min, and forced into C16 (3.5 g, 14.1 mmol). The mixture was refluxed for 30 min, EtOAc (EtOAc m.).

 Step 3

Referring to the synthesis method of S15 in Example 15, using intermediate D16 (80 mg, 0.256 mmol), 3-pentanone (132 mg, 1.53 mmol) and aluminum trichloride (68 mg, 0.511 mmol), The target product S16 was obtained as a yellow solid, 28 mg, yield 29%. ESI-MS (m/z): 382 [M+H] ⁺ .

toMR (400MHz, CDC1 ₃ ): δ 7.38 (1H, m), 7.15 (1H, m), 6.88 (1H, m),

5.47 (1H, s), 4.89 (2H, br s), 4.02 (2H, m), 3.99 (3H, s), 2.62 (2H, q, J = 7.6 Hz), 2.48 (3H, s), 1.95 ( 3H, s), 1.15 (6H, m).

 D17 S17

step 1

 Referring to the synthesis method of D15 in Example 15, 3-fluorobenzoic acid (1.5 g, 0.012 mol), decyl propionate (2.04 g, 0.015 mol), medium A (1.8 g, 0.012 mol) and ammonium acetate ( 1.1 g, 0.014 mol) gave the title intermediate D17 as a yellow solid 365 mg, yield 11%.

 Step 2

Referring to the synthesis method of S15 in Example 15, a wave reaction was carried out using intermediate D17 (150 mg, 0.5 mmol), 4-heptanone (510 mg, 5.0 mmol) and aluminum trichloride (133 mg, 1.0 mmol). Target product S17 yellow solid 11 mg, yield 6%. ESI-MS (m/z): 398 [M+H] ⁺ .

3⁄4 NMR (400 MHz, DMSO-d ₆ ): δ 9.19 (IH, s), 7.24-7.18 (IH, m), 7.14-7.09 (2H, m), 6.92-6.87 (IH, m), 5.46 (2H, Br s), 5.08 (IH, s), 3.55 (3H, s), 2.82-2.75 (IH, m), 2.74-2.60 (IH, m), 2.49-2.30 (4H, m), 1.61-1.52 (2H , m), 1.09 (3H, t, J = 7.2 Hz), 0.95-0.92 (6H, m).

step 1

Referring to the synthesis method of D15 in Example 15, 2-chlorobenzaldehyde (1.4g, 0.01 mol), three Ethyl fluoroacetate (2.4 g, 0.013 mol), intermediate A (1.5 g, 0.01 mol) and ammonium acetate (0.92 g, 0.012 mol) gave the title intermediate D18, 430 mg of yellow solid, yield 12 %.

 Step 2

Referring to the synthesis method of S15 in Example 15, using intermediate D18 (120 mg, 0.323 mmol), 3-pentanone (167 mg, 1.941 mmol) and aluminum trichloride (85.9 mg, 0.646 mmol), The target product S18 was obtained as a yellow solid, 51 mg, yield 36%. ESI-MS (m/z): 440 [M+H] ⁺ .

IfiNMR (400MHz, DMSO-d ₆ ): δ 9.52 (1H, br s), 7.41-7.35 (2H, m), 7.29 (1H, t, J = 7.2 Hz), 7.23-7.19 (1H, m), 5.36 (1H, s), 5.23 (2H, br s), 4.01-3.97 (2H, m), 2.58-2.55 (2H, m), 1.88 (3H, s), 1.10-1.09 (6H, m).

 S19

 Step 1 Synthesis of Compound C19

Ethyl acetoacetate ( 1.95g, 0.015 mol ), dissolved in 30mL of benzene, while adding m-trifluorophenyl aldehyde (2.61g, 0.015 mol), slowly adding 2 drops of piperidine during stirring, stirring 2min, then slowly add 2 drops of acetic acid, continue to stir, a large amount of white smoke is generated, after the reaction is stable, the above reaction system is heated to reflux in a 95 °C oil bath, TLC detection, after 4h, the reaction is stopped, cooled, and The reaction solvent was evaporated to dryness on a rotary evaporator. The crude material was purified by silica gel column chromatography, eluting with a gradient of petroleum ether and ethyl acetate at a ratio of 20:1-10:1 to give a pale yellow oily compound C19 (3.0 g), yield 70%. Step 2 Synthesis of Intermediate D19

 A ( 2.35 g, 0.015 mol) was placed in a 100 mL reaction flask, 30 mL of methanol was added, then ammonium acetate (3.0 g, 0.038 mol) was added, and the mixture was heated to reflux in an oil bath at 80 ° C, and stirred for 0.5 h. Stirring was stopped, C19 (3.0 g, 0.01 mol) was added to the system, reflux stirring was continued, TLC was detected, the reaction was stopped after 1 h, cooled, and the reaction solvent was evaporated to dryness on a rotary evaporator. Separation was carried out by eluting with a gradient of petroleum ether and ethyl acetate in a gradient of 4: 1-2:1 to afford white solid compound D19 (2 g).

 Step 3

D19 (70 mg, 0.20 mmol) was dissolved in 15 mL of 1,2-dichloroethane, 3-pentanone (100 mg, 1.2 mmol) was added, then aluminum trichloride (40 mg, 0.3 mmol) was added, Heat and reflux in 95 °C oil bath, TLC detection, stop the reaction after 48h, cool, pour the above reaction solution into 30mL tetrahydrofuran / water = 1: 1 mixed solution, slowly add 10% NaOH solution to adjust PH After the mixture is stirred for 0.5 h, the two phases are separated, and the aqueous phase is extracted with dichloromethane (3×10 mL). The combined organic phase is washed with brine, dried over anhydrous sodium sulfate, filtered, Chromatography was carried out to carry out elution using a gradient of petroleum ether and ethyl acetate in a ratio of 6:1 to 4:1 to give compound S19, 35 mg, yield 39.3%. ESI-MS [M+H] ⁺ = 420.2.

ifiNMR (400MHz, CDC1 ₃ ): δ 1.29 (6H, m), 1.99 (3H, s), 2.41 (3H, s), 2.66 (2H, m), 4.01 (2H, s), 4.13 (2H, m) , 5.10 (1H, s), 6.22 (1H, m), 7.36 (1H, t, J=8.0Hz), 7.43 (1H, d, J=7.6Hz), 7.50 (1H, d, J=7.6Hz) , 7.63 (1H, s).

 20: Synthesis of compound S20

step 1.

Weigh 2,2,6-trimethyl-4H-1,3-dioxin-4-one (5.4g, 0.037mol) in 60mL In diphenylene, propargyl alcohol (2.76 g, 0.049 mol) was slowly added dropwise, and the above system was heated to reflux in an oil bath at 115 ° C, detected by TLC, and the reaction was stopped after 4 h, cooled, and the reaction solvent was rotated. The product was evaporated to dryness on a EtOAc (EtOAc) elute elute , Yield 77.4%, ESI-MS [M+H]+ = 141.1.

 Step 2.

 Weigh the compound B20 (2.2g, 0.015 mol), dissolve it in 30mL of hydrazine, add m-fluorobenzaldehyde ( 1.94g, 0.015 mol), slowly add 2 drops of piperidine during the stirring, stir for 2min Then, slowly add 2 drops of acetic acid, continue to stir, and a large amount of white smoke is generated. After the reaction is stable, the reaction system is heated to reflux in an oil bath of 95 ° C, detected by TLC, and the reaction is stopped after 4 hours, cooled, and the reaction is repeated. The solvent was evaporated to dryness on a rotary evaporator. The crude material was purified by silica gel column chromatography, eluting with a gradient of petroleum ether and ethyl acetate at a ratio of 20:1-10:1 to give a pale yellow oily compound C20 ( 2.078g), yield 54%.

 Step 3.

 Compound A (1.5 g, O. Olmol) was placed in a 100 mL reaction flask, 75 mL of decyl alcohol was added, then ammonium acetate (1.6 g, O. Olmol) was added, and the mixture was heated to reflux in an oil bath at 80 ° C, and stirred 0.5. After h, the stirring was stopped, and the above-prepared compound C20 (2.1 g, O. Olmol) was added to the system, and reflux stirring was continued, TLC was detected, the reaction was stopped after 1 h, cooled, and the reaction solvent was evaporated to dryness on a rotary evaporator. The crude product was separated by silica gel column chromatography eluting eluting eluting eluting eluting eluting eluting eluting with

 Step 4.

The compound D20 (260 mg, 0.8 mmol) obtained above was dissolved in 15 mL of 1,2-dichloroethane, and 3-pentanone (345 mg, 4.2 mmol), aluminum trichloride (319 mg, 2.5 mmol), The above system was heated and refluxed in an oil bath at 95 ° C, and detected by TLC. After 48 hours, the reaction was stopped and cooled. The reaction solution was poured into a mixed solution of 30 mL of tetrahydrofuran/water = 1:1, and 10% NaOH was slowly added dropwise. The solution was adjusted to pH > 7.0, and after stirring for 0.5 h, the two phases were separated, and the aqueous phase was extracted with dichloromethane (3×10 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Separation by chromatography, using petroleum ether and ethyl acetate Elution was carried out with a gradient of 6:1 - 4:1 to give compound S20, 90 mg, yield 30%. ESI-MS [M+H] ⁺ = 380.2; ESI-MS [Μ-ΗΓ = 378.2.

ifiNMR (400MHz, CDC1 ₃ ): δ 1.23 (3H, t, J=7.6Hz), 1.99 (3H, s), 2.42 (3H, s), 2.47 (1H, m), 2.68 (2H, m), 4.04 (2H, s), 4.70 (2H, m), 5.07 (1H, s), 6.69 (1H, m), 6.87 (1H, m), 7.07 (1H, m), 7.20 (1H, m).

Example 21: Synthesis of Compound S21

Step 1 Synthesis of Compound C21

 Mix propylene acetoacetate ( 15.6 g, 0.1 mol) with acetic anhydride (7.5 g, 0.073 mol), add sulfuric acid (0.8 mL) with stirring in an ice bath, and add benzofural (11. 6 g, 0.11 mol) The solid was slowly dissolved. After stirring for 1 h, the reaction was completed by TLC. Water (5 mL), dichloromethane (20 mL 3), EtOAc (EtOAc) Petroleum ether: ethyl acetate = 10:1), product C21 was obtained as pale yellow oil, 10.98 g, yield 45%.

 Step 2 Synthesis of intermediate D21

 Add A ( 1.24 g, 8.4 mmol ), ammonium acetate ( 1.94 g, 25.2 mmol ) and 10 mL of sterol to the reaction flask, stir, reflux for 30 min, force into C21 (2.04 g, 84 mmol), continue to reflux 30 The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc)

 Step 3

Accurately weigh D21 (280 mg, 0.91 mmol), dissolve in 10 mL of 1,2-dichloroethane solution, stir to dissolve, then slowly add 3-pentanone (117 mg, 1.36 mmol), add A1C1 ₃ (181 mg, 1.36 mmol). Heating to reflux for 12 h, TLC detection without raw materials, cooling. Add THF:H ₂ 0 = 1:1 aqueous solution 10 mL to dilute. Add 1 mol/L NaOH aqueous solution to adjust the pH to alkaline, stir at room temperature for 30 min, dichloromethane extract 20 mL x 3, combine the organic layers, dry, column chromatography, dichloromethane: decyl alcohol = 100:1~40 :1, 50 mg of a pale yellow solid was obtained, yield 14.66%. ESI-MS: 378.1 [M + H] ⁺ .

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 0.86 (2Η, m), 1.24 (6Η, m), 1.64 (2H, m), 1.98 (3H, s), 2.11 (2H, m), 2.68 (3H, s) , 2.70 (1H, m), 4.21 (2H, m), 4.97 (1H, m), 7.19 (1H, m), 7.28 (2H, m), 7.36 (2H, m).

Example 22: Synthesis of Compound S22

Step 1 Synthesis of Compound C22

 Ethyl acetoacetate (15. 5 g, 0.1 mol) was mixed with acetic anhydride (7.5 g, 0.073 mol), sulfuric acid (0.8 mL) was added with stirring in an ice bath, and phenylfurfural (11. 6 g, 0.11 mol) was added. The solid was slowly dissolved. After stirring for 1 h, the reaction was completed by TLC. Water (5 mL), dichloromethane (20 mL 3 ), EtOAc, EtOAc (EtOAc) Petroleum ether: ethyl acetate = 10:1), mp.

 Step 2 Synthesis of intermediate D22

Add A ( 1.24 g, 8.4 mmol ), ammonium acetate ( 1.94 g, 25.2 mmol ) and 10 mL of sterol to the reaction flask, stir, reflux for 30 min, force into C22 (2.04 g, 84 mmol), continue reflux for 30 min. , TLC detection, complete reaction, concentration under vacuum, crude silica gel column chromatography (Petroleum ether: ethyl acetate = 3:1) gave yellow solid powder D22 (0.71 g). Step 3

Accurately weigh D22 (308 mg, 1 mmol), dissolve in 10 mL of 1,2-dichloroethane solution, stir to dissolve, then slowly add 3-pentanone (129 mg, 1.5 mmol), add A1C1 ₃ ( 200 mg, 1.5 mmol). Heating to reflux for 12 h, TLC detection without raw materials, cooling. Add THF:H ₂ 0 = 1:1 aqueous solution 10 mL to dilute. Add 1 mol/L NaOH aqueous solution to adjust the pH to alkaline, stir at room temperature for 30 min, dichlorosilane extract 20 mL x 3, combine the organic layers, dry, column chromatography, petroleum ether: ethyl acetate = 10:1~1: 1. A pale yellow solid S22 (30 mg) was obtained. ESI-MS: 377.0 [M + H] ⁺ ; 375.0 [MH] -.

3⁄4 NMR (400 MHz, DMSO-i ₆ ): δ 1.12 (3Η, t, J=1.6 Hz), 1.90 (3H, s),

2.33 (3H, s), 2.54 (2H, m), 2.88 (2H, m), 4.13 (2H, m), 5.01 (1H, s), 5.25 (2H, s), 7.08 (1H, m), 7.18 (2H, t, J = 7.6 Hz), 7.32 (2H, d, J = 7.2 Hz), 9.27 (1H, s).

Example 23: Synthesis of Compound S23

Step 1 Synthesis of Compound C23

Isopropyl acetoacetate (0.72 g, 5 mmol) was mixed with acetic anhydride (0.1 g, 0,9 mmol), sulfuric acid (0.01 mL) was added with stirring in an ice bath, and pyrimidine-5-furfural (0.54 g, 5 mmol ), the solid was slowly dissolved. After stirring for 1 h, the reaction was completed by TLC. Water was added 5 mL, dichloromethane (20 mL 3 ), organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, Column chromatography (petroleum ether: ethyl acetate = 10:1) afforded product C23 as pale yellow oil (yield: Step 2 Synthesis of intermediate D23

 A (0.56 g, 3.7 mmol), ammonium acetate (0.87 g, 11.1 mmol) and 10 mL of sterol were added to the reaction flask, stirred, refluxed for 30 min, C23 (0.88 g, 3.7 mmol) was added, and reflux was continued for 30 min. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc:EtOAc:

 Step 3

Accurately weigh D23 ( 125 mg, 0.42 mmol ), dissolve in 10 mL of 1,2-dichloroethane solution, stir to dissolve, then slowly add 3-pentanone (36 mg, 0.42 mmol), add A1C1 ₃ ( 84 mg, 0.63 mmol). The reaction was carried out at 98 ° C for 2 h, and no raw material was detected by TLC, and it was cooled. Add THF:H ₂ 0 = 1: 1 aqueous solution diluted 10 mL. Add 1 mol/L NaOH aqueous solution to adjust the pH to alkaline, stir at room temperature for 30 min, extract 20 mL x 3 with dichloromethane, combine the organic layers, dry, column chromatography, petroleum ether: acetone = 10: 1-3: 1 , a pale yellow solid 53.4 mg was obtained with a yield of 65.91 %. ESI-MS: 368.3 [M + H] ⁺ ; 366.0: [M - H] - .

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 0.91 (3Η, t, «/= 6.8 Hz), 1.22 (6H, m), 2.01 (3H, s), 2.42 (3H, s), 2.68 (2H, m), 4.02 (2H, s), 5.02 (1H, s), 5.05 (1H, m), 8.70 (2H, s), 9.03 (1H, s). Example 24: Detection of L-type Ca ²⁺ channel block activity by high content screening analyzer High-content screening analyzer (HCS) platform, real-time fluorescence method for determination of compounds (@10 μ Μ, @50 μ Μ ) The KC1 induced voltage-gated calcium ion influx inhibition activity of SH-SY5Y cells, thereby evaluating the calcium ion channel inhibitory activity of some of the compounds prepared in the examples.

In the experiment, the Fluo-4-AM calcium ion probe was used to load SH-SY5Y cells under physiological conditions, and then KC1 was used to induce voltage-gated calcium channel development. Calcium ions were flowed through the cell membrane calcium channel and combined with fluorescent probes. Fluorescence signal; at the same time, the high content records the intracellular real-time fluorescence signal, reflecting the calcium flow from the inflow intensity. Fluo-4-AM itself cannot be excited to produce fluorescence. When it enters the cell, it is cleaved by cytosolic esterase into Fluo-4, and then combined with calcium ions, it is excited by 488nm light to produce strong green fluorescence. KC1 acts as an agonist of the voltage-gated calcium channel: When K+ reaches a certain concentration, the voltage-gated calcium channel opens, and the calcium ion inflow enters the cell, which combines with the dye to produce fluorescence. If the calcium channel is inhibited by the compound, it enters the calcium ion inside the cell. Decreased, the fluorescence intensity decreases, and the degree of reduction is related to the degree of inhibition of the calcium channel by the compound. The L-type calcium channel is a voltage-gated calcium channel. In the SH-SY5Y cells used in this experiment, the voltage-gated calcium channel on the cell membrane surface is mainly L-type, so the calcium flux signal induced by KC1 is mostly L-type calcium channel signal.

 Materials and instruments:

 1640+10% FBS+1% P/S medium and trypsin were purchased from Gibico.

 SH-SY5Y cells are from the Cell Biology Laboratory of Nanjing Medical University.

 Fluo-4 DirectTM Calcium Assay Kits: purchased from Invitrogen, item number F 10471. High Content Screening Analyzer ( HCS ): Molecular Devices, Model:

Imagexpress.

 96-hole blackboard: Corning 3603.

 KCL inorganic reagent (analytical grade): purchased from sigma, formulated into 1M stock solution when used, diluted to 250 mM application solution when used.

 Experimental procedure

 Dye preparation process:

 Fully follow Fluo-4 DirectTM Calcium Assay Kits ( Invitrogen, article number

F10471) Instructions for the preparation of the dye application solution, as follows: One bottle of component A (dye solid) is dissolved in 10 mL of component C (buffer), and one pipe of component B (Probenecid) is added to 1 mL of component C (buffering) Liquid); then add 200 μM component to the dissolved component A dye to obtain 2xFluo-4-AM application solution; add 100 dye application solution per well to a new 96-well according to the hole corresponding to the cell well. Plate (corning 3599) and placed in the HCS instrument for use.

 2χ compound solution preparation process:

 This experiment measures the inhibition rate of calcium channels in all compounds at a high concentration of 50 μΜ and a low concentration of 10 μΜ. The specific formulation procedure is as follows: All compounds were first prepared in DMSO with a stock solution of 0.01 ,, then each compound was diluted with DMSO. Two concentrations of 5000 μΜ and 1000 μΜ were used, and each concentration was further diluted 50 times with 1640 complete medium (using DMSO as a pure solvent control) to obtain a 2x compound solution for use.

 Cell manipulation process:

SH-SY5Y cells with a confluency of about 90% were trypsinized and incubated at 20,000 cells/well. In a 96-well blackboard; after 24 hours of culture, the culture solution was removed, and 45 different concentrations of 2x compound solution (using DMSO as a pure solvent control) were added to each well, and 4 replicate wells were set for each concentration. The specific 96 wells were set as shown in Table 4. Show:

 Table 4 96 hole settings

 Set the HCS automatic sample loading program. The instrument automatically adds 45 L of 2xFluo-4-AM application solution completely in accordance with the instructions in each well. Set the parameters so that the time for adding dye to each well is the same as the time required for each hole. At the same time, the time required to add all the dyes to the well is the same as the dye incubation time (the incubation time of this experiment is 30 min)

 Set the HCS program, in the order of the dye-added holes, sequentially add each well (to ensure the same time for each dye incubation) 3 (^L concentration of 250 mM KC1 solution, and scan the fluorescence intensity change of each well in real time, add KC1 Fluorescence intensity of 10 time points before scanning, Fl, F2, F3, ... F10; after adding KC1, scan the fluorescence intensity of 40 time points: Fll, F12,

F13 F50.

 The results were processed and the results are shown in Table 5.

 Take the average value F0 of Fl, F2, ...F10, take the maximum value Fmax of Fll, F12, F13, ...F50, record A=Fmax - F0

 Inhibition rate = 100%* (Δ control group - Δ administration group) / Δ control group

Table 5 Compounds provided by the present invention for L-type Ca ²⁺ channel blocking activity The compound provided by the present invention is 10 μΜ 50 μΜ

 SI 26.1% 99.37%

 S2 2.4% 49.19%

 S3 10.37% 90.99%

S4 18.08% 29.80% S5 22.61% 98.30%

 S6 1.37% 70.71%

 S7 21.42% 24.67%

 S8 41.34% 83.01%

 S9 1.94% 85.45%

 S10 77.81% 100.37%

 Sll 3.90% 26.07%

 S12 42.92% 81.31%

 S13 70.26% 94.46%

 S14 51.79% 69.93%

 S15 1.37% 32.97%

 S16 7.01% 35.71%

 S17 34.75% 68.83%

 S18 1.91% 48.57%

 S19 21.11% 68.63%

 S20 20.08% 93.85%

 S21 44.84% 89.13%

 S22 25.56% 34.47%

 S23 52.34% 84.40%

Nimodipine 15.72% 33.87% The experimental results show that the compounds provided by the present invention have obvious blocking activity on the L-type Ca ²⁺ channel, and most of the compounds have better activity than the positive control drug Nimodipine. Example 25: Detection of acetylcholinesterase inhibitory activity of compounds

 Samples: Compounds prepared in Examples 1-22

 Materials and instruments:

Kit, A12217, invitrogen; 96-well blackboard, Costar #3925; Infinite M200 enzyme-labeled detector, Tecan. Kit stock solution configuration:

An Amplex Red reagent, Component A, 200μL·DMSO, Component B, -20°C protected from light; 5 x buffer, Component E is diluted to lx with deionized water according to the required volume. 1 X Reaction Buffer; —Hrp, Component C, add 1 mL 1 Reaction Buffer, store at -20 oC after dispensing; 5 μ 3.3 % of 3⁄40 ₂ , Component D, add to 234.1 deionized water to give 20 mmol/L H ₂ 0 ₂ working solution, now available; one Choline Oxidase, 600 μ 1 Reaction Buffer, stored at -20 ° C after dispensing; 5 mg Ach-cl, Componentg, 275 deionized water ratio configuration 100 mmol/L Ach application solution, now known as ready-to-use; One AchE, add 600 μΐ^ 1 X Reaction Buffer, and store at -20 °C after dispensing.

 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 mol/L, 200 μηιοΙ/L, 40 mol with DMSO. Concentration gradient of /L, 8 μηιοΙ/L, 1.6 μηιοΙ/L, 0.32 μηιοΙ/L, 0.064 μηιοΙ/L.

 4 X AchE application liquid configuration: according to the actual required volume according to the ratio of 1: 250

The AchE stock solution was diluted with 1 X Reaction Buffer.

 2 Configuration of working fluid: According to the actual required volume, each stock solution is mixed according to the ratio of 200 μ Aπφ\ex Red reagent : 100 Horseradish peroxidas: 100 Choline Oxidase: 10 Ach : 9590 1 Reaction Buffer to obtain 2 x working fluid.

Procedure: Add 48 μ of 1 X Reaction Buffer to each well of the designed 96-well black plate. Add a solution of 100 compound concentration to the wells of the above compound in the amount of 2 μL per well. 2 duplicate wells were set at the concentration; 2 μL DMSO + 4S μL lx Reaction Buffer was added to the positive control well, 100 μL of 20 mM 3⁄40 ₂ working solution was added directly to the positive test well, and 2 DMSO + 98 μΐ ^ 1 x Reaction Buffer was added to the negative control well. Two holes are set in each well; compound determination hole and positive control hole Each well is added with 50 4 X AchE application solution, all holes are added with 2 χ working solution per hole 100, mixed, and the enzymatic reaction is started. The total reaction system is 200 μΐ^, the final concentration of the compound thus obtained is l (^mol/L, 2 μηιοΙ/L, 0.4 μηιοΙ/L, 0.08 μηιοΙ/L, 0.016 μηιοΙ/L, 0.0032 μηιοΙ/L, 0.00064 ηηιοΙ/L; Incubate for 30 - 45 min at room temperature.

Fluorescence detection: The fluorescence value of each well at excitation wavelength 540 nm _: emission wavelength 590 nm was measured under Infinite M200 enzyme labeling instrument, and the gain value was set to optimize.

 Data processing: Calculate the average of all drug-administered and control groups and calculate the inhibition rate as follows:

^Metal group average 0D value - negative control average 0D value

 Column rate (1) X 100%

 The positive vs. average 0D value-negative control average 0D value is used to find the logarithm of the dosing concentration based on the base 10, the logarithmic value is the abscissa, the inhibition rate is the ordinate, and the original 6.0 is drawn, and a pharmacological fit is fitted. The dose-effect relationship was determined by the sigmoid curve, and the drug concentration corresponding to the 50% inhibition rate was determined, that is, the IC50 value of the compound for inhibiting acetylcholinesterase activity. The test results of the compounds for acetylcholinesterase inhibitory activity are shown in Table 6.

 Table 6 Test results of the inhibitory activity of the compound of the present invention on acetylcholinesterase

~ The compounds provided by the present invention inhibit the activity of IC ₅ Q ( nmol / L ) ~

 SI 1764

 S2 270

 S3 720

 S4 1080

 S5 630

 S6 1296

 S7 360

 S8 324

 S9 1242

 S10 306

 Sl l 310

 S12 918

 S13 625

S14 428 S15 2320

 S16 332

 S17 1350

 S18 1146

 S19 718

 S20 495

 S21 515

 S22 412

 The results of the tacrine 180 experiment showed that the compounds prepared in the examples were able to inhibit the activity of acetylcholinesterase.

 Conclusion: Based on the above experimental results, the compound of the present invention is a compound which can inhibit the activity of acetylcholinesterase and block the extracellular calcium from flowing into the cell through the calcium channel, has dual activity and has important potential therapeutic value. 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.

-I-

Claims

Rights request

 A compound of the formula I or a pharmaceutically acceptable salt thereof,

0 RNH ₂

R ¹ , ,,人, Υ人Υ丄

R ² HR ⁵

R ³ formula I

Wherein R is selected from aryl or heteroaryl, and the aryl or heteroaryl ring is optionally bonded to a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, an aryl group, a heteroaryl group, or a d a -doalkyl group, a C ₃ -C ₈ cycloalkyl group, a C ₂ -C ₈ chain group or a C ₂ -C ₈ alkynyl group, wherein the substituents at the two positions may be combined to form an aliphatic ring or a heterocyclic ring. , an aromatic ring or a heteroaryl ring, the d-Cu)alkyl group, a C ₃ -C ₈ cycloalkyl group, a C ₂ -C ₈ chain group or an optionally -CH ₂ - group in the C ₂ -C ₈ alkynyl group It may be substituted by one or more of -0-, -S-, -S0 ₂ -, -C(O)- or / and -NR ⁶ -, the d-do alkyl group, C ₃ -C ₈ cycloalkyl group Any hydrogen in the C ₂ -C ₈ chain group or the c ₂ -c ₈ alkynyl group may be substituted by one or more halogen atoms, an aryl group, a nitro group, a heteroalicyclic group, a hydroxyl group, -NR ⁸ R ⁹ ;

X is selected from -0-, -NR ⁷ -;

R ⁸ and R ^{9 are} independently selected from hydrogen, C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, or R ⁸ and R ⁹ Forming a heteroalicyclic group of 5 to 9 ring atoms;

R ⁶ and R ^{7 are} independently selected from the group consisting of hydrogen, -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl;

R ^{1 is} selected from the group consisting of hydrogen, hydroxy, aryl, heteroaryl, C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl optionally -CH ₂ - may be one or more -0-, -S -, -S0 ₂ -, -C(O)- or / and -NR ⁶ -, the dC ₈ alkyl group, c ₃ -c ₈ cycloalkyl group, c ₂ -c ₈ alkenyl group or c ₂ -c ₈ alkynyl group in any position may be substituted with one or more of the hydrogen atoms of halogen, atmosphere, nitro, aryl, heteroaryl, -NR ⁸ R ⁹ substituents;

R ^{2 is} selected from the group consisting of hydrogen, a halogen atom, a nitro group, an amino group, a hydroxyl group, a trihaloalkyl group, a dC ₈ alkyl group, a C ₃ -C ₈ cycloalkyl group, a C ₂ -C ₈ alkenyl group or a C ₂ -C ₈ alkyne. Any one of the -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group -CH ₂ - may be one or more - 0-, -S -, -S0 ₂ -, -C (O) - and / or -NR ⁶ - substitution, the C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group Any position of hydrogen may be substituted by one or more halogen atoms, an aryl group, a nitro group, -NR ⁸ R ⁹ ;

R ³ is selected from hydrogen, C _r C ₈ alkyl or C ₃ -C ₈ cycloalkyl group, a C _r C ₈ alkyl or C ₃ -C ₈ cycloalkyl group optionally substituted -CH ₂ - may be substituted with one or more _{-0-, -S -, -S0 2 -} , -C (O) - and / or -NR ⁶ - substitution, the C _r C ₈ alkyl or C ₃ -C ₈ cycloalkyl group Any position of hydrogen may be substituted by one or more of the prime atoms, cyano, nitro, -NR ⁸ R ⁹ ;

R ⁴ and R ^{5 are} independently selected from -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, said dC ₈ alkyl, c ₃ - The optional -CH ₂ - in the c ₈ cycloalkyl, c ₂ -c ₈ alkenyl or c ₂ -c ₈ alkynyl group may be one or more of -0-, -S-, -S0 ₂ -, - C(O)- or / and -NR ⁶ - substitution, anywhere in the dc ₈ alkyl group, C ₃ -C ₈ cycloalkyl group, C ₂ -C ₈ chain group or C ₂ -C ₈ alkynyl group Hydrogen may be substituted by one or more halogen atoms, an aryl group, a nitro group, an aryl group, a heteroaryl group, -NR ⁸ R ⁹ .

 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

R is selected from a C ₆ -C ₁₂ aryl group or a C ₃ -C ₁₂ heteroaryl group, the aryl or heteroaryl group optionally having a halogen atom, an amino group, a nitro group, a cyano group, a C ₆ -C ₁₂ aryl, C ₃ -C ₁₂ heteroaryl, cc ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl substituted, optionally two The substituents at the position may be taken together to form an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaryl ring, the c _r c ₈ alkyl group,

C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ women chain group or C ₂ -C ₈ alkynyl optionally -CH ₂ - may be substituted by one or more -0-, -S -, -S0 ₂ -, -C(O)- or / and -NR ⁶ - substitution, in the dC ₈ alkyl group, C ₃ -C ₈ cycloalkyl group, c ₂ -c ₈ alkenyl group or c ₂ -c ₈ alkynyl group Any position of hydrogen may be substituted by one or more atomic atoms, cyano group, hydroxyl group, -NR ⁸ R ⁹ ;

X is selected from -0-, -NR ⁷ -;

R ⁸ and R ^{9 are} independently selected from hydrogen, dC ₈ alkyl, C ₃ -C ₈ cycloalkyl, or R ⁸ and R ^{9 taken} together to form a heteroalicyclic group of 5 to 9 ring atoms;

R ⁶ and R ^{7 are} independently selected from the group consisting of hydrogen, C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl;

R ^{1 is} selected from dC ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, said C Cs alkyl, C ₃ -C ₈ cycloalkyl The optional -CH ₂ - in the C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group may be one or more of -0-, -S-, -C(O)- or/and-NR ⁶ - substitution, the -C ₈ alkyl group, C ₃ -C ₈ ring Alkyl, C ₂ -C ₈ alkenyl or alkynyl group _02-08 in any position may be substituted with one or more of the hydrogen atoms of halogen, atmosphere, nitro, C ₆ -C ₁₂ aryl group, C ₃ - C ₁₂ heteroaryl, -NR ⁸ R ⁹ substituted;

R ^{2 is} selected from! _3⁄4 atomic atom, dC ₈ alkyl group, C ₃ -C ₈ cycloalkyl group, C ₂ -C ₈ alkenyl group or C ₂ -C ₈ alkynyl group, the dC ₈ alkyl group, C ₃ -C ₈ cycloalkyl group , optionally substituted C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group of -CH ₂ - may be substituted by one or more -0-, -S- and / or -NR ⁶ - replacing, the dC Hydrogen at any position in the _8- alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ chain or C ₂ -C ₈ alkynyl group may be substituted by one or more halogen atoms, cyano, -NR ⁸ R ⁹ substitution;

R ³ is selected from hydrogen, C _r C ₈ alkyl or C ₃ -C ₈ cycloalkyl group, a C _r C ₈ alkyl or C ₃ -C ₈ cycloalkyl group optionally substituted -CH ₂ - may be substituted with one or more -0-, -S -, -C (O ) - and / or -NR ⁶ - substitution, the C _r C ₈ alkyl or C ₃ -C ₈ cycloalkyl group at any position of hydrogen can be Substituted by one or more prime atoms;

R ⁴ and R ^{5 are} independently selected from d-C4 alkyl, C ₃ -C ₄ cycloalkyl, C ₂ -C ₄ chain or C ₂ -C ₄ alkynyl, said c _r c ₄ alkyl, c The optional -CH ₂ - in the _3- c ₄ cycloalkyl, c ₂ -c ₄ alkenyl or c ₂ -c ₄ alkynyl group may be one or more of -0-, -S-, -S0 ₂ - , -C(O)- or / and -NR ⁶ -substituted, in the d-C4 alkyl group, C ₃ -C ₄ cycloalkyl group, C ₂ -C ₄ alkenyl group or C ₂ -C ₄ alkynyl group The hydrogen at any position may be substituted by one or more halogen atoms, a cyano group, a nitro group, a C ₆ -C ₁₂ aryl group, a C ₃ -C ₁₂ heteroaryl group, -NR ⁸ R ⁹ .

 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

R is selected from a C ₆ -C ₁₂ aryl group or a C ₃ -C ₁₂ heteroaryl group, the optional position on the ring of the aryl or heteroaryl group is [3⁄4 atom, nitro, aryl, -C ₈ alkane a C ₃ -C ₈ cycloalkyl group, a C ₂ -C ₈ alkenyl group or a c ₂ -c ₈ alkynyl group, wherein the substituents at two optional positions may be taken together to form an aliphatic ring, a heterocyclic ring, or an aromatic ring. Or a heteroaromatic ring, the _Cr C ₈ alkyl group, the C ₃ -C ₈ cycloalkyl group, the C ₂ -C ₈ alkenyl group or the optionally -CH ₂ - group of the C ₂ -C ₈ alkynyl group may be one Or a plurality of -0-, -S-, -S0 ₂ -, -C(O)- or / and -NR ⁶ - substitutions, said C _r C ₈ alkyl group, C ₃ -C ₈ cycloalkyl group, C _The hydrogen at any position in the _2- C ₈ alkenyl group or the C ₂ -C ₈ alkynyl group may be substituted by one or more halogen atoms, an aryl group, -NR ⁸ R ⁹ ;

X is selected from -0-, -NR ⁷ -;

R ⁸ and R ^{9 are} independently selected from hydrogen, C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl, or R ⁸ and R ^{9 taken} together to form a heteroalicyclic group of 5 to 9 ring atoms;

R ^{6 is} selected from the group consisting of hydrogen, C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl; R ^{7 is} selected from the group consisting of hydrogen, C _r C ₈ alkyl;

R ^{1 is} selected from dC ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, said C Cs alkyl, C ₃ -C ₈ cycloalkyl The optional -CH ₂ - in the C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group may be one or more of -0-, -S-, -C(O)- or/and-NR ⁶ -substitution, the -C ₈ alkyl group, the C ₃ -C ₈ cycloalkyl group, the C ₂ -C ₈ alkenyl group or the hydrogen at any position in the (3⁄4-0 ₈ alkynyl group) may be substituted by one or more halogen atoms , an aryl group, a C ₆ -C ₁₂ aryl group, a C ₃ -C ₁₂ heteroaryl group, a -NR ⁸ R ⁹ substituent;

R ² is selected from -C ₈ alkyl or C ₃ -C ₈ cycloalkyl group, a C _r C ₈ alkyl or C ₃ -C ₈ cycloalkyl group optionally substituted -CH ₂ - may be substituted with one or more -0-, -S- and / or -NR ⁶ - substitution, the C _r C ₈ alkyl or C ₃ -C ₈ cycloalkyl group at any position may be substituted with one or more of the hydrogen atoms prime, -NR ⁸ R ⁹ substituted; R ^{3 is} selected from hydrogen, dC ₈ alkyl;

R ⁴ and R ^{5 are} independently selected from C _r C ₄ alkyl, C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl group, a C C4 alkyl, C ₂ -C ₄ group or a C ₂ chain women The optional -CH ₂ - in the -C ₄ alkynyl group may be substituted by one or more of -0 -, -S -, -S0 ₂ - or / and -C(O)-, the d-C4 alkyl group, The hydrogen at any position in the c ₂ -c ₄ alkenyl group or the c ₂ -c ₄ alkynyl group may be substituted by one or more atomic atoms.

 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

R is selected from phenyl or C ₃ -C ₆ heteroaryl, the phenyl or heteroaryl group optionally substituted on the ring positions by a halogen atom, a nitro group atmosphere, C _r C ₈ alkyl, C ₂ -C ₈ -alkenyl or C ₂ -C ₈ alkynyl group substituted, wherein two adjacent substituents may be bonded together to form an aliphatic ring, a heterocyclic, aromatic ring or a heteroaromatic ring, a C _r C ₈ alkyl, C ₂ - The optional -CH ₂ - in the C ₈ chain or C ₂ -C ₈ alkynyl group is one or more of -0-, -S -, -S0 ₂ -, -C(O)- or / and -NR ⁶ - substitution, the C _r C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group in any position may be substituted with one or more of the hydrogen atoms of halogen, atmosphere group, -NR ⁸ R ⁹ substitution;

 X is -0-;

R ⁸ and R ^{9 are} independently selected from hydrogen, dC ₈ alkyl, C ₃ -C ₈ cycloalkyl, or R ⁸ and R ^{9 taken} together to form a heteroalicyclic group of 5 to 9 ring atoms;

R ^{6 is} selected from the group consisting of hydrogen, C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl;

R ^{1 is} selected from dC ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, said C Cs alkyl, C ₃ -C ₈ cycloalkyl , optionally substituted C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl group of -CH ₂ - may be substituted by one or more -0-, -S- and / or -NR ⁶ - replacing, the dC _8- alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ The hydrogen at any position in the alkenyl group or the C ₂ -C ₈ alkynyl group may be substituted by one or more atomic atoms, an aryl group, -NR ⁸ R ⁹ ;

R ^{2 is} selected from the group consisting of a trihaloalkyl group and a dC ₈ alkyl group;

R ^{3 is} selected from the group consisting of hydrogen and C 4 alkyl;

R ⁴ and R ^{5 are} independently selected from d-C4 alkyl, and optionally -CH ₂ - in said C _r C ₄ alkyl may be one or more -0-, -S-, -S0 ₂ - or And -C(O)-substituted, the hydrogen at any position in the C _r C ₄ alkyl group may be substituted by one or more ! 3⁄4 atom atoms.

 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

R is selected from a phenyl group or a C ₃ -C ₆ heteroaryl group, and the optional position on the ring of the phenyl or heteroaryl group is substituted by a halogen atom, a nitro group, an aryl group, a C _r C ₆ alkyl group, the C The optional -CH ₂ - in the _r C ₆ alkyl group is replaced by one or more of -0, -S -, -C(O)- or / and -NR ⁶ -, in the C _r C ₆ alkyl group Any position of hydrogen may be substituted by one or more halogen atoms, an aryl group, -NR ⁸ R ⁹ ;

 X is -0-;

R ⁸ and R ^{9 are} independently selected from hydrogen, C _r C ₈ alkyl, C ₃ -C ₆ cycloalkyl, or R ⁸ and R ^{9 taken} together to form a heteroalicyclic group of 5 to 9 ring atoms;

R ^{6 is} selected from the group consisting of hydrogen, C Cs alkyl, C ₃ -C ₆ cycloalkyl;

R ^{1 is} selected from dC ₈ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl, said C Cs alkyl, C ₃ -C ₆ cycloalkyl And optionally in the C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl group -CH ₂ - may be one or more of -0-, -S-, -C(O)- or/and-NR ⁶ -substitution, the hydrogen at any position in the -C ₈ alkyl group, the C ₃ -C ₆ cycloalkyl group, the c ₂ -c ₄ alkenyl group or the c ₂ -c ₄ alkynyl group may be substituted by one or more atomic atoms , cyano group, -NR ⁸ R ⁹ substituted;

R ^{2 is} selected from the group consisting of trihalofluorenyl, dC ₆ alkyl;

R ^{3 is} selected from the group consisting of hydrogen, decyl, and ethyl;

R ⁴ and R ^{5 are} independently selected from C _r C ₄ alkyl.

6. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of

Compound 1 : 5-Amino-7-ethyl-2,6-dimercapto-4-(3-nitrophenyl)-1,4-2H-1,8-naphthyridine-3-carboxylic acid decyl ester , as shown in S1;

 Compound 2: 5-Amino-7-ethyl-4-(3-decyloxyphenyl)-2,6-dimercapto-1,4-2H-1,8-naphthyridine-3-carboxylic acid Ester, such as S2

 Compound 3: 5-Amino-7-ethyl-4-(2,3-dichlorophenyl)-2,6-dimercapto-1,4-2H-1,8-naphthyridine-3-carboxylic acid hydrazine Ester, as indicated by S3;

Compound 4: 5-Amino-4-(3-nitrophenyl)-2-indolyl-6-ethyl-7-propyl-1,4-2H-1,8-naphthyridine-3-carboxylic acid An oxime ester, as shown by S4;

 S5

 Compound 5: 5-Amino-7-ethyl-2,6-diamidino-4-(3-chlorophenyl)-l,4-2H-l, 8-naphthyridin-3-carboxylic acid ethyl ester, As shown in S5;

 Compound 6: 5-Amino-6-ethyl-2-mercapto-4-(4-fluorophenyl)-7-propyl-1,4-2H-1,8-naphthyridine-3-carboxylic acid Ester, as shown in S6;

 Compound 7: 5-amino-4-(2-chlorophenyl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridine-3-carboxylic acid isopropyl ester , as shown in S7;

Compound 8: 5-amino-4-(2-fluorophenyl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridin-3-carboxylic acid isopropyl ester , as shown in S8;

 Compound 9: 5-Amino-4-(3-nitrophenyl)-6-ethyl-2-indolyl-7-propyl-1,4-2H-1,8-naphthyridine-3-carboxylic acid Isopropyl ester, as shown by S9;

 S10

 Compound 10: 5-amino-4-(2-chlorophenyl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridin-3-carboxylate , as S10

 Compound 11 : 5-amino-4-(2-chlorophenyl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridin-3-carboxylic acid-2- Ethoxyethyl ester, as shown in 11;

Compound 12: 5-Amino-4-(2-fluorophenyl)-6-ethyl-2-indolyl-7-propyl-1,4-2H-1,8-naphthyridin-3-carboxylic acid Propyl ester, as shown in S12;

 Compound 13: 5-amino-4-(3-nitrophenyl)-6-ethyl-2-indolyl-7-propyl-1,4-2H-1,8-naphthyridine-3-carboxylic acid -2,2,2-trifluoroethyl

 Compound 14: 5-amino-4-(2-fluorophenyl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridin-3-carboxylic acid-2, 2,2-trifluoroethyl ester, as shown in 14;

 Compound 15 : 5-amino-4-(2,3,4,5,6-pentafluorophenyl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthalene Pyridine-3-carboxylic acid-

Compound 16: 5-amino-4-(2-decyloxyphenyl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridine-3-carboxylic acid- Ethyl ester, as indicated by S 16;

 S17

 Compound 17: 5-Amino-4-(3-fluorophenyl)-2,6-diethyl-7-propyl-1,4-2H-1,8-naphthyridin-3-carboxylic acid-decyl ester , as shown in S17;

 Compound 18: 5-amino-4-(2-chlorophenyl)-2-trifluoromethyl-6-indolyl-7-ethyl-1,4-2H-1,8-naphthyridin-3-carboxylate Acid -

 Compound 19: 5-amino-4-(3-trifluorodecylphenyl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridine-3-carboxylic acid - ethyl ester, as shown by S19

Compound 20: 5-amino-4-(3-fluorophenyl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridin-3-carboxylic acid-propargyl Ester, as shown in S20;

Compound 21: 5-amino-4-phenyl-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridin-3-carboxylic acid-cyclopropenyl ester, such as S21

 S22

 Compound 22: 5-Amino-4-phenyl-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridine-3-carboxylic acid

- cyanoethyl ester, as indicated by S22;

Compound 23: 5-amino-4-(pyrimidin-5-yl)-7-ethyl-2,6-dimercapto-1,4-2H-1,8-naphthyridine-3-carboxylic acid-isopropyl Ester, as shown in S23.

 The use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the preparation of a calcium ion channel inhibitor drug.

 The use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the preparation of a acetylcholinesterase inhibitor drug.

 The use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for regulating calcium homeostasis, treating cardiovascular disease, cerebrovascular disease or dementia.

10. The use according to claim 9, wherein the dementia is Alzheimer's disease or vascular dementia.

A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.