Deuterated tetrahydroisoquinoline aminopyridone derivatives and their applications

Abstract

The present invention belongs to the field of medicine, and relates to a deuterated tetrahydroisoquinoline aminopyridone derivative and its application, specifically to a compound represented by the following general formula II or a pharmaceutically acceptable salt thereof, and its use as a medicine for the preparation of drugs for treating neuropsychiatric diseases; #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the medical field and relates to a deuterated tetrahydroisoquinoline aminopyridinone derivative having high sigma-1 receptor affinity, a pharmaceutical composition containing the compound, a preparation method thereof, and an application thereof in the medical field. Background Art

[0002] In psychiatry, depression is defined as an affective disorder. Depression is a chronic, highly recurrent, and highly disabling mental illness and is the first disease that causes people to lose their working and living abilities. Traditional antidepressants have a delayed effect and a slow onset time, usually taking more than 2 - 3 weeks to take effect; in addition, the response rate of traditional antidepressants is not high, among which 30% of depressed patients have no response and 30% only have partial response; moreover, traditional antidepressants are prone to drug resistance, and once drug resistance occurs, their therapeutic effect is greatly reduced.

[0003] Anxiety disorder, also known as anxiety neurosis, is a mental disorder with anxiety symptoms as the main clinical manifestation, including panic disorder, generalized anxiety disorder, and social anxiety disorder. Its clinical symptoms often manifest as mental symptoms of restlessness and fear and worry, accompanied by somatic symptoms of concurrent autonomic hyperfunction. The comorbidity rate of anxiety disorder is relatively high, and it can co-occur with one or more mental disorders at the same time. Its therapeutic drugs include common antidepressants, benzodiazepines, and 5-HT1A agonists represented by buspirone. Benzodiazepines have relatively large side effects, and the improvement degree of other drugs for anxiety is small, and the curative effect needs to be improved.

[0004] Sigma-1 receptor (σ1 receptor) is a newly emerging drug target in recent years and is a binding protein of various specific psychiatric drugs. Sigma-1 receptor is a ligand-regulated protein molecular chaperone, which plays its molecular chaperone role by interacting with receptors such as NMDA: regulating NMDA, APMA and other ion channels and downstream receptors, thereby regulating mitochondrial function and the release of neurotransmitters such as serotonin and dopamine.

[0005] Known sigma-1 receptor agonists such as opipramol, igmesine, SA-4503, ANAVEX2-73, etc. have shown antidepressant and anti-anxiety effects clinically. Compounds such as benzomorphans (SKF10047, dextromethorphan), SSRI antidepressants (fluvoxamine, sertraline, fluoxetine, etc.) all have high affinity for the Sigma-1 binding site.

[0006] Considering the potential applications of Sigma-1 receptors in the field of neuropsychiatric diseases such as depression and anxiety, and there is no single effective drug targeting Sigma-1 receptors on the market. Therefore, it is of great significance for clinical applications to find compounds with relatively high selectivity for Sigma-1 receptors and good "drugability". Summary of the Invention

[0007] Based on this, the object of the present invention is to provide a new deuterated tetrahydroisoquinoline aminopyridinone derivative, especially a deuterated 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one; the present invention also provides a pharmaceutical composition containing this compound, its preparation method, and its application in the medical field.

[0008] In the first aspect of the present invention, there is provided a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Wherein, R1, R2, and R3 are each independently selected from -CH3, -CH2D, -CHD2, or -CD3;

[0011] Provided that R1, R2, or R3 are not all -CH3;

[0012] R4, R5, R6, R7, R8, and R9 are independently selected from H or D.

[0013] In some embodiments of the present invention, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, R1 and R2 are both methyl, and R3 is selected from -CH2D, -CHD2, or -CD3;

[0014] In some embodiments of the present invention, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, R3 is methyl, and R1 and R2 are independently selected from -CH2D, -CHD2, or -CD3;

[0015] In some embodiments of the present invention, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, R3 is methyl, and R1 and R2 are both -CD3;

[0016] In some embodiments of the present invention, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, R1, R2, and R3 are independently selected from -CH2D, -CHD2, and -CD3;

[0017] In some embodiments of the present invention, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, R3 is -CH2D, and R1 and R2 are independently selected from -CH2D, -CHD2, and -CD3;

[0018] In some embodiments of the present invention, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, R3 is -CHD2, and R1 and R2 are independently selected from -CH2D, -CHD2, and -CD3;

[0019] In some embodiments of the present invention, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, R1, R2, and R3 are all -CD3.

[0020] In a preferred embodiment of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0021]

[0022] wherein, R1, R2, and R3 are each independently selected from -CH3, -CH2D, -CHD2, or -CD3;

[0023] provided that R1, R2, or R3 are not all -CH3.

[0024] In some embodiments of the present invention, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, R1 and R2 are both methyl, and R3 is selected from -CH2D, -CHD2, or -CD3.

[0025] In some embodiments of the present invention, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, R1 and R3 are both methyl, and R2 is selected from -CH2D, -CHD2, or -CD3. In some embodiments of the present invention, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, R3 is methyl, and R1 and R2 are independently selected from -CH2D, -CHD2, or -CD3.

[0026] In some embodiments of the present invention, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, R3 is methyl, and R1 and R2 are both -CD3.

[0027] In some embodiments of the present invention, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, R1 is -CH3, and R2 and R3 are independently selected from -CH2D, -CHD2, and -CD3.

[0028] In some embodiments of the present invention, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, R1, R2, and R3 are independently selected from -CH2D, -CHD2, and -CD3.

[0029] In some embodiments of the present invention, in the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, R3 is -CH2D, and R1 and R2 are independently selected from -CH2D, -CHD2, and -CD3. In some embodiments of the present invention, in the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, R3 is -CHD2, and R1 and R2 are independently selected from -CH2D, -CHD2, and -CD3.

[0030] In some embodiments of the present invention, in the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, R1, R2, and R3 are all -CD3.

[0031] In a second aspect of the present invention, there is provided a method for preparing a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0032] Subjecting intermediate Ia to a substitution reaction to obtain intermediate Ib, subjecting intermediate Ib to hydrogenation reduction to obtain intermediate Ic, subjecting intermediate Ic to reductive amination to obtain Id, and subjecting Id and IIe to a Buchwald–Hartwig coupling reaction to obtain compound II:

[0033]

[0034] wherein R1, R2, R3, R4, R5, R6, R7, R8, and R9 are as defined above.

[0035] Furthermore, the present invention provides a method for preparing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0036] Subjecting intermediate Ia to a substitution reaction to obtain intermediate Ib, subjecting intermediate Ib to hydrogenation reduction to obtain intermediate Ic, subjecting intermediate Ic to reductive amination to obtain Id, and subjecting Id and Ie to a Buchwald–Hartwig coupling reaction to obtain compound I:

[0037]

[0038] wherein R1, R2, and R3 are as defined above.

[0039] In a third aspect of the present invention, there is provided a pharmaceutical composition, which is characterized by comprising the deuterated compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0040] In a fourth aspect of the present invention, there is provided the use of a compound represented by general formula I or general formula II according to the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a medicament for treating and / or preventing sigma receptor-mediated related diseases.

[0041] Preferably, the sigma receptor-mediated related diseases are selected from neuropsychiatric diseases;

[0042] More preferably, the neuropsychiatric diseases are selected from any one of depression and anxiety. Detailed Description of the Invention

[0043] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other technicians in the art to more fully understand the technical solutions of the present invention, their principles and their practical applications, so that other technicians in the art can modify and implement the present invention in many forms to best meet the requirements of specific uses.

[0044] Explanation of Terms

[0045] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0046] As used herein, the term "comprising" is an open-ended expression, i.e., it includes the content specified in the present invention, but does not exclude other aspects. It should be understood that the term "comprising" can cover a closed meaning, i.e., "consisting of".

[0047] In the description mode "independently / independent" adopted in the present invention, it should be understood in a broad sense. It can either mean that among different groups, the specific options expressed between the same symbols do not affect each other, or it can also mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0048] Definition

[0049] As used herein, "methyl" and "-CH3" have the same meaning and can be replaced with each other; the term "deuterated" means that one or more hydrogens in a compound or group are replaced by deuterium, and the deuteration can be mono-substitution, di-substitution, tri-substitution or full substitution.

[0050] In another preferred example, the deuterium isotope content at the deuterium substitution position is greater than the natural deuterium isotope content (0.015%), more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably greater than 97%, more preferably greater than 99%, more preferably greater than 99.5%.

[0051] In another preferred embodiment, the deuterated compound represented by General Formula I contains at least 1 deuterium atom (D), more preferably 3 deuterium atoms, more preferably 6 deuterated atoms, and more preferably 9 deuterated atoms.

[0052] Active Ingredient

[0053] As used herein, the term "compound according to the present invention" refers to the compound represented by General Formula I or General Formula II. This term also includes various crystal forms, pharmaceutically acceptable salts, hydrates or solvates of the compound represented by General Formula I or General Formula (II).

[0054] The term "solvate" refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0055] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which can be prepared from the free form of the compound and a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, the base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compound of the present invention contains a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include nitric acid, carbonic acid, bicarbonate, hydroiodic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, citric acid, fumaric acid, tartaric acid and methanesulfonic acid and similar acids; it also includes salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid.

[0056] "Pharmaceutical composition" refers to a mixture formed by one or more compounds according to the present invention, their pharmaceutically acceptable salts or mixtures thereof and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0057] "Excipient" refers to a material that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound.

[0058] Technical Solution

[0059] Through research, the present inventor unexpectedly found that deuterated tetrahydroisoquinoline aminopyridinone derivatives, especially deuterated 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one and its pharmaceutically acceptable salts have good sigma-1 affinity and metabolic stability, and are therefore more suitable for the treatment of neuropsychiatric diseases and as drugs for sigma-1 receptor-related diseases.

[0060] The present inventor first studied and found that the compound 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one has good affinity and selectivity for the sigma-1 receptor, good safety and metabolic stability, and has very good application prospects in the treatment and prevention of central nervous system diseases, especially in the aspects of antidepressant and antianxiety. These contents are recorded in PCT / CN2021 / 103543, and all the contents recorded in this patent are incorporated into the present invention by reference. Further based on the study of the in vivo metabolic sites of the compound 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, the inventor designed and synthesized a series of deuterated 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, including deuterated compounds or their salts represented by general formula I and general formula II. Through binding experiments and verification, it was found that when at least one H in the methyl groups at the R1, R2, and R3 positions is replaced by D, the resulting compounds have improved pharmacokinetic properties, show good activity and metabolic stability, and have good medicinal prospects.

[0061] Specifically, the technical solution of the present invention is a compound represented by general formula (II) or its pharmaceutically acceptable salt:

[0062]

[0063] Wherein, R1, R2, and R3 are each independently selected from -CH3, -CH2D, -CHD2, or -CD3;

[0064] Provided that R1, R2, or R3 are not all -CH3;

[0065] R4, R5, R6, R7, R8, and R9 are independently selected from H or D.

[0066] In a preferred embodiment of the present invention, there is provided a compound represented by general formula (I) or its pharmaceutically acceptable salt:

[0067]

[0068] R1, R2, and R3 are each independently selected from -CH3, -CH2D, -CHD2, or -CD3;

[0069] provided that R1, R2, or R3 is not -CH3 simultaneously; that is, at least one hydrogen on the methyl group of R1, R2, or R3 is deuterated.

[0070] In some embodiments of the present invention, in the compound of formula (I) or its pharmaceutically acceptable salt, R1 and R2 are both methyl, and R3 is selected from -CH2D, -CHD2, or -CD3.

[0071] In some embodiments of the present invention, in the compound of formula (I) or its pharmaceutically acceptable salt, R3 is methyl, and R1 and R2 are independently selected from -CH2D, -CHD2, or -CD3. In some embodiments of the present invention, in the compound of formula (I) or its pharmaceutically acceptable salt, R3 is methyl, and R1 and R2 are both -CD3.

[0072] In a preferred embodiment of the present invention, there is provided a compound of formula (I) or its pharmaceutically acceptable salt:

[0073]

[0074] wherein, R1, R2, and R3 are selected from the following:

[0075]

[0076]

[0077] In a more preferred embodiment of the present invention, there are provided the following compounds:

[0078] 5 - ((2 - (cyclopropylmethyl) - 1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(isopropyl)amino) - 1 - (methyl - d3)pyridin - 2(1H) - one

[0079] 5 - ((2 - (cyclopropylmethyl) - 1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(prop - 2 - yl - 1,1,1,3,3,3 - d6)amino) - 1 - methylpyridin - 2(1H) - one

[0080]

[0081] 5 - ((2 - (cyclopropylmethyl) - 1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(prop - 2 - yl - 1,1,1,3,3,3 - d6)amino) - 1 - (methyl - d3)pyridin - 2(1H) - one

[0082]

[0083] 5 - ((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1-d1)amino)-1-methylpyridin-2(1H)-one

[0084]

[0085] 5 - ((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1-d2)amino)-1-methylpyridin-2(1H)-one

[0086]

[0087] 5 - ((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,3-d2)amino)-1-methylpyridin-2(1H)-one

[0088]

[0089] 5 - ((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,3-d3)amino)-1-methylpyridin-2(1H)-one

[0090]

[0091] 5 - ((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,3,3-d4)amino)-1-methylpyridin-2(1H)-one

[0092]

[0093] 5 - ((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,1,3,3-d5)amino)-1-methylpyridin-2(1H)-one

[0094]

[0095] 5 - ((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1-d1)amino)-1-(methyl-d1)pyridin-2(1H)-one

[0096]

[0097] 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl)amino)-1-(methyl-d1)pyridin-2(1H)-one

[0098]

[0099] 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl)amino)-1-(methyl-d2)pyridin-2(1H)-one

[0100]

[0101] 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1-d2)amino)-1-(methyl-d1)pyridin-2(1H)-one

[0102]

[0103] 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1-d2)amino)-1-(methyl-d2)pyridin-2(1H)-one

[0104]

[0105] 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,3-d3)amino)-1-(methyl-d2)pyridin-2(1H)-one

[0106]

[0107] 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,3,3-d4)amino)-1-(methyl-d2)pyridin-2(1H)-one

[0108]

[0109] 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,1,3,3-d5)amino)-1-(methyl-d2)pyridin-2(1H)-one

[0110]

[0111] 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,1,3,3,3-d6)amino)-1-(methyl-d2)pyridin-2(1H)-one

[0112]

[0113] 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,3,3-d4)amino)-1-(methyl-d3)pyridin-2(1H)-one

[0114]

[0115] Preparation Method

[0116] The present invention provides a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0117] Subjecting intermediate Ia to a substitution reaction to obtain intermediate Ib, subjecting intermediate Ib to hydrogenation reduction to obtain intermediate Ic, subjecting intermediate Ic to reductive amination to obtain Id, and subjecting Id and IIe to a Buchwald–Hartwig coupling reaction to obtain compound II:

[0118]

[0119] wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 are as defined above.

[0120] For example, intermediate Ia is subjected to a substitution reaction with IR3 (such as ICH3, ICH2D, ICHD2 or ICD3) under basic conditions to obtain intermediate Ib, intermediate Ib is subjected to hydrogenation reduction with Pd / C to obtain intermediate Ic, intermediate Ic is subjected to reductive amination with acetone or deuterated acetone (such as CH3COCH3, CH2DCOCH3, CHD2COCH3, CH2DCOCH2D, CHD2COCH2D, CHD2COCHD2, CD3COCH2D, CD3COCHD2, or CD3COCD3, etc.) using sodium triacetoxyborohydride to obtain intermediate Id, and intermediate Id and IIe are subjected to a Buchwald–Hartwig coupling reaction under basic conditions (such as cesium carbonate) and Pd2(dba)3, 2-dicyclohexylphosphino-2′ conditions to obtain compound II.

[0121] Furthermore, compound IIe is prepared by dissolving compound IIf and cyclopropanecarbaldehyde in an organic solvent and subjecting them to a reductive amination reaction:

[0122]

[0123] Wherein R4, R5, R6, R7, R8, and R9 are as defined above.

[0124] More specifically, the present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0125] Intermediate Ia is subjected to a substitution reaction to obtain Intermediate Ib, Intermediate Ib is subjected to hydrogenation reduction to obtain Intermediate Ic, Intermediate Ic is subjected to reductive amination to obtain Id, and Intermediate Id and Ie are subjected to a Buchwald–Hartwig coupling reaction to obtain Compound I:

[0126]

[0127] Wherein R1, R2, and R3 are as defined above.

[0128] For example, Intermediate Ia is subjected to a substitution reaction with IR3 (such as ICH3, ICH2D, ICHD2, or ICD3) under basic conditions to obtain Intermediate Ib, Intermediate Ib is subjected to hydrogenation reduction with Pd / C to obtain Intermediate Ic, Intermediate Ic is subjected to reductive amination with acetone or deuterated acetone (such as CH3COCH3, CH2DCOCH3, CHD2COCH3, CD3COCH3, CH2DCOCH2D, CHD2COCH2D, CHD2COCHD2, CD3COCH2D, CD3COCHD2, or CD3COCD3, etc.) with sodium triacetoxyborohydride to obtain Intermediate Id, and Intermediate Id and Ie are subjected to a Buchwald–Hartwig coupling reaction under basic conditions (such as cesium carbonate) and Pd2(dba)3, 2-dicyclohexylphosphino-2′ conditions to obtain Compound I.

[0129] Furthermore, the present invention also provides a method for preparing Compound Ie, comprising: dissolving Compound If and cyclopropanecarbaldehyde in an organic solvent and preparing Intermediate Ie through a reductive amination reaction.

[0130]

[0131] In a preferred embodiment of the present invention, Compound I-D3, I-D6, I-D9, and their preparation methods are provided, and the method comprises the following steps:

[0132]

[0133] Pharmaceutical Composition and Administration Method

[0134] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0135] In one embodiment of the present invention, the pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the present invention can be formulated into dosage forms for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration, or dosage forms suitable for administration by inhalation or insufflation. The compounds of the present invention or their pharmaceutically acceptable salts can also be formulated into sustained release dosage forms.

[0136] In one embodiment of the present invention, an effective dose of the compound of the present invention or its pharmaceutically acceptable salt can be orally administered together with an inert diluent or a carrier. According to some embodiments of the present invention, the compound of the present invention can be encapsulated in a gelatin capsule or compressed into tablets. For the purpose of oral treatment, the compounds of the present invention can be used with excipients and used in the form of tablets, lozenges, capsules, suspensions, syrups, etc. According to the embodiments of the present invention, the above preparations should contain at least 0.5% (w / w) of the active compound of the present invention, but can vary according to the specific dosage form, and it is convenient that 4% to about 70% by unit weight. The amount of the active compound in such a pharmaceutical composition should reach an appropriate dose.

[0137] In one embodiment of the present invention, for oral administration, the active compounds of the present invention can be formulated into tablets or capsules with pharmaceutically acceptable excipients by conventional means, such as binders, fillers, lubricants, disintegrants or wetting agents. Tablets can be coated by methods well known in the art. Liquid preparations for oral administration, such as solutions, syrups or suspensions, or can be volatilized into dry products and regenerated with water or other suitable carriers before use. Such liquid preparations can be prepared by conventional means using pharmaceutical additives, such as suspending agents, emulsifying agents, non-aqueous carriers and preservatives.

[0138] In one embodiment of the present invention, when the active compound of the present invention is used for parenteral administration, the compound provided by the present invention can be combined with sterile water or an organic medium to form an injectable solution or suspension.

[0139] In one embodiment of the present invention, 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.

[0140] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0141] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage during administration is the pharmaceutically effective dosage. For a drug, drug unit or active ingredient, "effective amount", "therapeutically effective amount" or "preventively effective amount" refers to a sufficient amount of a drug or agent that has acceptable side effects but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, and also depends on the specific active substance. The appropriate effective amount in a particular case can be determined by those skilled in the art according to routine tests.

[0142] Medical Use

[0143] The present invention also provides the use of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a drug for regulating the sigma receptor, wherein the drug optionally contains one or more other active agents for regulating the mammalian nervous system or relieving mental diseases.

[0144] In one embodiment of the present invention, the regulation includes, but is not limited to, the agonist activity of the receptor.

[0145] In one embodiment of the present invention, the present invention provides the use of the compound of the present invention, or a pharmaceutical composition thereof, in the preparation of a drug for treating and / or preventing sigma-1 receptor-related diseases or disease states.

[0146] In yet another embodiment of the present invention, the present invention also provides a method for treating and / or preventing sigma-1 receptor-related diseases or disease states, which includes administering the compound of the present invention and its pharmaceutical composition to an individual in need thereof.

[0147] In another embodiment of the present invention, the compound of the present invention, or a pharmaceutical composition thereof, is used for treating and / or preventing sigma-1 receptor-related diseases or disease states. Further, the sigma-1 receptor-related diseases are mental diseases such as depression, anxiety, Alzheimer's disease, etc., preferably depression.

[0148] Advantages of the Present Invention :

[0149] First, the present invention provides a series of novel compounds with good sigma-1 affinity, and these compounds have potential uses for treating mental and nervous system-related diseases, especially have good antidepressant and antianxiety effects.

[0150] At the same time, these deuterated compounds provided by the present invention have good metabolic stability, which is beneficial to increasing the drug concentration in animals to improve the drug efficacy and reduce side effects at the same time.

[0151] The present invention will be further described below in connection with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are calculated by weight.

[0152] Synthesis Example

[0153] Example 1: 7-Bromo-2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinoline (Ie)

[0154]

[0155] Dissolve 7-bromo-1,2,3,4-tetrahydroisoquinoline (4.71 g, 22.2 mmol) and cyclopropanecarbaldehyde (3.15 g, 23.13 mmol) in 150 mL of DCM, add NaBH(OAc)3 (4.9 g, 23.13 mmol), and stir magnetically overnight. After the reaction is completed, purify by silica gel column chromatography (PE / EA = 15 / 1) to obtain 5.8 g of 7-bromo-2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinoline (yield 98.3%).

[0156] Example 2: 5-Amino-1-(methyl-d3)pyridin-2(1H)-one

[0157]

[0158] Add 5-nitro-1,2-dihydropyridin-2-one (1.0 g, 7.14 mmol), deuterated iodomethane (1.04 g, 7.14 mmol), potassium carbonate (1.48 g, 10.71 mmol), and acetonitrile (50 mL) to a 50 mL single-necked flask, stir and react at 25 °C for 3 h. After the reaction is completed as detected by TLC (PE / EA = 3 / 1), filter and concentrate to obtain 2.4 g of the crude product of Ib-D3.

[0159] Ib-D3 (2.2 g, 14.00 mmol), di-tert-butyl dicarbonate (6.72 g, 30.8 mmol), sodium carbonate (2.23 g, 21.0 mmol) and Pd / C (0.8 g) were added into a three-necked flask, and hydrogen was displaced. The reaction was carried out at room temperature for 16 h. The reaction was monitored by TLC and stopped when it was complete. The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, slurried with petroleum ether for 2 h, and then filtered to obtain 1.4 g of crude product (the crude product was directly used for the next reaction without separation). The obtained crude product (1.40 g, 6.16 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3.06 g, 26.84 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 h. After the reaction was detected by TLC, water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 5). The organic phases were combined and concentrated under reduced pressure to obtain 1.66 g of crude product of Ic-D3.

[0160] Example 3: 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-(methyl-d3)pyridin-2(1H)-one

[0161]

[0162] Ic-D3 (1.1 g, 8.7 mmol) was dissolved in dichloromethane (10 mL). The reaction solution was cooled to 0 °C, and sodium cyanoborohydride (2.7 g, 13.0 mmol) was added. Acetone (0.45 g, 7.8 mmol) was dissolved in dichloromethane (10 mL) and added to the reaction solution in three portions. After the addition was complete, the reaction was continued at room temperature for 1 h. After the reaction was complete as monitored by TLC, the reaction was stopped. Water (10 mL) was added, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 1.0 g of blue oil of Id-D3.

[0163] The reactants 7-bromo-2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinoline (266 mg, 1.0 mmol), 5-(methylamino)-1-(methyl-d3)pyridin-2(1H)-one (152 mg, 1.1 mmol), 2-dicyclohexylphosphino-2' (48 mg, 0.10 mmol), Pd2(dba)3 (92 mg, 0.10 mmol), Cs2CO3 (630 mg, 1.9 mmol) and xylene (10 mL) were successively added to the reaction flask, and the reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with EA (30 mL x 2) and DCM (50 mL x 2). The organic phases were combined, concentrated, and purified by column chromatography (DCM / MeOH = 10:1) to obtain 159 mg of the oily product 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-(methyl-d3)pyridin-2(1H)-one, yield: 45.4%.

[0164] 1 H NMR (400 MHz, Chloroform-d) δ 7.13 (dd, J = 9.5, 2.8 Hz, 1H), 7.08 (d, J = 2.7 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.60 (d, J = 9.5 Hz, 1H), 6.51 (dd, J = 8.5, 2.7 Hz, 1H), 6.30 (d, J = 2.6 Hz, 1H), 4.18 (m, 1H), 3.76 (s, 2H), 2.93 (d, J = 5.6 Hz, 2H), 2.89 (d, J = 5.5 Hz, 2H), 2.54 (d, J = 6.7 Hz, 2H), 1.13 (d, J = 6.5 Hz, 6H), 1.10–0.99 (m, 1H), 0.68–0.57 (m, 2H), 0.24 (dt, J = 6.1, 4.6 Hz, 2H). MS (ESI) m / z = 355 ([M+H].[

[0165] Example 4: 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,1,3,3,3-d6)amino)-1-(methyl-d3)pyridin-2(1H)-one

[0166]

[0167] Dissolve Ic-D3 (1.12 g, 8.8 mmol) and deuterated acetone (0.62 g, 9.69 mmol) in dichloromethane (20 mL), displace nitrogen, add two drops of acetic acid, and stir at room temperature for 1 h. Slowly add sodium triacetoxyborohydride (2.9 g, 13.21 mmol) to the reaction solution. After the addition is complete, raise the temperature to room temperature and continue the reaction for 4 h. Monitor the reaction by TLC until completion, then stop the reaction. Quench the reaction with 10 mL of saturated sodium bicarbonate, extract with dichloromethane three times (20 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 1.54 g of crude product Id-D9 as a blue oil.

[0168] Add 7-bromo-2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinoline (Ie) (2.34 g, 8.8 mmol), Id-D9 (1.54 g, 8.8 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.22 g, 0.46 mmol), Pd2(dba)3 (0.41 mg, 0.44 mmol), potassium tert-butoxide (2.02 g, 18.04 mmol), and xylene (50 mL) successively into the reaction flask. Displace nitrogen three times, and stir at 35 °C for 15 h under nitrogen protection. Monitor the reaction by TLC until completion, then stop the reaction. Filter, quench the reaction with 10 mL of water, extract with dichloromethane three times (10 mL * 3), combine the organic phases, dry over anhydrous magnesium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain 0.46 g of the dark green product I-D9.

[0169] 1 H NMR (400 MHz, Methanol-d4) δ 7.64 (d, J = 2.5 Hz, 1H), 7.43 (d, J = 9.2 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.85–6.78 (m, 2H), 6.69 (s, 1H), 4.59 (d, J = 15.1 Hz, 1H), 4.37–4.20 (m, 2H), 3.54–3.31 (m, 2H), 3.27–3.02 (m, 4H), 0.89 - 0.87 (m, 1H), 0.80 - 0.79 (m, 2H), 0.51 - 0.48 (m, 2H). MS (ESI) m / z = 361 ([M + H].

[0170] Example 5: 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,1,3,3,3-d6)amino)-1-(methyl)pyridin-2(1H)-one

[0171]

[0172] Dissolve Ic-D0 (1.0 g, 8.06 mmol) and deuterated acetone (0.54 g, 8.46 mmol) in dichloromethane (20 mL), displace nitrogen, add two drops of acetic acid, and stir at room temperature for 1 h. Slowly add sodium borohydride acetate (2.56 g, 12.08 mmol) to the reaction solution. After the addition is complete, raise the temperature to room temperature and continue the reaction for 4 h. Monitor the reaction by TLC until completion, then stop the reaction. Quench the reaction with 10 mL of saturated sodium bicarbonate, extract with dichloromethane three times (20 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 1.39 g of crude product Id-D6 as a blue oil.

[0173] Add 7-bromo-2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinoline (Ie) (2.15 g, 8.8 mmol), Id-D6 (1.39 g, 8.06 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.22 g, 0.46 mmol), Pd2(dba)3 (0.41 mg, 0.44 mmol), potassium tert-butoxide (2.02 g, 18.04 mmol), and xylene (50 mL) into the reaction flask successively. Displace nitrogen three times, and stir at 35 °C for 15 h under nitrogen protection. Monitor the reaction by TLC until completion, then stop the reaction. Filter, quench the reaction with 10 mL of water, extract with dichloromethane three times (10 mL * 3), combine the organic phases, dry over anhydrous magnesium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain the product I-D6.

[0174] 1 H NMR (400 MHz, Methanol-d4) δ 7.64 (d, J = 2.5 Hz, 1H), 7.43 (d, J = 9.2 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.85–6.78 (m, 2H), 6.69 (s, 1H), 4.59 (d, J = 15.1 Hz, 1H), 4.37–4.20 (m, 2H), 3.78 (s, 3H), 3.54–3.31 (m, 2H), 3.27–3.02 (m, 4H), 0.89 - 0.87 (m, 1H), 0.80 - 0.79 (m, 2H), 0.51 - 0.48 (m, 2H). MS (ESI) m / z = 358 ([M + H].

[0175] Pharmacological Example

[0176] Test Example 1 : In vitro sigma receptor binding assay

[0177] The in vitro affinities of representative compounds of the present invention for sigma (σ-1 and σ-2) binding sites were tested. The specific test protocol is as follows:

[0178] Preparation of Test Compounds : All test samples were dissolved in DMSO with a final concentration of 1%. If the dissolution was poor or the suspension was uneven, HCl (10%, 10 μL) was appropriately added, and the initial concentration was 1.0×10 -5 M (i.e., 10 μM), and 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 standby.

[0179] sigma-1 binding activity test:

[0180] Preparation of Receptor Membranes : Guinea pig whole brain was homogenized with 10 mM Tris-HCl buffer containing 320 mM sucrose at pH = 7.4, the weight was adjusted, centrifuged at 1000 g for 10 min, the supernatant was taken and homogenized with 10 mM Tris-HCl buffer containing sucrose at pH = 7.4, then centrifuged at 1000 g at 4 °C for 10 min, the supernatant was taken, and centrifuged at 50000 g at 4 °C for 25 min. The precipitate was taken and homogenized with 10 mM Tris-HC buffer without sucrose at pH = 7.4, centrifuged at 50000 g at 4 °C for 25 min, and the precipitate was taken to repeat the previous operation. Finally, the precipitate was stored at -80 °C for standby.

[0181] Binding Assay : The prepared receptor membrane was made into a suspension of 220 mg / ml membrane with 10 mM Tris-HCl buffer without sucrose at pH = 7.4 for standby. 100 μL of the membrane preparation was added to each reaction tube. 100 μL of 10 mM Tris-HC buffer without sucrose at pH = 7.4 was added to the total binding tube (TB), 100 μL of haloperidol (final concentration 1.0×10 -5 M) was added to the non-specific binding tube (NB), and 100 μL of the test compound was added to each test compound tube (CB). 10 μL of radioactive ligand 4 nM 3 H]-Pentazocine was added to all reaction tubes. Each reaction tube was incubated at 25 °C for 135 min. After the reaction was completed, the bound ligand was quickly filtered under reduced pressure. Whatman GF / C filter paper was soaked in 0.5% PEI for more than 1 h in advance, washed thoroughly with ice-cold test buffer, the filter was taken out and placed in a 4 mL scintillation vial, 1 mL of toluene scintillation fluid was added and mixed evenly. Finally, the scintillation vial was placed in a HIDEX liquid scintillation counter for counting.

[0182] The test results show that the compounds represented by General Formula I and General Formula (II) provided by the present invention have significant affinity for the Sigma-1 receptor. Among them, the Ki values of Compound I-D3 and I-D9 for the Sigma-1 receptor are 109.56 nM and 31.92 nM respectively, indicating that Compound I-D3 and I-D9 have significant affinity for the Sigma-1 receptor.

[0183] Test Example 2 : Liver microsome metabolic stability test

[0184] Experimental method: The compounds of the examples were co-incubated with mouse, rat, dog, monkey and human liver microsomes (0.5 mg / mL) with or without cofactor (NADPH). The compound concentration in the incubation system was 1 μM and the incubation time was 60 minutes. Testosterone was used as the positive control. Samples were taken at different time points (0, 5, 10, 20, 40 and 60 minutes) during the incubation process, and the reaction was terminated by adding acetonitrile solution containing internal standard. The remaining percentage, intrinsic clearance rate and half-life were measured.

[0185] The test results show that the compounds represented by General Formula I and General Formula (II) provided by the present invention have improved pharmacokinetic parameter characteristics compared with the non-deuterated compounds, can increase the drug concentration of the compounds in animals and prolong the half-life. The test results of Compound I-D3 are shown in Table 1.

[0186] Table 1 Liver microsome metabolic stability results of Compound I-D3

[0187]

[0188] Test Example 3: Sigma-1 agonist function test

[0189] According to the literature report ([J]. Synapse, 2005, 55(3): 192-195.), phenytoin can change the conformation of the sigma-1 receptor. In the presence of phenytoin, the Ki value of the agonist becomes smaller compared with the normal Ki value, and the Ki value of the inhibitor becomes larger compared with the normal Ki value.

[0190] Referring to the specific operation in the reference ([J]. Synapse, 2005, 55(3): 192-195.), taking Compound I-D3 as an example, the Ki value of the compound of the present invention was detected. The detection method of the Ki value in the phenytoin group was to add phenytoin additionally to the test substance tube and detect the Ki value after adding phenytoin. If the normal Ki value / Ki value in the phenytoin group > 1, it can be determined as an agonist.

[0191] The experimental results indicate that the ratios of Compound I-D3, Compound I-D6, and Compound I-D9 (normal Ki / Ki of the phenytoin group) are all greater than 1, making them sigma-1 agonists.

[0192] Test Example 4: In Vivo Pharmacodynamic Test in Mice

[0193] Mouse Forced Swim Test (FST): Male ICR mice weighing 18 - 22 g were divided into a vehicle control group, a positive control group (duloxetine, 15 mg / kg), and a test group (the compound of the example, 30 mg / kg, 60 mg / kg, 90 mg / kg). The test group, the vehicle group, and the positive control group were intraperitoneally injected with the test substance or vehicle 30 minutes before the formal swim, and then the mouse forced swim test was carried out. The mice were placed in a transparent glass cylinder (water depth 15 cm, water temperature 23 - 25 °C) for 6 minutes, and the activity status of the mice was video-recorded. After the experiment, the cumulative immobility time results of the mice in the last 4 minutes during the 6-minute forced swim were analyzed using Forced Swim ScanTM 2.0 software.

[0194] The results of the FST test showed that in the mouse forced swim model, the duloxetine group (positive control) exhibited extremely significant pharmacodynamic effects (p < 0.0001). Compound I-D3 had no pharmacodynamic effect at 30 mg / kg, had significant pharmacodynamic effects at 60 mg / kg (p < 0.05), and had extremely significant pharmacodynamic effects at 90 mg / kg (p < 0.0001). Compound I-D6 and Compound I-D9 had similar effects.

Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt thereof: Among them, R1, R2, and R3 are each independently selected from -CH3, -CH2D, -CHD2, or -CD3; provided that R1, R2, or R3 are not all -CH3; R4, R5, R6, R7, R8, and R9 are independently selected from H or D.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 and R2 are both methyl, and R3 is selected from -CH2D, -CHD2, or -CD3; or R3 is methyl, and R1 and R2 are independently selected from -CH2D, -CHD2, or -CD3; or R3 is methyl, and R1 and R2 are both -CD3; or R1, R2, and R3 are independently selected from -CH2D, -CHD2, and -CD3; or R3 is -CH2D, and R1 and R2 are independently selected from -CH2D, -CHD2, and -CD3; or R3 is -CHD2, and R1 and R2 are independently selected from -CH2D, -CHD2, and -CD3; or R1, R2, and R3 are all -CD3.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, Having the structure shown in formula I below: R1, R2, and R3 are each independently selected from -CH3, -CH2D, -CHD2, or -CD3; provided that R1, R2, or R3 are not all -CH3.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are both methyl, and R3 is selected from -CH2D, -CHD2, or -CD3; or, R3 is methyl, and R1 and R2 are independently selected from -CH2D, -CHD2, or -CD3; or R3 is methyl, and R1 and R2 are both -CD3; or, R1, R2, and R3 are independently selected from -CH2D, -CHD2, and -CD3; or, R3 is -CHD2, and R1 and R2 are independently selected from -CH2D, -CHD2, and -CD3.

5. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, characterized in that, R1, R2, and R3 are all -CD3.

6. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, characterized in that, Selected from the following compounds: 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-(methyl-d3)pyridin-2(1H)-one; 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,1,3,3,3-d6)amino)-1-methylpyridin-2(1H)-one; 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,1,3,3,3-d6)amino)-1-(methyl-d3)pyridin-2(1H)-one; 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1-d1)amino)-1-methylpyridin-2(1H)-one; 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1-d2)amino)-1-methylpyridin-2(1H)-one; 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,3-d2)amino)-1-methylpyridin-2(1H)-one; 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,3-d3)amino)-1-methylpyridin-2(1H)-one; 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,3,3-d4)amino)-1-methylpyridin-2(1H)-one; 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,1,3,3-d5)amino)-1-methylpyridin-2(1H)-one; 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1-d1)amino)-1-(methyl-d1)pyridin-2(1H)-one; 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl)amino)-1-(methyl-d1)pyridin-2(1H)-one; 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl)amino)-1-(methyl-d2)pyridin-2(1H)-one; 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1-d2)amino)-1-(methyl-d1)pyridin-2(1H)-one; 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1-d2)amino)-1-(methyl-d2)pyridin-2(1H)-one; 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,3-d3)amino)-1-(methyl-d2)pyridin-2(1H)-one; 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,3,3-d4)amino)-1-(methyl-d2)pyridin-2(1H)-one; 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,1,3,3-d5)amino)-1-(methyl-d2)pyridin-2(1H)-one; 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,1,3,3,3-d6)amino)-1-(methyl-d2)pyridin-2(1H)-one; or 5-((2-(Cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(propan-2-yl-1,1,3,3-d4)amino)-1-(methyl-d3)pyridin-2(1H)-one.

7. A method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps: Intermediate Ia is subjected to a substitution reaction to obtain intermediate Ib, intermediate Ib is subjected to hydrogenation reduction to obtain intermediate Ic, intermediate Ic is subjected to reductive amination to obtain Id, and Id and IIe are subjected to a Buchwald–Hartwig coupling reaction to obtain compound II: wherein R1, R2, R3, R4, R5, R6, R7, R8, and R9 are as defined in any one of claims 1 to 2.

8. A method for preparing a deuterated compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: Intermediate Ia is subjected to a substitution reaction to obtain intermediate Ib, intermediate Ib is subjected to hydrogenation reduction to obtain intermediate Ic, intermediate Ic is subjected to reductive amination to obtain Id, and Id and Ie are subjected to a Buchwald–Hartwig coupling reaction to obtain compound I: wherein R1, R2, and R3 are as defined in any one of claims 3 to 5.

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

10. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 9 in the preparation of a drug for treating and / or preventing sigma receptor-mediated related diseases.

11. The use according to claim 10, characterized in that, The sigma receptor-mediated related diseases are selected from neuropsychiatric diseases.

12. According to the use described in claim 11, wherein, The neuropsychiatric diseases are selected from any one of depression and anxiety.

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