SERT-nNOS coupling antagonist and application thereof

Abstract

The invention discloses compounds as shown in formulas I-VIII as well as a preparation method and application thereof, the structural general formula of the compounds provided by the invention is as follows: # imgabs0, and the compounds can effectively antagonize SERT-nNOS coupling, and have the advantages of good anti-depression effect and quick response when being used for resisting depression.

Description

Technical Field

[0001] The present invention relates to a SERT-nNOS coupling antagonist and uses thereof. Background Art

[0002] The serotonin transporter protein (SERT) is one of the targets of currently used antidepressant drugs. When the activity of this protein is inhibited, the level of serotonin in the brain's synapses will increase, which can improve symptoms of depression and anxiety. Under physiological conditions, when the 5-HT1A autoreceptors on the dendritic cells of the dorsal raphe nucleus are activated, the neural discharge of serotonergic neurons will be inhibited, resulting in a decrease in serotonin levels. The antidepressant mechanism of SERT inhibitors is to block the SERT in the postsynaptic tissue, thereby activating the 5-HT1A receptors in this area, allowing the cells to reabsorb 5-HT and emit signals. However, in the dorsal raphe nucleus, the opposite effect is played. In order for SERT inhibitors to exert their antidepressant effects, it is necessary to wait for the 5-HT1A autoreceptors in the dorsal raphe nucleus to desensitize, so this type of drug will show the characteristics of slow onset. The desensitization behavior of 5-HT1A autoreceptors is unstable, so SERT inhibitors also have the disadvantage of unstable efficacy.

[0003] Neuronal nitric oxide synthase (nNOS) is a type of isozyme containing heme and similar in structure to cytochrome P450 reductase, which is widely distributed in the central nervous system. In vivo, nNOS uses L-arginine (L-Arg) and molecular oxygen as substrates. Under the condition that reduced nicotinamide adenine dinucleotide phosphate (NADPH) provides electrons as a cofactor, it transfers electrons from flavin adenine dinudeotide (FAD), flavin mononucleotide (FMN), and tetrahydrofolate (THF) to generate NO through oxidation reaction. In the nervous system, NO, as an important signaling molecule, participates in important neurophysiological activities such as learning and memory, and also has a regulatory effect on brain blood flow and participates in the immune defense of the nervous system. On the other hand, excessive NO is closely related to the occurrence and development of nervous system diseases such as cerebral ischemia, Alzheimer's disease and Parkinson's syndrome. Therefore, under normal physiological conditions, there are mechanisms in the nervous system that precisely regulate NO production, release, diffusion and inactivation in both time and space, and these are mainly achieved by regulating the activation and deactivation of nNOS. nNOS has a PDZ domain that can interact with a variety of proteins, and these interactions can affect the localization of nNOS in cells or directly affect the activity of nNOS.

[0004] The PDZ protein domain of nNOS can interact with the SERT C-terminal tail motif, thereby controlling its localization on the cell surface (B. Chanrion et al., Physical interaction between the serotonin transporter and neuronal nitric oxide synthase underlies reciprocal modulation of their activity. Proc. Natl. Acad. Sci. USA 104, 8119–8124 (2007)). Recent studies have found that the SERT-nNOS complex in the dorsal raphe nucleus is closely related to depressive behavior, and produces a better and faster antidepressant effect by dissociating it (Nan Sun et al., Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN. Science, 378, 390-398 (2022)). However, these studies on antidepressant drugs are far from enough, and it is still necessary to study and develop new coupling antagonists that dissociate SERT-nNOS interactions. Summary of the invention

[0005] In order to overcome the deficiencies of the prior art, one of the purposes of the present invention is to provide a compound represented by Formula I or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0006]

[0007] X is selected from a bond, -C(=O)-, -SO2- or -CH2-;

[0008] Y is selected from -C 1-6 Alkylene or -benzimidazolyl-C 1-3 Alkylene-C(=O)-, the C 1-6 Alkylene, -benzimidazolyl-C 1-3 Alkylene - C(=O)- is optionally further substituted with one or more C 1-6 Alkyl, phenyl or cyclopropyl substituted;

[0009] Z is selected from -O-, -NH- or -CH2-;

[0010] R 1 Selected from H, -C 1-6 Alkyl or -NR 4 R 5 , the C 1-6The alkyl group is optionally further substituted with one or more -NHCOR 6 or -NHSO2R 7 replaced by the R 6 , R 7 Each independently selected from -C 1-3 Alkyl or -NH2, the -C 1-3 The alkyl group and -NH2 may be further substituted by a phenyl group or a 5- to 6-membered heterocyclic group;

[0011] R 4 , R 5 Each independently selected from H, -C 1-6 Alkyl or phenyl, the C 1-6 The alkyl or phenyl group is optionally further substituted with one or more halogen atoms;

[0012] R 2 Selected from H, -C 1-6 Alkyl or benzyl;

[0013] R 3 Selected from H or -C 1-6 alkyl;

[0014] And the compound of formula I Excluded.

[0015] In a preferred embodiment of the present invention, the formula I is a compound represented by formula II or formula III or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:

[0016]

[0017] in,

[0018] Y1 is selected from -CH(CH(CH3)2)-, or -CH(CH3)CH2-;

[0019] Y2 is selected from -benzimidazolyl-C 1-3 Alkylene-C(=O)-, more preferably

[0020] X, Z, R 1 , R 2 and R 3 The definition of is as described in Formula I.

[0021] A preferred embodiment of the present invention is a compound represented by Formula I, Formula II or Formula III or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 1 Selected from -C 1-6 Alkyl or -NR 4 R 5 , the C 1-6The alkyl group is optionally further substituted with one or more -NHCOR 6 or -NHSO2R 7 replaced by the R 6 , R 7 Each independently selected from methyl or -NH2, wherein the -NH2 is optionally further substituted by phenyl or a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group is preferably

[0022] R 4 , R 5 Each is independently selected from H or phenyl, said phenyl being optionally further substituted with one or more F.

[0023] A preferred embodiment of the present invention is a compound represented by Formula I, Formula II or Formula III or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 2 Selected from H, -CH(CH3)2 or benzyl.

[0024] A preferred embodiment of the present invention is a compound represented by Formula I, Formula II or Formula III or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein Z is -O- or -NH-, R 3 It is H or -CH3.

[0025] The specific structures of the compounds of formula I represented by the present invention include, but are not limited to:

[0026]

[0027]

[0028] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0029] If there is a discrepancy between the drawn structure and the name given to that structure for a compound in the table, the drawn structure controls.

[0030] The present invention provides a pharmaceutical composition, which contains an effective dose of a compound represented by Formula I, Formula II or Formula III or its stereoisomers, tautomers or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0031] The present invention provides use of a compound represented by Formula I, Formula II or Formula III or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in preparing a drug for treating depression.

[0032] The present invention provides a method for treating depression, comprising administering to a subject in need thereof a compound represented by Formula I, Formula II or Formula III or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound represented by Formula I, Formula II or Formula III or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0033] Another object of the present invention is to provide the use of a compound of formula IV, formula V, formula VI, formula VII or formula VIII in the preparation of a drug for treating depression, characterized in that the compound of formula IV, formula V, formula VI, formula VII, formula VIII has the following structural formula:

[0034]

[0035] Wherein, in Formula IV

[0036] R 8 Selected from H, -C 1-6 Alkyl, -CONH2, -NR 11 R 12 or a 5- to 6-membered heterocyclic ring, wherein the C 1-6 The alkyl group is optionally further substituted with -NHCOR 13 or -NHSO2R 14 replaced by;

[0037] R 11 , R 12 Each independently selected from H, -C 1-6 alkyl or phenyl, the phenyl group is optionally further substituted by halogen, preferably F, the C 1-6 The alkyl group is optionally further substituted with -COOR 15 Replaced by R 15 is methyl or ethyl;

[0038] R 13 , R 14 Each independently selected from -C 1-3 Alkyl or -NR 11 R 12 ;

[0039] X' is selected from a bond, -C(=O)-, -SO2- or -CH2-;

[0040] R 9 Selected from H, -C 1-6 Alkyl or benzyl;

[0041] Y' is selected from -C 1-6 Alkylene, -C 1-3 Alkylene-Ar- or The C 1-6The alkylene group is optionally further substituted by a phenyl group or a cyclopropyl group, wherein Ar is a phenyl group, a pyridyl group or a benzimidazole group, wherein the phenyl group, the pyridyl group or the benzimidazole group is optionally further substituted by one or more -C 1-6 Alkyl substituted; or Y, R 9 Together with the N to which they are connected, they form a 6- to 10-membered ring, wherein the 6- to 10-membered ring structure is preferably:

[0042] Z' is selected from -O-, -NH- or -CH2-;

[0043] R 10 Selected from H or -C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with -OH,

[0044] and,

[0045] Formula IV excludes These two compounds;

[0046] Among them, in formula V

[0047] X" is -CH2- or -C(=O)-;

[0048] R 16 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-8 Cycloalkyl or aryl, or two adjacent R 16 Together with the carbon to which they are attached, a benzene ring is formed, the benzene ring being optionally further substituted with one or more selected from C 1-6 Alkyl or C 1-6 Alkoxy is substituted with a substituent; the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from -OH, -NH2 or halogen;

[0049] R 17 , R 18 are each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, -S(O)2-R 19 , -C(=O)-R 20 or -C(=S)-R 21 ; said C 1-6 The alkyl group is optionally further substituted with one or more selected from -OH, benzene ring or C 5-9 The benzene ring and C 5-9 The heterocycle is optionally further substituted with one or more methyl or methoxy groups; or R 17 , R18 Together with the N to which they are attached, they are cyclized to form a 3-8 membered heterocyclic group, which is optionally further substituted with a five-membered heterocyclic ring;

[0050] R 19 is selected from a benzene ring, the benzene ring is optionally further selected from one or more halogens, C 1-6 Alkyl or halogen substituted C 1-6 Alkyl substituted;

[0051] R 20 , R 21 Each independently selected from -NH2, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the -NH2 is optionally further substituted by a methyl or ethyl group, and the methyl or ethyl group is optionally further substituted by a furan ring or a tetrahydrofuran ring;

[0052] m is 0, 1, 2 or 3;

[0053] Among them, in Formula VI

[0054] R 22 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogen, six-membered heterocyclic ring, -NH2, wherein the -NH2 is optionally further replaced by C 1-6 Alkyl substituted, the C 1-6 The alkyl group is optionally further substituted by one or more groups selected from halogen, -OH, benzene ring, -COOH,

[0055] or two R 22 Together with the pyrimidine ring to which it is connected, it forms the following ring structure:

[0056]

[0057] R 24 Each independently selected from -CH3, -CH(CH3)2, or two R 24 Together they form -C(=O);

[0058] R 23 Selected from hydrogen, -CF3, benzene ring, cyclopentyl or -NR 25 R 26 ;

[0059] R 25 , R 26 Each is independently selected from hydrogen, a five-membered heterocyclic ring, C 1-6 Alkyl, -C(O)CH2SCH2COOCH3, The C 1-6 The alkyl group is optionally further -N(CH3)S(O)2CH3, or R 25 and R 26 Together with the N to which they are attached, they form a spiro ring

[0060] n is 0, 1, 2 or 3;

[0061] p is 0, 1, 2, 3 or 4;

[0062] Wherein, in Formula VII

[0063] Y" is N or S;

[0064] R 27 Selected from H, -C 1-6 Alkyl, -NHCOR 29 or -CONHR 30 ;

[0065] R 29 , R 30 Each independently selected from C 3-4 carboxyl, 5-6 membered heterocyclic ring, 5-7 membered carbocyclic ring, -CH2S-Ar, wherein the 5-6 membered heterocyclic ring, 5-7 membered carbocyclic ring is optionally further substituted by one or more -COOH, -OH, wherein Ar is selected from Optionally further substituted with one or more selected from methyl, ethyl, propyl or pyridyl;

[0066] R 28 Independently selected from H, -C 1-6 Alkyl, phenyl, the phenyl optionally further substituted by one or more halogen atoms, or two R 28 Together with the carbon atoms to which they are attached, they form a benzene ring or a 5- to 7-membered carbon ring, wherein the benzene ring is optionally further substituted by one or more halogen atoms or C 1-3 The 5- to 7-membered carbon ring is optionally further substituted by one or more oxo or methyl groups;

[0067] q is 0, 1 or 2;

[0068] Wherein, in Formula VIII

[0069] R 31 Selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3- to 6-membered heterocyclic group;

[0070] R 32 Selected from hydrogen, C 1-3 Alkyl, C 3-8 Cycloalkyl, the C 1-3The alkyl group is optionally further substituted by a phenyl group, and the phenyl group is optionally further substituted by one or more groups selected from halogen, methoxy;

[0071] R 33 is selected from hydrogen, phenyl, the phenyl being optionally further substituted by one or more selected from halogen, methoxy.

[0072] In a preferred embodiment of the present invention, the specific structures of Formula IV, Formula V, Formula VI, Formula VII, and Formula VIII include:

[0073]

[0074]

[0075]

[0076]

[0077] Explanation of terms

[0078] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0079] In the present invention, the subscript of an atom or a group represents the number or the range of the number of the atom or group, such as "C 1-6 "C1-C6 alkyl" and "alkyl" have the same meaning, that is, they are all alkyl groups containing 1 to 6 carbon atoms. The subscript numbers represent the number of carbon atoms. The meanings of the other subscripts are the same and will not be repeated here.

[0080] "Bond" means that the indicated substituent does not exist, and both end portions of the substituent are directly connected to form a bond.

[0081] "Alkyl" as a group or a part of a group refers to a group consisting of C1-C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10 Alkyl, more preferably C1-C6 alkyl, particularly preferably C1-C3 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl may be substituted or unsubstituted.

[0082] "Alkylene" is a divalent alkyl group. Preferably C1-C6 alkylene, more preferably C1-C3 alkylene. Examples of alkylene groups include, but are not limited to, methylene, ethylene, -C(CH3)2-, n-propylene, etc. Alkylene can be substituted or unsubstituted.

[0083] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, more preferably includes 3 to 8 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes cycloalkyl of spiro ring, condensed ring and bridge ring. Cycloalkyl can be optionally substituted or unsubstituted.

[0084] "Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably in this application and refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic non-aromatic heterocyclic group containing 3-12 ring atoms, wherein at least one ring atom is a heteroatom, such as oxygen, nitrogen, sulfur, etc. Preferably, it has a 3-6-membered monocyclic ring or a 7-10-membered bicyclic or tricyclic ring, more preferably a 5-6-membered monocyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heterocyclyl" include, but are not limited to Oxiranyl, morpholinyl, oxetane, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl. The heterocyclyl may be optionally substituted or unsubstituted.

[0085] "Ar" is "aryl" or "heteroaryl". "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be fused together. The term "aryl" includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl. Preferably, aryl is C 6-10 Aryl, more preferably phenyl and naphthyl, most preferably phenyl. Aryl can be substituted or unsubstituted. "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 9- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heteroaryl" include, but are not limited to, benzimidazolyl, pyridyl, pyrimidinyl, The heteroaryl groups may be optionally substituted or unsubstituted.

[0086] "Alkoxy" refers to a group of (alkyl-O-). Wherein, alkyl is as defined herein. C1-C6 alkoxy is preferred. 1- C3 alkoxy is more preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

[0087] "Alkylthio" refers to a group of (alkyl-S-). Wherein, alkyl is as defined herein. C1-C6 alkylthio is preferred. Examples include, but are not limited to: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, and the like.

[0088] "Haloalkyl" refers to an alkyl group further substituted with one or more halogens, wherein alkyl is as defined herein.

[0089] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0090] "Benzyl" refers to -CH2-phenyl.

[0091] "Carboxy" refers to -C(=O)OH.

[0092] "HOBt" refers to 1-hydroxybenzotriazole.

[0093] "DIPEA" refers to N,N-diisopropylethylamine.

[0094] "EDC·HCl" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0095] "DCM" refers to dichloromethane.

[0096] "Optional" means that the event described can but does not have to occur. For example, "A is optionally substituted with 1 to more R" includes the situation that the A group can be substituted with 1 to more R or not substituted with R.

[0097] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0098] "Pharmaceutically acceptable salts" refer to certain salts of the above compounds that can maintain the original biological activity and are suitable for medical use. Pharmaceutically acceptable salts of the compounds represented by Formula I, Formula II or Formula III can be metal salts or amine salts formed with suitable acids.

[0099] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0100] The definitions and conventions of stereochemistry used in this invention are generally based on the following documents: SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, atropisomers and mixtures thereof, such as racemic mixtures, constitute a part of the present invention. Diastereoisomers can be separated into individual diastereomers based on their physical chemical differences by methods such as chromatography, crystallization, distillation or sublimation. Enantiomers can be separated by converting a chiral isomeric mixture into a diastereomeric mixture by reacting with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers. The intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. These stereoisomers have the same order of atoms or groups of atoms attached to each other, but their stereostructures are different. Specific stereoisomers may be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions.

[0101] "Tautomers" refer to structural isomers of different energies that can be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions through proton migration, such as keto-enol and imine-enamine isomerizations. Valence (chemical valence) tautomers include interconversions by reorganization of bonding electrons. Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers are all within the scope of the present invention. DETAILED DESCRIPTION

[0102] The above contents of the present invention are further described in detail below through specific implementation modes, but this should not be construed as limiting the present invention.

[0103] The reagents required in the present invention were purchased from Anaiji Chemical, Titan Technology, Adamas, Sigma-Aldrich, etc.; silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Plant; the liquid superconducting nuclear magnetic resonance spectrometer model was AVANCE III 400, Bruker.

[0104] Unless otherwise specified, the reaction temperature in the present invention is room temperature, 25-30°C.

[0105] Example 1 Preparation of Compound I-1

[0106]

[0107] Step 1: Compound 1 (7.4 g) was mixed with sodium carbonate (9.3 g) and acetonitrile (25 mL) and stirred, and benzyl bromide (5.0 g) was added to react. The reaction was monitored by TLC. After the reaction was completed, the solid was filtered off, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain compound 2.

[0108] Step 2: Compound 2 (0.5 g) was dissolved in acetonitrile (2 mL) and DMF (0.5 mL), HOBt (0.34 g) and DIPEA (0.53 g) were added, and then placed in an ice-water bath, and EDC·HCl (0.48 g) and (S)-2-acetylaminopropionic acid (0.3 g) were added for reaction. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated to obtain an oily liquid, 50 mL of ethyl acetate was added, and 0.2 M HCl, 5% NaHCO3, and water were used to wash in sequence. The organic phase was evaporated under reduced pressure to obtain the target compound I-1.

[0109] 1H NMR(400MHz,Chloroform-d)δ7.32-7.24(m,6H),4.64-4.57(m,1H),4.52-4.43(m,1H),4.35-4.28(m,1H),4.24( d,J=7.7Hz,1H),3.66(s,3H),2.24-2.13(m,1H),1.92(s,3H),1.26(d,J=6.2Hz,3H),0.94(dd,J=7.3,0.9Hz,6H).

[0110] MS (ESI, m / z): 335.4 [M+H] + .

[0111] With reference to Example 1, compound I-2, compound I-4, compound I-5, compound I-6, compound I-7, compound IV-2, compound IV-4, compound IV-5, compound IV-7, compound IV-8, compound IV-9 and compound IV-11 can be prepared, Table 1:

[0112]

[0113]

[0114] Example 2 Preparation of Compound I-3

[0115]

[0116] Acetamido methanesulfonic acid (1.0 g) was mixed with thionyl chloride (10 mL), heated to reflux, and after 1 h, the thionyl chloride was removed. The obtained liquid and valine methyl ester (0.8 g) were dissolved in 10 mL of dichloromethane, and triethylamine (3 mL) was added for reaction. The reaction was monitored by TLC. After the reaction was completed, the mixture was directly concentrated to dryness and the target compound I-3 was obtained by column chromatography.

[0117] 1 H NMR(400MHz,Chloroform-d)δ8.13(t,J=8.4Hz,1H),5.60(d,J=11.4Hz,1H),4.69(dd,J=15.7,8.5Hz,1H),4.5 8(dd,J=15.7,8.4Hz,1H),3.68(s,3H),3.61(dd,J=11.4,7.9Hz,1H),2.04-1.92(m,4H),0.87(d,J=6.4Hz,6H).

[0118] MS (ESI, m / z): 267.3 [M+H] + .

[0119] Example 3 Preparation of Compound I-8

[0120]

[0121] Step 1: Compound 4 was prepared by referring to step 2 of compound I-1.

[0122] Step 2: Compound 4 (4.0 g) was mixed with 2.3 M HCl in dioxane and stirred for reaction. The reaction was monitored by TLC. After the reaction was completed, the mixture was directly concentrated to dryness to obtain Compound 5.

[0123] Step 3: Dissolve compound 5 (0.5 g) in 2.5 mL of dichloromethane, place in an ice-water bath, add triethylamine (0.63 g), then add 1-fluoro-4-isocyanatobenzene (0.31 g), remove the ice-water bath, monitor the reaction by TLC, and after the reaction is complete, directly concentrate to dryness and obtain the target compound I-8 by column chromatography.

[0124] 1 H NMR(400MHz,Chloroform-d)δ8.30(s,1H),7.45-7.39(m,2H),7.36(d,J=9.7Hz,1H),7.04-6.97(m,3H),4.41-4.32(m ,1H),4.29(dd,J=9.6,6.7Hz,1H),3.66(s,3H),2.33-1.99(m,1H),1.19(d,J=5.5Hz,3H),0.94(dd,J=6.8,1.5Hz,6H).

[0125] MS (ESI, m / z): 340.4 [M+H] + .

[0126] Example 4

[0127] Refer to Example 3 to prepare compound I-9 and compound IV-6; refer to the third step of Example 3 to prepare compound I-10 and compound IV-10.

[0128] Table 2:

[0129]

[0130]

[0131] Example 5 Preparation of Compound I-11

[0132]

[0133] Step 1: Dissolve compound 6, 3-nitro-4-fluorobenzoic acid ethyl ester (10.0 g) in N,N-dimethylformamide (50 mL), add sodium carbonate (9.94 g) and β-alanine amide hydrochloride, and heat to 40° C. Monitor the reaction by TLC. After the reaction is completed, add 100 mL of ethyl acetate and 150 mL of water, filter, and dry to obtain compound 7.

[0134] Step 2: Compound 7 (7.6 g) and iron powder (9.8 g) were mixed in glacial acetic acid (46 mL), stirred, and heated to 40° C. The reaction was monitored by TLC. After the reaction was completed, 150 mL of ethyl acetate and 50 mL of water were added, filtered, and the organic phase was adjusted to pH 7-8, separated, and the organic phase was washed with 8% sodium bicarbonate aqueous solution and water, respectively, and the organic phase was concentrated to obtain compound 8.

[0135] Step 3: Mix compound 8 (1.5 g) and triethylamine (1.08 g) in 20 mL of tetrahydrofuran and place in an ice-water bath. Add n-valeryl chloride (0.86 g) dropwise. After the addition is complete, remove the ice-water bath and monitor the reaction by TLC. After the reaction is completed, evaporate under reduced pressure to remove the solvent to obtain a solid. Mix the solid with 20 mL of glacial acetic acid, heat to 120°C, and monitor the reaction by TLC. After the reaction is completed, add 50 mL of ethyl acetate and 50 mL of water, adjust the pH to 7-8, and filter to obtain the target compound I-11.

[0136] 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),7.83(d,J=8.4Hz,1H),7.62(d,J=8.5Hz,1H),7.47(s,1H),6.95(s,1H),4.43(t,J=6.8Hz,2H),4.37- 4.17(m,2H),2.92(t,J=7.6Hz,2H),2.57(t,J=6.8Hz,2H),1.89-1.71(m,2H),1.50-1.38(m,2H),1.38–1.27(m,3H),0.95(t,J=7.4Hz,3H).

[0137] MS (ESI, m / z): 318.4 [M+H] + .

[0138] Referring to Example 5, compound I-12 can be prepared:

[0139] 1H NMR(400MHz,Chloroform-d)δ8.12-8.07(m,2H),7.73(m,1H),6.35(d,J=7.5Hz,1H),6.27(d,J=7.5Hz,1H),4.43-4.31(m, 4H), 2.80 (t, J = 7.0Hz, 2H), 2.68 (t, J = 6.7Hz, 2H), 1.68 (m, 2H), 1.46 (m, 2H), 1.38 (t, J = 6.4Hz, 3H), 0.94 (t, J = 7.2Hz, 3H).

[0140] MS (ESI, m / z): 318.4 [M+H] + .

[0141] Example 6 Preparation of Compound IV-12

[0142]

[0143] Compound 9 (0.50 g) was mixed with DCM (15 mL), placed in an ice-water bath, and N,N-diisopropylethylamine (0.43 g) and acetic anhydride (0.27 g) were added. The reaction was monitored by TLC. The system was clear. After the reaction was completed, it was concentrated, and then 40 mL of ethyl acetate was added. The mixture was washed with sodium bicarbonate aqueous solution (10%), and the solvent was removed by rotary evaporation under reduced pressure to obtain the target compound IV-12.

[0144] 1 H NMR(400MHz,Chloroform-d)δ7.87-7.77(m,2H),7.08(dt,J=8.4,1.0Hz,1H),4.61(d,J=0.9 Hz,2H),3.89(s,3H),3.80(dd,J=6.4,3.7Hz,1H),3.70(dd,J=6.4,3.6Hz,1H),2.89(m,2H).

[0145] MS (ESI, m / z): 234.3 [M+H] + .

[0146] Referring to Example 6, compound IV-13 and compound IV-14 can be prepared

[0147] Table 3:

[0148]

[0149] Biological experiments

[0150] i) Pull-down experiment, also known as pull-down experiment, is an in vitro affinity purification technology. Pull down technology can be used to verify the interaction of known proteins or peptides, and can also be used to screen unknown proteins or peptides that interact with known proteins or peptides. Principle: A protein is fixed on a certain matrix (such as Sepharose). When the cell extract passes through the matrix, the ligand protein that can interact with the fixed protein is adsorbed, and the "impurities" that are not adsorbed flow out with the eluent. The adsorbed protein can be recovered by changing the eluent or elution conditions. In order to more effectively utilize the pull down technology, the protein to be purified can be expressed in the form of a fusion protein, that is, the "bait" protein is fused with a ligand protein that is easy to purify. The uncoupling assay of the compounds of the present invention on serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) is carried out according to the method described in the document Proc.Natl.Acad.Sci.USA2007,104,8119-8124.

[0151] Table 4. Effects of the compounds of the present invention and ZZL-7 compound on SERT-nNOS uncoupling determined by the pull-down method

[0152]

[0153]

[0154] ii) Mouse head shaking test

[0155] 5-HTP-enhanced depression model in mice

[0156] This model was proposed by Corne et al. in 1963. The head shaking syndrome caused by 5-HT receptor excitation may be mediated by 5-HT2 receptors. The head shaking behavior induced by 5-HTP in mice is sensitive to antidepressants with different mechanisms of action.

[0157] Male C57 mice weighing 20-25 g (Shanghai Slake Experimental Animal Co., Ltd.) were intraperitoneally injected with 5-hydroxytryptophan (5-HTP) and the compound of the present invention (20 mg / kg) at a dose of 80 mg / kg, respectively. The number of head-shaking of the mice within 30 minutes after administration was recorded, and the difference in the number of head-shaking was compared.

[0158] Table 5. Comparison of the number of head shaking behaviors induced by the compounds of the present invention and ZZL-7 compounds

[0159] Compound No. Number of head shakes of mice ZZL-7 isomer 10 ZZL-7 13 I-1 17 I-5 17 I-8 20 I-9 16 I-10 19 I-11 26 I-12 19 IV-6 19 IV-12 18 V-3 20 V-5 20 VII-3 22 VII-6 20

[0160] Among them, ZZL-7 and ZZL-7 isomers in Table 4 and Table 5 are SERT-nNOS coupling antagonists reported in the literature Design of fast-onset antagonist by dissociating SERT from nNOS in the DRN. Nan Sun et al., Science, 378, 390-398 (2022). The structural formula of ZZL-7 is as follows:

[0161]

[0162] The structural formula of ZZL-7 isomers is as follows:

[0163]

[0164] The SERT-nNOS uncoupling values ​​in Table 4 indicate that the compounds of the present invention have better SERT-nNOS uncoupling effects than ZZL-7 and ZZL-7 isomers. The number of head shakings of mice in Table 5 indicate that the compounds of the present invention have better and faster antidepressant effects than ZZL-7 and ZZL-7 isomers.

Claims

1. A compound represented by formula I or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof: X is selected from a bond, -C(=O)-, -SO2- or -CH2-; Y is selected from -C 1-6 Alkylene or -benzimidazolyl-C 1-3 Alkylene-C(=O)-, the C 1-6 Alkylene, -benzimidazolyl-C 1-3 Alkylene - C(=O)- is optionally further substituted with one or more C 1-6 Alkyl, phenyl or cyclopropyl substituted; Z is selected from -O-, -NH- or -CH2-; R 1 Selected from H, -C 1-6 Alkyl or -NR 4 R 5 , the C 1-6 The alkyl group is optionally further substituted with one or more -NHCOR 6 or -NHSO2R 7 replaced by the R 6 , R 7 Each independently selected from -C 1-3 Alkyl or -NH2, the -C 1-3 The alkyl group and -NH2 may be further substituted by a phenyl group or a 5- to 6-membered heterocyclic group; R 4 , R 5 Each independently selected from H, -C 1-6 Alkyl or phenyl, the C 1-6 The alkyl or phenyl group is optionally further substituted with one or more halogen atoms; R 2 Selected from H, -C 1-6 Alkyl or benzyl; R 3 Selected from H or -C 1-6 alkyl; And the compound of formula I Excluded.

2. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound represented by formula II or formula III or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof: in, Y1 is selected from -CH(CH(CH3)2)-, or -CH(CH3)CH2-; Y2 is selected from -benzimidazolyl-C 1-3 Alkylene-C(=O)-, preferably X, Z, R 1 , R 2 and R 3 The definition is as stated in claim 1.

3. The compound according to claim 1 or 2, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: The R 1 Selected from -C 1-6 Alkyl or -NR 4 R 5 , the C 1-6 The alkyl group is optionally further substituted with one or more -NHCOR 6 or -NHSO2R 7 replaced by the R 6 , R 7 Each independently selected from methyl or -NH2, wherein the -NH2 is optionally further substituted by phenyl or a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group is preferably R 4 , R 5 Each is independently selected from H or phenyl, said phenyl being optionally further substituted with one or more F.

4. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: The R 2 Selected from H, -CH(CH3)2 or benzyl.

5. The compound according to any one of claims 1 to 4, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: The Z is -O- or -NH-, R 3 It is H or -CH3.

6. The compound according to any one of claims 1 to 5, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: The specific structure of the compound includes:

7. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1 to 6 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

8. Use of the compound according to any one of claims 1 to 6 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a drug for treating depression.

9. Use of a compound of formula IV, formula V, formula VI, formula VII or formula VIII in the preparation of a drug for treating depression, characterized in that: The compound of formula IV, formula V, formula VI, formula VII or formula VIII has the following structural formula: Wherein, in Formula IV R 8 Selected from H, -C 1-6 Alkyl, -CONH2, -NR 11 R 12 or a 5- to 6-membered heterocyclic ring, wherein the C 1-6 The alkyl group is optionally further substituted with -NHCOR 13 or -NHSO2R 14 replaced by; R 11 , R 12 Each independently selected from H, -C 1-6 alkyl or phenyl, the phenyl group is optionally further substituted by halogen, preferably F, the C 1-6 The alkyl group is optionally further substituted with -COOR 15 Replaced by R 15 is methyl or ethyl; R 13 , R 14 Each independently selected from -C 1-3 Alkyl or -NR 11 R 12 ; X' is selected from a bond, -C(=O)-, -SO2- or -CH2-; R 9 Selected from H, -C 1-6 Alkyl or benzyl; Y' is selected from -C 1-6 Alkylene, -C 1-3 Alkylene-Ar- or The C 1-6 The alkylene group is optionally further substituted by a phenyl group or a cyclopropyl group, wherein Ar is a phenyl group, a pyridyl group or a benzimidazole group, wherein the phenyl group, the pyridyl group or the benzimidazole group is optionally further substituted by one or more -C 1-6 Alkyl substituted; or Y, R 9 Together with the N to which they are connected, they form a 6- to 10-membered ring, wherein the 6- to 10-membered ring structure is preferably: Z' is selected from -O-, -NH- or -CH2-; R 10 Selected from H or -C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with -OH, and, Formula IV excludes These two compounds; Among them, in formula V X" is -CH2- or -C(=O)-; R 16 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-8 Cycloalkyl or aryl, or two adjacent R 16 Together with the carbon to which they are attached, a benzene ring is formed, the benzene ring being optionally further substituted with one or more selected from C 1-6 Alkyl or C 1-6 Alkoxy is substituted with a substituent; the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from -OH, -NH2 or halogen; R 17 , R 18 are each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, -S(O)2-R 19 , -C(=O)-R 20 or -C(=S)-R 21 ; said C 1-6 The alkyl group is optionally further substituted with one or more selected from -OH, benzene ring or C 5-9 The benzene ring and C 5-9 The heterocycle is optionally further substituted with one or more methyl or methoxy groups; or R 17 , R 18 Together with the N to which they are attached, they are cyclized to form a 3-8 membered heterocyclic group, which is optionally further substituted with a five-membered heterocyclic ring; R 19 is selected from phenyl, the phenyl group is optionally further selected from one or more halogen, C 1-6 Alkyl or C 1-6 substituted with haloalkyl; R 20 , R 21 Each independently selected from -NH2, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the -NH2 is optionally further substituted by a methyl or ethyl group, and the methyl or ethyl group is optionally further substituted by a furan ring or a tetrahydrofuran ring; m is 0, 1, 2 or 3; Among them, in Formula VI R 22 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogen, six-membered heterocyclic ring, -NH2, wherein the -NH2 is optionally further replaced by C 1-6 Alkyl substituted, the C 1-6 The alkyl group is optionally further substituted with one or more groups selected from halogen, -OH, phenyl, -COOH, or two R 22 Together with the pyrimidine ring to which it is connected, it forms the following ring structure: R 24 Each independently selected from -CH3, -CH(CH3)2, or two R 24 Together they form =O; p is 0, 1, 2, 3 or 4; R 23 Selected from hydrogen, -CF3, phenyl, cyclopentyl or -NR 25 R 26 ; R 25 , R 26 Each is independently selected from hydrogen, a five-membered heterocyclic ring, C 1-6 Alkyl, -C(O)CH2SCH2COOCH3, The C 1-6 The alkyl group is optionally further -N(CH3)S(O)2CH3, or R 25 and R 26 Together with the N to which they are attached, they form a spiro ring n is 0, 1, 2 or 3; Wherein, in Formula VII Y" is N or S; R 27 Selected from H, -C 1-6 Alkyl, -NHCOR 29 or -CONHR 30 ; R 29 , R 30 Each independently selected from C 3-4 carboxyl, 5-6 membered heterocyclic group, 5-7 membered cycloalkyl, -CH2S-Ar, wherein the 5-6 membered heterocyclic group, 5-7 membered cycloalkyl is optionally further substituted with one or more -COOH, -OH, wherein Ar is selected from Optionally further substituted with one or more selected from methyl, ethyl, propyl or pyridyl; R 28 Independently selected from H, -C 1-6 Alkyl, phenyl, the phenyl optionally further substituted by one or more halogen atoms, or two R 28 Together with the carbon atoms to which they are attached, they form a benzene ring or a 5-7 membered cycloalkyl group, wherein the benzene ring is optionally further substituted by one or more halogen atoms or C 1-3 The 5- to 7-membered cycloalkyl group is optionally further substituted by one or more oxo or methyl groups; q is 0, 1 or 2; Wherein, in Formula VIII R 31 Selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3- to 6-membered heterocyclic group; R 32 Selected from hydrogen, C 1-3 Alkyl, C 3-8 Cycloalkyl, the C 1-3 The alkyl group is optionally further substituted by a phenyl group, and the phenyl group is optionally further substituted by one or more groups selected from halogen, methoxy; R 33 is selected from hydrogen, phenyl, the phenyl being optionally further substituted by one or more selected from halogen, methoxy.

10. The use according to claim 9, characterized in that The specific structure of Formula IV, Formula V, Formula VI, Formula VII or Formula VIII includes:

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