5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3h)-one derivatives and uses thereof

Abstract

This invention relates to the field of chemical medicine, and more particularly to 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3H)-one derivatives and their applications, with specific structures shown in Formula I. This series exhibits good affinity and selectivity for σ1 receptors and is a highly selective agonist of σ1 receptors.

Description

Technical Field

[0001] This invention relates to the field of chemical medicine, and particularly to 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3H)-one derivatives and their applications. Background Technology

[0002] In psychiatry, depression is defined as an affective disorder. Depression is a chronic, highly relapsing, and highly disabling mental illness, and is the leading cause of loss of work and daily life abilities. Traditional antidepressants have a delayed effect, taking 2-3 weeks or more to take effect; furthermore, traditional antidepressants have low response rates, with 30% of depressed patients showing no response and 30% showing only a partial response; additionally, traditional antidepressants are prone to drug resistance, which significantly reduces their therapeutic efficacy once resistance develops.

[0003] Cognitive impairment caused by depression represents an unmet clinical need with a high incidence rate, severely impacting people's work and lives. Currently, available treatment options are limited, primarily involving acetylcholinesterase inhibitors such as donepezil; however, these drugs have significant side effects such as seizures and rigidity.

[0004] Anxiety disorders, also known as anxiety syndromes, are mental disorders characterized primarily by anxiety symptoms, including panic disorder, generalized anxiety disorder, and social anxiety disorder. Clinical symptoms often manifest as tension, restlessness, fear, and worry, accompanied by physical symptoms of autonomic hyperactivity. Anxiety disorders have a high comorbidity rate, often coexisting with one or more other mental disorders. Treatment medications include common antidepressants, benzodiazepines, and 5-HT1A agonists such as buspirone. Benzodiazepines have significant side effects, and other medications offer limited relief for anxiety, requiring further improvement in their efficacy.

[0005] The Sigma-1 receptor (σ1 receptor) is an emerging drug target in recent years, serving as a binding protein for various specific psychotropic drugs. The Sigma-1 receptor is a ligand-regulated protein chaperone that exerts its chaperone function by interacting with receptors such as NMDA: regulating ion channels and downstream receptors such as NMDA and APMA, thereby modulating mitochondrial function and the release of neurotransmitters such as serotonin and dopamine.

[0006] Known Sigma-1 receptor agonists such as opipiprolol, igmecillin, SA-4503, and ANAVEX2-73 have shown antidepressant and anti-anxiety effects in clinical practice. Compounds such as benzomorphine derivatives (SKF10047, dextromethorphan) and SSRI antidepressants (fluvoxamine, sertraline, fluoxetine, etc.) all have high affinity for the Sigma-1 binding site.

[0007] Currently, existing technologies disclose various Sigma-1 receptor agonists, such as Igmesine, Cutamesine, OPC-14523, Opipramol, PRE-084, SA-4503, ANAVEX2-73, ANAVEX1-41, and ANAVEX3-71d, which are ligand molecules with significant antidepressant effects; patent WO2017190109 discloses the structures of some Sigma-1 receptor agonists and their applications in CNS-related diseases.

[0008] Given the potential applications of Sigma-1 receptor agonists in neuropsychiatric disorders such as depression and anxiety, and the fact that no single effective Sigma-1 receptor agonist is currently marketed as an antidepressant, the search for compounds with effective and selective pharmacological activity against the Sigma-1 receptor and good "drug-approval" is of great significance for clinical application. Summary of the Invention

[0009] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, one object of the present invention is to provide a series of structurally unique 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3H)-one compounds, which all have high affinity and selectivity for Sigma-1 receptors and are strong selective agonists of Sigma-1 receptors, and can be used for the treatment of psychoneurotic diseases such as depression, anxiety, and neurodegeneration.

[0010] On one hand, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0011]

[0012] in

[0013] R1 is selected from any one of straight-chain or branched alkyl, cycloalkyl, and alkyl substituted with at least one halogen;

[0014] R2 is selected from any one of hydrogen, straight-chain or branched alkyl groups.

[0015] R3 is selected from any one of hydrogen, straight-chain or branched alkyl groups;

[0016] R4 is selected from benzene ring or substituted benzene ring, pyridine or substituted pyridine, wherein the substituents of the substituted phenyl or substituted pyridine are independently selected from any one of hydrogen, halogen, straight-chain or branched alkyl, alkyl substituted with at least one halogen, or alkoxy.

[0017] R5 is selected from hydrogen, halogen, straight-chain or branched alkyl, alkyl substituted with at least one halogen, or alkoxy.

[0018] In one embodiment of the present invention, a compound of Formula I or a pharmaceutically acceptable salt thereof is provided:

[0019]

[0020] in

[0021] R1 is selected from either straight chain or branched chain C. 1-8 alkyl, C 1-5 alkyl-substituted C 3-7 cycloalkyl groups, C substituted with at least one halogen 1-5 Any one of the alkyl groups;

[0022] R2 is selected from hydrogen, straight-chain or branched C. 1-5 Any one of the alkyl groups;

[0023] R3 is selected from any one of hydrogen, straight-chain or branched alkyl groups;

[0024] R4 is selected from benzene ring or substituted benzene ring, pyridine or substituted pyridine, wherein the substituent of the substituted phenyl or substituted pyridine is selected from any one of hydrogen, halogen, straight-chain or branched alkyl, alkyl substituted with at least one halogen, or alkoxy.

[0025] R5 is selected from hydrogen, halogen, straight-chain or branched alkyl, alkyl substituted with at least one halogen, or alkoxy.

[0026] In a preferred embodiment of the invention, a compound of formula I-1 or a pharmaceutically acceptable salt thereof is provided:

[0027]

[0028] R1' is selected from straight chain or branched chain C. 1-8 alkyl, C 1-5 alkyl-substituted C 3-7 Any one of cycloalkyl groups or alkyl groups substituted with at least one halogen;

[0029] R2' is selected from hydrogen, straight-chain or branched C. 1-5 any one of the alkyl groups

[0030] R3' is selected from hydrogen, straight-chain or branched C. 1-8 Any one of the alkyl groups;

[0031] R5' is selected from hydrogen, halogen, straight-chain or branched C. 1-8 Alkyl groups, C substituted with at least one halogen 1-5 alkyl, C 1-5 Alkoxy;

[0032] R6' is selected from either hydrogen or halogen;

[0033] R7' is selected from halogen, straight-chain or branched C. 1-8 Alkyl groups, C substituted with at least one halogen 1-8 alkyl, C 1-5 Alkoxy;

[0034] Z1 and Z2 are nitrogen, nitrogen-hydrogen, carbon, or hydrocarbon;

[0035] ------ indicates a single key or that the key does not exist.

[0036] In a preferred embodiment of the invention, a compound of formula I-2 or a pharmaceutically acceptable salt thereof is provided:

[0037] "R1" is selected from either a straight chain or a branch chain C. 1-8 alkyl, or Where n1 and n2 are integers from 1 to 5;

[0038] "R3" is selected from hydrogen, straight-chain or branched C. 1-8 Any one of the alkyl groups;

[0039] "R5" is selected from hydrogen, halogen, straight-chain or branched C. 1-8 Alkyl groups, C substituted with at least one halogen 1-8 alkyl, C 1-5 Alkoxy;

[0040] "R6" is selected from either hydrogen or halogen;

[0041] "R7" is selected from halogens, straight-chain or branched C. 1-8 Alkyl groups, C substituted with at least one halogen 1-8 alkyl, C 1-5 Alkoxy;

[0042] Z1 and Z2 are nitrogen, nitrogen-hydrogen, carbon, or hydrocarbon;

[0043] ------ indicates a single key or that the key does not exist.

[0044] In a preferred embodiment of the invention, a compound of formula I-2 or a pharmaceutically acceptable salt thereof is provided:

[0045] "R1" is selected from methyl, ethyl, propyl, butyl, isopropyl, pentyl, isobutyl, or... Where n1 is 1, 2 or 3, and n2 is 1, 2, 3 or 4;

[0046] "R3" is selected from any one of hydrogen, methyl, ethyl, propyl, butyl, isopropyl, pentyl, and isobutyl;

[0047] "R5" is selected from any one of hydrogen, halogen, methyl, ethyl, propyl, butyl, isopropyl, pentyl, isobutyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, monofluoromethyl, and monofluoroethyl.

[0048] "R6" is selected from either hydrogen or halogen;

[0049] "R7" is selected from any one of halogen, methyl, ethyl, propyl, butyl, isopropyl, pentyl, isobutyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, monofluoromethyl, monofluoroethyl, methoxy, ethoxy, propoxy, and butoxy.

[0050] Z1 and Z2 are independently selected from nitrogen, nitrogen-hydrogen, carbon, or hydrocarbon;

[0051] ------ indicates a single key or that the key does not exist.

[0052] In a preferred embodiment of the invention, a compound of formula I-3 or a pharmaceutically acceptable salt thereof is provided:

[0053]

[0054] Among them, R1”' is selected from straight chain or branched chain C. 1-8 alkyl or Where n1 and n2 are independently selected from integers 1 to 5;

[0055] R2”' is selected from hydrogen, straight-chain or branched C 1-8 Any one of the alkyl groups; R3”' is selected from hydrogen, straight-chain or branched C 1-8 Any one of the alkyl groups;

[0056] R5” is selected from hydrogen, halogen, straight-chain or branched C. 1-8 Alkyl groups, C substituted with at least one halogen 1-8 alkyl, C 1-5 Any one of the alkoxy groups;

[0057] R6”' is selected from halogens or is not present;

[0058] R7” is selected from halogen, straight-chain or branched C 1-8 Alkyl groups, C substituted with at least one halogen 1-8 alkyl, C 1-5 Any one of the alkoxy groups;

[0059] Z1 and Z2 are independently selected from nitrogen, carbon, or hydrocarbon.

[0060] In a preferred embodiment of the present invention, in the compounds represented by formulas I-3, R1”' is selected from methyl, ethyl, propyl, butyl, isopropyl, pentyl, isobutyl, or... Where n1 is 1, 2 or 3, and n2 is 1, 2, 3 or 4;

[0061] R2”' and R3”' are independently selected from any one of hydrogen, methyl, ethyl, propyl, butyl, isopropyl, pentyl, and isobutyl;

[0062] R5”' is selected from any one of hydrogen, halogen, methyl, ethyl, propyl, butyl, isopropyl, pentyl, isobutyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, monofluoromethyl, and monofluoroethyl;

[0063] R6”' is selected from halogens or is not present;

[0064] R7”' is selected from any one of halogen, methyl, ethyl, propyl, butyl, isopropyl, pentyl, isobutyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, monofluoromethyl, monofluoroethyl, methoxy, ethoxy, propoxy, and butoxy.

[0065] Z1 and Z2 are independently selected from nitrogen, carbon, or hydrocarbon.

[0066] In a more preferred embodiment of the present invention, in the compounds represented by Formulas I-3, R1”' is selected from methyl, ethyl, propyl, butyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl;

[0067] R2”' is selected from hydrogen;

[0068] R3”' is selected from any one of hydrogen, methyl, ethyl, and propyl;

[0069] R5”' is selected from any one of hydrogen, methyl, ethyl, and difluoromethyl;

[0070] R6”' is selected from chlorine or is not present;

[0071] R7”' is selected from any one of chloro, methyl, trifluoromethyl, and methoxy;

[0072] Z1 and Z2 are independently selected from nitrogen, carbon, or hydrocarbon.

[0073] In a preferred embodiment of the present invention, in the compounds represented by Formula I-3, R1”' is selected from methyl, ethyl, propyl, butyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl;

[0074] In a preferred embodiment of the present invention, R2”' is selected from hydrogen;

[0075] In a preferred embodiment of the present invention, R3”' is selected from any one of hydrogen, methyl, ethyl, and propyl;

[0076] In a preferred embodiment of the present invention, R5”' is selected from any one of hydrogen, methyl, ethyl, and difluoromethyl;

[0077] In a preferred embodiment of the present invention, R6”' is selected from chlorine;

[0078] In a preferred embodiment of the present invention, R7”' is selected from any one of chloro, methyl, trifluoromethyl, and methoxy;

[0079] In a preferred embodiment of the present invention, Z1 is hydrocarbon and Z2 is nitrogen, or both Z1 and Z2 are hydrocarbon, or one of Z1 and Z2 is hydrocarbon and the other is carbon.

[0080] Specifically, the compound described in this invention is selected from any one of the following compounds:

[0081] 6-(cyclopropylmethyl)-3-(3,4-dichlorobenzyl)-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0082] 6-(cyclopropylmethyl)-2-methyl-3-(4-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one;

[0083] 6-(cyclopropylmethyl)-2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4(3-hydro)-one;

[0084] 6-(cyclopropylmethyl)-2-methyl-3-((6-methylpyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0085] 6-(cyclopropylmethyl)-3-((6-methoxypyridin-3-yl)methyl)-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0086] 6-(cyclopropylmethyl)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0087] 6-(cyclopropylmethyl)-2-methyl-3-(1-(4-(trifluoromethyl)phenyl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0088] (S)-6-(cyclopropylmethyl)-2-methyl-3-(1-(4-(trifluoromethyl)phenyl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0089] (R)-6-(cyclopropylmethyl)-2-methyl-3-(1-(4-(trifluoromethyl)phenyl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0090] 6-(cyclopropylmethyl)-2-methyl-3-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0091] 6-(cyclopropylmethyl)-2-methyl-3-(1-(6-methylpyridinyl)-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0092] 6-(cyclopropylmethyl)-2-methyl-3-(1-(6-methylpyridinyl)-3-yl)propyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0093] 6-(cyclopropylmethyl)-2-methyl-3-(1-(6-methylpyridin-3-yl)butyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0094] 2,6-Dimethyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0095] 6-Ethyl-2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0096] 2-Methyl-6-propyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0097] 6-Butyl-2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0098] 6-(cyclopentylmethyl)-2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0099] 6-(cyclobutylmethyl)-2-methyl-3-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0100] 6-(cyclopentylmethyl)-2-methyl-3-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0101] 6-Ethyl-2-methyl-3-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0102] 6-Ethyl-3-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0103] 6-(cyclopropylmethyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0104] 6-(cyclopropylmethyl)-2-(difluoromethyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4(3-hydro)-one;

[0105] 6-(cyclopropylmethyl)-2-ethyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0106] 6-(cyclobutylmethyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0107] 6-(cyclopentylmethyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one;

[0108] 6-(cyclobutylmethyl)-3-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4(3-hydro)-one.

[0109] Pharmaceutical Compositions and Uses

[0110] A second aspect of the present invention provides a pharmaceutical composition comprising a compound of formula I, I-1, I-2, I-3 as described in the present invention, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.

[0111] In one embodiment of the present invention, the pharmaceutical composition can be formulated using one or more pharmaceutically acceptable carriers in a conventional manner. Therefore, the active compounds of the present invention can be formulated into dosage forms for oral, sublingual, intranasal, parenteral (e.g., intravenous, intramuscular, subcutaneous, intra-articular, or transdermal) or rectal administration, or suitable for inhalation or insufflation. The compounds of the present invention or pharmaceutically acceptable salts thereof can also be formulated into sustained-release or extended-release dosage forms.

[0112] In one embodiment of the invention, with respect to oral administration, the active compound of the invention may be formulated into tablets, pills, capsules, granules, drops, syrups or solutions by conventional means with pharmaceutically acceptable excipients, such as binders, fillers, lubricants, disintegrants or wetting agents.

[0113] Solid oral dosage forms can be prepared using methods well-known in the art, such as mixing, filling, and tableting. Liquid formulations for oral administration can be solutions, syrups, or suspensions, or evaporated into a dried product, regenerated with water or other suitable carriers before use. These liquid formulations can be prepared using pharmaceutical additives through conventional methods, such as suspending agents, emulsifiers, non-aqueous carriers, and preservatives.

[0114] This pharmaceutical composition is also suitable for parenteral administration, such as as a sterile solution, suspension, or rehydrated dried formulation, aerosol, or spray in a suitable unit dosage form. Sufficient excipients, such as fillers, buffers, or surfactants, may be used.

[0115] The compositions of the present invention can be formulated into a soluble state or an ointment for transdermal application.

[0116] The active compounds of the present invention can be formulated into rectal compositions, such as suppositories or retention enemas, for example containing conventional suppository bases, such as cocoa butter or other glycerides.

[0117] The compounds and compositions of the present invention can be used with other drugs to provide combination therapy.

[0118] The compounds of general formula (I) of the present invention, their corresponding isomers, their corresponding salts or corresponding solvates have a high affinity for sigma receptors, especially sigma-1 receptors, i.e., they are selective ligands for sigma receptors (especially sigma-1 receptors) and act as regulators of these receptors, such as agonists, antagonists or inverse agonists.

[0119] A third aspect of the present invention provides the use of the compounds represented by Formulas I, I-1, I-2, and I-3, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the compounds, in the preparation of medicaments for treating and / or preventing sigma receptor-related diseases or disease states; wherein the sigma receptor-related diseases are central nervous system diseases; and more preferably, the central nervous system diseases are depression, anxiety, or bipolar disorder.

[0120] The present invention also provides the use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of a medicament that modulates sigma receptors (especially sigma-1 receptors), wherein the medicament optionally comprises one or more other active agents that modulate the mammalian nervous system or alleviate mental illness.

[0121] According to specific embodiments, the pharmaceutical compositions of the present invention further include at least one compound described herein (preferably a compound of formula (I)) and at least one medicament currently used for treating pain associated with sigma-1 receptor-related diseases. The compositions may be administered simultaneously, alone, or sequentially for the treatment and / or prevention of sigma receptor (especially sigma-1 receptor)-mediated diseases.

[0122] The fourth aspect of the invention also provides a compound of formula VII or a pharmaceutically acceptable salt thereof.

[0123]

[0124] R2 is selected from any one of hydrogen, straight-chain or branched alkyl groups;

[0125] R3 is selected from any one of hydrogen, straight-chain or branched alkyl groups;

[0126] R4 is selected from benzene ring or substituted benzene ring, pyridine or substituted pyridine, wherein the substituent of the substituted phenyl or substituted pyridine is selected from any one of hydrogen, halogen, straight-chain or branched alkyl, alkyl substituted with at least one halogen, or alkoxy.

[0127] The preferred compound is 2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one, which has the following structure:

[0128]

[0129] The compound represented by Formula VII or a pharmaceutically acceptable salt thereof, such as 2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one, can be used as an intermediate to prepare the aforementioned compounds of the present invention.

[0130] Terminology Explanation

[0131] The straight-chain or branched alkyl group described in this invention is selected from C 1-8 Straight-chain or branched alkyl groups, particularly referring to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, and C8 alkyl groups; further preferably C... 1-5 Straight-chain or branched alkyl groups, examples of which include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), etc. The straight-chain or branched alkyl groups described in this invention also include straight-chain or branched alkyl groups substituted with one or more substituents, wherein the substituents are cycloalkyl, halogen, or alkoxy; in a preferred embodiment of this invention, the straight-chain or branched alkyl groups further include those substituted with C... 3-7 The alkyl group is substituted with a cycloalkyl group, examples of which include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl. Further, in a preferred embodiment of the present invention, the straight-chain or branched alkyl group is preferably methyl, ethyl, propyl, butyl, isopropyl, pentyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl.

[0132] The alkyl group substituted with at least one halogen is selected from C4 groups substituted with at least one halogen. 1-5 Alkyl groups refer to C 1-5 One or more hydrogen atoms on a straight-chain or branched alkyl group are substituted with halogens, and the alkyl group has a structure shown as "-(CH2)aCX3, -(CH2)aCHX2, -(CH2)aCH2X", wherein a is independently 0, 1 or 2, and X is independently any one of F, Cl, Br or I, such as difluoromethyl or trifluoromethyl.

[0133] The "cycloalkyl" is an alicyclic hydrocarbon. Typical cycloalkyl groups contain 1 to 4 monocyclic and / or fused rings and 3 to 18 carbon atoms, preferably 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, or adamantyl. In a preferred embodiment of the invention, the cycloalkyl group contains 3 to 7 carbon atoms, specifically the "C..."3-7 "Cycloalkyl" can be, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0134] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0135] In one embodiment of the present invention, the propyl group includes, but is not limited to, n-propyl (n-Pr, -CH2CH2CH3) or isopropyl (i-Pr, -CH(CH3)2); the butyl group includes, but is not limited to, n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3) or tert-butyl (t-Bu, -C(CH3)3); the pentyl group includes, but is not limited to, n-propyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), or tert-butyl (t-Bu, -C(CH3)3); the pentyl group includes, but is not limited to, n-propyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), isobutyl (s-Bu, -CH(CH3)CH2CH3), or isobutyl (t-Bu, -C(CH3)3). It is n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2) or 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3).

[0136] "Alkoxy" refers to a group containing one or more oxygen bonds (e.g., 1, 2, 3, or 4), and typically contains 1 to about 12, 1 to about 8, 1 to about 5, or 1 to about 3 carbon atoms, such as methoxy, ethoxy, propoxy, etc. In a preferred embodiment of the invention, the "alkoxy" group contains 1 to about 5 carbon atoms, i.e., C 1-5 Alkoxy groups, for example, can be methoxy, ethoxy, or propoxy.

[0137] The range (e.g., numerical range) described in this invention can encompass every value within the range and the various subranges formed by the values. Therefore, for example, stating that "n1, n2 are integers independently selected from 1-5" includes, for example, any integer from 1 to 5, any integer from 1 to 3, etc., such as 1, 2, 3, 4, 5. For example, in the compounds shown in formula I-2 or I-3 of this invention, the indicated substituents... Where n1 is an integer of 1, 2, 3, 4, 5, and n2 is an integer of 1, 2, 3, 4, 5; specifically, when both n1 and n2 are 1, the structure is cyclopropylmethyl, and when n1 is 1 and n2 is 2, the structure is cyclobutylmethyl.

[0138] Fragments in general formula I-3 This indicates that R6”' can replace the hydrogen at the C-2, C-3, C-5, or C-6 position in the aromatic ring skeleton, for example...

[0139] The term "salt" should be understood to refer to any form of the compound used according to the invention, wherein the compound is in ionic form or is a charged compound coupled to an oppositely charged ion (cation or anion) or is in solution. This definition also includes quaternary ammonium salts and complexes formed by active molecules with other molecules and ions, particularly complexes formed through ionic interactions. This definition particularly includes physiologically acceptable salts; the term should be understood to be equivalent to "pharmacologically acceptable salt" or "pharmaceutical-acceptable salt".

[0140] In the context of this invention, the term "pharmaceutically acceptable salt" refers to any physiologically compatible salt (generally meaning non-toxic, particularly because it contains ions with opposite charges) when used in a suitable manner for treatment, application, or use, especially for humans and / or mammals. In this invention, especially for use in humans and / or mammals, these physiologically acceptable salts can be formed from cations or bases and are understood to be salts formed by at least one compound used according to the invention—typically an acid (deprotonated)—such as an anion, and at least one physiologically compatible cation, preferably an inorganic ion. These physiologically acceptable salts can also be formed from anions or acids. In the context of this invention, especially for use in humans and / or mammals, the aforementioned physiologically acceptable salts should be understood to be salts formed by at least one compound provided by the invention—typically protonated, such as in nitrogen—such as a cation, and at least one physiologically tolerant anion. In this invention, especially for use in humans and / or mammals, this definition explicitly includes salts formed by physiologically compatible acids, i.e., salts formed by a specific active compound and a physiologically compatible organic or inorganic acid.

[0141] Any compound involved in this invention is intended to represent such a specific compound and certain variations or forms. In particular, the compounds involved herein may have an asymmetric center, and thus exist in different enantiomeric or diastereomeric forms. Therefore, any given compound involved in this invention is intended to represent any one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof of a racemic compound. Similarly, stereoisomers or geometric isomers of the compounds are also possible. All stereoisomers of the compounds involved, including enantiomers, diastereomerics, geometric isomers, and atorium isomers, and mixtures thereof, are within the scope of protection of this invention.

[0142] The compounds used in this invention, or their salts or solvates, are preferably in a pharmaceutically acceptable form or in substantially pure form. A pharmaceutically acceptable form means, in particular, having a pharmaceutically acceptable level of purity, excluding commonly used pharmaceutical additives such as diluents and carriers, and excluding materials considered toxic at normal dose levels. The purity level of the compound is preferably higher than 50%, more preferably higher than 70%, and most preferably higher than 90%. In a preferred embodiment, the purity of the compound of formula (I), or its pharmaceutically acceptable salt, solvate, or prodrug, is above 95%.

[0143] In this invention, the term "prevention" refers to the ability to avoid, minimize, or prevent the onset or development of a disease or condition through treatment before the onset of a sigma receptor-mediated disease.

[0144] Therefore, "treatment" and / or "prevention" as a whole refers to at least achieving the suppression or improvement of pain associated with an individual's ailment, wherein suppression and improvement are broadly defined to include at least a reduction in the magnitude of parameters such as symptoms associated with the treated ailment, i.e., pain associated with sigma receptor-mediated diseases. Thus, the method of the present invention also includes the possibility of complete suppression of the ailment, such as prevention or prevention of occurrence, such as termination, thereby freeing the subject from suffering from the ailment.

[0145] As used in this application, the term "compound that can bind to a σ receptor" is preferably defined as a compound having at least Ki < 5000 nM, preferably Ki < 1000 nM, and most preferably Ki < 100 nM, in a competitive binding test to a σ receptor using the 4 nM radioligand [3H]-Pentazocine, wherein the compound is specific for the σ receptor, and the σ receptor can be any σ receptor subtype. Preferably, the compound binds to the σ-1 receptor subtype. The aforementioned compounds that bind to σ receptors can be antagonists, inverse agonists, agonists, partial antagonists, and / or partial agonists.

[0146] In a preferred embodiment of the present invention, the σ receptor ligand is a selective σ-1 agonist or a partial agonist.

[0147] An "agonist" is defined as a compound that can bind to a receptor, has intrinsic activity, and thereby enhances the receptor's essential activity when it comes into contact with the receptor.

[0148] An "antagonist" is defined as a compound that competes with an agonist or inverse agonist for binding to a receptor, thereby blocking the action of the agonist or inverse agonist on the receptor. However, antagonists (also known as "neutral" antagonists) have no effect on constitutive receptor activity. Antagonists mediate their action by binding to the receptor's active or allosteric site, or by interacting at a specific binding site that is generally not involved in the biological regulation of receptor activity. Antagonist activity can be reversible or irreversible, depending on the lifetime of the antagonist-receptor complex, which in turn depends on the nature of the antagonist-receptor binding.

[0149] A "partial antagonist" is defined as a compound that binds to a receptor and produces an antagonistic response; however, a partial antagonist does not produce a complete antagonistic response. Partial antagonists are weak antagonists that partially block the action of agonists or inverse agonists on the receptor.

[0150] "Inverse agonists" are defined as compounds that produce an effect opposite to that of an agonist by occupying the same receptor, thereby reducing the receptor's basal activity (i.e., the signal transduction mediated by that receptor). These compounds are also known as negative antagonists. Inverse agonists are receptor ligands that cause the receptor to assume an inactive state relative to the receptor's basal state, which is the state of the receptor in the absence of any ligand. Therefore, while antagonists can inhibit the activity of agonists, inverse agonists are ligands that can alter receptor structure in the absence of an agonist.

[0151] Synthesis scheme

[0152] The present invention further provides a method for preparing the compound of general formula (I), comprising: after obtaining intermediate (III) by substitution reaction of compound (II), cyclizing it with compound reactant-2 to obtain core structure (IV), and then subjecting compound (IV) to electrophilic substitution reaction to prepare the compound of general formula (I), the reaction formula being as shown in Scheme 1 below.

[0153] Option 1:

[0154]

[0155] R1, R2, R3, R4, and R5 are as described above.

[0156] In one specific embodiment, the present invention further provides a method for preparing general formula I, comprising: cyclizing compound V with reagent-2 to obtain a parent structure (VI), then deprotecting it to obtain VII, and then preparing general formula I by reductive amination, the reaction formula being shown in Scheme 2 below.

[0157] Option 2:

[0158]

[0159] Among them, R1, R2, R3, R4, and R5 are as described above;

[0160] In one specific embodiment, the present invention further provides a method for preparing the following general formula Ia, comprising: reacting compound IIa with Rg1 under organic solvent (e.g., acetonitrile) and alkaline conditions (e.g., potassium carbonate) to obtain intermediate IIIa; reacting intermediate IIIa with acetamiprid hydrochloride under organic solvent (e.g., ethanol) and alkaline conditions (e.g., sodium ethoxide) to obtain compound IVa; and then converting compound Iva into compound Ia through an electrophilic substitution reaction, the reaction formula being shown in Scheme 3 below.

[0161] Option 3:

[0162]

[0163] Where n1 is 1, 2, 3, 4 or 5.

[0164] Technical effects:

[0165] The compounds provided by this invention have a significant affinity for the sigma-1 receptor and have demonstrated significant efficacy in vivo through a mouse forced swimming test (FST), suggesting potential applications in the treatment and prevention of central nervous system diseases. Attached Figure Description

[0166] Figure 1 The inhibition rate of compound 7 and the phenytoin-added group changed with concentration. Specific Implementation

[0167] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. Those skilled in the art will understand that various changes and modifications can be made to the present invention without departing from the spirit and scope thereof.

[0168] First, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0169]

[0170] R1, R2, R3, R4, and R5 are as described above.

[0171] Particularly preferred is a compound of formula I-3 or a pharmaceutically acceptable salt thereof:

[0172]

[0173] Among them, R1”', R2”', R3”', R5”', R6”', and R7”' are as described above.

[0174] Table 1 shows exemplary compounds of the compounds represented by general formula I, general formula I-1, general formula I-2 or general formula I-3 of the present invention.

[0175] Table 1 lists exemplary compounds of general formula I.

[0176]

[0177]

[0178]

[0179]

[0180]

[0181] The following specific embodiments further explain the synthesis methods and medicinal effects of the compounds described in this invention, especially the preferred compounds.

[0182] The compounds of Examples 1 to 8 were prepared using the synthesis method of Scheme 1.

[0183] Example 1: Preparation of 6-(cyclopropylmethyl)-3-(3,4-dichlorobenzyl)-2-methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one (Compound 1)

[0184]

[0185] (1) Synthesis of ethyl 1-(cyclopropylmethyl)-4-oxoperidine-3-carboxylic acid

[0186]

[0187] 4-Opiperidine-3-carboxylic acid ethyl ester hydrochloride (2.08 g, 10 mmol) and bromomethylcyclopropane (2.03 g, 15 mmol) were dissolved in acetonitrile (30 mL), and potassium carbonate (2.76 g, 20 mmol) was added. The reaction was stirred overnight at 45 °C. After the reaction was completed by TLC monitoring, the mixture was filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain 1-(cyclopropylmethyl)-4-oxoperidine-3-carboxylic acid ethyl ester (1.37 g, yield 60.8%).

[0188] (2) Synthesis of 6-(cyclopropylmethyl)-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one.

[0189]

[0190] Ethyl 1-(cyclopropylmethyl)-4-oxoperidin-3-carboxylate (0.50 g, 2.22 mmol) and acetamidine hydrochloride (0.64 g, 11.1 mmol) were dissolved in ethanol (2 mL), refluxed and stirred overnight. The reaction solution was monitored by TLC. After the reaction was completed, the solution was filtered and concentrated to obtain crude 6-(cyclopropylmethyl)-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one (250 mg, 51.4% yield).

[0191] (3) Synthesis of 6-(cyclopropylmethyl)-3-(3,4-dichlorobenzyl)-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one.

[0192]

[0193] 6-(cyclopropylmethyl)-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one (0.24 g, 1.09 mmol), 4-bromomethyl-1,2-dichlorobenzene (0.26 g, 1.09 mmol), and triethylamine (0.22 g, 2.18 mmol) were dissolved in DMF (2 mL) and stirred overnight at room temperature. The reaction solution was monitored by TLC. After the reaction was completed, water (50 mL) was added to quench the reaction, and then ethyl acetate (3 x 50 mL) was added for extraction. The organic layers were combined, washed with saturated NaCl (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. The crude product was then purified by preparative-TLC (DCM:MeOH:NH3.H2O = 20:1:0.1) to obtain the target product (0.07 g, yield: 14.6%).

[0194] 1 H NMR (400MHz, CD3OD) δ7.60–7.47(m,2H),7.27(d,J=8.0Hz,1H),5.39(s,2H),4.54(d,J=14.4Hz,1H),4.13(d,J=16.2Hz,1H),3.98-3.90(m, 1H),3.55-3.47(m,1H),3.33-3.29(m,3H),3.15-3.03(m,1H),2.68(s,3H),1.35-1.25(m,1H),0.83(d,J=7.4Hz,2H),0.55(d,J=4.2Hz,2H).

[0195] Example 2: Synthesis of 6-(cyclopropylmethyl)2-methyl-3-(4-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one (Compound 2)

[0196] The target product was prepared by replacing 4-bromomethyl-1,2-dichlorobenzene with 4-bromomethyl-1-(trifluoromethyl)benzene, following the method described in Example 1:

[0197]

[0198] 1 H NMR (400MHz, Methanol-d4) δ7.70(d,J=8.2Hz,2H),7.52(d,J=8.2Hz,2H),5.51(s,2H),4.54(d,J=17.7Hz,1H),4.14(d,J=14.0Hz,1H),3.98-3.90(m,1H) ,3.50(d,J=14.7Hz,1H),3.31–3.23(m,4H),3.07(d,J=17.6Hz,1H),2.69(dd ,J=4.7,2.6Hz,2H),1.30–1.24(m,1H),0.86-0.78(m,2H),0.59-0.50(m,2H).

[0199] Example 3: Synthesis of 6-(cyclopropylmethyl)-2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one (Compound 3)

[0200] The target product was prepared by replacing 4-bromomethyl-1,2-dichlorobenzene with 5-bromomethyl-2-(trifluoromethyl)pyridine, following the method described in Example 1.

[0201]

[0202] 1 H NMR (400MHz, CD3OD) δ8.75(s,1H),8.04(d,J=6.6Hz,1H),7.84(d,J=8.2Hz,1H),5.55(s,2H),4.59-4.47(m,1H),4.17-4.03(m,1H),3.98 -3.90(m,1H),3.56-3.48(m,1H),3.40–2.97(m,8H),1.32-1.22(m,1H),0.87-0.79(m,2H),0.58-0.50(m,2H).MS(ESI)m / z379.0.([M+H]+ ).

[0203] Example 4: Synthesis of 6-(cyclopropylmethyl)-2-methyl-3-((6-methylpyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one (Compound 4)

[0204] The target product was prepared by replacing 4-bromomethyl-1,2-dichlorobenzene with 5-bromomethyl-2-methylpyridine, following the method described in Example 1.

[0205]

[0206] 1 H NMR (400MHz, Methanol-d4) δ8.87–8.74 (m, 1H), 8.48 (dd, J = 8.4, 2.2Hz, 1H), 7.9 4(d,J=8.4Hz,1H),5.53(s,2H),4.50(d,J=16.0Hz,1H),4.08(d,J=16.8Hz,1H), 3.96-3.86(m,1H),3.56-3.44(m,1H),3.32-3.17(m,3H),3.11-2.98(m,1H),2.8 1(s,3H),2.69(s,3H),1.31–1.25(m,1H),0.89–0.79(m,2H),0.61–0.43(m,2H).

[0207] Example 5: Synthesis of 6-(cyclopropylmethyl)-3-((6-methoxypyridin-3-yl)2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one (Compound 5)

[0208] The target product was prepared by replacing 4-bromomethyl-1,2-dichlorobenzene with 5-bromomethyl-2-methoxypyridine using the method of Example 1.

[0209]

[0210] 1H NMR(400MHz,Methanol-d4)δ8.36(d,J=2.4Hz,1H),8.30(dd,J=9.1,2.4Hz,1H),7.3 9(d,J=9.0Hz,1H),5.37(s,2H),4.52-4.36(m,1H),4.11(s,3H),4.10–3.98(m,1H), 3.96-3.96(m,1H),3.50-3.26(m,1H),3.23-3.12(m,3H),3.04-2.90(m,1H),2.70(s ,3H),1.18(dd,J=7.4,3.8Hz,1H),0.79–0.73(m,2H),0.51–0.43(m,2H).MS(ESI)m / z 341([M+H] + ).

[0211] Example 6: Synthesis of 6-(cyclopropylmethyl)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one (Compound 6)

[0212] The target product was prepared by replacing 4-bromomethyl-1,2-dichlorobenzene with 2-bromomethyl-5-trifluoromethylpyridine, following the method described in Example 1.

[0213]

[0214] 1 H NMR (400MHz, Methanol-d4) δ8.77(d,J=2.1Hz,1H),8.13(dd,J=8.3,2.3Hz,1H),7.64(d,J=8.2Hz,1H),5.53(s,2H),3.66(s,2H),3.08 (t,J=6.0Hz,2H),2.85(t,J=6.0Hz,2H),2.67(d,J=6.9Hz,2H),2.60(s,3H),1.08-0.98(m,1H),0.73–0.54(m,2H),0.36–0.22(m,2H).

[0215] Example 7: 6-(cyclopropylmethyl)-2-methyl-3-(1-(4-(trifluoromethyl)phenyl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one (Compound 7)

[0216] The target product was prepared by replacing 4-bromomethyl-1,2-dichlorobenzene with 1-(1-bromoethyl)-4-trifluoromethylbenzene using the method of Example 1.

[0217]

[0218] 1 H NMR (400MHz, CDCl3) δ7.56(d,J=6.9Hz,2H),7.48(d,J=6.9Hz,2H),6.11-6.02(m,1H),4.36-4.18(m,1H),3.92-3.78(m,2H),3.39-3.31( m,1H),3.22-3.20(m,3H),2.99-2.91(m,1H),2.74(s,3H),1.91(d,J=4.8,3H),1.20-1.06(m,1H),0.75-0.65(m,2H),0.45-0.35(m,2H).

[0219] Example 10: Synthesis of 6-(cyclopropylmethyl)-2-methyl-3-(1-6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one (Compound 10)

[0220] The target product was prepared by replacing 4-bromomethyl-1,2-dichlorobenzene with 5-(1-bromoethyl)-2-trifluoromethylpyridine, following the method described in Example 1.

[0221]

[0222] 1 H NMR(400MHz, Methanol-d4)δ8.73(d,J=2.0Hz,1H),8.17–8.06(m,1H),7.77( d,J=8.2Hz,1H),6.01-5.96(m,1H),4.43-4.18(m,1H),4.13-3.78(m,2H),3. 57-3.34(m,1H),3.26–3.14(m,3H),3.12-2.82(m,4H),2.02(d,J=6.9Hz,3H) ,1.20-1.10(m,1H),0.74(q,J=4.9Hz,2H),0.45(q,J=5.0Hz,2H)MS(ESI)m / z 393([M+H] + ).

[0223] Example 8: Synthesis of 2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one

[0224]

[0225] (1) Synthesis of tert-butyl-2-methyl-4-oxo-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-6(4-hydro)-carboxylic acid ester

[0226]

[0227] 1-(tert-butyl)3-ethyl-4-oxoperidin-1,3-dicarboxylic acid ester (50.0 g, 184.3 mmol), acetamidine hydrochloride (52.3 g, 552.9 mol), and sodium ethoxide (62.7 g, 921.5 mmol) were added sequentially to a reaction flask, followed by ethanol (500 mL). The reaction mixture was refluxed and stirred for 12 h. After the reaction was completed, the mixture was concentrated, dissolved in water, and the pH was adjusted to 7-8. The aqueous phase was extracted with ethyl acetate (3 x 150 mL). The organic layers were combined and washed with saturated NaCl solution (3 x 80 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and rotary evaporated to obtain 26.7 g of a yellow solid intermediate, tert-butyl-2-methyl-4-oxo-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-6(4-hydro)-carboxylic acid ester.

[0228] (2) Synthesis of tert-butyl-2-methyl-4-oxo-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-6(4-hydro)carboxylic acid ester

[0229]

[0230] tert-butyl-2-methyl-4-oxo-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(4-hydro)-carboxylic acid ester (8.01 g, 30.19 mmol), 5-(bromomethyl)-2-(trifluoromethyl)pyridine (7.25 g, 30.19 mmol) and sodium tert-butoxide (3.48 g, 36.23 mmol) were added sequentially to a reaction flask, followed by tetrahydrofuran (300 mL). The mixture was stirred at room temperature for 10 minutes and then heated to reflux. After the reaction was complete, water was added to quench the reaction. The aqueous phase was extracted with dichloromethane (3*300mL), the organic layers were combined, washed with saturated NaCl solution (3*20mL), the organic layers were combined again, dried over anhydrous Na2SO4, filtered, concentrated by rotary evaporation, and then subjected to column chromatography (petroleum ether / ethyl acetate = from 3 / 1 to 1 / 1) to give 7.05g of tert-butyl-2-methyl-4-oxo-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-6(4-hydro)-carboxylic acid ester.

[0231] (3) Synthesis of 2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one

[0232]

[0233] 5.0 g (11.78 mmol) of tert-butyl 2-methyl-4-oxo-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(4-hydro)-carboxylic acid ester was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (1.71 g (17.67 mmol) was added at 20 °C. The mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC until the reaction was complete. The reaction solution was washed with saturated sodium carbonate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.5 g of the colorless oily product 2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one.

[0234] 1 H NMR(400MHz, Methanol-d4)δ8.78(s,1H),8.07(d,J=8.0Hz,1H),7.83(d,J=8.0Hz, 1H),5.56(s,2H),4.18(s,2H),3.67-3.59(m,2H),3.15-3.07(m,2H),2.84(s,3H).

[0235] Example 14: Synthesis of 2,6-dimethyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one (Compound 14)

[0236]

[0237] 2-Methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one (200 mg, 0.62 mmol) and paraformaldehyde (37 mg, 1.24 mmol) were dissolved in dichloromethane (10 mL) and acetic acid (3.72 mg, 0.062 mmol). The mixture was stirred at 20 °C for 30 min, and then sodium borohydride acetate (262 mg, 1.24 mmol) was added. After the addition was complete, the mixture was reacted at 20 °C for 2 hours. After the reaction was complete, the mixture was quenched with water, extracted twice with dichloromethane (2*10mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified to give 65mg of a yellow oily substance, which was 2,6-dimethyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one, with a yield of 53%.

[0238] 1H NMR (400MHz, Methanol-d4) δ8.73(d,J=1.8Hz,1H),8.07–7.94(m,1H),7.83(d,J=8.0Hz,1H),5.52(s,2H),4.47-4.42(d,J=15.8H z,1H),4.14–3.97(m,1H),3.86-3.76(m,1H),3.57-3.45(m,1H),3.19-3.06(m,1H),3.11(s,3H),3.08–2.98(m,1H),2.71(s,3H).

[0239] Example 15: 6-Ethyl-2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one (Compound 15)

[0240] The target product was prepared by replacing paraformaldehyde with acetaldehyde according to the synthesis method of Example 14.

[0241]

[0242] 1 H NMR (400MHz, Methanol-d4) δ8.81-8.63(m,1H),8.22–8.00(m,1H),7.77(d,J=8.3Hz,1H),5.53(s,2H),4.46-4-42(m,1H),4.12-4.3. 97(m,1H),3.34(q,J=7.3Hz,1H),3.11-2.91(m,4H),2.73(s,3H),2.05(t,J=7.3Hz,2H),1.38(t,J=7.3Hz,3H).MS(ESI)m / z353([M+H] + ).

[0243] Example 16: 2-Methyl-6-propyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one (Compound 16)

[0244] By replacing formaldehyde with propionaldehyde, the target product was prepared according to the synthesis method of Example 14:

[0245]

[0246] 1H NMR (400MHz, Methanol-d4) δ8.87–8.71(m,1H),8.17–8.02(m,1H),7.85(d,J=8.1Hz,1H),5.56(s,2H),4.48-4.42(m,1H),4.20–4.06(m, 1H), 4.00-3.78 (m, 1H), 3.53-3.41 (m, 1H), 3.40-3.30 (m, 3H), 3.15-3.07 (m, 1H), 2.84 (s, 3H), 1.53-1.41 (m, 2H), 1.05 (t, J = 7.3Hz, 3H). MS(ESI)m / z 367.

[0247] Example 17: 6-Butyl-2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one (Compound 17)

[0248] By replacing formaldehyde with butyraldehyde, the target product was prepared according to the synthesis method of Example 14:

[0249]

[0250] 1 H NMR(400MHz, Methanol-d4)δ8.87–8.72(m,1H),8.17–8.01(m,1H),7.84(d,J=8.1Hz,1H),5.56(s,2H),4.47-4.42(m,1H),4.21–4.05(m,1H),4.00 -3.79(m,1H),3.52-3.40(m,1H),3.39-3.30(m,3H),3.15-3.06(m,1H),2 .85(s,3H),1.95-1.82(m,2H),1.53-1.41(m,2H),1.03(t,J=7.3Hz,3H). MS(ESI)m / z 381.

[0251] Example 18: 6-(cyclobutylmethyl)-2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one (Compound 18)

[0252]

[0253] 1H NMR (400MHz, Methanol-d4) δ8.67(s,1H),7.99-7.93(m,1H),7.73(d,J=8.0Hz,1H),5.45(s,2H),4.31-4.21(m,1H),4.03-3.91(m,1H),3.77- 3.67(m,1H),3.48(s,3H),3.07-3.19(m,1H),2.91-3.01(m,1H),2.78- 2.88(m,1H),2.82-2.68(m,2H),2.22-2.12(m,2H),2.04-1.76(m,5H). MS(ESI)m / z 393.

[0254] Example 19: 6-(cyclopentylmethyl)-2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one (Compound 19)

[0255]

[0256] 1 H NMR (400MHz, Methanol-d4) δ8.74(s,1H),8.02(m,J=8.1,2.3Hz,1H),7.83(d,J=8.2Hz,1H ),5.53(s,2H),4.45(d,J=16.1Hz,1H),4.09(d,J=16.2Hz,1H),3.96-3.88(m,1H),3.54-3 .45(m,1H),3.37(d,J=7.4Hz,2H),3.29-3.21(m,1H),3.04(d,J=18.9Hz,1H),2.74(s,3H) ,2.44(m,J=7.9Hz,1H),1.98(d,J=10.4Hz,2H),1.79–1.64(m,4H),1.35(d,J=9.6Hz,2H). MS(ESI)m / z 407.

[0257] Example 23: 6-(cyclopropylmethyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one (Compound 23)

[0258]

[0259] 1H NMR(400MHz, Methanol-d4)δ8.74(d,J=2.1Hz,1H),8.71(s,1H),8.04(dd,J=8.3 ,2.1Hz,1H),7.77(d,J=8.2Hz,1H),5.27(s,2H),4.43(d,J=16.2Hz,1H),3.99(d ,J=16.2Hz,1H),3.91–3.74(m,1H),3.39(td,J=11.7,5.0Hz,1H),3.25–3.04(m, 3H),2.95-2.79(m,1H),1.22-1.12(m,1H),0.81–0.65(m,2H),0.50-0.38(m,2H). MS(ESI)m / z 365.

[0260] Example 25: 6-(cyclopropylmethyl)-2-ethyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one (Compound 25)

[0261]

[0262] 1 H NMR(400MHz, Methanol-d4)δ8.66(d,J=2.0Hz,1H),7.93(dd,J=8.2,2.1Hz,1H),7.81(d, J=8.2Hz,1H),5.51(s,2H),4.50(d,J=16.1Hz,1H),4.08(d,J=16.1Hz,1H),3.98-3.84(m ,1H),3.56-3.40(m,1H),3.30–3.12(m,3H),3.05-2.95(d,J=18.9Hz,1H),2.91(q,J=7.3 Hz, 2H), 1.29 (t, J = 7.3Hz, 3H), 1.27-1.21 (m, 1H), 0.88-0.78 (m, 2H), 0.59-0.45 (m, 2H). MS(ESI)m / z 393.

[0263] Example 26: 6-(cyclobutylmethyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one (Compound 26)

[0264]

[0265] 1H NMR (400MHz, Methanol-d4) δ8.74(d,J=2.1Hz,1H),8.71(s,1H),8.03(dd,J=8.2,2.1Hz ,1H),7.77(d,J=8.1Hz,1H),5.26(s,2H),4.24(d,J=16.1Hz,1H),3.91(d,J=16.2Hz,1H) ,3.74-3.64(m,1H),3.32(d,J=7.3Hz,2H),3.19-3.02(m,1H),2.99-2.87(m,1H),2.86-2 .76(m,1H),2.26-2.10(m,2H),2.06-1.98(m,1H),1.92-1.82(m,3H),0.89–0.77(m,1H). MS(ESI)m / z 379.

[0266] Example 27: 6-(cyclopentylmethyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one (Compound 27)

[0267]

[0268] 1 H NMR (400MHz, Methanol-d4) δ8.84 (s, 1H), 8.73 (d, J = 2.0Hz, 1H), 8.04 (dd, J = 8.3, 2.1Hz, 1H) ,7.75(d,J=8.2Hz,1H),5.27(s,2H),4.33(d,J=16.2Hz,1H),4.00=3.91(m,1H),3.90-3.75(m ,1H),3.45-3.32(m,1H),3.26(d,J=7.4Hz,2H),3.21-3.09(m,1H),2.95-2.73(m,1H),2.33( p,J=7.9Hz,1H),1.66-1.60(m,2H),1.28-1.20(m,2H),1.19-1.13(m,2H),0.86-0.76(m,2H). MS(ESI)m / z 393.

[0269] Example 28: 6-(cyclobutylmethyl)-3-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one (Compound 28)

[0270]

[0271] 1H NMR(400MHz, Methanol-d4)δ8.71(d,J=2.1Hz,1H),8.70(s,1H),8.06(dd,J=8.2 ,2.3Hz,1H),7.78(d,J=8.2Hz,1H),5.99(q,J=7.2Hz,1H),4.21(d,J=16.2Hz,1H ),3.89(d,J=16.1Hz,1H),3.76-3.62(m,1H),3.40-3.29(m,3H),3.16-3.04(m,1 H),2.95-2.86(m,1H),2.85-2.75(m,1H),2.23-2.12(m,2H),1.97–1.81(m,7H). MS(ESI)m / z 393.

[0272] Example 29: 6-Ethyl-2-methyl-3-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one (Compound 29)

[0273]

[0274] 1 H NMR(400MHz, Methanol-d4)δ8.81–8.63(m,1H),8.22–8.00(m,1H),7.77(d,J=8.3Hz,1H),6.06-5.96(m,1H),4.27-4.17(m ,1H),3.95-3.80(m,2H),3.47-3.30(m,3H),3.22-2.96(m,2H),2.91(s,3H),2.01(d,J=6.9Hz,3H),1.38(t,J=7.3Hz,3H). MS(ESI)m / z367.

[0275] Pharmacological Examples:

[0276] The affinity of representative compounds of this invention for the sigma-1 (σ-1) receptor and their activity as sigma-1 agonists were tested through the following experiments. The specific experimental protocol is as follows. The compounds mentioned in the following examples are all numbered consistent with the compounds listed in Table 1 of this invention. For example, compound 3 refers to the compound numbered 3 in Table 1, and similarly, compound 7 refers to the compound numbered 7 in Table 1.

[0277] Test Example 1: Affinity test of sigma-1 (σ-1) receptor

[0278] Preparation of test compoundsAll test samples were dissolved in 1% DMSO. If dissolution was poor or suspension was uneven, HCl (10% 10 μL) was added as needed. The initial concentration was 1.0 × 10⁻⁶. -5 M (i.e., 10 μM), then successively 1 μM, 333 nM, 100 nM, 33 nM, 10 nM, 3.3 nM, 1 nM, 0.33 nM, 0.1 nM, 0.01 nM, for later use.

[0279] σ-1 binding activity assay:

[0280] Receptor membrane preparation Homogenize guinea pig whole brain using 10mM Tris-HCl buffer containing 320mM sucrose at pH 7.4, adjust the weight, centrifuge at 1000g for 10 min, take the supernatant and add 10mM Tris-HCl buffer containing sucrose at pH 7.4 to homogenize, then centrifuge at 1000g at 4℃ for 10 min, take the supernatant, centrifuge at 50000g at 4℃ for 25 min, take the precipitate and add 10mM Tris-HCl buffer without sucrose at pH 7.4 to homogenize, centrifuge at 50000g at 4℃ for 25 min, take the precipitate and repeat the above operation, finally store the precipitate at -80℃ for later use.

[0281] Combined experiment Prepare a 220 mg / ml suspension of the receptor membrane using 10 mM Tris-HCl buffer (pH 7.4, sucrose-free) for later use. Add 100 μL of the membrane preparation to each reaction tube. Add 100 μL of 10 mM Tris-HCl buffer (pH 7.4, sucrose-free) to the total binding tube (TB), and add 100 μL of haloperidol (final concentration 1.0 × 10⁻⁶) to the nonspecific binding tube (NB). -5 M), 100 μL of the test compound was added to each test compound tube (CB). 4 nM of the radioactive ligand was added to each reaction tube. 3 10 μL of H-Pentazocine was added. Each reaction tube was incubated at 25°C for 135 min. After the reaction was complete, the bound ligands were rapidly filtered under reduced pressure. Whatman GF / C test strips were pre-soaked in 0.5% PEI for at least 1 h, thoroughly washed with ice-cold test buffer, and the filter was placed in a 4 mL scintillation cup. 1 mL of toluene scintillation solution was added and mixed well. Finally, the scintillation bottle was placed in a HIDEX liquid scintillation counter for counting. The experimental results are shown in Table 2 below.

[0282] Table 2 shows the Ki values ​​of the compounds on the sigma-1 receptor.

[0283] Compound numbering Kiσ1nM Compound numbering Kiσ1nM 1 1.52 16 / 2 30.85 17 170.52 3 45.56 18 48.08 4 395.99 19 67.64 5 908.63 20 / 6 242.08 21 / 7 28.88 22 451.35 8 / 23 9 / 24 / 10 208.05 25 1207.1 11 / 26 2.87 12 / 27 6.0 13 / 28 11.34 14 / 29 27.3 15 /

[0284] Test Example 2: Sigma-1 Receptor Agonist Function Test

[0285] According to literature reports ([J].Synapse,2005,55(3):192-195.), phenytoin can alter the conformation of the sigma-1 receptor. In the presence of phenytoin, the Ki value of the agonist is smaller than the normal Ki value, while the Ki value of the inhibitor is larger than the normal Ki value.

[0286] Specific procedure: Following the procedure in Example 8, the Ki value of compound 7 was detected. For the phenytoin group, the Ki value was detected by adding 1 mM phenytoin to the test tube and then detecting the Ki value of the compound after the addition of phenytoin. A normal Ki / phenytoin group Ki > 1 indicates that it is an agonist.

[0287] Figure 1 The experimental results in Table 3 indicate that the ratio of compound 7 (normal Ki / phenytoin group Ki) > 3.14, indicating that it is an agonist.

[0288] Table 3. Ki values ​​and ratios between the normal group and the phenytoin group

[0289] Ki value (nM) Sigma-1 (Normal Ki) 35.68 Sigma-1 (Phenytoin Ki) 11.38 ratio 3.14

[0290] Test Example 3: In vivo efficacy test in mice

[0291] Forced swimming test (FST) in mice

[0292] Forced swimming experiment in mice: Male ICR mice weighing 18-22g were used and divided into a solvent control group (10ml / kg) and a test group (compound 7, i.e., compound 7 of Example 7, 20, 40mg / kg). All mice in the test group, solvent group, and positive control group were intraperitoneally injected with the test substance or solvent 30 minutes before the formal swimming test, followed by the forced swimming experiment. Mice were placed in a transparent glass cylinder (water depth 15cm, water temperature 23-25℃) for 6 minutes, and their activity was recorded via video. After the experiment, the cumulative immobility time of the mice in the last 4 minutes of the 6-minute forced swimming period was analyzed using Forced Swim Scan™ 2.0 software.

[0293] The FST test results showed that, in the mouse forced swimming model, with the solvent group as the reference, compound 7 had significant efficacy at a dose of 40 mg / kg (p<0.1), with an inhibition rate of 36.3%.

[0294] Compound 3 was tested using the same method, with the test group replaced by compound 3 at doses of 20 mg / kg and 80 mg / kg. The FST test results showed that, with the solvent group as the reference, compound 3 had no significant efficacy at a dose of 20 mg / kg (inhibition rate of 20%), but had significant efficacy at a dose of 80 mg / kg (p<0.1), with an inhibition rate of 52.2%.

[0295] Test Example 4: BDNF Detection Experiment

[0296] Experimental methods:

[0297] Cell culture: U251 cells were cultured in 24-well plates with replicates for each group.

[0298] Cell drug administration: When cells have grown to confluence in 24-well plates, remove the old culture medium from the 24-well plates, add 250 μL of 10 μM GLYX-1310 and the test compound of this invention, replacing the blank group with fresh, drug-free culture medium; after timing for 15 min, transfer 200 μL of culture medium from each well to a labeled 96-well plate, centrifuge the culture medium at 1500 rpm for 10 min, and then transfer 160 μL of supernatant from each well to a new 96-well plate provided in the kit. Store the supernatant at -80℃.

[0299] The brain-derived neurotrophic factor (BDNF) assay kit (enzyme-linked immunosorbent assay, kit number: SEA011Mi, 96T) was used to detect the amount of BDNF, following the ELISA kit procedure.

[0300] ELLSA assay: Perform the experiment according to the instructions of the kit (number: SEA011Mi), and finally use an ELISA reader to detect the OD value at 450nm.

[0301] Add 100 μL of standard or test sample to each well and incubate at 37°C for 90 min. Remove the liquid from the wells without washing. Add 100 μL of ABC working solution to each well and incubate at 37°C for 30 min. Wash 5 times, then add 300 μL of 0.01M PBS (or TBS) to each well for 1-2 min. Add 90 μL of prepared TMB to each well and incubate at 37°C for 20-25 min in the dark; then add 100 μL of TMB stop solution. Pre-program the multi-plate reader to detect at 450 nm. The experimental results are shown in Table 4.

[0302] Table 4: BDNF Detection Results

[0303] Blank group GLYX-1310 Compound 7 Compound 19 Compound 27 BDNF increase factor 1.00 1.58 2.10 1.27 1.50 Standard error SEM 0.12 0.10 0.42 0.09 0.28

[0304] Note: GLYX-1310 (CAS: 117928-94-6) has a long-lasting antidepressant effect, and its structural formula is as follows:

[0305]

[0306] Sigma-1 receptor agonists can promote the secretion of BDNF (brain-derived neuroinfluencing factor), exhibiting rapid antidepressant effects and neuroprotective effects. As shown in Table 4, compounds 7, 19, and 27 significantly increased intracellular BDNF secretion levels, especially compound 7, which showed a very significant increase in BDNF secretion. This indicates that the compounds provided in this invention have rapid antidepressant effects and neuroprotective effects.

[0307] The above is merely an exemplary description to illustrate the beneficial effects of the compounds provided by the present invention. Other compounds provided by the present invention have been tested using the same experimental methods and have shown varying degrees of antidepressant effects.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, in, R1 is selected from either straight chain or branched chain C. 1-8 Alkyl groups, C substituted with at least one halogen 1-5 Any one of the alkyl groups; R2 is selected from hydrogen, straight-chain or branched C. 1-5 Any one of the alkyl groups; R3 is selected from hydrogen, straight-chain or branched C. 1-8 Any one of the alkyl groups; R4 is selected from benzene rings or substituted benzene rings, pyridine or substituted pyridine, wherein the substituents of the substituted benzene rings or substituted pyridines are each independently selected from hydrogen, halogens, straight-chain or branched C. 1-8 Alkyl groups, C substituted with at least one halogen 1-5 alkyl, C 1-5 Any one of the alkoxy groups; R5 is selected from hydrogen, halogen, straight-chain or branched C. 1-8 Alkyl groups, C substituted with at least one halogen 1-5 alkyl, C 1-5 Any one of the alkoxy groups.

2. A compound of formula I-3 or a pharmaceutically acceptable salt thereof: in, R1”' is selected from straight chain or branch chain C 1-8 alkyl or Where n1 and n2 are independently selected from integers 1 to 5; R2”' is selected from hydrogen, straight-chain or branched C 1-8 Any one of the alkyl groups; R3” is selected from hydrogen, straight-chain or branched C 1-8 Any one of the alkyl groups; R5” is selected from hydrogen, halogen, straight-chain or branched C. 1-8 Alkyl groups, C substituted with at least one halogen 1-8 alkyl, C 1-5 Any one of the alkoxy groups; R6”' is selected from halogens or is not present; R7” is selected from halogen, straight-chain or branched C 1-8 Alkyl groups, C substituted with at least one halogen 1-8 alkyl, C 1-5 Any one of the alkoxy groups; Z1 and Z2 are independently selected from nitrogen, carbon, or hydrocarbon.

3. The compounds of formulas I-3 according to claim 2, or pharmaceutically acceptable salts thereof, characterized in that, R1”' is selected from methyl, ethyl, propyl, butyl, isopropyl, pentyl, isobutyl or Where n1 is 1, 2 or 3, and n2 is 1, 2, 3 or 4; R2”' and R3”' are independently selected from any one of hydrogen, methyl, ethyl, propyl, butyl, isopropyl, pentyl, and isobutyl; R5”' is selected from any one of hydrogen, halogen, methyl, ethyl, propyl, butyl, isopropyl, pentyl, isobutyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, monofluoromethyl, and monofluoroethyl; R6”' is selected from halogens or is not present; R7”' is selected from any one of halogen, methyl, ethyl, propyl, butyl, isopropyl, pentyl, isobutyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, monofluoromethyl, monofluoroethyl, methoxy, ethoxy, propoxy, and butoxy. Z1 and Z2 are independently selected from nitrogen, carbon, or hydrocarbon.

4. The compound of formulas I-3 according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, R1”' is selected from methyl, ethyl, propyl, butyl, cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl; R2”' is selected from hydrogen; R3”' is selected from any one of hydrogen, methyl, ethyl, and propyl; R5”' is selected from any one of hydrogen, methyl, ethyl, and difluoromethyl; R6”' is either chlorine or absent; R7”' is selected from any one of chloro, methyl, trifluoromethyl, and methoxy; Z1 and Z2 are independently selected from nitrogen, carbon, or hydrocarbon.

5. The compound of formulas I-3 according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, R1”' is selected from propyl, cyclopropylmethyl or cyclobutylmethyl; R2”' is selected from hydrogen R3”' is selected from hydrogen or methyl; R5”' is selected from hydrogen or methyl; R6”' is selected from chlorine; R7”' is selected from chloro or trifluoromethyl; Z1 and Z2 are independently selected from nitrogen, carbon, or hydrocarbon.

6. A compound or a pharmaceutically acceptable salt thereof, characterized in that, Selected from any one of the following compounds: 6-(cyclopropylmethyl)-3-(3,4-dichlorobenzyl)-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclopropylmethyl)-2-methyl-3-(4-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4(3-hydro)-one; 6-(cyclopropylmethyl)-2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclopropylmethyl)-2-methyl-3-((6-methylpyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclopropylmethyl)-3-((6-methoxypyridin-3-yl)methyl)-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclopropylmethyl)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclopropylmethyl)-2-methyl-3-(1-(4-(trifluoromethyl)phenyl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; (S)-6-(cyclopropylmethyl)-2-methyl-3-(1-(4-(trifluoromethyl)phenyl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; (R)-6-(cyclopropylmethyl)-2-methyl-3-(1-(4-(trifluoromethyl)phenyl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclopropylmethyl)-2-methyl-3-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclopropylmethyl)-2-methyl-3-(1-(6-methylpyridinyl)-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclopropylmethyl)-2-methyl-3-(1-(6-methylpyridinyl)-3-yl)propyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclopropylmethyl)-2-methyl-3-(1-(6-methylpyridin-3-yl)butyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 2,6-Dimethyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-Ethyl-2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 2-Methyl-6-propyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-Butyl-2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclobutylmethyl)-2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclopentylmethyl)-2-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclobutylmethyl)-2-methyl-3-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclopentylmethyl)-2-methyl-3-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-Ethyl-2-methyl-3-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-Ethyl-3-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclopropylmethyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclopropylmethyl)-2-(difluoromethyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclopropylmethyl)-2-ethyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclobutylmethyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclopentylmethyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3-hydro)-one; 6-(cyclobutylmethyl)-3-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4(3-hydro)-one.

7. A pharmaceutical composition, characterized in that, It comprises the compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.

8. Use of the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and / or the pharmaceutical composition of claim 7 in the preparation of a medicament for treating and / or preventing sigma receptor-related disorders, said sigma receptor-related disorders being depression, anxiety disorder or bipolar disorder.

9. The compound represented by formula VII or a pharmaceutically acceptable salt thereof, in, R2 is selected from hydrogen, straight-chain or branched C. 1-8 Any one of the alkyl groups; R3 is selected from hydrogen, straight-chain or branched C. 1-8 Any one of the alkyl groups; R4 is selected from benzene rings or substituted benzene rings, pyridine or substituted pyridine, wherein the substituents of the substituted benzene rings or substituted pyridines are selected from hydrogen, halogens, straight-chain or branched C. 1-8 Alkyl groups, C substituted with at least one halogen 1-5 alkyl, C 1-5 Any one of the alkoxy groups.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, characterized in that, The following compounds 11. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, comprising the following steps: Scheme 1: Compound II undergoes a substitution reaction to obtain intermediate III, which then forms a ring with compound reactant-2 to obtain the parent structure IV. Compound IV then undergoes an electrophilic substitution reaction to prepare the compound shown in general formula I. Alternatively, scheme 2: Compound V is cyclized with reagent-2 to obtain the parent structure VI, which is then deprotected to obtain VII, and then reductively amination is performed to prepare general formula I: in, R1, R2, R3, R4, and R5 are as described in claim 1.

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