Aryl group-containing amine compounds, their preparation and use

Abstract

The present invention discloses an aryl group-containing amine compound, its preparation method, and use. The aryl group-containing amine compound is represented by formula (I), and has the function of regulating NMDA receptor and / or monoamine transporter and / or sigma receptor activity, and can be used to prepare a medicament for treating and / or preventing diseases associated with NMDA receptors and / or monoamine transporters and / or sigma receptors, particularly central nervous system diseases. JPEG2025538201000350.jpg4951

Description

[Technical Field]

[0001] The present invention relates to the field of medicinal chemistry. Specifically, the present invention relates to an aryl group-containing amine compound represented by formula (I), a method for preparing the same, a pharmaceutical composition, and its use in the manufacture of a medicament for preventing or treating diseases associated with NMDA receptors and / or monoamine transporters and / or sigma receptors, particularly central nervous system diseases. [Background technology]

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Chinese patent applications filed on November 9, 2022, bearing application number 202211401952.5, and filed on September 4, 2023, bearing application number 202311134131.4, entitled "Arylamine Compounds, Their Preparation Methods and Uses," the entire contents of which are incorporated herein by reference in their entirety.

[0003] Depression is a serious mental illness, characterized by low mood, inferiority complex, and depressed state as its main symptoms, and patients may even have suicidal ideation. Currently, the main medications used to treat depression are SSRIs / SSNIs (selective serotonin / norepinephrine reuptake inhibitors). However, these medications are ineffective in nearly one-third of patients, and generally have drawbacks such as a slow onset of effect and increased suicidal ideation in patients. There remains a significant unmet clinical need in this field.

[0004] NMDA (N-methyl-D-aspartic acid) glutamate receptors (abbreviated as NMDA receptors or NMDARs) are a type of ligand-gated ion channel receptor. These receptors mediate the transmission of excitatory signals between synapses by being activated by glutamate, the most important excitatory neurotransmitter in the central nervous system. When the ion channel of NMDARs is opened, Ca 2+ , K. + , Na + These mechanisms increase permeability to cations such as ATP, generating excitatory postsynaptic potentials and triggering a series of physiological and biochemical reactions. NMDARs have complex molecular structures, and various subtypes have distinct spatiotemporal distributions and pharmacological properties. Their quantity, composition, and distribution change dynamically during development and in different brain regions, contributing to numerous physiological activities and providing the molecular basis for complex neural activities, thereby ensuring the normal functioning of neural networks. NMDAR integration, localization, retrieval, and intra- and extrasynaptic distribution are dependent on the regulation of neural activity, and disruption of their functional homeostasis is highly correlated with numerous brain disorders, including depression, epilepsy, and schizophrenia.

[0005] Monoamine transporters are proteins found in the neuronal cell membranes of the central and peripheral nervous systems that transport neurotransmitters commonly used in synaptic transmission. Monoamine transporter inhibitors are typically used as antidepressants to treat depression and anxiety disorders, such as bupropion, which inhibits the norepinephrine transporter and dopamine transporter, and fluoxetine and citalopram, which inhibit the 5-HT transporter. Sigma receptors are primarily found in the central nervous system, but are also present in the endocrine and immune systems. They are closely related to central nervous system psychosis, depression, cognition, neuroprotection, and motor function. Sigma1 receptor agonists may have antidepressant and learning / memory-enhancing effects, while antagonists may have antipsychotic and analgesic effects. Sigma2 receptors are desirable molecular targets for treating central nervous system disorders such as Alzheimer's disease, schizophrenia, and traumatic brain injury, and Sigma2 receptor agonists and antagonists are potential treatments for neurodegenerative diseases.

[0006] Ketamine, an NMDA receptor antagonist, has been used medically as a preferred anesthetic for over 50 years. Research has shown that intravenous administration of subanesthetic doses of the NMDAR antagonist ketamine can rapidly relieve depressive symptoms within hours, with effects lasting for at least a week. Esketamine, developed by Johnson & Johnson, received FDA approval in 2019 for the treatment of treatment-resistant depression. Given that ketamine's primary molecular target is the NMDAR, many have suggested that its inhibition of this target may also be responsible for its antidepressant effects. This mechanism suggests that ketamine's antidepressant effects and dissociative side effects may be closely related at the mechanistic level. However, a growing body of evidence has cast doubt on this assumption (J Psychiatry Neurosci. 2017, 42(4), 222). First, the R-enantiomer of ketamine (R-ket) was found to be more effective and durable as an antidepressant than the S-enantiomer (S-ket) in rodent models, despite the significantly weaker affinity of R-ket for NMDARs (Pharmacol Biochem Behav. 2014, 116, 137). Similarly, the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has been shown to induce antidepressant effects in rodent models, but does not bind to NMDARs in vivo at doses that induce antidepressant effects (Nature. 2016, 533(7604), 481; Proc Natl Acad Sci USA. 2019, 116(11), 5160; and Org Lett. 2017, 19(17), 4572). Thus, both R-ket and HNK can induce antidepressant effects while limiting the dissociative effects of ketamine.However, other strategies proposed to attenuate ketamine's dissociative side effects, such as targeting the NR2B subunit of NMDAR or using compounds with poor trapping properties, have not yielded satisfactory results (Nature. 2016, 533(7604), 481; Sci Rep. 2017, 7(1), 15725; Int J Neuropsychopharmacol. 2019, 22(2), 119; J Psychiatr Res. 2017, 86, 55; and Psychiatry Res. 2016, 239, 281). Therefore, the precise molecular mechanisms underlying ketamine's antidepressant effects remain poorly understood and may involve other, yet unidentified, targets. Furthermore, the magnitude of the antidepressant and associated dissociative effects of NMDAR modulators is generally highly unpredictable. These findings suggest the intriguing possibility that the antidepressant effects of ketamine may be substantially separate from its dissociative side effects.

[0007] The dissociative side effects and poor oral bioavailability of ketamine and esketamine severely limit their clinical use. Although other orally administered NMDAR antagonists have been developed, no drugs have been proven to have the rapid antidepressant clinical therapeutic effect of ketamine to date. Therefore, there is still a strong need for new antidepressants with strong clinical efficacy, low or no dissociative side effects, and good oral bioavailability. Drugs that maintain rapid antidepressant activity like ketamine, while also having reduced dissociative side effects and good oral bioavailability, would provide a new treatment option, which, due to its reduced dissociative effects and the associated reduced potential for abuse, may be easier to administer and may even be feasible for home use. Summary of the Invention [Problem to be solved by the invention]

[0008] The object of the present invention is to provide a novel aryl group-containing amine compound having an activity of modulating NMDA receptors and / or monoamine transporters and / or sigma receptors, as well as a method for producing the same and its use.

[0009] One object of the present invention is to provide an aryl group-containing amine compound represented by formula (I), or a stereoisomer, geometric isomer, conformational isomer, tautomer, pharmaceutically acceptable salt, crystalline polymorph, solvate, hydrate or isotope-labeled compound thereof. [ka]

[0010] Another object of the present invention is to provide a method for preparing the aryl group-containing amine compounds of formula (I). It is yet another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of a compound of formula (I), its stereoisomers, geometric isomers, conformers, tautomers, pharmaceutically acceptable salts, crystalline polymorphs, solvates, hydrates and isotopically labeled compounds, and optionally one or more pharmaceutically acceptable carriers, diluents or excipients.

[0011] Another object of the present invention is to provide use of one or more selected from the group consisting of the compound of formula (I), its stereoisomers, geometric isomers, conformers, tautomers, pharmaceutically acceptable salts, crystalline polymorphs, solvates, hydrates and isotopically labeled compounds, or the pharmaceutical compositions described above, in the manufacture of a medicament for modulating NMDA receptor and / or monoamine transporter and / or sigma receptor activity.

[0012] A further object of the present invention is to provide use of one or more selected from the group consisting of the compound of formula (I), its stereoisomers, geometric isomers, conformers, tautomers, pharmaceutically acceptable salts, crystalline polymorphs, solvates, hydrates and isotope-labeled compounds, or the pharmaceutical compositions described above, in the manufacture of a medicament for preventing and / or treating a disease associated with an NMDA receptor and / or a monoamine transporter and / or a sigma receptor, particularly a central nervous system disease. [Means for solving the problem]

[0013] According to a first aspect of the present invention, there is provided a compound of formula (I) or a stereoisomer, geometric isomer, conformational isomer, tautomer, pharmaceutically acceptable salt, crystalline polymorph, solvate, hydrate or isotopically labeled compound thereof:

[0014] [ka] Among them, Ring A is selected from a 4- to 10-membered heterocycle containing 1 to 3, for example, 1, 2 or 3, heteroatoms selected from N, O and S, or a 4- to 10-membered heterocycle fused with a C6 to C10 aromatic ring, and the 4- to 10-membered heterocycle is, for example, a 5-, 6-, 7-, 8- or 9-membered heterocycle, preferably a 5- to 8-membered heterocycle, and preferably, the heterocycle in ring A contains one N atom and one S atom, or two N atoms, or one S atom, or two N atoms and one S atom, or one N atom and one O atom; The A ring is optionally substituted with one or more R5, and each R5 independently represents a halogen, a hydroxy group, an amino group, a cyano group, a carboxy group, an oxo group, a C1-C6 alkyl group, a haloC1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkanoyl group, a carbamoyl group (-CONH2), a carbamoyl group substituted with a C1-C6 alkyl group, an amino group substituted with one or two C1-C6 alkyl groups, an amino group substituted with one or two haloC1-C6 alkyl groups, or a C1-C6 alkanoyl group. selected from an amino group, a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkyl group, a 4-10 membered heterocycloalkyl group, a C6-14 aryl group, a 5-10 membered heteroaryl group, a C6-C14 aryl C1-C6 alkyloxy group, or a 5-10 membered heteroaryl C1-C6 alkyloxy group, preferably each R5 independently represents a halogen, a hydroxy group, an amino group, a cyano group, a carboxy group, an oxo group, a C1-C4 alkyl group, a halo C1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 alkanoyl group, a carbamoyl group ( -CONH2), a carbamoyl group substituted with a C1-C4 alkyl group, an amino group substituted with one or two C1-C4 alkyl groups, an amino group substituted with one or two haloC1-C4 alkyl groups, an amino group substituted with one or two C1-C4 alkanoyl groups, a C1-C4 alkoxycarbonyl group, a C3-C6 cycloalkyl group, a 4-8 membered heterocycloalkyl group, a C6-10 aryl group, a 5-10 membered heteroaryl group, a C6-C10 arylC1-C4 alkyloxy group or a 5-10 membered heteroarylC1-C4 alkyloxy group. More preferably, each R5 is independently selected from halogen (particularly bromine), amino, hydroxy, cyano, carboxy, C1-C3 alkyl (particularly methyl, ethyl, isopropyl), halo C1-C3 alkyl (particularly trifluoromethyl), C1-C3 alkoxy (particularly methoxy, ethoxy), C1-C3 alkanoyl (particularly formyl, acetyl), carbamoyl (-CONH2), formylamino, acetylamino, methylamino, ethylamino, N,N-dimethylamino, 2,2,selected from a 2-trifluoroethylamino group, a C1-C3 alkoxycarbonyl group (particularly a methoxycarbonyl group or an ethoxycarbonyl group), a C3-C5 cycloalkyl group (particularly a cyclopropyl group), a phenyl group, a pyridyl group, a pyrrolidinyl group, a piperidinyl group, a morpholinyl group, or a benzyloxy group, Ring B is a 3- to 10-membered carbocyclic ring, preferably a 5- to 8-membered carbocyclic ring, for example a 5-, 6-, 7-, or 8-membered carbocyclic ring, more preferably a 5-, 6-, or 7-membered carbocyclic ring; R1 and [ka] are attached to the same ring carbon atom in ring B, x is an integer of 0 to 2, for example, 0, 1, or 2; R2 and R3 each independently represent hydrogen, a C1-C6 alkyl group, a halo C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C6-C14 aryl C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkanoyl group, a halo C1-C6 alkanoyl group, a C3-C6 cycloalkyl C1-C6 alkanoyl group, a C6-C14 aryl C1-C6 alkanoyl group, are each independently selected from a C1-C6 alkylsulfonyl group, a C1-C6 alkylsulfoxide group, or a C3-C6 cycloalkyl C1-C6 alkyl group, and preferably each independently selected from hydrogen, a C1-C4 alkyl group, a halo C1-C4 alkyl group, a C1-C4 alkoxy C1-C4 alkyl group, a hydroxy C1-C4 alkyl group, a C6-C14 aryl C1-C4 alkyl group, a C3-C6 cycloalkyl group, a C1-C4 alkanoyl group, a halo C1-C4 alkyl group, a selected from a C4 alkanoyl group, a C3-C6 cycloalkyl C1-C4 alkanoyl group, a C6-14 aryl C1-C4 alkanoyl group, a C1-C4 alkylsulfonyl group, a C1-C4 alkylsulfoxide group, or a C3-C6 cycloalkyl C1-C4 alkyl group, preferably selected from hydrogen, a C1-C4 alkyl group (particularly a methyl group, an ethyl group, a propyl group, an isopropyl group, or a tert-butyl group), a halo C1-C4 alkyl group (particularly a 1,1,1-trifluoroethyl group), a methoxyethyl group, a hydroxymethyl group, a hydroxyethyl group, a C3-C6 cycloalkylmethyl group (particularly a cyclopropylmethyl group or a cyclobutylmethyl group), a benzyl group, a C3-C6 cycloalkyl group (particularly a cyclopropyl group), a C1-C3 alkylacyl group (particularly an acetyl group or a propionyl group), a cyclopropylformyl group, a benzoyl group, or a tert-butylsulfoxide group; Alternatively, R2 and R3 together with the nitrogen atom to which they are connected form a 3- to 9-membered heterocycloalkyl group, the 3- to 9-membered heterocycloalkyl group ring optionally containing one or more additional nitrogen atoms or oxygen atoms, the 3- to 9-membered heterocycloalkyl group optionally being substituted with one or more C1-C6 alkyl groups, preferably C1-C4 alkyl groups, and preferably R2 and R3 together with the nitrogen atom to which they are connected form an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, an azepanyl group or a morpholinyl group; R1 is selected from a C6-C14 aryl group, a 5- to 10-membered heteroaryl group, a 4- to 10-membered heterocyclyl group, a 4- to 10-membered carbocyclic ring fused with a C6-C10 aryl group (e.g., an indanyl group), or a 4- to 10-membered heterocyclic ring fused with a C6-C10 aryl group (e.g., a 1,2-methylenedioxyphenyl group, a 2,3-dihydrobenzofuryl group), preferably a C6-C14 aryl group or a 5- to 10-membered heteroaryl group, more preferably a phenyl group, a naphthyl group, a quinolyl group, an isoquinolinyl group, a pyridyl group, a pyrimidine group, a pyrazinyl group, a pyridazinyl group, a thienyl group, or a thiazolyl group, even more preferably a phenyl group, a naphthyl group, a pyrimidine group, a pyridyl group, a pyrazinyl group, a pyridazinyl group, or a quinolyl group, and still more preferably a phenyl group; the C6-C14 aryl group, the 5- to 10-membered heteroaryl group, the 4- to 10-membered heterocyclyl group, the 4- to 10-membered carbocyclic ring fused with a C6-C10 aryl group, or the 4- to 10-membered heterocyclic ring fused with a C6-C10 aryl group is optionally substituted with one or more R6; R6 each independently represents a halogen, a hydroxy group, a mercapto group, a cyano group, a carbamoyl group (NH2CO-), an aminosulfonyl group (NH2SO2-), a C1-C6 alkyl group, a halo C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a C3-C6 cycloalkyl group substituted with a C1-C3 alkyl group, a C3-C6 cycloalkoxy group substituted with a C1-C3 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a halo C1-6 alkoxy group, a C1-C6 alkylthio group, a halo C1-6 alkoxy group, a C1-C6 alkylthio group, a C1-C6 alkylthio group, a C1-C6 alkylthio group, a C1-C6 alkylthio group, a C1-C6 alkylthio group, a C1-C6 alkylthio group, a C1-C6 alkylthio group, a C1-C6 alkoxy ... alkoxythio group, a C1-C6 alkylthio group, a C1-C6 alkoxythio group, a C1-C6 alkoxythio group, a C1-C6 alkylthio group, a C1-C6 alkoxythio group, a R6 is selected from a hydroxy group, a C3-C6 cycloalkyl C1-C6 alkoxy group, a C1-C6 alkanoyloxy group, a C6-C14 aryl group, a 5-10 membered heteroaryl group, a C6-C14 aryl C1-C6 alkoxy group, and a 5-10 membered heteroaryl C1-C6 alkoxy group, and preferably, R6 is each independently a halogen, a cyano group, a hydroxy group, a carbamoyl group (NH2CO-), an aminosulfonyl group (NH2SO2-), a C1-C4 alkyl group, a haloC1-C4 alkyl group, a hydroxyC1-C4 alkyl group, a C3-C6 cycloalkyl C1-C6 alkoxy group, a C1-C6 alkanoyloxy group, a C6-C14 aryl group, a 5-10 membered heteroaryl C1-C6 alkoxy group, and preferably, R6 is each independently a halogen, a cyano group, a hydroxy group, a carbamoyl group (NH2CO-), an aminosulfonyl group (NH2SO2-), a C1-C4 alkyl group, a haloC1-C4 alkyl group, a hydroxyC1-C4 alkyl group, a C3-C6 cycloalkyl C1-C6 alkoxy group, a C6-C14 aryl group, a 5-10 membered heteroaryl C1-C6 alkoxy group, and a C1-C4 alkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a C3-C6 cycloalkyl group substituted with a C1-C3 alkyl group, a C3-C6 cycloalkoxy group substituted with a C1-C3 alkyl group, a C1-C4 alkoxy group, a C1-C4 alkylthio group, a halo C1-C4 alkoxy group, a C3-C6 cycloalkyl C1-C3 alkoxy group, a C1-C3 alkanoyloxy group, a C6-C10 aryl group, a 5-6 membered heteroaryl group, a C6-C10 aryl C1-C4 alkoxy group, and a 5-6 membered heteroaryl C1-C4 alkoxy group. More preferably, R6 each independently represents fluorine, chlorine, bromine, a cyano group, a hydroxy group, a methyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a hydroxymethyl group, a methylcyclopropyloxy group, a methoxy group, an ethoxy group, an isopropoxy group, an isobutyloxy group, a methylthio group, a cyclopropyl group, a cyclopropyloxy group, a carbamoyl group (NH2CO-), an aminosulfonyl group (NH2SO2-), a difluoromethoxy group, a trifluoromethoxy group, or a 1,1,1-trifluoroethoxy group. , Shiselected from a chloropropyl group, a methoxy group, an acetoxy group, a phenyl group, a pyridyl group, and a benzyloxy group; m is an integer of 0 to 3, for example, 0, 1, 2, or 3; R4 is R1 on the B ring [ka] are linked to any carbon atom other than the carbon atom to which they are both linked, and R4 is independently selected from a hydroxy group, a halogen atom, and a C1 to C6 alkyl group.

[0015] In some embodiments, the compound of Formula (I) is selected from compounds of Formulas (IA)-(ID): [ka] Among them, ring A, R1, m, R4, [ka] , R2, R3, and x are as defined above.

[0016] In some embodiments, the A ring is selected from a 5- or 6-membered heterocycle or a 5- or 6-membered benzo heterocycle, preferably [ka] , [ka] , [ka] , [ka] , [ka] , [ka] Selected from wherein Z1, Z2, and Z4 are independently selected from N and CR7, each Z3 is independently selected from NR7, O, and S, and Z1, Z2, and Z4 are not simultaneously CR7, and each R7 is independently selected from hydrogen, halogen, cyano group, hydroxy group, amino group, carbamoyl group (-CONH2), carbamoyl group substituted with C1-C6 alkyl group, carboxy group, C1-C6 alkyl group, C1-C6 alkoxy group, haloC1-C6 alkyl group, C1-C6 alkyl group, An amino group substituted with a C6 alkyl group, an amino group substituted with a halo C1-C6 alkyl group, an amino group substituted with a C1-C6 alkanoyl group, a C1-C6 alkanoyl group, a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkyl group, a 4-8 membered heterocycloalkyl group, a C6-10 aryl group, a 5-10 membered heteroaryl group, a C6-C10 aryl C1-C4 alkyloxy group or a 5-10 membered heteroaryl C1-C4 each R7 is independently selected from hydrogen, halogen (particularly bromine), amino, hydroxy, cyano, carboxy, C1-C3 alkyl (particularly methyl, ethyl, isopropyl), halo C1-C3 alkyl (particularly trifluoromethyl), C1-C3 alkoxy (particularly methoxy, ethoxy), C1-C3 alkanoyl (particularly formyl, acetyl), carbamoyl (-CONH2), formylamino, acetylamino, methylamino, ethylamino, N,N-dimethylamino, 2,2,2-trifluoroethylamino, C1-C3 alkoxycarbonyl (particularly methoxycarbonyl, ethoxycarbonyl), C3-C5 cycloalkyl (particularly cyclopropyl), phenyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, or benzyloxy; More preferably, the A ring is [ka] ,

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[0017] In some embodiments, R1 is a phenyl group optionally substituted with one or more R6, where R6 is defined above. In some embodiments, R1 is a naphthyl group optionally substituted with one or more R6, where R6 is defined above.

[0018] In some embodiments, one of R2 and R3 is hydrogen, or both R2 and R3 are hydrogen. In some embodiments, R1 is a phenyl group optionally substituted with one or more R6, and one of R2 and R3 is hydrogen, or R2 and R3 are both hydrogen.

[0019] In some embodiments, R1 is a naphthyl group optionally substituted with one or more R6, and one of R2 and R3 is hydrogen, or both R2 and R3 are hydrogen. In some embodiments, ring B is a 6-membered carbocyclic ring, R1 is a phenyl group optionally substituted with one or more R6, and one of R2 and R3 is hydrogen, or both R2 and R3 are hydrogen.

[0020] In some embodiments, ring B is a 6-membered carbocyclic ring, R1 is a naphthyl group optionally substituted with one or more R6, and one of R2 and R3 is hydrogen, or both R2 and R3 are hydrogen. In some embodiments, ring B is a 5-membered carbocyclic ring, R1 is a phenyl group optionally substituted with one or more R6, and R2 and R3 are both hydrogen.

[0021] In some embodiments, ring B is a 7-membered carbocyclic ring, R1 is a phenyl group optionally substituted with one or more R6, and R2 and R3 are both hydrogen. In some embodiments, the compound of formula (I) is selected from the following compounds: [ka] Wherein, x, Z1, Z2, Z3, Z4, R2, R3, and R6 are defined as above.

[0022] In some embodiments, the compound of formula (I) is selected from the following compounds: [ka] [ka] Among them, R2, R3, R6, and R7 are defined as above, and a phenyl group, a pyridyl group, a naphthyl group, a quinolyl group, a pyrimidine group, a pyrazinyl group or a pyridazinyl group and -NR2R3; [ka] or [ka] are attached to the same ring carbon atom of the carbocycle to which they are attached.

[0023] In some embodiments, the compound of formula (I) is selected from the following compounds: [ka] [ka] Among them, R2, R3, R6, and R7 are defined as above.

[0024] Unless otherwise specified, the definitions of each group in this specification are as follows: As used herein, the term "halogen" generally refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine. As used herein, the term "alkyl group" refers to a linear or branched saturated hydrocarbon group, for example, a C1-C6 alkyl group refers to a linear or branched saturated hydrocarbon group containing 1 to 6 carbon atoms, such as a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1-ethylpropyl group, isopentyl group, neopentyl group, isohexyl group, 3-methylpentyl group, or n-hexyl group, and preferably a methyl group, ethyl group, n-propyl group, isopropyl group, butyl group, or isobutyl group.

[0025] As used herein, the term "halo C1-C6 alkyl group" refers to a linear or branched saturated hydrocarbon group containing 1 to 6 carbon atoms in which a hydrogen atom is substituted with one or more identical or different halogen atoms, and the term "halo C1-C4 alkyl group" is similar thereto, and includes, for example, a trifluoromethyl group, a fluoromethyl group, a difluoromethyl group, a chloromethyl group, a bromomethyl group, a dichlorofluoromethyl group, a chloroethyl group, a bromopropyl group, a 2-chlorobutyl group, and a pentafluoroethyl group.

[0026] As used herein, a "C1-C6 alkoxy group" refers to a straight-chain or branched-chain alkoxy group containing 1 to 6 carbon atoms, and a "C1-C4 alkoxy group" and a "C1-C3 alkoxy group" are similar, such as a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group, n-pentyloxy group, isopentyloxy group, neopentyloxy group, isohexyloxy group, 3-methylpentyloxy group, or n-hexyloxy group, and preferably a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, or isobutoxy group.

[0027] As used herein, a "halo C1-C6 alkoxy group" refers to a straight or branched chain alkoxy group containing 1 to 6 carbon atoms in which a hydrogen atom is substituted with one or more identical or different halogen atoms, and a "halo C1-C4 alkoxy group" is equivalent thereto, such as, for example, -OCF3, -OCH2CH2Cl, -OCHBrCH2Cl, or -OCF2CF3.

[0028] As used herein, a "C1-C6 alkanoyl group" refers to a straight-chain or branched-chain alkanoyl group containing 1 to 6 carbon atoms, and a "C1-C4 alkanoyl group" and a "C1-C3 alkanoyl group" are similar thereto, such as a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, etc., and preferably a formyl group, an acetyl group, or a propionyl group.

[0029] As used herein, a "halo C1-C6 alkanoyl group" refers to a straight-chain or branched-chain alkanoyl group of 1 to 6 carbon atoms in which a hydrogen atom is substituted by one or more identical or different halogen atoms, and the terms "halo C1-C4 alkanoyl group" and "halo C1-C3 alkanoyl group" are equivalent.

[0030] As used herein, an "oxo group" refers to an "=O" group, i.e., an oxygen atom linked to another atom by a double bond. As used herein, the term "amino group substituted with a C1-C6 alkyl group" refers to an amino group in which one or two hydrogen atoms on the amino group are replaced with the same or different C1-C6 alkyl group. C6 It refers to a group substituted with an alkyl group, such as -NHMe, -NHEt, -N(Me)Et, or -NEt2.

[0031] As used herein, the term "amino group substituted with a C1-C6 alkanoyl group" refers to an amino group in which one or two hydrogen atoms on the amino group are substituted with the same or different C1-C6 alkanoyl groups, such as -NHCHO, -NHCOCH3, or -NHCOCH2CH3.

[0032] As used herein, a "C1-C6 alkoxy C1-C6 alkyl group" refers to a C1-C6 alkoxy group in which the oxygen atom is linked to a C1-C6 alkyl group, such as -CH2OCH2CH3, -CH2CH2OCH2CH3, or -CH2CH2OCH3.

[0033] As used herein, a "C1-C6 alkoxycarbonyl group" refers to a C1-C6 alkoxy group in which the oxygen atom is linked to a carbonyl group, such as -C=OOCH2CH3, -C=OOCH2CH2CH3, -C=OOCH2CH(CH3)2, etc.

[0034] As used herein, a "C3-C6 cycloalkyl group" refers to a saturated cyclic hydrocarbon group containing 3 to 6 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0035] As used herein, a "hydroxy C1-C6 alkyl group" refers to a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, where one carbon atom is linked to a hydroxy group, such as, for example, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, or -CH2CH(CH3)CH2OH.

[0036] As used herein, the term "C6-C14 aryl group" refers to a monocyclic or polycyclic aromatic ring group containing 6 to 14 ring atoms but no heteroatoms among the ring atoms, and the term "C6-C12 aryl group" is similar thereto, such as a phenyl group or a naphthyl group.

[0037] As used herein, "3- to 10-membered carbocyclic ring" refers to a saturated or unsaturated monocyclic hydrocarbon group containing 3 to 10 carbon atoms, where the carbocyclic ring preferably has 5 to 8 ring carbon atoms, more preferably 5 to 6 carbon atoms, such as cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, and the like.

[0038] As used herein, "C6-C14 aryl C1-C6 alkyl group" refers to a C6-C14 aryl group linked to a C1-C6 alkyl group, such as a benzyl group, a phenethyl group, or a phenylpropyl group.

[0039] As used herein, a "C3-C6 cycloalkyl C1-C6 alkanoyl group" refers to a C3-C6 cycloalkyl group in which a ring carbon is linked to an alkyl carbon of a C1-C6 alkanoyl group, and examples thereof include a cyclopropylformyl group, a cyclopropylacetyl group, a cyclobutylformyl group, and a cyclopentylformyl group.

[0040] As used herein, a "C6-C14 aryl C1-C6 alkanoyl group" refers to a C6-C14 aryl group linked to an alkyl carbon of a C1-C6 alkanoyl group, such as a benzoyl group or a phenylacetyl group.

[0041] As used herein, a "C1-C6 alkylsulfonyl group" is a C1-C6 alkyl group linked to a sulfonyl -S(=O)2-, such as a methylsulfonyl group or an ethylsulfonyl group.

[0042] As used herein, the term "C1-C6 alkyl sulfoxide group" refers to a C1-C6 alkyl group linked to a sulfoxide group (>S=O), such as a methyl sulfoxide group, ethyl sulfoxide group, propyl sulfoxide group, butyl sulfoxide group, or tert-butyl sulfoxide group.

[0043] As used herein, a "C3-C6 cycloalkyl C1-C6 alkyl group" refers to a C3-C6 cycloalkyl group linked to a C1-C6 alkyl group, such as a cyclopropylmethyl group or a cyclobutylmethyl group.

[0044] As used herein, the term "heterocycle" refers to a monocyclic or polycyclic group containing at least one heteroatom selected from N, O, and S as a ring member, and may be an aromatic or non-aromatic group. In the present specification, the term is preferably a monocyclic group. A 4- to 10-membered heterocycle refers to a heterocyclyl group containing 4 to 10 ring atoms, such as a pyridyl group, a piperidinyl group, a morpholinyl group, a furyl group, a thienyl group, a thiazolyl group, an imidazolyl group, a pyrrolyl group, a pyrazinyl group, a pyridazinyl group, or a pyrimidine group.

[0045] As used herein, the term "heterocycloalkyl group" refers to a saturated monocyclic or polycyclic group containing at least one heteroatom selected from N, O, and S as a ring member, and examples of 3- to 9-membered heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, and morpholinyl groups.

[0046] As used herein, the term "heteroaryl group" refers to a monocyclic or bicyclic aromatic ring group containing at least one heteroatom selected from nitrogen, oxygen, or sulfur as a ring member, and 5- to 10-membered heteroaryl groups include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidine, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, and quinolyl groups.

[0047] As used herein, the terms "optionally," "optionally," or "optionally" mean that the subsequently described event may or may not occur, and include cases where the event occurs and cases where the event does not occur. For example, an "optionally substituted alkyl group" includes an "unsubstituted alkyl group" and a "substituted alkyl group" as defined herein. "Optionally substituted with halogen" includes both "substituted with halogen" and "not substituted with halogen," e.g., substitution with 0 to 3 halogens. Those skilled in the art should understand that for any group containing one or more substituents, the group does not include any substitution patterns that are spatially impractical, chemically inappropriate, synthetically infeasible, and / or inherently unstable.

[0048] When formula (I) is referred to herein, the designation also includes its subformulas, such as formulas (I-1-a), (I-1-b), (I-2-a), (I-2-b) or (II-1) (II-2).

[0049] The aryl group-containing amine compounds of the present invention represented by general formula (I) and their geometric isomers, conformational isomers, and tautomers also include solvate forms such as hydrates and alcoholates, and the above solvates are also included within the scope of the present invention. The pharmaceutically acceptable salts of the heterocyclic compounds of the present invention represented by general formula (I) and their geometric isomers, conformational isomers, and tautomers refer to those obtained by treating the aryl group-containing amine compounds of the present invention represented by general formula (I) or their stereoisomers with an appropriate acid to convert them into non-toxic addition salt forms having therapeutic activity. Examples of such salts include hydrochlorides, hydrobromides, hydroiodides, sulfates or hydrogensulfates, nitrates, phosphates or acid phosphates, perchlorates, formates, acetates, trifluoroacetates, propionates, pyruvates, glycolates, oxalates, malonates, succinates, glutarates, maleates, fumarates, lactates, malates, citrates, tartrates, picrates, glutamates, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, salicylates, ascorbates, camphorates, camphorsulfonates, etc. Conversely, salt forms may be converted to the free base form by treatment with a base.

[0050] The term "pharmaceutically acceptable salts" as used above also includes solvates thereof, and such solvates are included within the scope of the present invention. Examples of solvates include, for example, hydrates, alcoholates, etc.

[0051] Those skilled in the art will recognize that the compounds of the present invention may contain chiral centers and therefore may exist in different isomeric forms. "Isomers," as used herein, refer to different compounds that have the same molecular formula but differ in the arrangement and configuration of the atoms.

[0052] "Stereoisomer" refers to an isomer formed by differences in the spatial arrangement of atoms in a molecule, and may be divided into two types: cis-trans isomers and enantiomers, or into two types: enantiomers and diastereomers.

[0053] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. In some cases, the term is used to refer to a racemic mixture. When describing the stereochemistry of the compounds of the present invention, the conventional RS system designates single stereoisomers of known relative and absolute configuration with two chiral centers (e.g., (1S,2S)), while single stereoisomers of known relative configuration but unknown absolute configuration are labeled with an asterisk (e.g., (1R*,2R*)). A racemate with two letters is, for example, (1RS,2RS) is a racemic mixture of (1R,2R) and (1S,2S), and (1RS,2SR) is a racemic mixture of (1R,2S) and (1S,2R)). "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is designated according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be described as R or S. Resolved compounds of unknown absolute configuration can be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane-polarized light at the sodium D line wavelength. Alternatively, resolved compounds can be defined by the retention times of the corresponding enantiomers / diastereomers by chiral HPLC.

[0054] When a compound contains a double bond or some other feature that imparts a degree of structural rigidity to the molecule, geometric isomers can be produced. When a compound contains a double bond, the substituent can be in the E or Z conformation. When a compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent can have a cis or trans configuration.

[0055] "Conformational isomers" are isomers that differ by rotation about one or more valence bonds. "Tautomer" refers to an isomer formed when a proton moves from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are included within the scope of the present invention.

[0056] "Crystalline polymorphs" refers to crystalline forms that have the same chemical structure / composition but differ in the spatial arrangement of the molecules and / or ions that form the crystal. The compounds of the present invention may be provided as amorphous solids or crystalline solids. Freeze-drying methods can be used to provide the compounds of the present invention as solids.

[0057] A "solvate" refers to a physical association of a compound of the present invention with one or more organic or inorganic solvent molecules. This physical association involves hydrogen bonding. In some cases, the solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in a solvate may be present in an ordered and / or irregular arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" includes solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are known in the art.

[0058] The present invention further includes all suitable isotopic variations of the compounds of the present invention or their pharmaceutically acceptable salts. An isotopic variation of a compound of the present invention or its pharmaceutically acceptable salt is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from that commonly found in nature. Isotopes that can be incorporated into the compounds of the present invention and their pharmaceutically acceptable salts include isotopes of H, C, N and O, for example, 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 35 S, 18 F, 36 Cl and 125Isotopic variations of the compounds according to the present invention or pharmaceutically acceptable salts thereof can be prepared by conventional techniques using appropriate isotopic variations of suitable reagents.

[0059] According to the present invention, the aryl group-containing amine compound represented by formula (I) is selected from the following structures:

[0060] [Table 1]

[0061] [Table 2]

[0062] [Table 3]

[0063] [Table 4]

[0064] [Table 5]

[0065] [Table 6]

[0066] [Table 7]

[0067] [Table 8]

[0068] [Table 9]

[0069] Table 10

[0070] Table 11

[0071] Table 12

[0072] Table 13

[0073] Table 14

[0074] Table 15

[0075] Table 16

[0076] Table 17

[0077] Table 18

[0078] Table 19 As commonly understood in this field, "Bn" represents a benzyl group, "Bz" represents a benzoyl group, "Me" represents a methyl group, "Et" represents an ethyl group, and "Ph" represents a phenyl group.

[0079] According to a second aspect of the present invention, there is provided a method for preparing an aryl group-containing amine compound represented by formula (I), which can be carried out by one or a combination of the following methods 1 to 3:

[0080] Method 1: As shown in reaction equation 1, a) condensing a compound of formula (II) with a compound of formula (III) to form a compound of formula (IV); b) nucleophilic addition reaction of a compound of formula (IV) with a compound of formula (V) to produce a compound of formula (Ia); Including, [ka] Among them, ring A, ring B and R1 are as defined above, and preferred ones are as defined above; G represents a leaving group, and is, for example, a C1-C6 alkylsulfinyl group, a benzenesulfinyl group, a naphthalenesulfinyl group, or a benzyl group, and the C1-C6 alkylsulfinyl group, benzenesulfinyl group, naphthalenesulfinyl group, or benzyl group is optionally further substituted with one or more groups selected from a halogen, a C1-C6 alkyl group, a nitro group, a hydroxy group, an amino group, a C1-C6 alkanoyl group, a C1-C6 alkoxy group, and a phenyl group; G is a C1-C4 alkylsulfinyl group, a benzenesulfinyl group, a naphthalenesulfinyl group, a benzyl group, or a C1-C4 alkylsulfinyl group. a benzyl group is preferred, and the C1-C4 alkylsulfinyl group, benzenesulfinyl group, naphthalenesulfinyl group and benzyl group are optionally further substituted with one or more groups selected from a halogen, a C1-C4 alkyl group, a nitro group, a hydroxy group, an amino group, a C1-C4 alkanoyl group, a C1-C4 alkoxy group and a phenyl group; G is more preferably a tert-butylsulfinyl group, a p-toluenesulfinyl group, a trifluoromethylsulfinyl group, a p-bromosulfinyl group, a benzyl group, a p-methoxybenzyl group or a triphenylmethyl group; M represents a leaving group, for example, a metal element, a halogen, a metal compound, a borane, a silane, a diazonium salt, or the like, and is preferably -MgBr, -MgCl, or -Li; Step a) may be carried out in the presence or absence of an acid in a solvent, said solvent may be selected from ethers such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, etc.; aromatics such as benzene, toluene, nitrobenzene, chlorobenzene, etc.; alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol, etc.; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride, etc.; esters such as ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, etc.; others such as dimethyl sulfoxide, acetonitrile, etc., or a mixture of the above solvents, The acid may be selected from organic acids, inorganic acids, or Lewis acids. Inorganic acids may include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid. Organic acids may include formic acid, acetic acid, trifluoroacetic acid, propionic acid, pyruvic acid, glycolic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, maleic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, picric acid, glutamic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, ascorbic acid, camphorsulfonic acid, and camphorsulfonic acid. Lewis acids include aluminum chloride, iron chloride, boron trifluoride, and ethyl titanate. These acids may be used alone or in combination of two or more. Step b) may be carried out in a solvent, said solvent may be selected from ethers such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, aromatics such as benzene, toluene, nitrobenzene, chlorobenzene, ketones such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride, esters such as ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, others such as dimethyl sulfoxide, acetonitrile or mixtures of the above solvents,

[0081] Method 2 is as shown in Reaction Scheme 2: c) nucleophilic addition reaction of a compound of formula (II) with a compound of formula (V) to produce a compound of formula (VI); d) performing a substitution reaction between the compound of formula (VI) and an azide compound to produce a compound of formula (VII); e) reducing the compound of formula (VII) to form a compound of formula (Ia); Including, [ka] Among them, ring A, ring B and R1 are as defined above, and preferred ones are as defined above; M represents a leaving group, for example, a metal element, a halogen, a metal compound, a borane, a silane, a diazonium salt, or the like, and is preferably -MgBr, -MgCl, or -Li; Step c) may be carried out in a solvent, said solvent may be selected from ethers such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, aromatics such as benzene, toluene, nitrobenzene, chlorobenzene, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride, esters such as ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, others such as dimethyl sulfoxide, acetonitrile or mixtures of the above solvents, Step d) may be carried out in a solvent under acid catalysis conditions, and the acid may include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, acetic acid, etc.; the azide compound may include sodium azide, potassium azide, trimethylsilyl azide, etc.; and the reaction solvent may be water, dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, or other ethers; benzene, toluene, nitro aromatics such as chlorobenzene and chlorobenzene; ketones such as acetone, methyl ethyl ketone and 4-methyl-2-pentanone; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane and carbon tetrachloride; esters such as ethyl acetate, ethyl formate, methyl acetate and isopropyl acetate; others such as dimethyl sulfoxide, acetonitrile, acetic acid, formic acid and pivalic acid, or a mixture of the above solvents, Step e) may be carried out in a solvent under reducing agent conditions, and the reducing agent system includes catalytic hydrogenation with a Pd / C catalyst, catalytic hydrogenation with a Pd / BaSO4 catalyst, catalytic hydrogenation with a PtO2 catalyst, catalytic hydrogenation with a Raney Ni catalyst, PPh3-THF-H2O system, LAH, etc., and the desired solvent is selected from ethers such as water, dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, etc.; aromatic hydrocarbons such as benzene, toluene, nitrobenzene, chlorobenzene, etc.; alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol, etc., or a mixture of the above solvents;

[0082] Method 3: The compound of formula (Ia) obtained by methods 1 and 2 is subjected to functional group conversion of the amino group, for example, by alkylation reaction, acylation reaction, etc., to obtain another aryl group-containing amine compound represented by formula (I); The alkylation reaction may be carried out in the presence of an alkylating reagent, including, but not limited to, iodomethane, iodoethane, 2-bromopropane, bromocyclopropane, tert-butyl bromide, and the like; The acylation reaction may be carried out in the presence of an acylating reagent, including, but not limited to, acetic anhydride, acetyl chloride, benzoyl chloride, formic acetic anhydride, propionic anhydride, cyclopropanecarboxylic anhydride, etc. The compounds of formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) are commercially available compounds or are prepared according to methods known in the art, or are prepared according to methods of analogous compounds.

[0083] The starting compounds used in each of the above reaction schemes may be in the form of a suitable salt, including alkali metal salts and alkaline earth metal salts such as sodium salt, potassium salt, calcium salt, and magnesium salt; organic base salts such as pyridine salt and triethylamine salt; inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and organic acid salts such as formate, acetate, propionate, glycolate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, picrate, glutamate, methanesulfonate, and benzenesulfonate.

[0084] The starting compounds used in the above reaction schemes may also include solvate forms such as hydrates and alcoholates. Each target compound obtained in each reaction scheme can be isolated and purified from the reaction mixture by cooling the reaction mixture, isolating the crude product by methods such as filtration, extraction, or concentration, and then purifying it by conventional methods such as column chromatography, slurrying, or recrystallization.

[0085] According to a third aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of a compound of formula (I), its stereoisomers, geometric isomers, conformers, tautomers, pharmaceutically acceptable salts, crystalline polymorphs, solvates, hydrates and isotopically labeled compounds, and optionally one or more pharmaceutically acceptable carriers, diluents or excipients.

[0086] The compounds of the present invention have multiple targeting effects on NMDA receptors and / or monoamine transporters and / or sigma receptors, and are applicable to the treatment of various central nervous system disorders, particularly disorders such as depression, bipolar disorder, schizophrenia, anxiety disorders, phobias, autism, Alzheimer's disease, bipolar disorder, hysteria, obsessive-compulsive disorder, hyperactivity disorder, and epilepsy.

[0087] Therefore, according to a fourth aspect of the present invention, there is provided use of one or more selected from the group consisting of a compound represented by formula (I), a stereoisomer, a geometric isomer, a conformer, a tautomer, a pharmaceutically acceptable salt thereof, a crystalline polymorph, a solvate, a hydrate and an isotope-labeled compound thereof, or the pharmaceutical composition, in the production of a medicament that modulates NMDA receptor and / or monoamine transporter and / or sigma receptor activity, specifically, use in the production of an NMDA receptor antagonist, use in the production of a monoamine transporter inhibitor, or use in the production of a sigma receptor agonist or antagonist.

[0088] According to a fifth aspect of the present invention, there is further provided use of one or more selected from the group consisting of aryl group-containing amine compounds represented by the above formula (I), stereoisomers, geometric isomers, conformers, tautomers, pharmaceutically acceptable salts thereof, crystalline polymorphs, solvates, hydrates and isotope-labeled compounds thereof, or the above pharmaceutical composition, in the manufacture of a medicament for preventing and / or treating a disease associated with an NMDA receptor and / or a monoamine transporter and / or a sigma receptor, particularly a central nervous system disease.

[0089] The central nervous system disease is selected from cerebral ischemia, stroke, cerebral infarction, traumatic brain injury, anti-NMDA receptor encephalitis, epilepsy, amyotrophic lateral sclerosis, schizophrenia, uncontrolled, unmanageable or chronic schizophrenia, affective disorder, psychotic disorder, mood disorder, bipolar I disorder, bipolar II disorder, depression, endogenous depression, major depression, uncontrolled depression, dysthymic disorder, cyclothymic disorder, panic attack, panic disorder, social anxiety disorder, obsessive-compulsive disorder, impulsive disorder, post-traumatic stress disorder, anxiety disorder, acute stress disorder, hysteria, anorexia nervosa, sleep disorder, adjustment disorder, cognitive disorder, autism, neuropathic pain, mania, Parkinson's disease, Huntington's disease, Alzheimer's disease, various dementias, memory disorders, hyperactivity disorder, attention-deficit / hyperactivity disorder, tic disorders and other nervous system events or neurodegeneration resulting from NMDA receptor activation.

[0090] In some embodiments, the neuropathic pain comprises diabetic peripheral neuropathy, post-herpetic neuralgia, complex regional pain syndrome, peripheral neuropathy, chemotherapy-induced neuropathic pain, cancer neuropathic pain, neuropathic lower back pain, HIV neuropathic pain, trigeminal neuralgia, and central post-stroke pain.

[0091] In some preferred embodiments, the central nervous system disorder is selected from bipolar I disorder, bipolar II disorder, depression, endogenous depression, major depression, uncontrolled depression, dysthymic disorder, cyclothymic disorder, panic attack, panic disorder, social anxiety disorder, obsessive-compulsive disorder, impulsive disorder, post-traumatic stress disorder, anxiety disorder, acute stress disorder, Parkinson's disease, diabetic peripheral neuropathy, postherpetic neuralgia, and complex regional pain syndrome.

[0092] According to a sixth aspect of the present invention, there is further provided a method for treating and / or preventing a disease associated with an NMDA receptor and / or a monoamine transporter and / or a sigma receptor, particularly a central nervous system disease, which comprises administering to a human or animal an aryl group-containing amine compound represented by the above formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof.

[0093] The present invention 7According to another aspect, there is further provided a method for producing the pharmaceutical composition, which comprises mixing the aryl group-containing amine compound represented by the above formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof with a medicament carrier.

[0094] The pharmaceutical composition of the present invention can be in a variety of pharmaceutical formulation forms, depending on the therapeutic purpose, including, but not limited to, tablets, pills, capsules, granules, suspensions, solutions, creams, ointments, powders, suppositories, aerosols, and injections (e.g., fat-soluble or oil-soluble injections).

[0095] A "therapeutically effective amount" of a compound of the invention refers to an amount of a compound of the invention that is capable of eliciting an individual's biological or medical response, ameliorating symptoms, slowing or delaying the progression of a disease, or preventing a disease. A "therapeutically effective amount" can be determined by the attending physician or veterinarian and will vary depending on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the individual, the route and form of administration, the judgment of the attending physician or veterinarian, etc.

[0096] As used herein, "individual" refers to an animal. Preferably, the animal is a mammal. Individual also refers to, for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In one preferred embodiment, the individual is a human.

[0097] As used herein, "inhibition" means the reduction or prevention of a particular disease, symptom, condition or disorder, or a significant decrease in the baseline activity of a biological activity or process.

[0098] As used herein, in one embodiment, the term "treatment" of any disease or condition means ameliorating the disease or condition (i.e., arresting or alleviating the progression of the disease or at least one clinical symptom thereof). In another embodiment, "treatment" refers to improving at least one physical parameter, which may not be discernible by the patient. In another embodiment, "treatment" refers to modulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both.

[0099] As used herein, "prevention" means preventing an individual from acquiring a disease by administering one or more pharmaceutical substances, particularly the compounds of the present invention and / or their pharmaceutically acceptable salts, to an individual who has a predisposition to the disease. [Effects of the Invention]

[0100] The present invention provides a novel NMDAR antagonist, which belongs to the channel pore blocker class, and inhibits the channel opening caused by overactivation of NMDA in pathological conditions without affecting the normal function of NMDAR, thereby suppressing Ca 2+ The NMDAR antagonists described in the present invention are reversible NMDAR antagonists that dissociate very quickly after binding without affecting the normal function of the NMDA receptor.

[0101] The compounds of the present invention have the following beneficial effects: 1) The compounds of the present invention can modulate NMDA receptor activity and can therefore be used to treat and / or prevent diseases associated with NMDA receptors. 2) In vitro studies have shown that the compounds of the present invention have a faster dissociation rate from NMDAR, which is significantly superior to ketamine, suggesting that the compounds of the present invention have a lower risk of psychotic side effects and a wider safety margin. 3) The compounds of the present invention have a good inhibitory effect on monoamine transporters (5-HT transporter and / or norepinephrine transporter and / or dopamine transporter) and can improve anxiety disorders, depression, or comorbidities such as anxiety and depression associated with other central nervous system diseases. 4) The compounds of the present invention have good binding activity to sigma receptors and can exert effects such as neuroprotection, cognitive regulation, amelioration of drug addiction, and amelioration of motor dysfunction by regulating sigma receptors in the central nervous system. 5) The compounds of the present invention have the characteristics of high oral bioavailability, low effective dose, and minimal toxicity and side effects, and are effective in treating diseases of the central nervous system, particularly central nervous system events caused by NMDA receptor activation. In summary, compared with conventional NMDAR antagonists, the compounds of the present invention have advantages such as multi-target action, lower effective dose, less toxicity and side effects, better safety and tolerance, etc., and have high overall drug discovery potential and good prospects for clinical use. DETAILED DESCRIPTION OF THE INVENTION

[0102] The following examples and pharmacological experiments further illustrate the present invention but are not intended to limit the scope of the invention. Unless otherwise specified, the raw materials, reagents, methods, etc. used in the examples and pharmacological examples are all conventional raw materials, reagents, and methods in this field.

[0103] Abbreviation [Table 20]

[0104] The following examples relate to the procedure of chiral separation, and the chiral separation conditions are as follows: Column: DAICEL CHIRALCEL OD-H 4.6 x 250 mm, 5 μm, mobile phase: n-hexane / 0.1% diethylamine isopropanol = 50 / 50, flow rate: 0.8 mL / min, column temperature: 35°C, detection wavelength: 270 nm. Chiral separation of different compounds can be achieved by adjusting the ratio and flow rate of the mobile phase under the above conditions. [Example]

[0105] Example 1 Preparation of 6-phenyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (Compound A1) [ka]

[0106] Step 1: Compound A1-1 (765 mg) was dissolved in dichloromethane (20 mL), and DMAP (444 mg) and di-tert-butyl dicarbonate (1.5 g) were added. The mixture was allowed to react at room temperature overnight. The reaction solution was concentrated and subjected to column chromatography to obtain 250 mg of off-white solid compound A1-2.

[0107] Step 2: Anhydrous THF (5 mL) and phenylmagnesium chloride (4.7 mL) were added to a 50 mL reaction flask, and the mixture was cooled to 0-5°C under nitrogen gas protection. A solution of compound A1-2 (500 mg) in THF (5 mL) was added dropwise and allowed to react at room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride, and the reaction solution was extracted with ethyl acetate, dried, concentrated, and purified by column chromatography to give approximately 385 mg of compound A1-3.

[0108] Step 3: Compound A1-3 (500 mg) was dissolved in DCM (10 mL), sodium azide (470 mg, 5 eq) was added, and TFA (1.32 g, 8 eq) was added dropwise in an ice bath. The mixture was allowed to react in an ice bath for 30 min, then transferred to room temperature and left overnight in the dark. Ice water was added to the reaction mixture, and the pH was adjusted to 9 with aqueous ammonia. The mixture was transferred to a separatory funnel and extracted with DCM. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give 350 mg of a brown solid, compound A1-4.

[0109] Step 4: Compound A1-4 (1.0 g) was dissolved in methanol (25 mL), palladium carbon (10%, 100 mg) was added, hydrogen gas was introduced, and the mixture was allowed to react at room temperature overnight. The reaction mixture was filtered, concentrated, and slurried with dichloromethane to obtain 434 mg of a solid. The mother liquor was concentrated and purified by column chromatography to obtain 172 mg of a solid, yielding a total of approximately 606 mg of compound A1. LRMS-ESI (m / z): 246.16 [M + H] + .

[0110] 1 H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J = 7.3 Hz, 2H), 7.28 (t, J = 7.6 Hz, 2H), 7.18 (t, J = 7.3 Hz, 1H), 6.60 (s, 2H), 2.98 (d, J = 16.0 Hz, 1H), 2.58 (d, J = 16.0 Hz, 1H), 2.49 (m, 1H), 2.10 (m, 2H), 1.91 (br, 2H), 1.79 (m, 1H).

[0111] Chiral column separation gave isomers A1-P1 (R configuration) and A1-P2 (S configuration): [ka]

[0112] A1-P1 (R configuration): HPLC purity: >99%, retention time: 6.534min. Chiral purity: 100%, retention time: 9.186min. A1-P2 (S configuration): HPLC purity: >99%, retention time: 6.553 min. Chiral purity: 100%, retention time: 14.432 min.

[0113] Example 2 Preparation of N-(2-amino-6-phenyl-4,5,6,7-tetrahydrobenzothiazol-6-yl)formamide (Compound A2) [ka]

[0114] A 50 mL reaction flask was charged with formic acid (920 mg) and acetic anhydride (2.04 g). The mixture was refluxed at 60 °C under nitrogen gas protection for 2 h, cooled to room temperature, and dichloromethane (40 mL) was added to obtain a 0.5 M formic acid acetic anhydride solution. This was ready for use. Compound A1 (3.8 g) was added to dichloromethane (50 mL), and the above 0.5 M formic acid acetic anhydride solution (35 mL) was added dropwise. The mixture was reacted at room temperature for 1 h. The pH was adjusted to 9 with saturated aqueous sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain 3.8 g of an off-white solid, compound A2.

[0115] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.97 (s, 1H), 7.38 (m, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.20 (t, J = 7.1 Hz, 1H), 6.65 (s, 2H), 2.99 (dd, J = 29.1, 16.3 Hz, 2H), 2.56 (m, 1H), 2.40 (m, 1H), 2.25 (m, 1H), 2.16 (m , 1H). LRMS-ESI (m / z): 274.16 [M + H] + .

[0116] Example 3 N 6 -methyl-6-phenyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (Compound A3) and its hydrochloride [ka]

[0117] Compound A2 (3.8 g) was taken and added to anhydrous THF (60 mL). BMS (136 mL) was added dropwise and the reaction was allowed to proceed at 65°C overnight. The mixture was cooled to room temperature, quenched by adding methanol dropwise, and concentrated to dryness to remove the solvent. Methanol (50 mL) and water (50 mL) were added and the mixture was refluxed for 2 hours. The mixture was extracted with DCM, dried, concentrated, and purified by column chromatography to give the off-white solid (2.8 g) of basic A3. Methanol (30 mL) was added to clarify the reaction. 4M HCl / EA (3.2 mL) was added dropwise and the reaction was allowed to proceed with stirring. The mixture was concentrated to dryness to remove the solvent. The mixture was slurried with MTBE and filtered to give the hydrochloride salt of compound A3 (2.9 g).

[0118] 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (m, 1H), 9.82 (m, 1H), 9.26 (br, 2H), 7.61 (m, 2H), 7.46 (m, 3H), 3.64 (d, J = 16.5 Hz, 1H), 3.27 (d, J LRMS-ESI (m / z): 246.16 [M + H] + .

[0119] Chiral column separation gave isomers A3-P1 (R configuration) and A3-P2 (S configuration): [ka]

[0120] A3-P1 (R configuration): HPLC purity: >98%, retention time: 6.914 min. Chiral purity: >95%, retention time: 6.847 min. A3-P2 (S configuration): HPLC purity: >95%, retention time: 6.924min. Chiral purity: >95%, retention time: 6.782min.

[0121] Example 4 Preparation of N-(2-amino-6-phenyl-4,5,6,7-tetrahydrobenzothiazol-6-yl)acetamide (Compound A4) [ka]

[0122] Compound A1 (400 mg) was taken and added to dichloromethane (20 mL), and acetic anhydride (167 mg, 1.1 eq) was added dropwise, followed by reaction overnight at 25° C. The pH was adjusted to 9 with saturated aqueous sodium bicarbonate, extracted with dichloromethane, dried, concentrated, and subjected to column chromatography to obtain compound A4 as an off-white solid (359 mg, 76.5% yield).

[0123] Example 5 N 6 Preparation of 4,5,6,7-ethyl-6-phenyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (Compound A5) and its hydrochloride [ka]

[0124] Compound A4 (320 mg) was added to dichloromethane (20 mL), TMSCl (500 mg, 5 eq) was added dropwise, and the mixture was stirred for 30 min. Lithium aluminum tetrahydride (480 mg, 12 eq) was added, and the mixture was reacted at 25 °C for 5 h. The reaction was quenched with 2 M aqueous sodium hydroxide (1 mL), anhydrous magnesium sulfate was added, and the mixture was stirred with dichloromethane, filtered, concentrated, and purified by column chromatography to give a white solid (247 mg). Ethyl acetate (3 mL) was added, and 2 M hydrogen chloride ethyl acetate solution (0.5 mL) was added dropwise. The mixture was stirred for 30 min. The mixture was filtered to give the hydrochloride salt of compound A5 (250 mg).

[0125] 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.33 (s, 1H), 7.57 (m, J = 7.4 Hz, 2H), 7.44 (m, 3H), 6.81 (s, 2H), 3.61 (d, J = 15.8 Hz, 1H), 3.21 (d, J = 15.1 Hz, 1H), 2.78 (m, 1H), 2.60 (m, 1H), 2.43 (m, 2H), 2.27 (m, 1H), 1.71 (m, 1H), 1.14 (t, J = 6.8 Hz, 3H). LRMS-ESI (m / z): 274.17 [M+H] + .

[0126] Example 6 Preparation of N-(2-amino-6-phenyl-4,5,6,7-tetrahydrobenzothiazol-6-yl)propanamide (Compound A6) [ka]

[0127] Compound A1 (400 mg) was taken and added to dichloromethane (20 mL), and propionic anhydride (234 mg, 1.1 eq) was added dropwise, followed by reaction overnight at 25° C. The mixture was adjusted to pH 9 with saturated aqueous sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain compound A6 as an off-white solid (274 mg, yield 55.8%).

[0128] Example 7 6-phenyl-N 6 Preparation of 4,5,6,7-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (Compound A7) and its hydrochloride [ka]

[0129] Compound A6 (274 mg) was taken and added to dichloromethane (20 mL), TMSCl (990 mg, 10 eq) was added dropwise, and the mixture was stirred for 30 min. Lithium aluminum tetrahydride (968 mg, 28 eq) was added and the mixture was refluxed for 24 h. The reaction was quenched with 2 M aqueous sodium hydroxide (1 mL), anhydrous magnesium sulfate was added, and the mixture was stirred with dichloromethane, filtered, concentrated, and purified by column chromatography to obtain a white solid (229 mg). Ethyl acetate (3 mL) was added, and 2 M hydrogen chloride ethyl acetate solution (0.5 mL) was added dropwise. The mixture was stirred for 30 min. The mixture was filtered to obtain the hydrochloride salt of compound A7 (240 mg).

[0130] LRMS-ESI (m / z): 288.19 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 9.14 (s, 1H), 7.55 (m, 2H), 7.43 (m, 3H), 6.78 (s, 2H), 3.64 (d, J = 16.3 Hz, 1H), 3.15 (d, J = 16.2 Hz, 1H), 2.71 (m, 1H), 2.65-2.31 (m, 3H), 2.19 (m, 1H), 1.73 (m, 1H), 1.56 (m, 2H), 0.80 (t, J = 7.4 Hz, 3H).

[0131] Example 8 Preparation of 6-(2-fluorophenyl)-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (Compound A9) [ka]

[0132] Step 1: o-Fluorobromobenzene (5g, 1eq), lithium chloride (0.6g, 0 .The mixture was cooled to below -10°C under nitrogen gas protection, and a 2.0 M solution of isopropyl magnesium chloride in THF (14.3 mL, 1 eq) was added. After the addition was complete, the mixture was stirred for 3 hours at a controlled temperature of -5 to -10°C.

[0133] Separately, A1-2 (1 g, 0.13 eq) was dispersed in 10 mL of THF and added dropwise to the above system. The temperature was controlled at −5 to −10° C. for 2 h to react. Methanol and water were added to quench the reaction, and EA (100 mL) was added and stirred. The mixture was filtered, and the filtrate was washed with water (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.95 g of an off-white solid, A9-1 (yield 70.5%).

[0134] Step 2: 900 mg of A9-1 was dissolved in DCM (10 mL), sodium azide (0.83 g, 5 eq) was added, and TFA (9 mL) was added dropwise in an ice bath. The mixture was allowed to react for 30 min in an ice bath, then transferred to room temperature and left overnight in the dark. Ice water (50 mL) was added, and the pH was adjusted to 9 with aqueous ammonia. Extraction with DCM was performed. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain 70 mg of A9-2.

[0135] Step 3: A9-2 (70 mg) was dissolved in methanol (70 mL), 10% palladium on carbon (50 mg) was added, hydrogen gas was introduced, and the mixture was allowed to react at room temperature overnight. After filtration, the filtrate was concentrated and purified by column chromatography to give 38 mg of compound A9 as a white solid in a 59% yield.

[0136] 1H NMR (400 MHz, DMSO-d6) δ7.47 (t, J = 16.3 Hz ,1H), 7.31-7.26 (m, 1H), 7.17-7.11 (m, 2H), 6.63 (s, 2H), 3.10 (d, J = 16 Hz, 1H), 2.62-2.50 (m, 2H), 2.35-2.31 (m, 1H), 2.16-2.12 (m, 1H), 1.82-1.78 (m, 1H). ESI (m / z): 264.13 [M + H] + .HPLC purity: >97%, retention time: 6.229min.

[0137] Example 9 Preparation of 5-phenyl-5-(pyrrolidin-1-yl)-4,5,6,7-tetrahydro-1H-indazole (Compound A12) and its hydrochloride salt [ka]

[0138] Step 1: Triazole (12.4 g, 1.1 eq), tetrahydropyrrole (13.35 g, 1.2 eq), and 1,4-cyclohexanedione monoethylene ketal A12-1 (25.0 g, 160 mmol) were dissolved in toluene and refluxed for 18 h to separate water. The temperature was then lowered to room temperature to obtain a solution of A12-2, which was ready for use.

[0139] Step 2: Bromobenzene (75 g, 3 eq) was dissolved in anhydrous THF, and n-butyllithium (2.5 M) (150 mL, 3.3 eq) was slowly added dropwise at -78°C. After the addition was completed, the mixture was kept at -78°C for 1 hour, and the A12-2 solution prepared above was added dropwise. After the addition was completed, the mixture was kept at -78°C and stirred for 1 hour, and then stirred at room temperature for 12 hours. 10.5 g of A12-3 was obtained by column chromatography.

[0140] Step 3: Compound A12-3 (10.5 g, 6.5 mmol) was dissolved in ethanol, concentrated hydrochloric acid (12 M, 3 eq) was added, the mixture was stirred at room temperature overnight, concentrated to dryness to remove the solvent, and the mixture was adjusted to pH 11-12 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with DCM, dried, filtered, and concentrated by column chromatography to obtain 8.5 g of compound A12-4.

[0141] Step 4: Compound A12-4 (3.0 g, 11.1 mmol) was dissolved in toluene, dried over anhydrous magnesium sulfate for 2 days, filtered, and prepared for use. Sodium tert-butoxide (2.46 g, 2 eq) and ethyl formate (1.38 g, 1.5 eq) were added to toluene, and the A12-4 solution was added at 0-10°C and stirred overnight at room temperature. The reaction mixture was extracted twice with toluene, and the aqueous phase was adjusted to pH 6-7. The mixture was extracted three times with dichloromethane, dried, filtered, concentrated, and purified by column chromatography to obtain 2.5 g of compound A12-5.

[0142] Step 5: Compound A12-5 (200 mg, 7.3 mmol) was dissolved in ethanol, 0.5 mL of hydrazine hydrate was added, and the mixture was heated under reflux for 7 hours. The mixture was concentrated to dryness to remove the solvent, and the residue was subjected to column chromatography to obtain approximately 60 mg of A12. The product obtained by column chromatography was dissolved in methyl tert-butyl ether, and a commercially available 4 M hydrogen chloride / dioxane solution (1 eq, 0.056 mL) was added to precipitate a solid. The solid was filtered and dried to obtain 25 mg of the hydrochloride salt of compound A12.

[0143] LRMS-ESI (m / z): 268.49 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 7.75 (m, 2H), 7.64 (s, 1H), 7.42 (m, 3H), 3.87 (d, J = 14.2 Hz, 1H), 3.48 (m, 1H), 3.32 (d, J = 15.3 Hz, 1H), 3.21 (m, 1H), 3.10 (m, 1H), 3.00 (m, 2H), 2.83 (dd, J = 16.8, 5.1 Hz, 1H), 2.55 (m, 1H), 2.13 (m, 1H), 1.83 (m, 2H), 1.66 (m, 2H).

[0144] Chiral column separation gave isomers A12-P1 (S configuration) and A12-P2 (R configuration): [ka]

[0145] A12-P1 (S configuration): HPLC purity: >99%, retention time: 8.786min. Chiral purity: >99%, retention time: 7.703min. A12-P2 (R configuration): HPLC purity: >99%, retention time: 8.778min. Chiral purity: >95%, retention time: 10.236min.

[0146] Example 10 Preparation of N-methyl-6-phenyl-4,5,6,7-tetrahydrobenzothiazol-6-amine (Compound A13) and its hydrochloride [ka]

[0147] Compound A3 (450 mg) was added to 85% phosphoric acid (25 mL), cooled to -10°C, an aqueous solution of sodium nitrite (6 eq) was added, and the mixture was stirred at -10°C for 1 hour. After that, the mixture was added dropwise to 50% hypophosphorous acid solution (7 mL) at 0°C and stirred at 0°C for 1.5 hours. The pH was neutralized to 8-9 with saturated sodium carbonate, and the mixture was extracted three times with EA. The organic phases were combined and concentrated. The A13 sample obtained by column chromatography was added to 50 mL of EA, and a salt was formed by adding HCl / EA solution to obtain 190 mg of the hydrochloride salt of compound A13.

[0148] LRMS-ESI (m / z): 245.16 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (m, 1H), 9.75 (m, 1H), 8.95 (s, 1H), 7.57 (d, J = 6.9 Hz, 2H), 7.41 (m, 3H), 4.03 (d, J = 16.7 Hz, 1H), 3.48 (d, J = 16.7 Hz, 1H), 2.91 (d, J = 16.4 Hz, 1H), 2.72 (m, 1H), 2.55 (m, 1H), 2.19 (t, J = 5.2 Hz, 3H), 2.10 (m, 1H).

[0149] Chiral column separation gave isomers A13-P1 (R configuration) and A13-P2 (S configuration): [ka]

[0150] A13-P1 (R configuration): HPLC purity: >95%, retention time: 10.144min. Chiral purity: >99%, retention time: 4.501min. A13-P2 (S configuration): HPLC purity: >95%, retention time: 10.151min. Chiral purity: >99%, retention time: 6.418min.

[0151] Example 11 Preparation of 6-phenyl-4,5,6,7-tetrahydrobenzothiazol-6-amine (Compound A14) and its hydrochloride [ka]

[0152] Compound A1 (300 mg) was added to concentrated hydrochloric acid (12 M, 8 mL) and stirred until the mixture became clear. The mixture was then cooled to -30°C, and 1 M aqueous sodium nitrite solution (1.7 eq, 2 mL) was added dropwise. After the addition, the mixture was kept warm and stirred for 1 hour. Hypophosphorous acid (0.2 mL) was added, and the mixture was stirred in an ice-water bath for 1 hour. The mixture was then cooled to -30°C and neutralized with saturated aqueous sodium carbonate solution. The mixture was extracted with dichloromethane-methanol, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by column chromatography to obtain 60 mg of A14 sample. 2 mL of EA was added, and hydrogen chloride ethyl acetate solution was added dropwise to precipitate a solid. The solid was filtered and dried to obtain 35 mg of the hydrochloride salt of compound A14.

[0153] LRMS-ESI (m / z): 231.12 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.93 (br, 3H), 7.58 (d, 2H), 7.40 (m, 3H), 3.78 (d, J = 16.6 Hz, 1H), 3.47 (d, J = 16.6 Hz, 1H), 2.90 (m, 1H), 2.59 (m, 1H), 2.44 (m, 1H), 2.27 (m, 1H).

[0154] Chiral column separation gave isomers A14-P1 (R configuration) and A14-P2 (S configuration): [ka]

[0155] A14-P1 (R configuration): HPLC purity: >98%, retention time: 9.514 min. Chiral purity: 100%, retention time: 7.835 min. A14-P2 (S configuration): HPLC purity: >95%, retention time: 9.607 min. Chiral purity: 100%, retention time: 21.014 min.

[0156] Example 12 Preparation of 2-methyl-N-(4-phenyl-4,5,6,7-tetrahydrobenzothiophen-4-yl)propane-2-sulfonamide (Compound A15) [ka]

[0157] Step 1: A reaction flask was charged with A15-1 (5 g, 1 eq), tert-butylsulfenamide (5.57 g, 1.4 eq), titanium ethoxide (8.24 g, 1.1 eq), and THF. The mixture was refluxed under nitrogen for 24 h (70 °C). After cooling to room temperature, the reaction mixture was poured into ice-water and EA was added. The mixture was stirred and filtered. The organic phase was separated and the aqueous phase was extracted with EA. The combined organic phase was washed with saturated brine, dried, concentrated, and purified by column chromatography to give 2.69 g of compound A15-2 in a 32.1% yield.

[0158] Step 2: Iodobenzene (1.0 g, 2.5 eq) was added to DCM (10 mL) and cooled to -60 °C under nitrogen gas protection. Butyllithium (1.64 mL, 2.5 M, 2.1 eq) was added dropwise and the mixture was allowed to react for 1.5 h. This reaction mixture was designated as Reaction Solution 2 and prepared for use. Compound A15-2 (500 mg, 1 eq) was added to DCM (10 mL) and clarified. This reaction mixture was designated as Reaction Solution 1 and prepared for use. The temperature of Reaction Solution 1 was controlled at approximately -60 °C, and the mixture was added dropwise to Reaction Solution 2 and allowed to react for 2 h. The reaction was quenched with ammonium chloride, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 322 mg of compound A15 as a solid in a 49.3% yield.

[0159] Example 13 Preparation of 4-phenyl-4,5,6,7-tetrahydrobenzothiophene-4-amine (Compound A16) [ka]

[0160] Compound A15 (322 mg, 1 eq) was taken and added to dioxane (9.7 mL), and a solution of hydrochloric acid in ethyl acetate (0.73 mL, 4 M, 3 eq) was added dropwise. The mixture was allowed to react at room temperature for 0.5 h. The mixture was neutralized with saturated aqueous sodium bicarbonate, extracted with EA, washed with saturated brine, dried, concentrated, and purified by column chromatography to give 192 mg of compound A16 in an 86.7% yield. 2 mL of DCM was added, and 0.3 mL of a 4 M solution of hydrogen chloride in ethyl acetate was added dropwise. The mixture was concentrated, slurried with isopropanol, and filtered to give the hydrochloride salt form of A16. HPLC: 96.7%.

[0161] 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 3H), 7.49 (d, J = 5.3 Hz, 1H), 7.44 - 7.33 (m, 3H), 7.30 - 7.22 (m, 2H), 7.03 (d, J = 5.3 Hz, 1H), 2.85 (m, 2H), 2.23 (t, J = 4.8 Hz, 1H), 1.95 (m, 1H), 1.49 (m, 1H).

[0162] Example 14 Preparation of N-(4-phenyl-4,5,6,7-tetrahydrobenzothiophen-4-yl)formamide (Compound A17) [ka]

[0163] A reaction flask was charged with formic anhydride (347 mg, 9 eq) and acetic anhydride (770 mg, 9 eq). The mixture was heated to 60°C under nitrogen gas protection and reacted for 2 hours. The temperature was then lowered to room temperature (approximately 25°C). A solution of compound A16 (192 mg, 1 eq) in DCM (4 mL) was added and stirred at room temperature for 0.5 hours. A saturated aqueous solution of sodium bicarbonate was added to quench the reaction, and the mixture was extracted with DCM and concentrated to give 226 mg of an oily liquid, compound A17.

[0164] Example 15 Preparation of N-(4-phenyl-4,5,6,7-tetrahydrobenzothiophen-4-yl)formamide (Compound A18) and its hydrochloride [ka]

[0165] Compound A17 (226 mg, 1 eq. in excess of theoretical amount) was added to a solution of THF (10 mL). Under nitrogen gas protection, 1.0 M borane in tetrahydrofuran (8.4 mL, 10 eq., 1.0 M) was added dropwise, and the mixture was heated to reflux and allowed to react for 3 hours. The reaction was quenched with methanol and concentrated to dryness. A 1:1 mixture of methanol and water (5 mL) was added, and the mixture was heated to reflux. TLC showed completion of the reaction. The mixture was cooled to room temperature, extracted with DCM, and concentrated to give crude A18. 2 mL of DCM was added, and 0.3 mL of a 4 M solution of hydrogen chloride in ethyl acetate was added dropwise. The mixture was concentrated to dryness, slurried with isopropanol, and filtered to give 150 mg of the hydrochloride salt form of A18 as an off-white solid in 73.6% yield. HPLC: 98.3%.

[0166] 1 H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.75 (s, 1H), 7.57 (d, J = 5.3 Hz, 1H), 7.49 - 7.37 (m, 3H), 7.36 - 7.31 (m, 2H), 7.10 (d, J = 5.3 Hz, 1H), 2.92 - 2.78 (m, 2H), 2.41 (t, J = 5.2 Hz, 3H), 2.35 (dd, J = 12.5, 2.4 Hz, 1H), 2.25 (m, 1H), 1.94 (m, 1H), 1.40 (m, 1H).

[0167] Example 16 Preparation of 6-phenyl-4,5,6,7-tetrahydrobenzothiophene-6-amine (Compound A19) [ka]

[0168] Step 1: Compound A19-1 (10 g, 1 eq), malonic acid (13 g, 1.4 eq), and 12 mL of pyridine were added to a 100 mL reaction flask in this order, and the mixture was heated to 100 ° C. and reacted for 6 hours. After cooling the reaction mixture, 3 M hydrochloric acid was added to adjust the pH to 3, and the solid was precipitated, filtered, rinsed with water, and then rinsed with n-heptane (50 mL * 2), yielding 13.6 g of off-white solid compound A19-2.

[0169] Step 2: Compound A19-2 (13.6 g), ammonium formate (22.47 g, 4 eq), 10% palladium-carbon (10 g), and isopropanol (150 mL) were added to a 500 mL reaction flask and heated to 90 °C under nitrogen gas protection for 36 h. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth to remove the palladium-carbon, concentrated to remove most of the isopropanol, diluted with 2 M hydrochloric acid (300 mL, pH = 2-3), extracted with EA (200 mL), dried over sodium sulfate, and concentrated to give 10.5 g of a solid, compound A19-3, for a two-step yield of 76.09%.

[0170] Step 3: Polyphosphoric acid (PPA) (50 g) was added to a 250 mL reaction flask and heated to 120 °C. Once the PPA was stirred, compound A19-3 (5 g, 1 eq) was added in several portions and allowed to react for 1 h. The oil bath was removed, and the reaction was quenched by slowly adding ice to the hot mixture (a total of 100 mL of ice water was added). After the mixture had cooled to room temperature, EA (100 mL) was added and stirred. The black residue was removed by filtration through diatomaceous earth, and the mixture was allowed to stand. The aqueous phase was back-extracted once with 50 mL of EA. The combined organic phases were washed once with saturated sodium bicarbonate (100 mL), washed with water (100 mL), dried, filtered through silica gel, and concentrated to give 2.5 g of a tan solid, compound A19-4, in 56.56% yield.

[0171] Step 4: Methyltriphenylphosphonium bromide (19.40 g, 1.5 eq) and anhydrous tetrahydrofuran (40 mL) were added to a 250 mL three-neck flask, the temperature was controlled at approximately 0 °C, and 2.5 M butyllithium (2.10 mL, 1.4 eq) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h. The temperature was controlled at approximately 0 °C, and a solution of compound A19-4 (5 g, 1 eq) in tetrahydrofuran (10 mL) was added dropwise to the reaction system. After the addition was complete, the reaction was allowed to proceed at room temperature overnight. Ice water (100 mL) and EA (100 mL) were added to the raw material solution, which was then filtered through diatomaceous earth and allowed to stand for liquid separation. The organic phase was concentrated to a minimum volume and subjected to column chromatography to obtain 1.1 g of an oily product, compound A19-5, in a yield of 22.31%.

[0172] Step 5: Compound A19-5 (1.3 g, 1 eq) and methanol-water (volume ratio 95 / 5, total 39 mL) were added to a 100 mL reaction flask, and HTIB oxidant (3.56 g, 0.95 eq) was added in several portions in an ice-water bath. After the addition was complete, the reaction mixture was allowed to react at room temperature for 20 min. The reaction mixture was concentrated to remove most of the methanol (35 °C), and DCM and water (20 mL each) were added. The mixture was stirred at room temperature for 20 min, separated, and the DCM phase was concentrated and purified by column chromatography to give compound A19-6 (630 mg, 43.45% yield) as an oil.

[0173] Step 6: Compound A19-6 (358 mg, 1 eq) and DCM (5 mL) were added to a 25 mL reaction flask, and under nitrogen gas protection, 2 M phenylmagnesium chloride (1.18 mL, 1 eq) was added dropwise while controlling the temperature at 0-10 °C. After the addition was completed, the reaction was allowed to proceed for 30 min. The reaction mixture was poured into saturated ammonium chloride, and the DCM was separated. The mixture was dried, concentrated, and purified by column chromatography to obtain 263 mg of an oily product, compound A19-7, in a yield of 48.52%.

[0174] Step 7: Compound A19-7 (263 mg, 1 eq), sodium azide (1.11 g, 15 eq), and DCM (26.3 mL) were added to a 50 mL reaction flask, and TFA (13 mL) was added dropwise in an ice-water bath under nitrogen gas protection. After the addition was complete, the mixture was allowed to react for 30 min. The reaction mixture was poured into ice-water (20 mL), the pH was adjusted to 9 with aqueous ammonia, and the DCM phase was separated by standing, dried, and purified by column chromatography to obtain compound A19-8.

[0175] Step 8: Compound A19-8 was dissolved in methanol (13 mL), palladium-carbon (0.52 g) was added, the atmosphere was purged with hydrogen gas, and the reaction was carried out at atmospheric pressure for 2 h. The palladium-carbon was filtered off from the reaction mixture, and the mixture was concentrated to give 90 mg of solid compound A19, with a two-step yield of 34.35%.

[0176] LRMS-ESI (m / z): 230.14 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.3 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.25 (m, 1H), 7.11 (d, J = 5.1 Hz, 1H), 6.79 (d, J = 5.1 Hz, 1H), 3.34 (d, J = 16.6 Hz, 1H), 2.94 (d, J = 16.2 Hz, 1H), 2.87 - 2.74 (m, 1H), 2.61 (dt, J = 16.7, 5.5 Hz, 1H), 2.32 - 2.17 (m, 1H), 2.04 - 1.92 (m, 1H).

[0177] Chiral column separation gave isomers A19-P1 (R configuration) and A19-P2 (S configuration): [ka]

[0178] A19-P1 (R configuration): HPLC purity: >93%, retention time: 13.149min. Chiral purity: 99%, retention time: 9.196min. A19-P2 (S configuration): HPLC purity: >97%, retention time: 13.279min. Chiral purity: 98.8%, retention time: 10.021min.

[0179] Example 17 Preparation of N-(6-phenyl-4,5,6,7-tetrahydrobenzothiophen-6-yl)formamide (Compound A20) [ka]

[0180] Preparation of formic acetic anhydride: Acetic anhydride (0.51 mL, 28 eq) and 98% formic acid (0.21 mL, 28 eq) were added to a 10 mL reaction flask and stirred at 65 °C for 1-2 h. The mixture was then cooled to room temperature to obtain formic acetic anhydride, ready for use. A solution of compound A19 (45 mg, 1 eq, basic) in DCM / THF was added dropwise to the homemade formic acetic anhydride in an ice-water bath and stirred at room temperature for 1 h. Saturated aqueous sodium bicarbonate was slowly added to the reaction mixture to adjust the pH to 8. The DCM phase was separated, concentrated, and purified by column chromatography to obtain 37 mg of compound A20 as a gel, with a yield of 73.27%.

[0181] Example 18 Preparation of N-methyl-6-phenyl-4,5,6,7-tetrahydrobenzothiophen-6-amine (Compound A21) and its hydrochloride [ka]

[0182] Compound A20 (37 mg, 1 eq) was dissolved in THF (3.7 mL). Lithium aluminum hydride (55 mg, 10 eq) was added in portions in an ice-water bath under nitrogen gas protection. The mixture was heated to reflux and reacted for 3 h. The reaction mixture was cooled to 0-10 °C, and 0.05 mL of water and 0.05 mL of 20% sodium hydroxide solution were added dropwise. The mixture was filtered through diatomaceous earth and concentrated to a minimum volume. 1 mL of 4 M hydrogen chloride in ethyl acetate was added, stirred for 10 min, concentrated, and then 0.5 mL of EA was added. The mixture was stirred and crystallized. The mixture was filtered to give 23 mg of compound A21 as an off-white solid in the hydrochloride form (57.5% yield).

[0183] 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.53 (s, 1H), 7.56 (d, J = 6.9 Hz, 2H), 7.46 - 7.36 (m, 3H), 7.31 (d, J = 5.1 Hz, 1H), 6.70 (d, LRMS-ESI (m / z): 244.18 [M+H] + .

[0184] Example 19 Preparation of 5-phenyl-4,5,6,7-tetrahydrobenzothiophene-5-amine (Compound A22) [ka]

[0185] Step 1: A22-1 (195 mg, 1.3 mmol) was placed in a 50 mL three-neck flask, and after purging with nitrogen gas, dry THF (5 mL) was added. The temperature was lowered to 0°C, and PhMgCl (1 mL, 1.97 mmol, 1.5 eq.) was added dropwise. After the dropwise addition was completed, the reaction was carried out at 0°C for 2 hours. A saturated aqueous solution of ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, filtered, concentrated to dryness, and purified by column chromatography to obtain 115 mg of product A22-2 as a yellow oil.

[0186] Step 2: A22-2 (115 mg, 0.5 mmol) was dissolved in DCM (3 mL), NaN3 (65 mg, 1 mmol, 2 eq.) was added, and the atmosphere was purged with nitrogen gas. The mixture was then cooled to 0 °C, and TFA (0.2 mL, 2.56 mmol, 5 eq.) was added dropwise. After the addition was complete, the mixture was allowed to react at 0 °C for 2.5 h. After dilution with water in an ice-water bath, the reaction was quenched by adding aqueous ammonia, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried, filtered, and concentrated to give A22-3.

[0187] Step 3: A22-3 was dissolved in MeOH (10 mL), Pd / C (150 mg) was added, the mixture was purged with hydrogen gas, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction mixture was filtered to remove the Pd / C, and then concentrated. The residue was dissolved in MTBE (10 mL), and 4 M hydrogen chloride / ethyl acetate solution (0.1 mL) was added dropwise. A white solid precipitated, which was filtered to give 30 mg of compound A22 as an off-white solid. The three-step yield was 8.8%.

[0188] 1H NMR (400 MHz, CD3OH) δ 7.52-7.50 (m, 2H), 7.46-7.38 (m, 3H), 7.28 (d, J = 4.0 Hz, 1H), 6.92 (d, J = 4.0 Hz, 1H), 3.62 (d, J = 16 Hz, 1H), 3.15 (d, J = 16 Hz, 1H), 2.97-2.92 (m,1H), 2.64-2.59 (m,1H), 2.55-2.47 (m,1H), 2.44-2.38 (m,1H). LRMS-ESI (m / z): 213.17 [M - NH2] + .

[0189] Chiral column separation gave isomers A22-P1 (S configuration) and A22-P2 (R configuration): [ka]

[0190] A22-P1 (R configuration): HPLC purity: >97%, retention time: 13.319min. Chiral purity: 99%, retention time: 10.137min. A22-P2 (S configuration): HPLC purity: >97%, retention time: 13.321min. Chiral purity: 98.8%, retention time: 10.871min.

[0191] Example 20 Preparation of 5-(N-methylbenzamido)-5-phenyl-4,5,6,7-tetrahydrobenzothiophene-2-carboxylic acid (Compound A23) [ka]

[0192] Step 1: A reaction flask was charged with 8 g of compound A23-1, N-methylbenzylamine (6.83 g, 1.1 eq), 1,2,3-triazole (4.25 g, 1.2 eq), and 50 mL of toluene. The mixture was refluxed overnight to separate water and cooled to room temperature. Another reaction flask was charged with phenylmagnesium bromide (4 eq in THF). The reaction mixture was added dropwise to the flask in an ice bath and stirred for 90 min. The reaction mixture was poured into an aqueous ammonium chloride solution, EA was added, and the organic phase was washed with water, dried, concentrated, and purified by column chromatography to give 3.85 g of a pale yellow oil, compound A23-2, in a 22% yield.

[0193] Step 2: A reaction flask was charged with 3.85 g of compound A23-2, 460 mg of Pd(OH)2 / C, 50 mL of ethanol, and 6.75 g of ammonium formate (10 eq). The mixture was purged with nitrogen gas and refluxed for 50 min. Insoluble matter was removed by filtration, the residue was rinsed with ethanol, the filtrates were combined, concentrated, and the residue was diluted with DCM, washed once with water and once with saturated sodium chloride solution, dried, and concentrated to give 2.49 g of a colorless oil, compound A23-3, in a 92% yield.

[0194] Step 3: A reaction flask was charged with 2.49 g of compound A23-3, DCM, and 1.5 eq of DIPEA. 1.1 eq of benzoyl chloride was added in an ice bath. After the addition was complete, the mixture was allowed to react at room temperature overnight. The mixture was diluted with EA, washed once with an aqueous ammonium chloride solution and once with a saturated aqueous sodium chloride solution, dried, concentrated, and slurried in 15 mL of n-heptane to give 2.97 g of a pale yellow solid, compound A23-4. The yield was 84%.

[0195] Step 4: A reaction flask was charged with 2.9 g of compound A23-4, 80 mL of acetone, 40 mL of water, and 0.2 eq of p-toluenesulfonic acid, and the mixture was refluxed for 5 h. The mixture was diluted with EA, washed once with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride, dried, concentrated, and purified by column chromatography to give 2.34 g of a colorless oil, compound A23-5, in a 92% yield.

[0196] Step 5: 4 eq of DMF was dissolved in 30 mL of dry DCM and stirred in an ice bath for 20 min. 3 eq of phosphorus oxychloride was added dropwise to the mixture. After the addition was complete, the mixture was stirred at room temperature for 1 h and then stirred again in an ice bath for 10 min. Compound A23-5 (2 g, 1 eq) was dissolved in 15 mL of dry DCM and rapidly added to the above reaction solution. Under nitrogen gas protection, the mixture was allowed to warm to room temperature and stirred overnight. The reaction solution was poured into ice water, the pH was adjusted to slightly alkaline, the organic phase was separated, washed with saturated brine, dried, concentrated, and purified by column chromatography to obtain 1.04 g of compound A23-6 as a pale yellow oil. The yield was 45%.

[0197] Step 6: Sodium block (3 eq) was added to absolute ethanol in an ice bath and allowed to react completely. After this, 2 eq of ethyl mercaptoacetate was added, followed by a solution of compound A23-6 (1 g, 1 eq) in absolute ethanol. The mixture was stirred at room temperature for 3 h under nitrogen gas protection. 5N aqueous sodium hydroxide (4 eq of NaOH) was added directly, and the mixture was stirred at 60 °C for 4 h. After the reaction was complete, the mixture was diluted with water, MTBE was added to separate the layers, the organic layer was discarded, and the aqueous layer was separated. The pH was adjusted to approximately 2 with 1 M hydrochloric acid and extracted with EA. The organic phase was washed with saturated brine, dried, and concentrated to give 1.03 g of compound A23 as a pale yellow solid.

[0198] Example 21 Preparation of N-methyl-N-(5-phenyl-4,5,6,7-tetrahydrobenzothiophen-5-yl)benzamide (Compound A24) [ka]

[0199] A reaction flask was charged with 600 mg of compound A23, and then 0.5 eq of cuprous oxide, 0.4 eq of DBU, and a small amount of DMF were added. The mixture was purged with nitrogen gas several times and reacted at 160°C for 5 hours. The reaction solution was cooled, and excess EA was added and stirred. Insoluble matter was removed by filtration. The filter residue was rinsed with EA. The filtrate was diluted with EA, washed once with an aqueous ammonium chloride solution and once with saturated brine, dried, concentrated, and subjected to column chromatography to obtain 405 mg of compound A24 as a white solid.

[0200] Example 22 Preparation of N-methyl-5-phenyl-4,5,6,7-tetrahydrobenzothiophen-5-amine (Compound A25) and its hydrochloride [ka]

[0201] A reaction flask was charged with dry THF and 360 mg of compound A24, stirred to dissolve, cooled in an ice bath, and 2 eq. of LAH was added in portions. After the addition was complete, the mixture was allowed to warm to ambient temperature under nitrogen gas protection and stirred for 3 h. The reaction mixture was poured into an ice-water solution containing 2.7 g of potassium sodium tartrate tetrahydrate, extracted with EA, and the organic phase was washed with saturated brine, dried, and concentrated. Approximately 220 mg of A25 was obtained as a colorless oil by column chromatography on basic aluminum oxide. This was dissolved in methanol, and hydrogen chloride / methanol solution (approximately 1 eq. of HCl) was added dropwise in an ice bath. After the addition was complete, the mixture was stirred for 30 min and concentrated. An appropriate amount of acetonitrile was added to the residue, stirred, and a white solid precipitated. This was filtered and dried to give 210 mg of the hydrochloride salt of compound A25 as a white solid.

[0202] 1H NMR (400 MHz, DMSO-d6) δ 10.21 (q, J = 6.2 Hz, 1H), 9.67 (m, 1H), 7.58 - 7.50 (m, 2H), 7.45 - 7.36 (m, 3H), 7.34 (d, J = 5.1 Hz, 1H), 6.94 (d, J = 5.1 Hz, 1H), 3.72 (dd, J = 16.1, 2.0 Hz, 1H), 3.25 (dd, J = 16.0, 2.3 Hz, 1H), 2.87 (dq, J = 16.9, 2.4 Hz, 1H), 2.67 (ddt, J = 12.8, 5.2, 2.4 Hz, 1H), 2.47 (m, 1H), 2.19 (t, J = 5.3 Hz, 3H), 2.14 - 2.00 (m, 1H). LRMS-ESI (m / z): 244.14 [M + H] + .

[0203] Example 23 Preparation of methyl 7-(N-methylformamido)-7-phenyl-4,5,6,7-tetrahydrobenzothiophene-2-carboxylate (Compound A27) [ka]

[0204] Step 1: Preparation of formic acetic anhydride: Acetic anhydride (127.8 mg, 3 eq) and formic anhydride (57.6 mg, 3 eq) were added to a 10 mL reaction flask, stirred at 65 °C for 1-2 h, and cooled to room temperature to obtain formic acetic anhydride, which was ready for use. Compound A27-1 (100 mg) was suspended in DCM, 5 eq. of DIPEA was added, and 3 eq. of homemade formic acid acetic anhydride was added dropwise in an ice bath. After the addition was complete, the mixture was allowed to react at ambient temperature for 40 min, and TLC showed the reaction was complete. The mixture was diluted with DCM, washed with dilute hydrochloric acid, washed with brine, dried, and concentrated to obtain 90 mg of off-white solid compound A27-2. 1.1 g of compound A27-2 was again prepared in this manner.

[0205] Step 2: A reaction flask was charged with 540 mg of compound A27-2, 2 eq. of triethylamine, and 5 mL of a DMF-DMA mixture, and the mixture was allowed to react at 95 °C overnight. The solvent was removed by concentration, and the residue was diluted with DCM. It was washed with aqueous ammonium chloride and saturated brine, dried, and concentrated to give a yellow oil. Another reaction flask was charged with 2.5 eq. of DMF (from A27-2), mixed with dry DCM, and placed in an ice bath with stirring. 2.5 eq. of phosphorus oxychloride was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 40 min. The yellow oil obtained previously was dissolved in a small amount of dry DCM and added dropwise. After the addition was complete, the mixture was stirred at room temperature for 3 h under nitrogen gas protection. The mixture was diluted with DCM, washed with aqueous sodium hydroxide, washed with saturated brine, dried, and concentrated. This mixture was purified by column chromatography to give 613 mg of a pale yellow oil, compound A27-3, in 94% yield.

[0206] Step 3: Sodium block (2.5 eq) was added to anhydrous methanol in an ice bath, and after the reaction was completed, 1.1 eq of ethyl mercaptoacetate was added, followed by an anhydrous methanol solution of compound A27-3 (610 mg, 1 eq), and the mixture was stirred at room temperature for 3 hours. A small amount of the reaction mixture was mixed with ammonium chloride solution, extracted with EA, and the organic phase was dried and concentrated, followed by column chromatography to obtain the title compound A27.

[0207] 1 H NMR (400 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.51 (s, 1H), 7.45 - 7.30 (m, 5H), 3.81 (s, 3H), 2.78 (s, 3H), 2.75 (m, 2H), 2.50 - 2.41 (m, 2H), 1.88 (m, 2H).

[0208] Example 24 Preparation of 7-(N-methylformamido)-7-phenyl-4,5,6,7-tetrahydrobenzothiophene-2-carboxylic acid (Compound A28) [ka]

[0209] The reaction mixture of compound A27 was mixed with 5M aqueous sodium hydroxide (4 eq. NaOH) and stirred overnight at room temperature. Water was added to dilute the mixture, MTBE was added, and the layers were separated. The organic layer was discarded, and the aqueous layer was separated and adjusted to pH 2 with 4M hydrochloric acid. DCM was added for extraction. The organic layer was washed with saturated brine, dried, and concentrated to give 730 mg of compound A28 as a pale yellow oil in 100% yield.

[0210] LRMS-ESI (m / z): 314.39 [M - H] - .

[0211] Example 25 Preparation of N-methyl-N-(7-phenyl-4,5,6,7-tetrahydrobenzothiophen-7-yl)formamide (Compound A29) [ka]

[0212] 720 mg of compound A28 was added, 0.5 eq of cuprous oxide, 0.4 eq of DBU, and a small amount of DMF were added, and the mixture was purged with nitrogen gas several times. The mixture was reacted at 160°C for 4 hours. The reaction mixture was cooled, and excess EA was added and stirred. Insoluble matter was removed by filtration. The residue was washed with EA. The filtrate was diluted with EA, washed once with saturated aqueous ammonium chloride solution and once with saturated brine, dried, concentrated, and subjected to column chromatography to obtain 350 mg of compound A29 as a white solid. The yield was 60%.

[0213] 1 H NMR (400 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.44 - 7.30 (m, 5H), 7.22 (d, J = 5.2 Hz, 1H), 6.79 (d, J = 5.2 Hz, 1H), 2.76 (s, 3H), 2.74 (m, 2H), 2.53 - 2.40 (m, 2H), 1.93 (m, 1H), 1.83 (m, 1H).

[0214] Example 26 Preparation of N-methyl-7-phenyl-4,5,6,7-tetrahydrobenzothiophen-7-amine (Compound A30) and its hydrochloride [ka]

[0215] 350 mg of compound A29 was added and dissolved in dry THF. The mixture was cooled in an ice bath, and 2 eq of lithium aluminum hydride was added in portions. After the addition was complete, the mixture was allowed to warm to room temperature under nitrogen gas protection and stirred for 40 min. The reaction mixture was poured into an ice-water solution of potassium sodium tartrate tetrahydrate, extracted with EA, and allowed to separate. The organic phase was washed with saturated brine, dried, and concentrated. 210 mg of a colorless oil, A30, was obtained by neutral aluminum oxide column chromatography. This oil was dissolved in methanol, cooled in an ice bath for 10 min, and then a hydrogen chloride / methanol solution (approximately 1 eq of HCl) was added dropwise. After the addition was complete, the mixture was stirred for 10 min and concentrated under reduced pressure to dryness. 2 mL of acetonitrile was added, stirred overnight at ambient temperature, filtered, and dried to give 170 mg of compound A30 hydrochloride as a white solid.

[0216] 1 H NMR (500 MHz, Methanol-d4) δ 7.63 (d, J = 5.2 Hz, 1H), 7.51 - 7.41 (m, 3H), 7.36 - 7.33 (m, 2H), 7.03 (d, J = 5.2 Hz, 1H), 2.88 - 2.73 (m, LRMS-ESI (m / z): 213.07 [M - NHMe] + .

[0217] Example 27 Preparation of 2-methyl-N-(4-phenyl-4,5,6,7-tetrahydrobenzothiazol-4-yl)propane-2-sulfonamide (Compound A31) [ka]

[0218] Step 1: Compound A31-1 (20 g, 1 eq) was added to glacial acetic acid (200 mL), and a solution of liquid bromine (29 g, 1 eq) in acetic acid (20 mL) was slowly added dropwise under nitrogen gas protection. The mixture was allowed to react at room temperature for 2 h. Thiourea (27.4 g, 2 eq) was added, and the mixture was heated to reflux for 3 h. The mixture was concentrated to dryness to remove the solvent. Ethanol was added to form a slurry, and the mixture was filtered to give compound A31-2 (15 g, 50%).

[0219] Step 2: Compound A31-2 (20.6 g, 1 eq) was added to THF, cooled to 0-5°C under nitrogen gas protection, and isoamyl nitrite (17.3 g, 1.2 eq) was added dropwise. After the addition was completed, the temperature was raised to 45°C and the reaction was continued for 2 hours. The reaction mixture was quenched with ammonium chloride, extracted with DCM, washed with saturated brine, dried, concentrated, and purified by column chromatography to obtain 5.7 g of compound A31-3 as a dark brown solid.

[0220] Step 3: A reaction flask was charged with compound A31-3 (300 mg, 1 eq), tert-butylsulfenamide (330 mg, 1.4 eq), titanium ethoxide (489 mg, 1.1 eq), and THF. The mixture was reacted overnight at 40°C under nitrogen gas protection. After cooling to room temperature, the reaction mixture was poured into ice-water and EA was added. The mixture was stirred and filtered, separated, extracted with EA, washed with saturated brine, dried, concentrated, and purified by column chromatography to obtain approximately 288 mg of compound A31-4. Compound A31-4 was produced on a gram scale using the same method.

[0221] Step 4: Iodobenzene (35.4 g, 2.5 eq) was added to DCM (356 mL) and cooled to -60 °C under nitrogen gas protection. Butyllithium (58.3 mL, 2.5 M, 2.1 eq) was added dropwise and the mixture was allowed to react for 3 h. This reaction mixture was designated as Reaction Solution 2 and prepared for use. Compound A31-4 (17.8 g, 1 eq) was added to DCM (338 mL) and clarified. This reaction mixture was designated as Reaction Solution 1 and prepared for use. The temperature of Reaction Solution 1 was controlled at approximately -60 °C, and the mixture was added dropwise to Reaction Solution 2 and allowed to react for 2 h. The reaction was quenched with ammonium chloride, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 5.5 g of Compound A31.

[0222] Example 28 Preparation of 4-phenyl-4,5,6,7-tetrahydrobenzothiazol-4-amine (Compound A32) [ka]

[0223] Compound A31 (5.5 g, 1 eq) was added to dioxane (165 mL), and a solution of hydrochloric acid in ethyl acetate (12.4 mL, 4 M, 3 eq) was added dropwise. The mixture was allowed to react at room temperature for 0.5 h. The mixture was neutralized with saturated aqueous sodium bicarbonate, extracted with EA, washed with saturated brine, dried, concentrated, and purified by column chromatography to give 2.81 g of compound A32.

[0224] 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 7.68 - 6.74 (m, 5H), 2.85 (m, 2H), 2.27 (s, 2H), 1.92 (m, 2H), 1.85 (m, 1H), 1.56 (m, 1H). LRMS-ESI (m / z): 214.09 [M - NH2] + .

[0225] Example 29 Preparation of N-(4-phenyl-4,5,6,7-tetrahydrobenzothiazol-4-yl)formamide (Compound A33) [ka]

[0226] Formic anhydride (1.8 g, 9 eq) was added to acetic anhydride (3.99 g, 9 eq). The mixture was heated to 60°C under nitrogen gas protection and reacted for 2 hours. The mixture was then cooled to room temperature (approximately 25°C), and a solution of compound A32 (1.0 g, 1 eq) in DCM (20 mL) was added and stirred at room temperature for 1.5 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with DCM, and the organic phase was concentrated and purified by column chromatography to obtain 952 mg of compound A33 as a pale yellow solid.

[0227] Example 30 Preparation of N-methyl-4-phenyl-4,5,6,7-tetrahydrobenzothiazol-4-amine (Compound A34) and its hydrochloride [ka]

[0228] Compound A33 (950 mg, 1 eq) was added to a THF (40 mL) solution, and under nitrogen gas protection, borane tetrahydrofuran (36.8 mL, 10 eq, 1.0 M) was added dropwise. The mixture was heated to reflux and reacted for 2 hours. TLC showed that the reaction was complete. The temperature was lowered to 0-5 ° C., and methanol was added in an ice bath to quench the reaction. The mixture was concentrated to dryness. Methanol and water were added in a 1:1 ratio (17 mL) and stirred at room temperature. TLC showed that the reaction was complete. The mixture was extracted with DCM, and the organic phase was concentrated and purified by column chromatography to obtain 364 mg of crude product. 10 mL of DCM was added, and a hydrogen chloride ethyl acetate solution (0.37 mL, 1.0 eq, 4.0 M) was added dropwise. The mixture was concentrated to dryness under reduced pressure, and isopropyl ether was added to form a slurry. The mixture was filtered to obtain 330 mg of compound A34.

[0229] 1H NMR (400 MHz, DMSO-d6) δ 9.94 (m, 2H), 9.21 (s, 1H), 7.46-7.36 (m, 3H), 7.29 (m, 2H), 2.90 (m, 2H), 2.47 (m, 1H), 2.43 (t, J = 5.2 Hz, 3H), 2.36 (td, J = 13.1, 2.4 Hz, 1H), 2.00 (m, 1H), 1.43 (m, 1H). LRMS-ESI (m / z): 214.08 [M - NHCH3] + .

[0230] Example 31 Preparation of 4-phenyl-4,5,6,7-tetrahydrobenzothiazole-2,4-diamine (Compound A35) [ka]

[0231] Step 1: Compound A35-1 (800 mg) was added to dichloromethane (20 mL), and DMAP (464 mg) and di-tert-butyl dicarbonate (1.57 g) were added, and the mixture was allowed to react at room temperature overnight. The mixture was concentrated and subjected to column chromatography to obtain 250 mg of an off-white solid, compound A35-2.

[0232] Step 2: A 100 mL three-neck flask was charged with 2.7 mL (26.087 mmol, 7 eq) of bromobenzene and 6 mL of anhydrous tetrahydrofuran, and the mixture was placed in a low-temperature reactor at -78 °C under nitrogen gas protection and stirred. After the internal temperature reached -60 °C or below, 10.4 mL (26.087 mmol, 7 eq) of 2.5 M n-butyllithium was added dropwise, maintaining the internal temperature below -60 °C. After 1 h, 1 g (3.726 mmol, 1 eq) of compound A35-2 in 10 mL of THF was slowly added. The internal temperature was maintained below -60 °C. After the addition was completed, the mixture was stirred at -78 °C for 5 h. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with EA. The EA phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 1.13 g of compound A35-3 as a pale yellow solid.

[0233] LRMS-ESI (m / z): 347.18 [M+H] + .

[0234] Step 3: 1.13 g (3.261 mmol, 1 eq) of compound A35-3 was placed in a 50 mL three-neck flask, 8 mL of DCM was added, and the mixture was stirred in an ice bath under nitrogen gas protection for 10 min. 2.1 g (32.61 mmol, 10 eq) of NaN3 was then added. After the addition was complete, 4 mL of CF3COOH was slowly added dropwise and the mixture was stirred at room temperature overnight. The mixture was poured into an appropriate amount of ice water, and the pH was adjusted to approximately 10 by slowly adding aqueous ammonia. The mixture was then extracted with an appropriate amount of DCM. The DCM phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound A35-4 as an oil.

[0235] LRMS-ESI (m / z): 272.06 [M+H] + .

[0236] Step 4: To the oil A35-4 obtained in the previous step, 2 mL of THF and 122 mg (0.2 eq) of cobalt chloride hexahydrate were added and stirred under nitrogen gas protection. A solution of 390 mg (4 eq) of NaBH4 in 10 mL of water was slowly added dropwise and stirred at room temperature for 2 h. The pH was adjusted to approximately 3 with 2 M hydrochloric acid, filtered, and the insoluble matter was removed. The pH was further adjusted to approximately 10 with saturated sodium carbonate solution. The mixture was extracted with DCM / MeOH (20:1), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 320 mg of a white solid, compound A35.

[0237] 1 H NMR (400 MHz, DMSO-d6) δ 7.30-7.22 (m, 4H), 7.16-7.12 (m, 1H), 6.67 (s, 2H), 2.57-2.54 (m, 2H),2.22 (s, 2H), 1.84-1.81(m, 2H), 1.78-1.72 (m, 1H), 1.54-1.43 (m, 1H). LRMS-ESI (m / z): 274.17 [M-NH2] + . HPLC purity: >97%, retention time: 10.848min.

[0238] Examples 32 to 35 N-(2-amino-4-phenyl-4,5,6,7-tetrahydrobenzothiazol-4-yl)formamide (Compound A36), N,N'-(4-phenyl-4,5,6,7-tetrahydrobenzothiazol-2,4-diyl)diformamide (Compound A37), N 4 -methyl-4-phenyl-4,5,6,7-tetrahydrobenzothiazole-2,4-diamine (compound A38), N 4 Preparation of 4-methyl-4-phenyl-4,5,6,7-tetrahydrobenzothiazole-2,4-diamine (Compound A39) [ka]

[0239] Step 1: 240 mg of compound A35 was placed in a 25 mL single-neck flask, 8 mL of ethyl formate was added, and the mixture was refluxed overnight under nitrogen gas protection. The reaction mixture was concentrated to dryness, and an appropriate amount of DCM:MeOH = 20:1 was added. The organic phase was washed once with saturated brine, dried over sodium sulfate, and concentrated to yield 200 mg of a yellow-brown solid. A small amount was separated by column chromatography to yield compounds A36 and A37.

[0240] A36:LRMS-ESI (m / z): 274.17 [M + H] + . A37:LRMS-ESI (m / z): 320.20 [M + H] + .

[0241] Step 2: A mixture of A36 and A37 was added to 5 mL of borane in tetrahydrofuran and refluxed overnight under nitrogen gas protection. The system was cooled to room temperature, and methanol was slowly added dropwise to quench the unnecessary borane. The mixture was concentrated, and 6 mL of methanol and 2 drops of concentrated hydrochloric acid were added. The mixture was refluxed overnight under nitrogen gas protection. The system was cooled to room temperature, and a small amount of aqueous ammonia was added to adjust the pH to 8-9. The mixture was concentrated and subjected to column chromatography to obtain 50 mg of compound A39. This was then salified with HCl / MeOH to obtain 56 mg of a pale yellow powder. Mass spectrometry revealed a fragment peak. LRMS-ESI (m / z): 243.32 [M-NHCH3] + .

[0242] 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (br, 1H), 7.57 (m, 1H), 7.39 (m, 4H), 7.35 (m, 1H), 2.80 (d, J = 4.7 Hz, 3H), 2.60 (m, 2H), 2.43 (s, 3H), 2.22 (m, 2H), 1.85 (m, 1H), 1.33 (m, 1H).

[0243] Further, 18 mg of compound A38 was obtained by column chromatography. 1H NMR (400 MHz, DMSO-d6) δ 7.25 (d, J = 4.0 Hz, 4H), 7.19-7.14 (m, 1H), 6.69 (s, 2H), 2.56-2.54 (m, 2H), 2.17 (s, 3H), 2.05-1.98 (m, 1H), 1.78-1.66 (m, 2H), 1.49-1.39 (m, 1H). LRMS-ESI (m / z): 260.21 [M + H] + .

[0244] Example 36 Preparation of N-(2-amino-5-phenyl-4,5,6,7-tetrahydrobenzothiazol-5-yl)formamide (Compound A40) [ka]

[0245] Step 1: Compound A40-1 (5.0 g, 43.1 mmol) was dissolved in DMF, and imidazole (6.5 g, 2 eq) was added. TBDPSCl (12 g, 1.1 eq) was added at 0-10°C. The mixture was stirred at room temperature overnight, quenched by adding water, extracted with EA / water, and the organic phase was dried and concentrated. 6.0 g of a pale yellow oil, compound A40-2, was obtained by column chromatography.

[0246] Step 2: Compound A40-2 (6.0 g, 16.9 mmol) was dissolved in DCM, Dess-Martin reagent (24 g, 1.5 eq) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with EA, dried, concentrated, and purified by column chromatography to give 5.0 g of compound A40-3.

[0247] Step 3: Compound A40-3 (5.0 g, 14.2 mmol) was dissolved in anhydrous THF, tert-butylsulfenamide (2.6 g, 1.5 eq) was added, and ethyl titanate (11 mL, 3 eq) was added dropwise at 0-10°C. The mixture was then left at room temperature overnight. The reaction mixture was poured into water, filtered, and the filtrate was extracted with EA, dried, concentrated, and purified by column chromatography to give 6.6 g of compound A40-4.

[0248] Step 4: Preparation of Grignard reagent: Mg (3.4 g, 10 eq) was suspended in anhydrous THF, purged with nitrogen gas three times, and bromobenzene (29 g, 10 eq) was slowly added dropwise. The mixture was heated at 50°C for 1 h, cooled to -10 to 0°C, and prepared for use.

[0249] Compound A40-4 (6.6 g, 14.2 mol) was dissolved in anhydrous THF, and the Grignard reagent was slowly added dropwise. The mixture was stirred at 0-10°C for 2 hours and then at room temperature for 1 hour. 2M hydrochloric acid was added and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, adjusted to pH 8-9, extracted with dichloromethane, dried, concentrated, and subjected to column chromatography to obtain 3.5 g of compound A40-5.

[0250] Step 5: Compound A40-5 (3.5 g) was dissolved in ethyl formate and heated under reflux for 24 hours. The solution was concentrated to dryness to remove the solvent, and 3.5 g of compound A40-6 was obtained by column chromatography.

[0251] Step 6: Compound A40-6 (3.5 g) was dissolved in THF, TABF (1 M) (16 mL, 2 eq) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated to dryness to remove the solvent, and 110 mg of compound A40-7 was obtained by column chromatography.

[0252] Step 7: Compound A40-7 (1.1 g, 5.1 mmol) was dissolved in DCM, Dess-Martin reagent (3.8 g, 2 eq) was added, and the mixture was stirred at room temperature overnight. The reaction was quenched by adding sodium thiosulfate, extracted with dichloromethane, dried, filtered, concentrated, and purified by column chromatography to give 700 mg of compound A40-8.

[0253] Step 8: Compound A40-8 (350 mg, 1.6 mmol) was dissolved in DCM and added with pyridinium tribromide onium (700 mg, 1.1 eq) at 0-10°C. The mixture was stirred at room temperature for 3 h. Sodium thiosulfate was added to quench the reaction, and the mixture was extracted with dichloromethane, dried, filtered, and concentrated. 380 mg of the brominated intermediate was obtained as a pale yellow solid. The above pale yellow solid was dissolved in dioxane, and thiourea (350 mg, 3 eq) and diisopropylethylamine (400 mg, 2 eq) were added. The mixture was stirred at 80-90°C for 5 h. DCM / water was added for extraction, and the organic phase was dried, filtered, and concentrated. 200 mg of the title compound was obtained by column chromatography.

[0254] 1 H NMR (400 MHz, DMSO-d6) δ 8.31-8.19 (m, 1H), 8.02-7.97 (m, 1H), 7.42-7.19 (m, 5H), 6.72-6.70 (m, 2H), 2.97-2.90 (m, 2H), 2.67-2.62 (m, 1H), 2.52-2.47 (m, 1H), 2.41-2.32 (m, 1H), 2.28-2.14 (m, 1H).

[0255] Example 37 Preparation of N-(2-amino-7-phenyl-4,5,6,7-tetrahydrobenzothiazol-7-yl)formamide (Compound A41) [ka]

[0256] Compound A40 (200 mg, 0.73 mmol) was suspended in THF, and a solution of borane in tetrahydrofuran (10 eq) was added. The mixture was heated to reflux for 3 h. The reaction was quenched by adding methanol, concentrated to dryness to remove the solvent, added methanol / water, refluxed overnight, extracted with chloroform, dried, concentrated, and purified by column chromatography to give 100 mg of compound A41.

[0257] 1 H NMR (400 MHz, DMSO-d6) δ 7.40 (m, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 6.9 Hz, 1H), 6.69 (s, 2H), 3.09 (d, J = 16.7 Hz, 1H), 2.69 (d, J = 16.2 Hz, 1H), 2.16 (m, 2H), 2.00 (m, 5H). LRMS-ESI (m / z): 260.19 [M + H] + .

[0258] Example 38 Preparation of N-(2-amino-7-phenyl-4,5,6,7-tetrahydrobenzothiazol-7-yl)formamide (Compound A42) [ka]

[0259] Compound A41 (350 mg, 1.6 mmol) was dissolved in DCM and heated to reflux. Pyridinium tribromide onium (700 mg, 1.1 eq) was added and stirred for 1 h. Sodium thiosulfate was added to quench the reaction, and the mixture was extracted with dichloromethane, dried, filtered, concentrated, and purified by column chromatography to give 380 mg of the brominated intermediate as a pale yellow solid. The above pale yellow solid was dissolved in dioxane, and thiourea (350 mg, 3 eq) and diisopropylethylamine (400 mg, 2 eq) were added. The mixture was heated at 80-90 °C for 5 h. DCM / water was added for extraction, and the organic phase was dried, filtered, concentrated, and purified by column chromatography to give 150 mg of compound A42.

[0260] Example 39 N 7 Preparation of 4,5,6,7-methyl-7-phenyl-4,5,6,7-tetrahydrobenzothiazole-2,7-diamine (Compound A43) [ka]

[0261] Compound A42 (150 mg, 0.56 mmol) was suspended in THF, 10 eq of borane in tetrahydrofuran was added, and the mixture was heated to reflux for 3 h. The reaction was quenched by adding methanol, concentrated to dryness to remove the solvent, and an equal volume of a mixture of methanol and water was added. The mixture was refluxed overnight, extracted with chloroform, dried, filtered, and purified by column chromatography to give 80 mg of compound A43.

[0262] 1 H NMR (400 MHz, DMSO-d6) δ 7.36 (m, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.19 (t, J = 7.1 Hz, 1H), 6.63 (s, 2H), 2.92 (d, J = 16.3 Hz, 1H), 2.55 (d, J = 16.6 Hz, 1H), 2.03 (m, 3H), 1.92 (s, 3H), 1.88 (m, 1H). LRMS-ESI (m / z): 260.18 [M + H] + .

[0263] Example 40 Preparation of ethyl 5-morpholine-5-phenyl-4,5,6,7-tetrahydrobenzothiophene-2-carboxylate (Compound A44) and its hydrochloride [ka]

[0264] Step 1: 5 g of compound A23-1, 1.1 eq of morpholine, and 1.2 eq of triazole were mixed in 40 mL of toluene, and the mixture was refluxed overnight to separate water, thereby obtaining a solution containing compound A44-1.

[0265] Step 2: Under nitrogen gas protection, 4 eq of phenylmagnesium bromide tetrahydrofuran solution was placed in an ice bath and stirred for 10 min, and then the solution of compound A44-1 above was added dropwise to the reaction system. After the addition was completed, the mixture was stirred at room temperature for 2 h, and the reaction solution was poured into an aqueous ammonium chloride solution and extracted with EA. The organic phase was washed twice with water and directly concentrated to obtain a crude product containing compound A44-2.

[0266] Step 3: Compound A44-2 was dissolved in 20 mL of tetrahydrofuran, and 20 mL of 1 M hydrochloric acid was added. The mixture was allowed to react overnight at 40 °C. The pH was adjusted to a weak alkaline level, and the mixture was extracted with EA. The organic phase was washed with water and saturated brine, dried, concentrated, and purified by column chromatography to give 4.4 g of an oily substance, compound A44-3, with a three-step yield of 53%. The mixture was slurried in PE and filtered to give 3.4 g of a yellow solid.

[0267] Step 4: In an ice bath and under nitrogen gas protection, 2 eq of phosphorus oxychloride was added dropwise to a dichloromethane solution containing 1.6 eq of DMF. After the addition was complete, the mixture was stirred at room temperature for 20 minutes, and then cooled again in an ice bath. 200 mg of compound A44-3 (1 eq) was added to the reaction mixture in several portions. After the addition was complete, the mixture was allowed to react at room temperature overnight. Aqueous sodium bicarbonate solution was added, the layers were separated, and the organic phase was washed with saturated brine, concentrated, and purified by column chromatography to obtain 115 mg of compound A44-4.

[0268] Step 5: Two equivalents of sodium metal were added to absolute ethanol in an ice bath. Under nitrogen gas protection, after the sodium block had completely disappeared from the solution, 1.1 equivalents of ethyl mercaptoacetate was added, and then an ethanol solution of compound A44-4 (110 mg, 1 equivalent) was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature overnight. Ammonium chloride was added to quench the reaction, and the mixture was extracted with DCM. The organic phase was dried, concentrated, and purified by column chromatography to obtain 105 mg of a colorless oil. The hydrochloride salt was formed by adding a hydrogen chloride / methanol solution to methanol, which was then slurried in EA and filtered to obtain 85 mg of the hydrochloride salt of compound A44 as a white solid.

[0269] 1 H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 7.69 (m, 2H), 7.57 (s, 1H), 7.52 - 7.42 (m, 3H), 4.23 (q, J = 7.1 Hz, 2H), 4.20 - 3.82 (m, 5H), 3.60 - 3.50 (m, 3H), 3.24 (d, J = 12.5 Hz, 1H), 3.12 - 3.03 (m, 1H), 2.70 - 2.55 (m, 3H), 2.35 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H). LRMS-ESI (m / z): 372.43 [M + H] + .

[0270] Example 41 Preparation of ethyl 3-amino-5-morpholine-5-phenyl-4,5,6,7-tetrahydrobenzothiophene-2-carboxylate (Compound A45) and its hydrochloride [ka]

[0271] 200 mg of compound A44-3, 1.5 eq of ethyl cyanoacetate, 1.5 eq of morpholine, and 1.5 eq of elemental sulfur were mixed in ethanol and stirred overnight at 50° C. After cooling the reaction mixture, a solid precipitated and was filtered. The filter cake was purified by column chromatography to obtain 80 mg of A45 solid, which was dissolved in methanol and added with a hydrogen chloride / methanol solution to form the hydrochloride salt, which was then slurried in acetonitrile and filtered to obtain 65 mg of the hydrochloride salt of the title compound A45 as a pale yellow solid.

[0272] 1 H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 7.67 (s, 2H), 7.48 (m, 3H), 7.25 (m, 2H), 4.16 - 3.82 (m, 7H), 3.65 - 3.40 (m, 3H), 3.09 (d, J = 12.9 Hz, 1H), 2.99 - 2.89 (m, 1H), 2.55 (m, 2H), 2.39 (m, 1H), 2.11 (m, 1H), 1.17 (t, J = 7.1 Hz, 3H). LRMS-ESI (m / z): 387.39 [M+H] + .

[0273] Example 42 Preparation of 5-morpholine-5-phenyl-4,5,6,7-tetrahydrobenzothiophene-2-carboxylic acid (Compound A46) [ka]

[0274] 590 mg of compound A44 was added to a reaction flask, and ethanol and 1.27 mL of a 5N aqueous solution of sodium hydroxide (4 eq) were added. The mixture was reacted at 60°C for 8 hours, diluted with water, MTBE was added, the aqueous phase was separated, the pH was adjusted to neutral, and the mixture was extracted with DCM (5 mL x 5). The organic phases were combined, washed with a small amount of saturated brine, dried, and concentrated to give 455 mg of crude product, which was slurried with MTBE, filtered, and the filter cake was dried to give 320 mg of a pale pink solid, compound A46.

[0275] 1 H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 7.53 (s, 1H), 7.35 - 7.17 (m, 5H), 3.50 (t, J = 4.5 Hz, 4H), 3.23 (d, J = 16.5 Hz, 1H), 3.00 (d, J = 16.4 Hz, 1H), 2.80 (dt, J = 17.0, 4.4 Hz, 1H), 2.45 (m, 2H), 2.27 (m, 3H), 2.19 - 2.01 (m, 2H). LRMS-ESI (m / z): 344.47 [M + H] + .

[0276] Example 43 Preparation of 4-(5-phenyl-4,5,6,7-tetrahydrobenzothiophen-5-yl)morpholine (Compound A47) and its hydrochloride [ka]

[0277] 235 mg of compound A46, 0.5 eq of cuprous oxide, and 0.4 eq of DBU were mixed in a small amount of DMF, the mixture was purged with nitrogen gas several times, and the mixture was reacted at 160°C for 4 hours. After cooling, the mixture was diluted with EA, washed with an aqueous ammonium chloride solution and then with saturated brine, dried, concentrated, and subjected to column chromatography to obtain 100 mg of a white solid, A47, which was converted into a hydrochloride salt by adding a hydrogen chloride / methanol solution in methanol, slurried in acetonitrile, and filtered to obtain 100 mg of the hydrochloride salt of compound A47 as a white solid.

[0278] 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 7.77 - 7.60 (m, 2H), 7.45 (m, 3H), 7.28 (d, J = 5.1 Hz, 1H), 6.87 (d, J = 5.1 Hz, 1H), 4.17 - 3.81 (m, 5H), 3.63 (d, J = 12.4 Hz, 1H), 3.49 (d, J = 14.4 Hz, 2H), 3.21 (q, J = 4.5 Hz, 1H), 2.98 (dd, J = 17.2, 5.4 Hz, 1H), 2.60 (m, 3H), 2.29 (m, 1H). LRMS-ESI (m / z): 300.45 [M + H] + .

[0279] Example 44 Preparation of 6-phenyl-6-(piperidin-1-yl)-4,5,6,7-tetrahydrobenzothiazol-2-amine (Compound A48) and its hydrochloride salt [ka]

[0280] Step 1: Preparation of Grignard reagent: Magnesium (345.6 mg, 4.8 eq) was suspended in dry tetrahydrofuran, bromobenzene (200 mg, 0.48 eq) was added dropwise, and the temperature was raised to 50-60°C to initiate the reaction. Further bromobenzene (1.8 g, 3.6 eq) was added dropwise, and while maintaining a slight boil, the mixture was added dropwise for 30 minutes. After that, the temperature was raised to 60°C and the mixture was stirred for 1 hour until almost all of the magnesium was consumed, and the temperature was lowered to 0-10°C in preparation for use.

[0281] In a separate reaction flask, triazole (1.0 g, 1.2 eq), piperidine (1.4 mL, 1.2 eq), and 1,4-cyclohexanedione monoethylene ketal A23-1 (2.0 g, 12.8 mmol) were added and dissolved in toluene. The mixture was refluxed for 18 hours to separate the water, yielding a toluene solution of A48-1. The temperature was lowered to room temperature, and the mixture was added dropwise to the Grignard reagent prepared above (0-10°C). After the addition was complete, the mixture was stirred at room temperature for 12 hours, and 1.0 g of compound A48-2 was obtained by column chromatography.

[0282] Step 2: Compound A48-2 (900 mg) was dissolved in ethanol, hydrochloric acid was added, and the mixture was heated to 70°C and stirred for 12 hours. The reaction mixture was concentrated to dryness, extracted with methyl tert-ether / water, and the aqueous phase was adjusted to pH 11-12 with sodium hydroxide solution, extracted with dichloromethane, dried, filtered, and concentrated to obtain 500 mg of compound A48-3.

[0283] Step 3: Compound A48-3 (500 mg, 2 mmol) was dissolved in acetic acid, tribromopyridine (800 mg, 1.2 eq) was added, and the mixture was heated under reflux for 3 h. Thiourea (300 mg, 2 eq) was added, and the mixture was heated under reflux for 18 h. The mixture was concentrated to dryness to remove the solvent, saturated sodium carbonate solution was added, the pH was adjusted to 9-10, and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated, and then purified by column chromatography to obtain 200 mg of A48 as a white solid. Methanol (5 mL) was added to clarify the reaction, and an HCl / EA solution was added dropwise to the mixture while stirring. The mixture was concentrated to dryness to remove the solvent, and the hydrochloride salt of compound A48 was obtained as a white solid.

[0284] LRMS-ESI (m / z): 314.28 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.69 (br, 2H), 7.45 (m, 3H), 7.15 (br, 2H), 3.99 (d, J = 15.1 Hz, 1H), 3.68 (d, J = 10.9 Hz, 1H), 3.61 (d, J = 11.2 Hz, 1H), 3.47 (d, J = 15.0 Hz, 1H), 3.11 (m, 1H), 2.55 (m, 2H), 2.32 (m, 2H), 2.10 (m, 1H), 1.71 (d, J = 13.2 Hz, 2H), 1.60 (d, J = 11.7 Hz, 1H), 1.18 (m, 1H).

[0285] Example 45 Preparation of 6-(3-chlorophenyl)-6-(piperidin-1-yl)-4,5,6,7-tetrahydrobenzothiazol-2-amine (Compound A49) [ka]

[0286] Step 1: m-Chloriodobenzene (12 g, 2 eq) was dissolved in anhydrous THF, and n-butyllithium (2.5 M) (23 mL, 1.1 eq) was slowly added dropwise at -78°C. After the addition was completed, the mixture was kept at -78°C for 1 hour, and a freshly prepared toluene solution of A48-1 was added dropwise. After the addition was completed, the mixture was kept at -78°C and stirred for 1 hour, and then stirred at room temperature for 12 hours. 3.0 g of compound A49-1 was obtained by column chromatography.

[0287] Step 2: Compound A49-1 (3.0 g, 1.35 mmol) was dissolved in ethanol, concentrated hydrochloric acid (3 eq, 12 M) was added, the mixture was stirred at room temperature overnight, concentrated to dryness to remove the solvent, adjusted to pH 11-12 with saturated sodium bicarbonate, extracted with DCM, dried, filtered, concentrated, and purified by column chromatography to obtain 1.8 g of compound A49-2.

[0288] Step 3: Compound A49-2 (200 mg, 0.7 mmol) was dissolved in acetic acid, pyridinium tribromide onium (1.1 g, 4 eq) was added, and the mixture was heated under reflux for 4 hours. Subsequently, thiourea (420 mg, 8 mmol) was added, and the mixture was heated under reflux for 18 hours. The mixture was concentrated to dryness to remove the solvent, and saturated sodium carbonate solution was added to adjust the pH to 9-10. The mixture was extracted with dichloromethane, dried, filtered, concentrated, and purified by column chromatography to obtain 25 mg of the title compound A49.

[0289] LRMS-ESI (m / z): 348.38 [M+H] + .

[0290] Example 46 Preparation of 6-phenyl-6-(pyrrolidin-1-yl)-4,5,6,7-tetrahydrobenzothiazol-2-amine (Compound A50) [ka]

[0291] Step 1: Triazole (12.4 g, 1.1 eq), tetrahydropyrrole (13.35 g, 1.2 eq), and 1,4-cyclohexanedione monoethylene ketal (25.0 g, 160 mmol) were dissolved in toluene, refluxed for 18 hours to separate water, and cooled to room temperature to obtain a toluene solution of compound A50-1, which was ready for use.

[0292] Step 2: Bromobenzene (75 g, 3 eq) was dissolved in anhydrous THF, and n-butyllithium (2.5 M) (150 mL, 3.3 eq) was slowly added dropwise at −78°C. After the addition was completed, the mixture was kept at −78°C for 1 hour, and the toluene solution of A50-1 prepared above was added dropwise. After the addition was completed, the mixture was kept at −78°C and stirred for 1 hour, and then stirred at room temperature for 12 hours. 10.5 g of compound A50-2 was obtained by column chromatography.

[0293] Step 3: Compound A50-2 (10.5 g, 6.5 mmol) was dissolved in ethanol, concentrated hydrochloric acid (12 M, 1.6 mL) was added, the mixture was stirred at room temperature overnight, concentrated to dryness to remove the solvent, adjusted to pH 11-12 with saturated sodium bicarbonate, extracted with DCM, dried, filtered, concentrated, and purified by column chromatography to obtain 8.5 g of compound A50-3.

[0294] Step 4: Compound A50-3 (200 mg, 0.7 mmol) was dissolved in acetic acid, pyridinium tribromide onium (1.1 g, 4 eq) was added, and the mixture was heated under reflux for 4 hours. Subsequently, thiourea (420 mg, 8 mmol) was added, and the mixture was heated under reflux for 18 hours. The mixture was concentrated to dryness to remove the solvent, and saturated sodium carbonate solution was added to adjust the pH to 9-10. The mixture was extracted with dichloromethane, dried, filtered, concentrated, and purified by column chromatography to obtain 200 mg of the title compound.

[0295] LRMS-ESI (m / z): 300.33 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.37 (m, 2H), 7.28 (t, J = 7.4 Hz, 2H), 7.20 (t, J = 6.9 Hz, 1H), 6.59 (s, 2H), 3.15 (d, J = 14.6 Hz, 1H), 2.89 (d, J = 15.7 Hz, 1H), 2.55 (br, 2H), 2.39 (m, 3H), 2.16 (m, 2H), 1.73 (m, 1H), 1.56 (br, 4H).

[0296] Chiral column separation gave isomers A50-P1 (S configuration) and A50-P2 (R configuration): [ka]

[0297] A50-P1 (S configuration): HPLC purity: >99%, retention time: 5.761 min. Chiral purity: >95%, retention time: 7.617 min. A50-P2 (R configuration): HPLC purity: >99%, retention time: 7.452 min. Chiral purity: >95%, retention time: 7.623 min.

[0298] Example 47 Preparation of 6-(3-chlorophenyl)-6-(pyrrolidin-1-yl)-4,5,6,7-tetrahydrobenzothiazol-2-amine (Compound A51) [ka]

[0299] Step 1: m-Chloriodobenzene (45 g, 1.2 eq) was dissolved in anhydrous THF, and n-butyllithium (2.5 M) (88 mL, 1.5 eq) was slowly added dropwise at -78°C. After the addition was completed, the mixture was kept at -78°C for 1 hour, and then a freshly prepared toluene solution of A50-1 was added dropwise. After the addition was completed, the mixture was kept at -78°C and stirred for 1 hour, and then stirred at room temperature for 12 hours. 8.5 g of compound A51-1 was obtained by column chromatography.

[0300] Step 2: Compound A51-1 (8.5 g, 6.5 mmol) was dissolved in ethanol, concentrated hydrochloric acid (12 M, 1.6 mL) was added, the mixture was stirred at room temperature overnight, concentrated to dryness to remove the solvent, and the pH was adjusted to 11-12 with saturated sodium bicarbonate solution. The mixture was extracted with DCM, dried, filtered, concentrated, and purified by column chromatography to obtain 5.2 g of compound A51-2.

[0301] Step 3: Compound A51-2 (300 mg, 9.4 mmol) was dissolved in acetic acid, pyridinium tribromide onium (1.02 g, 4 eq) was added, and the mixture was heated under reflux for 4 hours to produce the brominated intermediate. Dimethylthiourea (560 mg, 8 eq) was then added, and the mixture was heated under reflux for 18 hours. The mixture was then concentrated to dryness to remove the solvent, and saturated sodium carbonate solution was added to adjust the pH to 9-10. The mixture was extracted with dichloromethane, dried, filtered, concentrated, and purified by column chromatography to obtain 90 mg of compound A51 as a white solid.

[0302] LRMS-ESI (m / z): 334.39 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.29 (m, 3H), 6.62 (s, 2H), 3.13 (d, J = 16.2 Hz, 1H), 2.88 (d, J = 16.0 Hz, 1H), 2.55 (br, 2H), 2.37 (m, 3H), 2.15 (m, 2H), 1.70 (m, 1H), 1.58 (br, 4H).

[0303] Example 48 Preparation of 5-phenyl-5-(pyrrolidin-1-yl)-4,5,6,7-tetrahydrobenzothiophene-2-carboxylic acid (Compound A52) [ka]

[0304] Step 1: Phosphorus oxychloride (126 mg, 2 eq) was added dropwise to a solution of DMF (50 mg, 1.5 eq) in dichloromethane at 0-10°C and stirred for 2 h in an ice bath. Compound A50-3 (100 mg, 0.5 mmol) was dissolved in dichloromethane and added to the above reaction solution. The mixture was stirred at room temperature overnight. Slowly added dropwise to an aqueous sodium acetate solution, the layers were separated, and the organic phase was dried, filtered, and concentrated to give compound A52-1 as an oil.

[0305] Step 2: The oil A52-1 was dissolved in ethanol, ethyl mercaptoacetate (74 mg, 1.5 eq) was added, and the mixture was stirred for 10 min. Sodium ethanol (55 mg, 4 eq) was added in an ice bath, and the mixture was allowed to react at room temperature overnight. Water was added, and the mixture was heated to reflux for 2 h. The ethanol was concentrated, and the pH was adjusted to 5-6 with 1 M hydrochloric acid solution. The mixture was extracted with dichloromethane, and the organic phase was dried and concentrated. 55 mg of a pale yellow oil, compound A52, was obtained by column chromatography.

[0306] Example 49 Preparation of 1-(5-phenyl-4,5,6,7-tetrahydrobenzothiophen-5-yl)pyrrolidine (Compound A53) [ka]

[0307] Compound A52 (55 mg, 0.17 mmol) was dissolved in NMP, and cuprous oxide (24 mg, 1 eq) and quinoline (26 mg, 1.1 eq) were added. The mixture was heated to 140°C and the starting materials were reacted almost completely for 12 hours. The reaction mixture was poured into water, extracted with dichloromethane, dried, filtered, and concentrated to give 20 mg of compound A53.

[0308] Example 50 Preparation of 6-phenyl-6-(pyrrolidin-1-yl)-4,5,6,7-tetrahydrobenzothiadiazole (Compound A54) [ka]

[0309] Compound A50-3 (200 mg, 0.9 mmol) was dissolved in methanol, semicarbazide (200 mg, 2 eq) and potassium acetate (200 mg, 2.1 eq) were added, and the mixture was heated to reflux for 6 hours. The mixture was concentrated to dryness to remove the solvent, extracted with dichloromethane / water, dried, filtered, and concentrated to obtain 300 mg of a solid. The solid obtained above was dissolved in dichloromethane and slowly added dropwise to thionyl chloride at -20 °C and stirred at room temperature for 1 hour. The reaction mixture was poured into water, adjusted to pH 12 with sodium hydroxide, extracted with dichloromethane, dried, filtered, concentrated, and purified by column chromatography to obtain 100 mg of compound A54.

[0310] 1H NMR (400 MHz, CDCl3) δ 7.29 (m, 5H) 3.65 (d, J = 17.3 Hz, 1H), 3.41 (d, J = 17.1 Hz, 1H), 3.28 (dt, J = 16.4, 4.4 Hz, 1H), 2.64 (m, 3H), 2.55 (m, 2H), 2.43 (m, 2H), 1.68 (m, 4H). LRMS-ESI (m / z): 286.35 [M + H] + .

[0311] Example 51 Preparation of 5-phenyl-5-(pyrrolidin-1-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole (Compound A55) [ka]

[0312] Step 1: Compound A50-3 (300 mg, 0.7 mmol) was dissolved in toluene, dried over anhydrous magnesium sulfate for 2 days, filtered, and prepared for use. Sodium tert-butoxide (246 mg, 2 eq) and ethyl formate (138 mg, 1.5 eq) were added to the toluene, and the toluene solution of A50-3 was added at 0-10°C and stirred overnight at room temperature. The reaction mixture was extracted twice with toluene, and the remaining aqueous phase was adjusted to pH 6-7 with 1 M hydrochloric acid solution. The mixture was extracted three times with dichloromethane, dried, filtered, concentrated, and purified by column chromatography to obtain 800 mg of compound A55-1.

[0313] Step 2: Compound A55-1 (110 mg) was dissolved in acetic acid, hydroxylamine hydrochloride (70 mg, 2 eq) was added, and the mixture was heated to 80°C for 5 hours. The mixture was concentrated to dryness to remove the solvent, and the pH was adjusted to 9-10 with saturated sodium carbonate. The mixture was extracted with dichloromethane, dried, filtered, concentrated, and subjected to column chromatography to obtain 66 mg of compound A55.

[0314] ESI-MS m / z 269.36 [M+H] + .

[0315] Example 52 Preparation of N,N-dimethyl-6-phenyl-6-(pyrrolidin-1-yl)-4,5,6,7-tetrahydrobenzothiazol-2-amine (Compound A56) [ka]

[0316] Compound A50-3 (50 mg, 0.16 mmol) was dissolved in acetic acid and pyridinium tribromide onium (300 m g, 4 eq) was added and heated to reflux for 4 hours to obtain a brominated intermediate. Subsequently, dimethylthiourea (100 mg, 8 mmol) was added and heated to reflux for 18 hours. The mixture was concentrated to dryness to remove the solvent, and saturated aqueous sodium carbonate solution was added to adjust the pH to 9-10. The mixture was extracted with dichloromethane, dried, filtered, concentrated, and subjected to column chromatography to obtain 10 mg of compound A56.

[0317] LRMS-ESI (m / z): 328.45 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.36 (m, 2H) 7.31 (t, J = 7.6 Hz, 2H), 7.21 (t, J = 7.1 Hz, 1H), 2.97 (d, J = 16.8 Hz, 1H), 2.94 (s, 3H), 2.83 (s, 3H), 2.78 (d, J = 16.8 Hz, 1H), 2.50 (m, 2H), 2.46-2.33 (m, 3H), 2.26 (m, 1H), 2.15 (m, 1H), 1.68 (m, 1H), 1.55 (m, 4H).

[0318] Example 53 Preparation of 6-(3-chlorophenyl)-N,N-dimethyl-6-(pyrrolidin-1-yl)-4,5,6,7-tetrahydrobenzothiazol-2-amine (Compound A57) and its hydrochloride salt [ka]

[0319] Compound A51-2 (300 mg, 9.4 mmol) was dissolved in acetic acid, pyridinium tribromide onium (1.1 g, 4 eq) was added, and the mixture was heated to reflux for 4 hours to produce the brominated intermediate. Subsequently, dimethylthiourea (600 mg, 8 eq) was added, and the mixture was heated to reflux for 18 hours. The mixture was concentrated to dryness to remove the solvent, and saturated aqueous sodium carbonate was added to adjust the pH to 9-10. The mixture was extracted with dichloromethane, dried, filtered, concentrated, and purified by column chromatography to obtain 150 mg of oily product A57. The oily product was dissolved in methyl tert-butyl ether and adjusted to pH 2-3 with 12 M concentrated hydrochloric acid. A large amount of solid precipitated, which was filtered and dried to obtain 95 mg of the hydrochloride salt of compound A57.

[0320] 1 H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 10.32 (s, 1H), 7.93 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.53 (m, 2H), 4.15 (d, J = 16.3 Hz, 1H), 3.57 (d, J = 17.9 Hz, 1H), 3.40 (s, 3H), 3.35 (m, 1H), 3.17 (m, 1H), 2.96 (s, 3H), 2.88 (m, 4H), 2.63 (td, J = 13.1, 5.9 Hz, 1H), 2.11 (m, 1H), 1.84 (m, 2H), 1.67 (m, 2H). LRMS-ESI (m / z): 362.41 [M + H] + .

[0321] Example 54 Preparation of 6-(3-chlorophenyl)-6-(piperidin-1-yl)-4,5,6,7-tetrahydrobenzothiadiazole (Compound A58) and its maleate salt [ka]

[0322] Compound A49-2 (300 mg, 1.3 mmol) was dissolved in methanol, semicarbazide (300 mg, 2 eq) and potassium acetate (300 mg, 2.1 eq) were added, and the mixture was heated to reflux for 6 hours. The mixture was concentrated to dryness to remove the solvent, extracted with dichloromethane / water, and the organic phase was dried, filtered, and concentrated to obtain 300 mg of a solid. The solid was dissolved in dichloromethane and slowly added dropwise to thionyl chloride at -20 °C and stirred at room temperature for 1 hour. The reaction mixture was poured into water, adjusted to pH 12 with sodium hydroxide solution, extracted with dichloromethane, dried, filtered, and purified by column chromatography to obtain 100 mg of a solid, basic compound A58. The solid was dissolved in acetone, maleic acid was added, and the mixture was stirred. A large amount of solid precipitated, which was filtered and dried to obtain 100 mg of the maleate salt of compound A58 as a white solid.

[0323] 1 H NMR (400 MHz, DMSO-d6) δ 7.58 (br, 1H), 7.41 (m, 3H), 6.16 (s, 2H), 3.54 (d, J = 17.3 Hz, 1H), 3.30 (d, J = 14.6 Hz, 1H), 2.99-2.37 (m, 8H), 1.58 (br, 4H), 1.39 (br, 2H). ESI-MS m / z 334.38 [M+H] + .

[0324] Example 55 6-(3-chlorophenyl)-N 6 Preparation of -methyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (Compound A59) [ka]

[0325] Step 1: Triazole (1.0 g, 1.2 eq), N-methylbenzylamine (1.8 mL, 1.2 eq), and 1,4-cyclohexanedione monoethylene ketal (2.0 g, 1.28 mmol) were dissolved in toluene, refluxed for 18 h to separate water, and cooled to room temperature to obtain a solution containing A59-1, which was ready for use.

[0326] Step 2: m-Chloriodobenzene (6 g, 2 eq) was dissolved in anhydrous THF, and n-butyllithium (2.5 M) (6 mL, 1.1 eq) was slowly added dropwise at −78°C. After the addition was completed, the mixture was kept at −78°C for 1 hour, and the above-prepared A59-1 was added dropwise. After the addition was completed, the mixture was kept at −78°C and stirred for 1 hour, and then stirred at room temperature for 12 hours. 600 mg of compound A59-2 was obtained by column chromatography.

[0327] Step 3: Compound A59-2 (500 mg, 1.35 mmol) was dissolved in toluene, DIAD (275 mg, 1.1 eq) was added, and the mixture was heated under reflux for 18 hours. The mixture was concentrated to dryness to remove the toluene, and saturated aqueous ammonium chloride and ethanol were added. The mixture was refluxed for 18 hours, and the ethanol was removed by concentration. The pH was adjusted to 7-8 with aqueous ammonia, extracted with EA, dried, concentrated, and subjected to column chromatography to obtain 120 mg of compound A59-3.

[0328] Step 4: Compound A59-3 (50 mg) was dissolved in ethanol, concentrated hydrochloric acid (12 M, 3 eq) was added, and the mixture was stirred at room temperature for 12 h. The mixture was concentrated to dryness to remove the solvent, saturated sodium carbonate was added, the pH was adjusted to 9-10, and the mixture was extracted with dichloromethane, dried, filtered, concentrated, and purified by column chromatography to obtain 20 mg of compound A59-4.

[0329] Step 5: Compound A59-4 (20 mg, 0.09 mmol) was dissolved in acetic acid, pyridinium tribromide onium (135 mg, 0.36 mmol) was added, and the mixture was heated to reflux for 4 hours to produce the brominated intermediate. Subsequently, thiourea (54 mg, 0.72 mmol) was added, and the mixture was heated to reflux for 18 hours. The mixture was concentrated to dryness to remove the solvent, and saturated aqueous sodium carbonate was added to adjust the pH to 9-10. The mixture was extracted with dichloromethane, dried, filtered, concentrated, and purified by column chromatography to obtain 5 mg of compound A59.

[0330] 1H NMR (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 6.72 (s, 2H), 3.10 (m, 3H), 3.00 (d, J = 15.8 Hz, 1H), 2.67 (d, J = 16.0 Hz, 1H), 2.50 (m, 2H), 2.32 (d, J = 10.7 Hz, 1H), 1.90 (dd, J = 10.6, 3.0 Hz, 1H). ESI-MS m / z 294.33 [M+H] + .

[0331] Example 56 Preparation of 4-(2-chlorophenyl)-4,5,6,7-tetrahydrobenzothiazole-2,4-diamine (Compound A60) and its maleate salt [ka]

[0332] Step 1: o-Chlorobromobenzene (24.83 g, 130 mmol) was dissolved in dry THF (100 mL) and cooled to -78 °C. n-BuLi (48 mL, 2.5 M) was added dropwise over approximately 1 h. After 1 h, a solution of A35-2 (5.340 g, 20 mmol) in THF (80 mL) was added dropwise, and the temperature was controlled at -78 °C and stirred for 5 h. The reaction was quenched with saturated aqueous ammonium chloride, extracted with EA, and the organic phase was washed with saturated aqueous sodium chloride, dried, concentrated, and purified by column chromatography to give compound A60-1 (2.8 g) as a yellow foamy solid.

[0333] Step 2: Compound A60-1 (2.3 g, 6.0 mmol) was dissolved in DCM (100 mL), sodium azide (7.8 g, 120 mmol) was added, and TFA (80 mL) was added dropwise in an ice bath. The addition was completed within 1 h. After the addition was completed, the reaction was continued in an ice bath for 1 h and then left at room temperature overnight. 100 mL of ice water was added, the pH was adjusted to 9 with 5 M aqueous ammonia, and the mixture was extracted with DCM. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound A60-2 (1.050 g), a white foamy solid.

[0334] Step 3: Compound A60-2 (1.050 g) was dissolved in THF (20 mL), cobalt chloride hexahydrate (167 mg) was added, and an aqueous solution (20 mL) of sodium borohydride (260 mg) was added dropwise. The mixture was allowed to react at room temperature for 30 minutes. 1 M hydrochloric acid was added to quench the reaction, and the pH was adjusted to 12. The mixture was extracted with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain basic compound A60 (light brown solid). This was converted to a maleate salt by referring to the method of Example 54 to obtain the maleate salt of compound A60 (682 mg).

[0335] 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (br, 2H), 7.44 (m, 2H), 7.38 (m, 1H), 7.30 (d, J = 7.5 Hz, 1H), 6.92 (s, 2H), 6.02 (s, 2H), 2.71 (m, 1H), 2.61 (m, 1H), 2.43 (m, 1H), 2.04 (m, 2H), 1.80 (m, 1H). ESI-MS m / z 308.11 [M+H] + .

[0336] Example 57 Preparation of N-(2-amino-4-(2-chlorophenyl)-4,5,6,7-tetrahydrobenzothiazol-4-yl)formamide (Compound A61) [ka]

[0337] Compound A60 (260 mg) was dissolved in ethyl formate (12 mL) and heated at 90° C. for 18 hours. The reaction mixture was concentrated to dryness and subjected to column chromatography to obtain compound A61.

[0338] Example 58 4-(2-chlorophenyl)-N 4 Preparation of -methyl-4,5,6,7-tetrahydrobenzothiazole-2,4-diamine (compound A62) and its maleate salt [ka]

[0339] Compound A61 was dissolved in dry THF (20 mL), and borane dimethyl sulfide solution (3.8 mL, 2 M) was added dropwise. The mixture was stirred at room temperature for 20 minutes and then refluxed for 5 hours. After cooling to room temperature, methanol (15 mL) was carefully added to quench the reaction, and the mixture was concentrated to remove the solvent. Methanol (30 mL) was added, and the mixture was refluxed overnight. The mixture was concentrated and purified by column chromatography to obtain basic compound A62 (a light brown solid). This was converted to a maleate salt according to the method described in Example 54 to obtain the maleate salt of compound A62.

[0340] 1 H NMR (400 MHz, MeOD) δ 7.58 (d, J = 7.2 Hz, 1H), 7.46 (t, J = 7.0 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.31 (s, 3H), 2.94 (m, 1H), 2.85 (s, 3H), 2.71 (m, 2H), 2.20 (t, J = 11.9 Hz, 1H), 1.97 (m, 1H), 1.46 (m, 1H). ESI-MS m / z 294.05 [M+H] + .

[0341] Example 59 4-(2-chlorophenyl)-N 4Preparation of 4,5,6,7-ethyl-4,5,6,7-tetrahydrobenzothiazole-2,4-diamine (Compound A63) [ka]

[0342] Compound A60 (195 mg, 0.7 mmol) was dissolved in MeOH (5 mL), acetic acid (84 mg, 1.4 mmol), and acetaldehyde (168 μL, 5 M in THF) were added, and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (91 mg) was added, and the mixture was allowed to react at room temperature for 24 h. After that, acetaldehyde (42 μL) and sodium cyanoborohydride (23 mg) were added, and the reaction was continued for 20 h. 2 M sodium hydroxide solution was added to adjust the pH to 12, and the mixture was extracted with DCM, dried, concentrated, and purified by column chromatography to give 72 mg of a pale yellow oil, compound A63.

[0343] 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (s, 1H), 7.37-7.12 (m, 4H), 6.61 (br, 2H), 2.58 (m, 3H), 2.21 (m, 1H), 2.05 (m, 2H), 1.67 (m, 2H), 1.01 (m, 3H). ESI-MS m / z 308.11 [M+H] + .

[0344] Example 60 4-(2-chlorophenyl)-N 4 Preparation of 4,5,6,7-propyl-4,5,6,7-tetrahydrobenzothiazole-2,4-diamine (Compound A64) [ka]

[0345] Compound A60 (20 mg, 0.07 mmol) was dissolved in methanol (1 mL), acetic acid (9 mg, 0.14 mmol), and propionaldehyde (5 mg, 1.2 eq) were added, followed by stirring for 5 h. 10 mL of water was added, and the pH was adjusted to 10 with 1 M sodium hydroxide solution. The mixture was extracted with DCM, dried, concentrated, and purified by column chromatography to give compound A64 as a white solid (13 mg).

[0346] 1 H NMR (400 MHz, MeOD) δ 7.49 (d, J = 7.8 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.06 (s, 1H), 3.37 (m, 1H), 2.79 (m, 1H), 2.74-2.56 (m, 3H), 2.09 (m, 1H), 1.97 (m, 1H), 1.68 (m, 2H), 1.49 (m, 1H), 0.97 (t, J = 7.4 Hz, 3H).

[0347] Example 61 Preparation of 5-phenyl-4,5,6,7-tetrahydro-1H-indazol-5-amine (Compound A65) [ka]

[0348] Step 1: Compound A23-1 (1 eq, 5 g), tert-butylsulfenamide (1.5 eq, 5.82 g), and titanium ethoxide (3 eq, 21 g) were dissolved in ultra-dry tetrahydrofuran (100 mL) and stirred overnight at room temperature under nitrogen gas protection. The mixture was quenched with saturated aqueous sodium bicarbonate solution. After filtration, the filtrate was extracted three times with ethyl acetate. The mixture was dried, concentrated, and purified by column chromatography to give 7.06 g of A65-1 in an 85% yield.

[0349] Step 2: Under nitrogen gas protection, phenylmagnesium chloride (3 eq, 20 mL) was added to a 250 mL three-neck flask. A solution of A65-1 in tetrahydrofuran was slowly added in an ice bath. After the addition was complete, the mixture was stirred for 20 min, then the ice bath was removed and the mixture was stirred at room temperature. After the completion of the reaction was monitored by TLC, a saturated aqueous ammonium chloride solution was added to quench the reaction. After filtration, the mixture was extracted three times with EA. The mixture was dried, concentrated, and subjected to column chromatography to obtain 3.01 g of a white solid, A65-2.

[0350] Step 3: A65-2 (1 eq, 2.5 g) was dissolved in 40 mL of a mixed solvent of acetone and water (acetone:water = 3:1). PTSA (0.5 eq, 0.705 g) was added and stirred. After completion of the reaction was monitored by TLC, the reaction was quenched by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with EA, dried, and concentrated to give 1.675 g of a reddish-brown liquid, A65-3, in a yield of 77.15%.

[0351] Step 4: A65-3 (1 eq, 1.675 g) and DMF-DMA (5 eq, 3.79 mL) were heated to reflux overnight at 110° C. After the reaction was completed, A65-4 solution was obtained and used in the next step without further treatment.

[0352] Step 5: The A65-4 solution obtained in the previous step and hydrazine hydrate (5 eq, 1.68 g) were dissolved in methanol and heated at 80° C. overnight. Concentration to dryness gave 2 g of a reddish-brown liquid, A65-5.

[0353] Step 6: A65-5 (1 eq, 500 mg) was dissolved in 2 mL of absolute ethanol. After stirring for 10 minutes, 2 M hydrochloric acid solution was added and stirred for 2 hours. The mixture was quenched with saturated aqueous sodium bicarbonate, the pH was adjusted to 8-9, extracted three times with EA, dried, concentrated, and purified by amino column chromatography to obtain 340 mg of a dark red compound, Compound A65.

[0354] 1 H NMR (500 MHz, Chloroform-d) δ 7.58-7.52 (m, 2H), 7.40 (s, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.26 (s, 1H), 3.67 (d, J = 2.0 Hz, 2H), 3.17 (d, J = 15.6 Hz, 1H), 2.88 (dt, J = 15.7, 7.9 Hz, 1H), 2.76 (d, J = 15.6 Hz, 1H), 2.69-2.58 (m, 1H), 2.31 (ddd, J = 14.2, 8.8, 6.0 Hz, 1H), 2.06 (dq, J = 13.6, 6.8, 5.8 Hz, 1H). ESI-MS m / z 197.34 [M+H] + .

[0355] Example 62 Preparation of N-(2-amino-6-phenyl-4,5,6,7-tetrahydrobenzothiazol-6-yl)cyclopropaneformamide (Compound A66) [ka]

[0356] A1 (15 mg, 1 eq) was dissolved in 2 mL of THF, triethylamine (9 mg, 1.1 eq) was added, the temperature was lowered to 0 °C in an ice-water bath, cyclopropanecarboxylic anhydride (14 mg, 1.1 eq) was slowly added, and the reaction was allowed to proceed at room temperature for 14 hours. The reaction was quenched by adding saturated sodium bicarbonate solution, extracted three times with DCM, and the organic phases were combined, dried, concentrated, and purified by column chromatography to give 18 mg of compound A66.

[0357] 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.34 (d, J = 7.6 Hz, 2H), 7.28 (t, J = 7.6 Hz, 2H), 7.18 (t, J = 7.1 Hz, 1H), 6.63 (s, 2H), 3.04 ESI-MS m / z 314.22 [M+H] + .

[0358] Example 63 6-phenyl-N 6 Preparation of -(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (compound A67) hydrochloride [ka]

[0359] A1 (150 mg, 1 eq) was dissolved in 2 mL of DCM, cyclopropaneformaldehyde (43 mg, 1 eq) was added, and the mixture was allowed to react at room temperature for 14 hours. Sodium triacetoxyborohydride (130 mg, 1 eq) was slowly added, and the mixture was allowed to react at room temperature for 1 hour. The mixture was quenched by adding water, extracted three times with DCM, and the organic phases were combined, dried, concentrated, and purified by column chromatography. The residue A67 was converted into a hydrochloride salt by adding a hydrogen chloride / methanol solution in methanol, and concentrated to obtain 105 mg of compound A67 in hydrochloride form.

[0360] 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.59 (s, 1H), 9.16 (br, 2H), 7.59 (m, 2H), 7.44 (m, 3H), 3.60 (m, 2H), 2.78-2.53 (m, 4H), 2.13 (m, 1H), 1.76 (m, 1H), 0.98 (m, 1H), 0.50 (d, J = 8.0 Hz, 2H), 0.24 (m, 1H), 0.064 (m, 1H).

[0361] ESI-MS m / z 300.18 [M+H] + .

[0362] Example 64 Preparation of N-benzyl-N-methyl-5-phenyl-4,5,6,7-tetrahydro-1H-indazol-5-amine (Compound A68) [ka]

[0363] Step 1: Compound A23-2 (1 eq) was dissolved in ethanol, concentrated hydrochloric acid (12M, 3 eq) was added, and the mixture was stirred overnight at room temperature. Sodium sulfate was added to the mixture to dry, and the mixture was then concentrated to remove the solvent. The pH was adjusted to 11-12 with saturated aqueous sodium bicarbonate, extracted with DCM, dried, filtered, and concentrated. Compound A68-1 was obtained by column chromatography in an 83% yield.

[0364] Step 2: Compound A68-1 was dissolved in toluene, dried over anhydrous magnesium sulfate, and filtered for use. To a separate reaction flask, toluene, sodium tert-butoxide (2 eq), and ethyl formate (1.5 eq) were added. The solution of compound A68-1 was added at 0-10°C and stirred overnight at room temperature. The reaction mixture was extracted twice with toluene, and the remaining aqueous phase was adjusted to pH 6-7 with 1M hydrochloric acid. The mixture was extracted three times with dichloromethane, dried, concentrated, and purified by column chromatography to obtain compound A68-2 in a 93% yield.

[0365] Step 3: Compound A68-2 (1 eq, 90 mg) was dissolved in ethanol, and 85% hydrazine hydrate (3 eq, 97 mg) was added. The mixture was heated to 85°C for 5 hours. After drying with anhydrous sodium sulfate, the mixture was concentrated to dryness to remove the solvent. The residue was subjected to column chromatography to obtain compound A68 as a white solid in 98% yield.

[0366] 1 H NMR (500 MHz, Chloroform-d) δ 7.63 - 7.51 (m, 2H), 7.47 (s, 1H), 7.31 (d, J = 8.1 Hz, 3H), 7.27 (d, J = 2.5 Hz, 3H), 7.23 (qd, J = 6.9, 3.7 Hz, 2H), 3.57 (d, J = 13.3 Hz, 1H), 3.43 (d, J = 13.3 Hz, 1H), 3.16 (s, 2H), 2.70 (ddd, J = 16.0, 4.9, 3.0 Hz, 1H), 2.43 (td, J = 12.2, 5.0 Hz, 1H), 2.24 (s, 3H), 2.21 (s, 1H), 1.97 (ddd, J = 16.4, 11.9, 4.8 Hz, 1H). ESI-MS m / z 318.18 [M+H] + .

[0367] Example 65 Preparation of N-methyl-5-phenyl-4,5,6,7-tetrahydro-1H-indazol-5-amine (Compound A69) [ka]

[0368] Compound A68 (1 eq, 25 mg) was dissolved in nitromethane and Oxone oxidant (3 eq, 81 mg) was added at room temperature. The mixture was stirred at 30°C for 24 h. Sodium thiosulfate was added to quench the reaction, and the mixture was extracted with EA three times, washed with saturated brine twice, dried, concentrated, and purified by column chromatography to give compound A69.

[0369] 1 H NMR (500 MHz, Chloroform-d) δ 7.50 - 7.40 (m, 2H), 7.35 (s, 1H), 7.32 (dd, J = 8.4, 7.0 Hz, 2H), 7.25 - 7.21 (m, 1H), 3.13 (d, J = 15.5 Hz, 1H), 2.82 (d, J = 15.5 Hz, 1H), 2.73 (ddd, J = 16.3, 7.4, 5.6 Hz, 1H), 2.46 (dt, J = 16.9, 6.6 Hz, 1H), 2.30 (q, J = 6.7 Hz, 2H), 2.13 (s, 3H). ESI-MS m / z 228.11 [M+H] + .

[0370] Example 66 Preparation of 5-phenyl-5-(piperidin-1-yl)-4,5,6,7-tetrahydro-1H-indazole (Compound A70) [ka]

[0371] Step 1: Compound A48-3 (1 eq, 0.7 g) was dissolved in toluene, dried over anhydrous magnesium sulfate, and filtered for use. To a separate reaction flask, toluene, sodium tert-butoxide (2 eq, 523 mg), and ethyl formate (1.5 eq, 303 mg) were added. The toluene solution of compound A48-3 was added at 0-10°C and stirred overnight at room temperature. The reaction mixture was extracted twice with toluene, and the remaining aqueous phase was adjusted to pH 6-7 with 1 M hydrochloric acid. The mixture was extracted three times with dichloromethane, dried, concentrated, and purified by column chromatography to obtain 0.72 g of compound A70-1 in a 93% yield.

[0372] Step 2: Compound A70-1 (1 eq, 90 mg) was dissolved in ethanol, and 85% hydrazine hydrate (3 eq, 97 mg) was added. The mixture was heated to 85°C for 5 h. After drying with anhydrous sodium sulfate, the mixture was concentrated to dryness to remove the solvent. The residue was subjected to column chromatography to obtain 87 mg of compound A70 as a white solid in a 98% yield.

[0373] 1 H NMR (500 MHz, Chloroform-d) δ 7.46 - 7.32 (m, 3H), 7.19 (dt, J = 14.0, 7.0 Hz, 3H), 3.37 - 2.83 (m, 2H), 2.61 (d, J = 15.9 Hz, 3H), 2.34 (s, 3H), 2.10 - 1.75 (m, 2H), 1.68 - 1.21 (m, 6H). ESI-MS m / z 282.31 [M+H] + .

[0374] Chiral column separation gave isomers A70-P1 (S configuration) and A70-P2 (R configuration): [ka]

[0375] A70-P1 (S configuration): HPLC purity: >95%, retention time: 10.024min. Chiral purity: >99%, retention time: 6.319min. A70-P2 (R configuration): HPLC purity: >95%, retention time: 10.009 min. Chiral purity: >95%, retention time: 7.971 min.

[0376] Example 67 Preparation of 6-phenyl-6-(piperidin-1-yl)-4,5,6,7-tetrahydrobenzothiazole (Compound A71) [ka]

[0377] Basic A48 (160 mg, 1.0 eq) was dissolved in THF (2 mL), tert-butyl nitrite (65 mg, 1.1 eq) was added, and the reaction was allowed to proceed for 5 h at 60° C. The mixture was quenched by adding saturated sodium bicarbonate solution, extracted with ethyl acetate, concentrated, and purified by column chromatography to give 25 mg of a colorless oil, compound A71. 1 H NMR (500 MHz, Chloroform-d) δ 8.57 (s, 1H), 7.33 (m, 2H), 7.22 (m, 3H), 3.27 (m, 2H), 2.84 (d, J = 15.4 Hz, 1H), 2.60 (m, 2H), 2.36 (m, 3H), 2.05 (m, 2H), 1.80 - 1.33 (m, 6H). ESI-MS m / z 299.20 [M+H] + .

[0378] Example 68 Preparation of 6-((methylamino)methyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (Compound A252) [ka]

[0379] Step 1: A 250 mL three-neck flask was charged with A252-1 (5.5 g, 1.0 eq), ethylene glycol (1.7 g, 1.05 eq), and toluene (100 mL). The mixture was heated to 120°C under nitrogen gas protection and reacted for 2-3 h. The reaction mixture was cooled to room temperature and washed with 100 mL of saturated sodium bicarbonate. The organic phase was collected, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5.2 g of an oily product, A252-2.

[0380] Step 2: The above oil A252-2 and 50 mL of tetrahydrofuran were added to a 250 mL three-neck flask, stirred to clarify, purged with nitrogen gas, cooled to approximately 0°C in an ice-water bath, and lithium aluminum hydride (1.5 g, 1.5 eq) was added in several portions. After the addition was complete, the temperature was raised to approximately 70°C and stirred for 2 hours. The reaction mixture was cooled to 0°C in an ice-water bath, quenched with saturated ammonium chloride solution, extracted with 100 mL of ethyl acetate, and the organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5.5 g of an off-white solid, A252-3.

[0381] Step 3: A252-3 (2.2 g) and 20 mL of ethyl formate were added to a 100 mL three-neck flask and dissolved with stirring. The mixture was heated to 70 °C under nitrogen gas protection and reacted for approximately 2 hours. The mixture was concentrated under reduced pressure to obtain 2 g of an off-white solid, A252-4.

[0382] Step 4: A252-4 (650 mg) and 10 mL of dichloromethane were added to a 50 mL three-neck flask and stirred to clarify the reaction. Pyridinium tribromide onium (950 mg, 1.1 eq) was added and stirred at room temperature for 4-5 h. The reaction was quenched with 5 mL of saturated sodium thiosulfate solution and extracted with 20 mL of dichloromethane. The organic phases were combined, dried, and concentrated to give 450 mg of an off-white solid. 10 mL of dioxane was added and stirred to clarify the reaction. Thiourea (615 mg, 3.0 eq) and DIPEA (700 mg, 2.0 eq) were added, and the mixture was heated to 80-90 °C and stirred overnight. The reaction mixture was cooled to room temperature and extracted with 10 mL each of water and dichloromethane. The organic phase was dried, concentrated, and purified by column chromatography to give 350 mg of an off-white solid, A252-5.

[0383] Step 5: A 50 mL three-neck flask was charged with A252-5 (200 mg) and 10 mL of tetrahydrofuran, and the mixture was stirred to clarify. Under nitrogen gas protection, borane in tetrahydrofuran (7 mL, 10 eq) was added, and the mixture was heated to 60 °C and maintained at that temperature for 2 h. The mixture was then cooled to approximately 0 °C, and 5 mL of methanol was added dropwise to quench the reaction. The solvent was then concentrated and removed. 10 mL each of water and methanol were added, the mixture was heated to 70 °C, and the mixture was stirred for 1-2 h. The mixture was then cooled to room temperature, and 20 mL of dichloromethane was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 100 mg of an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.43 (s, 1H), 7.37-7.26 (m, 3H), 7.24-7.17 (m, 1H), 6.63 (s, 2H), 5.48 (s, 1H), 3.44 (d, J = 16.2 Hz, 1H), 3.05-2.94 (m, 2H), 2.88 (d, J = 15.7 Hz, 1H), 2.83-2.78 (m, 1H), 2.20-2.06 (m, 2H), 1.87-1.79 (m, 1H), 1.70 (d, J = 5.2 Hz, 3H). ESI-MS m / z 274.18 [M+H] +

[0384] Compounds A8, A10, A11, A26, and A72 shown in the table below ~ A396 is prepared in the same manner as in the above examples, except that starting materials and intermediates corresponding to the final product are used.

[0385] [Table 21]

[0386] [Table 22]

[0387] [Table 23]

[0388] [Table 24]

[0389] [Table 25]

[0390] [Table 26]

[0391] [Table 27]

[0392] [Table 28]

[0393] [Table 29]

[0394] Table 30

[0395] Table 31

[0396] Table 32

[0397] Table 33

[0398] Table 34

[0399] Table 35

[0400] Table 36

[0401] Table 37

[0402] Table 38

[0403] Table 39

[0404] Table 40

[0405] Table 41

[0406] Table 42

[0407] Table 43

[0408] Table 44

[0409] Table 45

[0410] Table 46

[0411] Table 47

[0412] Table 48

[0413] Table 49

[0414] Table 50

[0415] Table 51

[0416] Table 52

[0417] Table 53

[0418] Table 54

[0419] Table 55

[0420] Table 56

[0421] Table 57

[0422] Table 58

[0423] Table 59

[0424] Table 60

[0425] Table 61

[0426] Table 62

[0427] Table 63

[0428] Table 64

[0429] Table 65

[0430] Table 66

[0431] Table 67

[0432] Table 68

[0433] Table 69

[0434] Table 70

[0435] Table 71

[0436] Table 72

[0437] Table 73

[0438] Table 74

[0439] Table 75

[0440] Table 76

[0441] Table 77

[0442] Table 78

[0443] Table 79

[0444] Table 80

[0445] Table 81

[0446] Table 82

[0447] Table 83

[0448] Table 84

[0449] Table 85

[0450] Table 86

[0451] Table 87

[0452] Table 88

[0453] Table 89

[0454] Table 90

[0455] Table 91

[0456] Table 92

[0457] Table 93

[0458] Table 94

[0459] Table 95

[0460] Table 96

[0461] Table 97

[0462] Table 98

[0463] Table 99

[0464] Table 100

[0465] Table 101

[0466] Table 102

[0467] Table 103

[0468] Table 104

[0469] Table 105

[0470] Table 106

[0471] Table 107

[0472] Table 108

[0473] Table 109

[0474] Table 110

[0475] Table 111

[0476] Table 112

[0477] Table 113

[0478] Table 114

[0479] Table 115

[0480] Table 116

[0481] Table 117

[0482] Table 118

[0483] Table 119

[0484] Table 120

[0485] Table 121

[0486] Table 122

[0487] Table 123

[0488] Table 124

[0489] Table 125

[0490] Table 126

[0491] Table 127

[0492] Table 128

[0493] Table 129

[0494] Table 130

[0495] Table 131

[0496] Table 132

[0497] Table 133

[0498] In the pharmacological examples that follow, the compounds tested are racemic and are designated "rac" and the pure enantiomers are designated "R" or "S".

[0499] Pharmacological Example 1 NMDA receptor antagonist activity test The effect of test compounds on NMDA receptor (N-methyl-D-aspartate receptor, NR1 / 2A) channel current was examined using the electrophysiological whole-cell manual patch clamp technique.

[0500] Experimental equipment: Patch clamp amplifier (Multiclamp 700B, Axopatch 200B, Axon, USA) Digital-to-analog converter (Digidata 1440A, Digidata 1550B, Axon, USA) Inverted microscope (IX71, IX51, Olympus, Japan) High-speed administration system (RSC-200, Bio-Logic, France) Micromanipulator (MX7600R, Syskiyou, USA) Electrode puller (P-97, Sutter, USA) Glass electrode (BF150-86-10, Sutter, USA) Anti-vibration table and shielding net (63-534, TMC, USA) Data collection and analysis software (pClamp, Axon, USA) Carbon dioxide incubator (HERAcell 150i, Thermo, USA) Biological safety cabinet (MODEL 1384, Thermo, USA) Pure water meter (Milli Q, Millipore, USA)

[0501] reagent: Sodium chloride (NaCl) (Sigma, Cat: S7653) Potassium chloride (KCl) (Sigma, Cat: P9333) Cesium chloride (CsCl) (Sigma, Cat: V900481) Cesium fluoride (CsF) (Sigma, Cat: 289345) Calcium chloride (CaCl2) (Sigma, Cat: 21115) Glucose (Sigma, Cat: G7528) 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (abbreviated as HEPES) (Sigma, Cat: H3375) Ethylene glycol bis(2-aminoethyl ether)tetraacetic acid (abbreviated as EGTA) (Sigma, Cat: E3889) Lipofectamine 3000 Transfection Reagent Kit (Gibco, Cat: L3000015) (Contains two reagents: Lipofectamine 3000 and P3000) DMEM (Gibco, Cat: C11995500BT) Fetal bovine serum (FBS) (Gibco, Cat: 10099141) Opti-MEM (Gibco, Cat:31985070) Sodium hydroxide (NaOH) (Kokuyaku, Cat: 10019718) Cesium hydroxide (CsOH) (Sigma, Cat: 232068) Dimethyl sulfoxide (DMSO) (Sigma, Cat: 276855) Glutamic acid (Sigma, Cat: G1626-100G) Glycine (Amresco, Cat: 0167-1KG) Extracellular solution formulation (mM): 140 NaCl, 2.8 KCl, 1 CaCl2, 10 HEPES, and 20 Sucrose, pH adjusted to 7.4 with NaOH. Intracellular solution formulation (mM): 10 CsCl, 115 CsF, 10 EGTA, and 10 HEPES, pH adjusted to 7.2 with CsOH.

[0502] Specific operations: a. Cell culture and treatment The HEK293 cell line was cultured in DMEM medium containing 10% fetal bovine serum at a culture temperature of 37°C and a carbon dioxide concentration of 5%.

[0503] Cell passage: After removing the old medium and washing once with PBS, 1 mL of 0.25% Trypsin-EDTA solution was added and incubated at room temperature for 1 minute. Once the cells detached from the bottom of the dish, 3 mL of complete medium (90% DMEM + 10% FBS) preheated to 37°C was added. The cell suspension was gently pipetted to separate the collected cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 800 rpm for 3 minutes to collect the cells. For expansion or maintenance culture, the cells were seeded into a T25 cell culture flask at a ratio of 1:5 (final volume: 6 mL).

[0504] Transient transfection: HEK-293 cells were cultured at a cell density of approximately 80% for 24 hours prior to the transient transfection. 2 The inoculum size of each cell culture dish was 3 × 10 5 It was a cell.

[0505] For each well, the following volumes of transient transfection reagent were prepared: 1) Add 7.5 μL of Lipofectamine 3000 to 250 μL of Opti-MEM medium, gently pipette to mix evenly, and incubate at room temperature for 5 minutes as Component A. 2) Add 3.6 μg of pCDNA5-FRT-TO-hNR1-T2A-2A plasmid, 0.4 μg of GFP plasmid, and 7.5 μL of P3000 to 250 μL of Opti-MEM medium, gently pipette to mix evenly, and incubate at room temperature for 5 minutes as Component B. 3) Add component B to component A, gently pipette to mix evenly, and incubate at room temperature for 15 minutes to form a DNA-liposome mixture. 4) DNA-liposome mixture 35 mm2 Add 500 μL of the solution to each well of the cell culture dish. Place the dish in an incubator and continue culturing. 5) After 6 hours, change the solution and add 35mm 2 The medium in the cell culture dish was completely removed by suction, and 2 mL / well of complete medium (90% DMEM + 10% FBS) was added. After culturing for 18 hours, patch clamp detection was performed.

[0506] b. Compound preparation: On the day of testing, the mother solution of the compound of the present invention was diluted with DMSO to an intermediate concentration, and then diluted with extracellular solution (containing 100 μM glutamic acid and 100 μM glycine) to obtain the final concentration to be tested. The DMSO content in the final test concentration was 0.2% or less.

[0507] c. Electrophysiological recording process Currents induced by 100 μM glutamic acid (containing 100 μM glycine) were recorded at room temperature using the whole-cell patch clamp technique in HEK293 cells transiently expressing NMDA receptor channels. Glass microelectrodes were prepared by pulling them from glass electrode blanks (BF150-86-10, Sutter) using a microelectrode puller. After injection of the electrode solution, the tip resistance was approximately 2–5 MΩ. The glass microelectrode was inserted into the amplifier probe and connected to a patch clamp amplifier. The clamp voltage and data recording were controlled and recorded by a computer using pClamp software. The sampling frequency was 10 kHz and the filtering frequency was 2 kHz. After whole-cell recordings, cells were clamped at -70 mV and 100 μM glutamic acid (containing 100 μM glycine) was administered gravitationally using a high-speed administration system to induce channel currents. Once the current stabilized, 100 μM glutamic acid (containing 100 μM glycine) containing compound was administered to observe changes in current amplitude. Compounds were administered sequentially from low to high concentrations, and finally, 100 μM glutamic acid (containing 100 μM glycine) was administered again. Compounds were administered for at least 20 s per test concentration, and at least two cells (n ≥ 2) were tested per concentration.

[0508] d. Processing of data For data analysis, pClamp, GraphPad Prism 8, and Excel software were used. The degree of inhibition of the channel current (current amplitude induced by 100 μM glutamic acid (containing 100 μM glycine) at −70 mV) by different compound concentrations was calculated using the following formula:

[0509] Inhibition%=[1-(I / Io)]×100%

[0510] Among them, Inhibition% represents the rate of inhibition of NMDA channel current by the compound, and I and Io represent the amplitude of the current induced by 100 μM glutamic acid (containing 100 μM glycine) before and after administration, respectively.

[0511] Compound IC 50 was calculated using GraphPad Prism 8 software by fitting the following equation: Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0512] Where, X is the logarithm of the detected concentration of the test substance, Y is the percentage inhibition at the corresponding concentration, and Bottom and Top are the minimum and maximum percentage inhibition, respectively. The test results for some compounds are shown in Table 1.

[0513] Table 1: [Table 134]

[0514] [Table 135]

[0515] [Table 136]

[0516] As shown by the above data, the compounds of the examples of the present invention have a certain antagonistic activity against NMDA receptors and are expected to have therapeutic effects on central nervous system diseases associated with NMDA receptors.

[0517] Pharmacological Example 2: Human Liver Microsome Experiments Controls and reagents: NADPH, magnesium chloride, testosterone, phosphate buffer, etc. were provided by Dalian Meilun Biotechnology Co., Ltd., etc. Liver microsomes: Human liver microsomes were provided by Corning.

[0518] Experimental Procedure: Liver microsome incubations were performed in a 96-well plate. Each incubation system contained 200 μL of 0.1 M phosphate buffer (pH 7.4) containing 0.2 mg / mL liver microsomes, 1 μM test drug, 3.0 mM MgCl2, 0.01% DMSO, 0.5% acetonitrile, and 2.0 mM NADPH. After preincubation at 37°C for 5 min in the NADPH-free incubation system, NADPH was added to initiate the reaction. After uniform mixing at 0, 5, 15, 30, and 60 min, 20 μL samples were removed from the incubation system and added to 200 μL of acetonitrile containing the internal standard to terminate the reaction. Testosterone (1 μM) was used as a positive control under the same conditions to test the reliability of the reaction system. As a negative control, phosphate buffer was used instead of NADPH, and other incubation conditions were the same as above. After 60 min of homogeneous mixing, 20 μL of the sample was taken out and added to 200 μL of stop solution containing the internal standard to stop the reaction.

[0519] Sample analysis: After the incubation samples were treated with organic solvents to extract and precipitate proteins, the concentrations of the test drug or positive control drug in the samples were measured semi-quantitatively by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The concentrations in the samples were expressed as the ratio of the analyte peak area to the internal standard peak area.

[0520] Data processing and analysis: Using Excel software, the ln residual rate of the drug in the incubation system was plotted against the incubation time, and linear regression was performed to obtain the slope k, and the half-life T was calculated according to the following formula: 1 / 2 (min) and intrinsic clearance CL int (mL / min / kg) was calculated:

[0521] T 1 / 2 =-0.693 / k

number

[0522] The results of the experiment are shown in Table 2 below:

[0523] Table 2 [Table 137] NA: Uncalculable.

[0524] As shown by the above data, the compounds of the examples of the present invention have good metabolic stability in human liver microsomes.

[0525] Pharmacological Example 3: In vivo metabolism experiments in mice Animals: Male ICR mice. Animals were randomly assigned to treatment groups and fasted 12 h prior to dosing. Drugs: The compounds of the present invention were dissolved in a solvent (5% DMSO + 5% Solutol HS15 + 90% saline). For intravenous injection (iv), the dose was 2.5 mg / kg, with a volume of 5 mL / kg. For oral administration (po), the dose was 10 mg / kg, with a volume of 10 mL / kg body weight. Sample collection and bioanalysis: Mice were bled via the orbit at 0.083, 0.25, 0.5, 1, 2, 4, 6, and 8 h (n=3 per time point) and placed in EP tubes containing sodium heparin. Mice were sacrificed immediately after blood collection by cervical dislocation, and the brains of the mice at the corresponding time points were removed. All samples were immediately collected, quickly frozen, and stored at -70°C for use. Plasma samples were obtained by centrifugation of whole blood. 10 μL of plasma was then homogenously mixed with 190 μL of an internal standard solution (20 ng / mL dissolved in acetonitrile containing 0.1% formic acid). After homogenization, the mixture was centrifuged at 13,000 rpm for 10 min. 120 μL of the supernatant was collected, and 0.5-10 μL (depending on the sensitivity of the compound) was analyzed for drug content by an appropriate liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. Standards for each analyte were used for calibration and identification. For brain tissue: Extract (50% acetonitrile) / The mixture was homogenized in an OMNI Bead Ruptor 24 Elite homogenizer using five 3 mm magnetic beads at a speed of 3.2 m / s for 2 minutes in a ratio of 1 (g):8 (mL) of water. The mixture was then centrifuged at 4°C and 3,000 g for 3 minutes. 50 μL of the supernatant was taken, and 200 μL of an internal standard solution (20 ng / mL dissolved in 80% acetonitrile / water) was added and mixed uniformly. After mixing uniformly, the mixture was centrifuged at 13,000 rpm for 10 minutes. 120 μL of the supernatant was taken, and 0.5 to 10 μL of the supernatant (depending on the sensitivity of the compound) was used for drug analysis by an appropriate LC-MS / MS method. Standards for each analyte were used for calibration and identification.

[0526] Data Analysis: Drug concentrations below the lower limit of quantitation (LLOQ) were set to zero. Pharmacokinetic data were analyzed in PK Solver using a non-compartmental, bolus, or extravascular administration analysis model. Data points below the LLOQ were assigned a t 1 / 2To improve the efficiency of the calculations, this was not included in the analysis. The experimental results are shown in Table 3 below:

[0527] Table 3 [Table 138] As shown by the above data, the compounds of the examples of the present invention have good oral bioavailability in the body of mice.

[0528] Pharmacological Example 4: Sigma receptor affinity experiments 4.1 Materials and Reagents Cell membrane: The membrane proteins used in this experiment were extracted from HEK293 cell lines stably expressing the Sigma1 receptor and Sigma2 receptor, which were constructed at Yakult Kotoku.

[0529] reagent: [3H]-DTG (PerkinElmer, Cat:NET986250UC) Haloperidol (Sigma, Cat:Sigma-H1512-5G) Tris-HCl (Sigma, Cat:T3038-1L) NaCl (Sigma, Cat: S5150-1L) PEI (Poly ethyleneimine) (Sigma, Cat:P3143) Microscint 20 cocktail (PerkinElmer, Cat:6013329) Haloperidol (Sigma, Sigma-H1512-5G)

[0530] Equipment and supplies: Top Seal-A Plate Sealing Film (Perkin Elmer, Cat# 6050185) 96 well conical polypropylene plates (Agilent, Cat#50421385) 96-well cell collection device (PerkinElmer, Cat# C961961) Unifilter-96 GF / C filter plate (Perkin Elmer, Cat# 6005174) Microbeta (PerkinElmer)

[0531] 4.2 Methods and steps 1) Detection buffer: 50 mM Tris-HCl, pH = 7.4, stored at 4°C; 2) Sigma 1R Experimental Plate Wash Buffer: 50 mM Tris-HCl, pH=7.4, stored at 4°C; Sigma2R Experimental Plate Wash Buffer: 50 mM Tris-HCl, 100 mM NaCl, pH=7.4, stored at 4°C; 3) Compounds were diluted to their working concentrations: 8 concentrations were diluted 4-fold in a gradient. 4) The cell membrane solution and isotope solution were prepared using pre-cooled detection buffer, and the membrane concentration was 10 μg / well and the final concentration of the isotope ligand [ 3 H]-DTG was 5 nM according to the manufacturer's information. 5) Compounds to be measured and positive controls were diluted to working concentrations and added to the experimental plate at 1 μL / well. For Sigma 1R experiments, 1 μL of DMSO was added to the high signal control wells (High control), and 1 μL of 100 μM haloperidol (final concentration 500 nM) was added to the low signal control wells (Low control). For Sigma 2R experiments, 1 μL of DMSO was added to the high signal control wells (High control), and 1 μL of 400 μM haloperidol (final concentration 2 μM) was added to the low signal control wells (Low control). 6) 100 μL / well of cell membranes were added to the experimental plate, followed by the addition of 100 μL of the corresponding isotope ligand. 7) The experimental plate was sealed and incubated with shaking for 2 hours at 37°C. The GF / C filter plate was soaked in 0.3% PEI for at least 30 minutes. 8) After the incubation, the cell membranes were collected onto a GF / C filter plate using a cell collection device and washed four times with pre-cooled plate washing buffer. The GF / C filter plate was then placed in a 50°C oven and dried for 1 hour. 9) The bottom of the dried GF / C filter plate was sealed with film, and 50 μL of scintillation fluid was added to each well to seal. 10) The values ​​were read using Microbeta. 11) Analyze the data using GraphPad Prism and calculate IC 50 The affinity inhibition constant Ki was calculated using the Cheng Prusoff equation: Ki = IC 50 / (1+L / K D ).

[0532] The results of the experiment are shown in Table 4 below: Table 4 [Table 139]

[0533] As shown by the data in Table 4 above, the compounds of the examples of the present invention have relatively good affinity for sigma receptors and are expected to have therapeutic effects on central nervous system diseases associated with sigma receptors.

[0534] Pharmacological Example 5: Forced Swim Test: Drug: The compound of the present invention was first mixed homogeneously with 5% DMSO and 5% solutol® HS 15. Then, saline was added to make the final volume 90%. The mixture was adjusted to the appropriate concentration just before use.

[0535] Animals: Male C57 mice, approximately 22 g. The animals were randomly divided into a blank control group and each test compound group, with eight animals in each group. Mice in each group were administered the vehicle or test compound by intraperitoneal injection.

[0536] Experimental procedure: The mice underwent a forced swimming test 0.5 hours after administration. The water level in the forced swimming apparatus was 45 cm, and the water temperature was 25°C. The mice were placed in the laboratory for 1 hour before the start of the experiment to allow them to adapt to the environment. At the start of the experiment, the mice were placed in the apparatus for 6 minutes, and the entire process was recorded with a camera. For data analysis, only the immobility time of the mice in the final 4 minutes was counted.

[0537] The results of the experiment are shown in Table 5 below:

[0538] Table 5 [Table 140]

[0539] As shown by the above data, all drug groups showed significant antidepressant-like effects at low doses of 1 to 5 mg / kg.

[0540] Pharmacological Example 6: Monoamine transporter inhibitory activity test (1) 5-HT transporter inhibitory activity test:

[0541] Main reagents and equipment: HEPES (Invitrogen, Cat:15630-106) HBSS (Invitrogen, Cat: 14025) Bovine Serum Albumin(Sigma, Cat:B2064-100G) Neurotransmitter transporter uptake assay kit (Molecular devices, Cat:R8174) Incubator (Thermo, 240) Envision(Perkin Elmer,envision2014) 384-well plate (Greiner, Cat: 784075) The inhibitory effect of the compound on human SERT transporter was detected using the Neurotransmitter Transporter Uptake Assay Kit (Molecular Devices) in human SERT-overexpressing HEK-293 cells. The test was performed according to the instructions in the kit, and citalopram was used as a positive control. The specific procedure is as follows:

[0542] a) HEK-293-hSERT cells were seeded into a 384-well plate at 20,000 cells / well, and the 384-well plate was then transferred to an incubator and placed at 37°C overnight. b) The next day, test solutions of citalopram and the compounds of the present invention were prepared in a 384-well plate using an experimental buffer (HBSS solution containing 0.1% BSA and 20 mM HEPES), with citalopram at an initial test concentration of 1 μM and diluted 3 times, and the compounds to be measured at an initial test concentration of 10 μM or 100 μM and diluted 3 times, with each concentration repeated twice. c) Remove the 384-well plate in which HEK-293-hSERT cells have been cultured from the incubator, remove the medium from the wells, add 25 μL of a compound solution to be measured to each well, and incubate at 37°C in the incubator for 30 minutes. d) Add 25 μL of dye to each well and incubate at 37° C. for 30 min in an incubator; e) Fluorescence values ​​were read using Envision and the data were analyzed using Graphpad Prism software, and the results are shown in Table 6.

[0543] (2) DAT and NET transporter inhibitory activity test: Main reagents and equipment: [Table 141]

[0544] The transporter inhibitory effect of compounds on HEK-293 cells expressing human DAT and NET was detected using a neurotransmitter transporter uptake assay kit. The test was performed according to the instructions in the kit, and centanafadine was used as a positive control. The specific procedure is as follows:

[0545] Preparing cells for NET transient transfection: On the first day, HEK 293T cells were digested with trypsin, centrifuged, resuspended in medium, counted, and seeded onto a 6 cm culture dish at a seeding density of 3 x 10 cells. 6 cells / well,

[0546] Cell transfection the next day: After fluid exchange of HEK 293T cells, the NET-pcDNA5 / FRT plasmid to be transfected was prepared in two tubes, A and B. Tube A contained 200 μL of Opti-MEM, followed by 10 μL of Lipofectamine™ 3000 and mixing thoroughly. Tube B contained 200 μL of Opti-MEM, followed by 5 μg of NET-pcDNA5 / FRT plasmid and mixing thoroughly. Tube B contained 10 μL of P3000™ and mixing thoroughly (the ratio of plasmid to transfection reagent was 1 μg:2 μL). The diluted solution in Tube A was added to the diluted solution in Tube B, mixed thoroughly, and incubated at room temperature for 15 minutes. Finally, the mixture was gently added to the cells after fluid exchange, gently shaken to mix, and then cultured overnight in an incubator at 37°C with 5% carbon dioxide. After 18-20 hours of transfection, the cells were used to measure the functional activity of the compounds.

[0547] Preparation of DAT stable transformants: Culture of DAT stable transformants: DAT-HEK cell lines were cultured in DMEM medium containing 10% fetal bovine serum and 0.2 mg / mL hygromycin B at a culture temperature of 37°C and a carbon dioxide concentration of 5%.

[0548] Passaging of DAT stable transformants: After removing the old medium and washing once with PBS, 1 mL of TrypLE™ Express solution was added and incubated at 37°C for approximately 2 minutes. Once the cells had detached from the bottom of the dish, 5 mL of complete medium preheated to 37°C was added. The cell suspension was gently pipetted to separate the collected cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000 rpm for 5 minutes. To maintain the physiological activity of the cells, the degree of confluence of the experimental cells was controlled at approximately 80%.

[0549] Functional activity assay: a) NET cells were transfected overnight, then digested with trypsin, resuspended in DMEM + 10% dialyzed FBS medium, and seeded at 20,000 cells / well in a 384-well plate for overnight culture. Stably transformed DAT cells were digested with trypsin, resuspended in DMEM + 10% dialyzed FBS medium, and seeded at 2,500 cells / well in a 384-well plate for overnight culture. b) Prepare 1x Assay Buffer according to the instructions in the reagent kit and prepare for use. Dilute the positive compounds and compounds to be measured with DMSO gradient, then dilute to 2x with 1x Assay Buffer. c) centrifuging to remove the medium in the 384-well plate; d) Add 16 μL of the compound prepared in step b) to the corresponding experimental wells, of which 2× the initial concentration of the positive control compound is added to the positive control wells, and 0.2% DMSO buffer is added to the negative control wells. After centrifugation, place at 37°C and incubate for 30 minutes. e) Prepare a detection reagent using 1x HBSS, add 16 μL of the detection reagent to each well, centrifuge, and then incubate at 37 ° C for 60 minutes. f) After incubation, the values ​​at 510 nm were detected using a microplate reader under excitation at a wavelength of 425 nm, and curve fitting was performed using the GraphPad Prism software using the nonlinear regression method, and the IC 50 was calculated, and the results are shown in Table 6 below.

[0550] Table 6 [Table 142]

[0551] [Table 143]

[0552] [Table 144]

[0553] [Table 145]

[0554] As shown by the above data, the compounds of the present invention have a certain antagonistic activity against monoamine transporters and are expected to have therapeutic effects on central nervous system diseases associated with monoamine transporters.

Claims

1. A compound of formula (I) or a stereoisomer, geometric isomer, conformational isomer, tautomer, pharmaceutically acceptable salt, crystalline polymorph, solvate, hydrate or isotopically labeled compound thereof, 【Chemistry 1】 Among them, Ring A is selected from a 4- to 10-membered heterocycle or a 4- to 10-membered heterocycle fused with a C6-C10 aromatic ring, the 4- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, and is preferably a 5- to 8-membered heterocycle, and preferably the heterocycle in ring A contains one N atom and one S atom, or two N atoms, or one S atom, or two N atoms and one S atom, or one N atom and one O atom; The A ring may optionally be one or more R ５ and each R ５ are independently a halogen, a hydroxy group, an amino group, a cyano group, a carboxy group, an oxo group, a C1 to C6 alkyl group, a halo C1 to C6 alkyl group, a C1 to C6 alkoxy group, a C1 to C6 alkanoyl group, a carbamoyl group (-CONH ２ ), a carbamoyl group substituted with a C1 to C6 alkyl group, an amino group substituted with one or two C1 to C6 alkyl groups, an amino group substituted with one or two halo C1 to C6 alkyl groups, an amino group substituted with one or two C1 to C6 alkanoyl groups, a C1 to C6 alkoxycarbonyl group, a C3 to C6 cycloalkyl group, a 4 to 10-membered heterocycloalkyl group, a C6 to C14 aryl group, a 5 to 10-membered heteroaryl group, a C6 to C14 aryl C1 to C6 alkyloxy group, or a 5 to 10-membered heteroaryl C1 to C6 alkyloxy group, preferably, each R ５ are independently a halogen, a hydroxy group, an amino group, a cyano group, a carboxy group, an oxo group, a C1-C4 alkyl group, a haloC1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 alkanoyl group, a carbamoyl group (-CONH ２ ), a carbamoyl group substituted with a C1 to C4 alkyl group, an amino group substituted with one or two C1 to C4 alkyl groups, an amino group substituted with one or two halo C1 to C4 alkyl groups, an amino group substituted with one or two C1 to C4 alkanoyl groups, a C1 to C4 alkoxycarbonyl group, a C3 to C6 cycloalkyl group, a 4 to 8 membered heterocycloalkyl group, a C6 to C10 aryl group, a 5 to 10 membered heteroaryl group, a C6 to C10 aryl C1 to C4 alkyloxy group or a 5 to 10 membered heteroaryl C1 to C4 alkyloxy group, more preferably, each R ５ are independently selected from halogen (particularly bromine), amino group, hydroxy group, cyano group, carboxy group, C1-C3 alkyl group (particularly methyl group, ethyl group, isopropyl group), halo C1-C3 alkyl group (particularly trifluoromethyl group), C1-C3 alkoxy group (particularly methoxy group, ethoxy group), C1-C3 alkanoyl group (particularly formyl group, acetyl group), carbamoyl group (-CONH ２ ), a formylamino group, an acetylamino group, a methylamino group, an ethylamino group, an N,N-dimethylamino group, a 2,2,2-trifluoroethylamino group, a C1-C3 alkoxycarbonyl group (particularly a methoxycarbonyl group or an ethoxycarbonyl group), a C3-C5 cycloalkyl group (particularly a cyclopropyl group), a phenyl group, a pyridyl group, a pyrrolidinyl group, a piperidinyl group, a morpholinyl group or a benzyloxy group; Ring B is a 3- to 10-membered carbocyclic ring, preferably a 5- to 8-membered carbocyclic ring, for example a 5-, 6-, 7-, or 8-membered carbocyclic ring, more preferably a 5-, 6-, or 7-membered carbocyclic ring; R １ and 【Chemistry 2】 are attached to the same ring carbon atom in ring B, x is an integer from 0 to 2; R ２ and R ３ are each independently hydrogen, a C1 to C6 alkyl group, a halo C1 to C6 alkyl group, a C1 to C6 alkoxy C1 to C6 alkyl group, a hydroxy C1 to C6 alkyl group, a C6 to C14 aryl C1 to C6 alkyl group, a C3 to C6 cycloalkyl group, a C1 to C6 alkanoyl group, a halo C1 to C6 alkanoyl group, a C3 to C6 cycloalkyl C1 to C6 alkanoyl group, a C6 to C14 aryl C1 to C6 alkanoyl group, a C1 to C6 alkylsulfonyl group, C1-C6 alkylsulfoxide group, or C3-C6 cycloalkyl C1-C6 alkyl group, and preferably each independently is selected from hydrogen, C1-C4 alkyl group, halo C1-C4 alkyl group, C1-C4 alkoxy C1-C4 alkyl group, hydroxy C1-C4 alkyl group, C6-C14 aryl C1-C4 alkyl group, C3-C6 cycloalkyl group, C1-C4 alkanoyl group, halo C1-C4 alkyl group, a C1-C4 alkanoyl group, a C3-C6 cycloalkyl C1-C4 alkanoyl group, a C6-14 aryl C1-C4 alkanoyl group, a C1-C4 alkylsulfonyl group, a C1-C4 alkylsulfoxide group or a C3-C6 cycloalkyl C1-C4 alkyl group, preferably selected from hydrogen, a C1-C4 alkyl group (particularly a methyl group, an ethyl group, a propyl group, an isopropyl group or a tert-butyl group), a halo C1-C4 alkyl group (particularly a 1,1,1-trifluoroethyl group), a methoxyethyl group, a hydroxymethyl group, a hydroxyethyl group, a C3-C6 cycloalkylmethyl group (particularly a cyclopropylmethyl group or a cyclobutylmethyl group), a benzyl group, a C3-C6 cycloalkyl group (particularly a cyclopropyl group), a C1-C3 alkylacyl group (particularly an acetyl group or a propionyl group), a cyclopropylformyl group, a benzoyl group or a tert-butylsulfoxide group; Or, R ２ , R ３ together with the nitrogen atom to which it is attached form a 3- to 9-membered heterocycloalkyl group, said 3- to 9-membered heterocycloalkyl group ring optionally containing one or more additional nitrogen or oxygen atoms, said 3- to 9-membered heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl groups, preferably C1-C4 alkyl groups, and preferably R ２ , R ３ forms an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, an azepanyl group, or a morpholinyl group together with the nitrogen atom to which it is linked, R １ is selected from a C6 to C14 aryl group, a 5 to 10-membered heteroaryl group, a 4 to 10-membered heterocyclyl group, a 4 to 10-membered carbocyclic ring fused with a C6 to C10 aryl group (e.g., an indanyl group), or a 4 to 10-membered heterocyclic ring fused with a C6 to C10 aryl group (e.g., a 1,2-methylenedioxyphenyl group, a 2,3-dihydrobenzofuryl group), preferably selected from a C6 to C14 aryl group or a 5 to 10-membered heteroaryl group, more preferably a phenyl group, a naphthyl group, a quinolyl group, an isoquinolinyl group, a pyridyl group, a pyrimidine group, a pyrazinyl group, a pyridazinyl group, a thienyl group, or a thiazolyl group, even more preferably a phenyl group, a naphthyl group, a pyrimidine group, a pyridyl group, a pyrazinyl group, a pyridazinyl group, or a quinolyl group, and still more preferably a phenyl group; The C6-C14 aryl group, 5- to 10-membered heteroaryl group, 4- to 10-membered heterocyclyl group, 4- to 10-membered carbocyclic ring fused with a C6-C10 aryl group, or 4- to 10-membered heterocyclic ring fused with a C6-C10 aryl group may optionally be one or more R ６ is replaced by R ６ are each independently a halogen, a hydroxy group, a mercapto group, a cyano group, a carbamoyl group (NH ２ CO-), aminosulfonyl group (NH ２ SO ２ -), C1 to C6 alkyl group, halo C1 to C6 alkyl group, hydroxy C1 to C6 alkyl group, C3 to C6 cycloalkyl group, C3 to C6 cycloalkoxy group, C3 to C6 cycloalkyl group substituted with C1 to C3 alkyl group, C3 to C6 cycloalkoxy group substituted with C1 to C3 alkyl group, C1 to C6 alkoxy group, C1 to C6 alkylthio group, halo C1-6 alkoxy group, C3 to C6 cycloalkyl C1 to C6 alkoxy group, C1 to C6 alkanoyloxy group, C6 to C14 aryl group, 5 to 10 membered heteroaryl group, C6 to C14 aryl C1 to C6 alkoxy group, 5 to 10 membered heteroaryl C1 to C6 alkoxy group, preferably R ６ are each independently a halogen, a cyano group, a hydroxy group, a carbamoyl group (NH ２ CO-), aminosulfonyl group (NH ２ SO ２ -), C1 to C4 alkyl group, halo C1 to C4 alkyl group, hydroxy C1 to C4 alkyl group, C3 to C6 cycloalkyl group, C3 to C6 cycloalkoxy group, C3 to C6 cycloalkyl group substituted with C1 to C3 alkyl group, C3 to C6 cycloalkoxy group substituted with C1 to C3 alkyl group, C1 to C4 alkoxy group, C1 to C4 alkylthio group, halo C1 to C4 alkoxy group, C3 to C6 cycloalkyl C1 to C3 alkoxy group, C1 to C3 alkanoyloxy group, C6 to C10 aryl group, 5-6 membered heteroaryl group, C6 to C10 aryl C1 to C4 alkoxy group, 5-6 membered heteroaryl C1 to C4 alkoxy group, more preferably R ６ each independently represents fluorine, chlorine, bromine, cyano, hydroxy, methyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methylcyclopropyloxy, methoxy, ethoxy, isopropoxy, isobutyloxy, methylthio, cyclopropyl, cyclopropyloxy, or carbamoyl (NH ２ CO-), aminosulfonyl group (NH ２ SO ２ -), a difluoromethoxy group, a trifluoromethoxy group, a 1,1,1-trifluoroethoxy group, a cyano group, a cyclopropyl group, a methoxy group, an acetoxy group, a phenyl group, a pyridyl group, or a benzyloxy group; m is an integer from 0 to 3; R ４ is R in ring B １ and 【Transformation 3】 are connected to any carbon atom other than the carbon atoms to which R ４ are each independently selected from a hydroxy group, a halogen, and a C1 to C6 alkyl group; A compound of formula (I) or a stereoisomer, geometric isomer, conformational isomer, tautomer, pharmaceutically acceptable salt, crystalline polymorph, solvate, hydrate or isotopically labeled compound thereof.

2. Ring A is selected from a 5- or 6-membered heterocycle or a 5- or 6-membered benzoheterocycle; Preferably, the A ring is 【Chemistry 4】 、 【Transformation 5】 、 【Transformation 6】 、 【Transformation 7】 、 【Transformation 8】 、 【Chemistry 9】 Selected from Among them, Z １ , Z ２ , Z ４ are independently N, CR ７ Selected from Z ３ is NR ７ , O, S, and Z １ , Z ２ , Z ４ At the same time, CR ７ Instead, each R ７ are independently hydrogen, halogen, cyano group, hydroxy group, amino group, carbamoyl group (-CONH ２ ), a carbamoyl group substituted with a C1 to C6 alkyl group, a carboxy group, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halo C1 to C6 alkyl group, an amino group substituted with a C1 to C6 alkyl group, an amino group substituted with a halo C1 to C6 alkyl group, an amino group substituted with a C1 to C6 alkanoyl group, a C1 to C6 alkanoyl group, a C1 to C6 alkoxycarbonyl group, a C3 to C6 cycloalkyl group, a 4 to 8 membered heterocycloalkyl group, a C6 to 10 aryl group, a 5 to 10 membered heteroaryl group, a C6 to C10 aryl C1 to C4 alkyloxy group or a 5 to 10 membered heteroaryl C1 to C4 alkyloxy group; More preferably, ring A is 【Chemistry 10】 、 【Chemistry 11】 、 【Chemistry 12】 、 【Chemistry 13】 、 【Chemistry 14】 、 【Chemistry 15】 、 【Chemistry 16】 、 【Chemistry 17】 、 [Chemistry 18] 、 【Chemistry 19】 、 【Chemistry 20】 、 【Chemistry 21】 、 【Chemistry 22】 、 【Chemistry 23】 、 【Chemistry 24】 、 【Chemistry 25】 、 【Chemistry 26】 、 【Chemistry 27】 、 【Chemistry 28】 、 【Chemistry 29】 Selected from Of these, each R ７ are independently hydrogen, halogen (particularly bromine), amino group, hydroxy group, cyano group, carboxy group, C1-C3 alkyl group (particularly methyl group, ethyl group, isopropyl group), halo C1-C3 alkyl group (particularly trifluoromethyl group), C1-C3 alkoxy group (particularly methoxy group, ethoxy group), C1-C3 alkanoyl group (particularly formyl group, acetyl group), carbamoyl group (-CONH ２ ), a formylamino group, an acetylamino group, a methylamino group, an ethylamino group, an N,N-dimethylamino group, a 2,2,2-trifluoroethylamino group, a C1 to C3 alkoxycarbonyl group (particularly a methoxycarbonyl group or an ethoxycarbonyl group), a C3 to C5 cycloalkyl group (particularly a cyclopropyl group), a morpholinyl group, a phenyl group, pyridine, a pyrrolidinyl group, a piperidinyl group or a benzyloxy group; 2. The compound of formula (I) according to claim 1, or a stereoisomer, geometric isomer, conformational isomer, tautomer, pharmaceutically acceptable salt thereof, crystalline polymorph, solvate, hydrate or isotope-labeled compound thereof.

3. R １ optionally one or more R ６ is a phenyl or naphthyl group substituted with R ６ is defined as set forth in claim 1, 3. A compound of formula (I) according to claim 1 or 2, or a stereoisomer, geometric isomer, conformational isomer, tautomer, pharmaceutically acceptable salt thereof, crystalline polymorph, solvate, hydrate or isotope-labeled compound thereof.

4. R ２ and R ３ is hydrogen, or R ２ and R ３ are hydrogen, 4. The compound of formula (I) according to claim 3, or a stereoisomer, geometric isomer, conformational isomer, tautomer, pharmaceutically acceptable salt thereof, crystalline polymorph, solvate, hydrate or isotope-labeled compound thereof.

5. The compound of formula (I) is 【Transformation 30】 【Chemistry 31】 The compounds are selected from Among them, x and Z １ , Z ２ , Z ３ , Z ４ , R ２ , R ３ , R ６ is defined as set forth in claim 2.

3. The compound of formula (I) according to claim 2, or a stereoisomer, geometric isomer, conformational isomer, tautomer, pharmaceutically acceptable salt thereof, crystalline polymorph, solvate, hydrate or isotope-labeled compound thereof.

6. The compound of formula (I) is 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Chemistry 58】 【Chemistry 59】 【Transformation 60】 【Chemistry 61】 【Transformation 62】 【Transformation 63】 The compounds are selected from R ２ , R ３ , R ６ , R ７ is defined as set forth in claim 1, and a phenyl group, a pyridyl group, a naphthyl group, a quinolyl group, a pyrimidine group, a pyrazinyl group, or a pyridazinyl group, and -NR ２ R ３ , 【Chemistry 64】 or 【Transformation 65】 are attached to the same ring carbon atom of the carbocycle to which they are attached, 2. The compound of formula (I) according to claim 1, or a stereoisomer, geometric isomer, conformational isomer, tautomer, pharmaceutically acceptable salt thereof, crystalline polymorph, solvate, hydrate or isotope-labeled compound thereof.

7. The compound of formula (I) is selected from the following structures: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 An aryl group-containing amine compound represented by general formula (I) according to any one of claims 1 to 6, and its stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, crystalline polymorphs, solvates, hydrates and isotope-labeled compounds.

8. A method for producing an aryl group-containing amine compound represented by formula (I) according to any one of claims 1 to 7, comprising the steps of: The production method is carried out by one or a combination of the following methods 1 to 3: Method 1: As shown in reaction equation 1, a) condensing a compound of formula (II) with a compound of formula (III) to produce a compound of formula (IV); b) subjecting a compound of formula (IV) to a nucleophilic addition reaction with a compound of formula (V) to produce a compound of formula (I-a); Including, 【Chemical Formula 66】 Among them, A ring, B ring, R １ is as defined in the corresponding claim, G represents a leaving group and is selected from a C1 to C6 alkylsulfinyl group, a benzenesulfinyl group, a naphthalenesulfinyl group, and a benzyl group, and the C1 to C6 alkylsulfinyl group, benzenesulfinyl group, naphthalenesulfinyl group, and benzyl group are optionally substituted with one or more groups selected from a halogen, a C1 to C6 alkyl group, a nitro group, a hydroxy group, an amino group, a C1 to C6 alkanoyl group, a C1 to C6 alkoxy group, and a phenyl group; M represents a leaving group selected from a metal element, a halogen, a metal compound, a borane, a silane, and a diazonium salt, and is preferably —MgBr, —MgCl, or —Li; Method 2: As shown in reaction equation 2, c) nucleophilic addition reaction of a compound of formula (II) with a compound of formula (V) to produce a compound of formula (VI); d) performing a substitution reaction between a compound of formula (VI) and an azide compound to produce a compound of formula (VII); e) reducing the compound of formula (VII) to produce a compound of formula (Ia); Including, 【Transformation 67】 Among them, A ring, B ring, R １ is as defined in the corresponding claim, M represents a leaving group, for example, a metal element, a halogen, a metal compound, a borane, a silane, a diazonium salt, or the like, and is preferably —MgBr, —MgCl, or —Li; Method 3: The compound of formula (I-a) obtained by methods 1 and 2 is subjected to functional group conversion of the amino group to obtain another aryl group-containing amine compound represented by formula (I). Manufacturing method.

9. A therapeutically effective amount of one or more selected from the group consisting of an aryl group-containing amine compound represented by formula (I) according to any one of claims 1 to 7, its stereoisomers, geometric isomers, conformers, tautomers, pharmaceutically acceptable salts thereof, crystalline polymorphs, solvates, hydrates and isotope-labeled compounds, and optionally one or more pharmaceutically acceptable carriers, diluents or excipients. Pharmaceutical compositions.

10. Use of one or more of the aryl group-containing amine compounds represented by formula (I) according to any one of claims 1 to 7, their stereoisomers, geometric isomers, conformers, tautomers, pharmaceutically acceptable salts thereof, crystalline polymorphs, solvates, hydrates and isotope-labeled compounds, or the pharmaceutical composition according to claim 9, in the manufacture of a medicament for modulating NMDA receptor and / or monoamine transporter and / or sigma receptor activity, In particular, the agent is a) NMDA receptor antagonists, b) monoamine transporter inhibitors, and c) sigma receptor agonists or antagonists; That is, use.

11. Use of one or more of the aryl group-containing amine compounds represented by formula (I) according to any one of claims 1 to 7, their stereoisomers, geometric isomers, conformers, tautomers, pharmaceutically acceptable salts, crystalline polymorphs, solvates, hydrates and isotope-labeled compounds, or the pharmaceutical composition according to claim 9, in the manufacture of a medicament for preventing and / or treating a disease associated with an NMDA receptor and / or a monoamine transporter and / or a sigma receptor, particularly a central nervous system disease, Preferably, the central nervous system disease is cerebral ischemia, stroke, cerebral infarction, traumatic brain injury, anti-NMDA receptor encephalitis, epilepsy, amyotrophic lateral sclerosis, schizophrenia, hard-to-control, hard-to-cope or chronic schizophrenia, affective disorder, mental disorder, mood disorder, bipolar I disorder, bipolar II disorder, depression, endogenous depression, major depression, hard-to-control depression, dysthymic disorder, cyclothymic disorder, panic attack, panic disorder, social anxiety disorder, obsessive-compulsive disorder, impulsive disorder, post-traumatic stress disorder, anxiety disorder, acute stress disorder, hysteria, anorexia nervosa selected from tremors, sleep disorders, adjustment disorders, cognitive disorders, autism, neuropathic pain, mania, Parkinson's disease, Huntington's disease, Alzheimer's disease, dementia, memory disorders, hyperactivity disorders, attention deficit / hyperactivity disorders, tic disorders and other nervous system events or neurodegeneration resulting from NMDA receptor activation, preferably said neuropathic pain comprising diabetic peripheral neuropathy, postherpetic neuralgia, complex regional pain syndrome, peripheral neuropathy, chemotherapy-induced neuropathic pain, cancer neuropathic pain, neuropathic lower back pain, HIV neuropathic pain, trigeminal neuralgia and central post-stroke pain; More preferably, the central nervous system disease is selected from bipolar I disorder, bipolar II disorder, depression, endogenous depression, major depression, uncontrolled depression, dysthymic disorder, cyclothymic disorder, panic attack, panic disorder, social anxiety disorder, obsessive-compulsive disorder, impulsive disorder, post-traumatic stress disorder, anxiety disorder, acute stress disorder, Parkinson's disease, diabetic peripheral neuropathy, postherpetic neuralgia, and complex regional pain syndrome. use.

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