Heterocyclic compounds as TAAR1 ligand agonists

Abstract

The present invention provides heterocyclic compounds as TAAR1 agonists, and further provides methods for preparing the compounds, pharmaceutical compositions containing the compounds, and their use as TAAR1 agonists in the prevention and / or treatment of various CNS-related disorders, wherein each substituent in general formula (IA) is defined as in the specification. TIFF2025525370000149.tif34170

Description

[Technical Field]

[0001] The present disclosure relates to heterocyclic compounds and methods for their preparation and use as TAAR1 agonists in the treatment of related diseases. [Background technology]

[0002] Trace amine receptors (TAARs) are a family of endogenous biogenic amine-activated G protein-coupled receptors. Six TAARs and three pseudogenes have been identified in humans. TAAR1 is the most extensively studied of all TAARs and is widely expressed in the mammalian brain, particularly in limbic and monoaminergic regions. TAAR1 can regulate presynaptic dopaminergic neurotransmission, induce activation of G protein-coupled inwardly rectifying potassium ion channels, and reduce neuronal discharge frequency. TAAR1 may be a potential therapeutic target for treating psychiatric disorders such as schizophrenia, depression, psychotic disorders in Parkinson's disease, behavioral symptoms of dementia, anxiety, migraine, and hyperactivity disorder.

[0003] Currently, there are four drugs that act on TAAR1: amphetamine, RG-7906, RO-5263397, and SEP-363856. Amphetamine was approved by the FDA in 2016 for the treatment of attention-deficit hyperactivity disorder (ADHD). However, this compound has a relatively strong central nervous system excitatory effect and can cause accelerated heart rate, elevated blood pressure, a sense of pleasure, and reduced fatigue in the short term. Long-term use can cause adverse reactions such as insomnia, irritability, delusions and hallucinations, and violent and aggressive behavior. Therefore, it is already designated as a controlled substance. RG-7906, RO-5263397, and SEP-363856 are all selective TAAR1 agonists under investigation. Of these, RG-7906 is in Phase II clinical trials, RO-5263397 is dormant in Phase I clinical trials, and SEP-363856, the most advanced, is in Phase III clinical trials. Therefore, there is a need to develop novel TAAR1 agonists with improved safety and efficacy to meet patient needs. Summary of the Invention

[0004] In one embodiment of the present disclosure, there is provided a compound of formula (IA), a pharmaceutically acceptable salt, or stereoisomer thereof: TIFF2025525370000002.tif34170Of which, A1 is selected from CR2 or a N atom; A2 is selected from CR2 or an O atom; R1 is H, halogen, C 1-6 Alkyl group or C 1-6 selected from alkoxy groups, Each R2 is independently H or C 1-6 It is selected from alkyl groups.

[0005] In some aspects of the disclosure, in a compound of formula (IA), a pharmaceutically acceptable salt, or stereoisomer thereof, A1 is selected from CR2 or a N atom; A2 is selected from CR2 or an O atom; R1 is selected from H, F, Cl, Br, I, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an s-butyl group, a t-butyl group, a methoxy group, an ethoxy group, an n-propoxy group, and an isopropoxy group; Each R2 is independently selected from H, a methyl group, or an ethyl group.

[0006] In some aspects of the disclosure, in a compound of formula (IA), a pharmaceutically acceptable salt, or stereoisomer thereof, A1 is selected from CR2 or a N atom; A2 is selected from CR2 or an O atom; R1 is selected from H, F, a methyl group, or a methoxy group; Each R2 is independently selected from H or a methyl group.

[0007] In one embodiment of the present disclosure, there is provided a compound represented by formula (IA-1) or (IA-2), or a pharmaceutically acceptable salt thereof: TIFF2025525370000003.tif34170A1 is selected from CR2 or N atoms, A2 is selected from CR2 or an O atom; R1 is selected from H, F, a methyl group, or a methoxy group; R2 is independently selected from H or a methyl group.

[0008] In one embodiment of the present disclosure, there is provided a compound represented by formula (IA-3) or (IA-4), or a pharmaceutically acceptable salt thereof: TIFF2025525370000004.tif36170Of which, A1 is selected from CH or N atoms; A2 is selected from CH2 or an O atom; R1 is H, halogen, C 1-6 Alkyl group or C 1-6 selected from alkoxy groups, R2 is H, C 1-6 alkyl groups or groups represented by the formula: TIFF2025525370000005.tif9170Of which, Z1 is a bond or C 1-3 alkyl groups, Z2 is selected from a bond, —O—, —NH—, —S—, —(C═O)—, —O(C═O)—, or —(C═O)O—; Z3 is a bond, C 1-6 selected from an alkyl group, a phenyl group, -CH(NHAc)-CH2CH2-, -CH(CH3)-NHC(=O)-CH(CH3)-, -CH(CH3)-OC(=O)-, and -CH2CH2CH2CH2CH(NH2)-; Z4 is selected from a bond, -O-, -NH-, -S-, -(C=O)-, -O(C=O)-, or -(C=O)O-; Z5 is H, C 1-12 Alkyl groups, -P(=O)(OH)2, Selected from TIFF2025525370000006.tif11170.

[0009] In some embodiments of the present disclosure, the compound of formula (IA-3) or (IA-4), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, A1 is selected from CH or N atoms; A2 is selected from CH2 or an O atom; R1 is selected from H, F, a methyl group, or a methoxy group; R2 is selected from H, a methyl group, or a group represented by the formula: TIFF2025525370000007.tif9170Of which, Z1 is selected from a bond, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group; Z2 is selected from a bond, —O—, —NH—, —S—, —(C═O)—, —O(C═O)—, or —(C═O)O—; Z3 is selected from a bond, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a s-butyl group, a t-butyl group, an n-pentyl group, an n-hexyl group, a phenyl group, -CH(NHAc)-CH2CH2-, -CH(CH3)-NHC(=O)-CH(CH3)-, -CH(CH3)-OC(=O)-, and -CH2CH2CH2CH2CH(NH2)-; Z4 is selected from a bond, -O-, -NH-, -S-, -(C=O)-, -O(C=O)-, or -(C=O)O-; Z5 is H, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, n-undecyl group, n-dodecyl group, -P(=O)(OH)2, Selected from TIFF2025525370000008.tif11170.

[0010] In some embodiments of the present disclosure, the compound of formula (IA-3) or (IA-4), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, A1 is selected from CH or N atoms; A2 is selected from CH2 or an O atom; R1 is selected from H, F, a methyl group, or a methoxy group; R2 is H, methyl group, isopropyl group, OH, Selected from TIFF2025525370000009.tif90170.

[0011] In some aspects of the disclosure, a compound of formula (IA-3) or (IA-4), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof is a prodrug of a compound of formula (IA-1) or (IA-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0012] In one embodiment of the present disclosure, there is provided a compound of formula (IB), a pharmaceutically acceptable salt, or stereoisomer thereof: TIFF2025525370000010.tif31170Of these, (1) A1 is selected from an O atom or a S atom; R1 is F, C 1-6 Alkoxy group, C 3-6 Cycloalkoxy groups, halogenated C 1-6 Alkoxy group, C 3-6 Cycloalkyl group, or C 1-6 alkyl-(C=O)-; Each R2 is independently H or C 1-6 alkyl groups, or (2) A1 is selected from NH; R1 is C 1-6 Alkoxy group, C 3-6 Cycloalkoxy groups, halogenated C 1-6 Alkoxy group, C 3-6 Cycloalkyl group, or C 1-6 alkyl-(C=O)-; Each R2 is independently H or C 1-6 alkyl groups, or (3) A1 is selected from CH2; R1 is C 2-6 Alkoxy group, C3-6 Cycloalkoxy groups, halogenated C 1-6 Alkoxy group, C 3-6 Cycloalkyl group, or C 1-6 alkyl-(C=O)-; Each R2 is independently H or C 1-6 It is selected from alkyl groups.

[0013] In some aspects of the disclosure, the compound of formula (IB), a pharmaceutically acceptable salt, or stereoisomer thereof, A1 is selected from an O atom or a S atom; R1 is selected from F, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, pentachloroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl-(C=O)-, or ethyl-(C=O)-; R2 is independently selected from H or a methyl group.

[0014] In some aspects of the disclosure, the compound of formula (IB), a pharmaceutically acceptable salt, or stereoisomer thereof, A1 is selected from NH; R1 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, pentachloroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl-(C=O)-, or ethyl-(C=O)-; R2 is independently selected from H or a methyl group.

[0015] In some aspects of the disclosure, the compound of formula (IB), a pharmaceutically acceptable salt, or stereoisomer thereof, A1 is selected from CH2; R1 is selected from ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, pentachloroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl-(C=O)-, or ethyl-(C=O)-; R2 is independently selected from H or a methyl group.

[0016] In one embodiment of the present disclosure, there is provided a compound represented by formula (IB-1) or (IB-2), or a pharmaceutically acceptable salt thereof: TIFF2025525370000011.tif31170Of these, (1) A1 is selected from an O atom or a S atom; R1 is selected from F, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, pentachloroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl-(C=O)-, or ethyl-(C=O)-; each R2 is independently selected from H or a methyl group; or (2) A1 is selected from NH; R1 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, pentachloroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl-(C=O)-, or ethyl-(C=O)-; each R2 is independently selected from H or a methyl group; or (3) A1 is selected from CH2; R1 is selected from ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, pentachloroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl-(C=O)-, or ethyl-(C=O)-; Each R2 is independently selected from H or a methyl group.

[0017] In one embodiment of the present disclosure, there is provided a compound of formula (II), a pharmaceutically acceptable salt, or stereoisomer thereof: TIFF2025525370000012.tif48170Of which, X1 is selected from an S atom or an O atom, and X2 is selected from CH, or X2 is selected from an S atom or an O atom, and X1 is selected from CH; (1) Y1 is selected from O atoms, TIFF2025525370000013.tif3170 is optionally a single bond or a double bond; When TIFF2025525370000014.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6a R 6b ) are selected from If TIFF2025525370000015.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b One of the groups is selected from H and the other is C 1-6 alkyl groups or R 3a and R 3b are all C 1-6alkyl groups, R 5a , R 5b , R 6a and R 6b are independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, or R 5a and R 5b , R 6a and R 6b together form an oxo (-C=O) and R 5a , R 5b , R 6a and R 6b At least one of the is not hydrogen, or (2) Y1 is selected from NR4 or an S atom; TIFF2025525370000016.tif3170 is optionally a single bond or a double bond; When TIFF2025525370000017.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6a R 6b ) are selected from If TIFF2025525370000018.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b One of the groups is selected from H and the other is C 1-6 alkyl groups or R 3a and R 3b are all selected from H, R4 is independently H or C 1-6 alkyl groups, R 5a , R 5b , R 6a and R 6b are independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C1-3 Alkyl group or C 6-10 aryl groups, or R 5a and R 5b , R 6a and R 6b together form oxo (-C=O), or (3) Y3 is selected from an O atom, NR6, or S atom; TIFF2025525370000019.tif3170 is a single bond, and Y1 is C(R 4a R 4b ), or Y1 is absent and Y2 is selected from C(R 5a R 5b ) are selected from R 3a and R 3b are independently H or C 1-6 alkyl groups, R 4a , R 4b , R 5a and R 5b are independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, or R 4a and R 4b , R 5a and R 5b together form oxo (-C=O), R6 is independently H or C 1-6 It is selected from alkyl groups.

[0018] In some aspects of the present disclosure, in a compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, (1) Y1 is selected from O atoms, TIFF2025525370000020.tif3170 is optionally a single bond or a double bond; When TIFF2025525370000021.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6aR 6b ) are selected from If TIFF2025525370000022.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b One of the groups is selected from H and the other is C 1-6 alkyl groups or R 3a and R 3b are all C 1-6 alkyl groups, R 5a , R 5b , R 6a are independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, R 6b are independently H, C 2-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, or R 5a and R 5b , R 6a and R 6b together form an oxo (-C=O) and R 5a , R 5b , R 6a and R 6b At least one of the is not hydrogen, or R 5a , R 5b are independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, R 6a and R 6b At the same time, C 1-6 alkyl groups, or R 5a and R 5b At the same time, C 1-6 alkyl groups, R 6a , R 6bare independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, or (2) Y1 is selected from NR4 or an S atom; TIFF2025525370000023.tif3170 is optionally a single bond or a double bond; When TIFF2025525370000024.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6a R 6b ) are selected from If TIFF2025525370000025.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b One of the groups is selected from H and the other is C 1-6 alkyl groups, R4 is independently H or C 1-6 alkyl groups, R 5a , R 5b , R 6a and R 6b are independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, or R 5a and R 5b , R 6a and R 6b together form oxo (-C=O), or (3) Y3 is selected from an O atom, NR6, or S atom; TIFF2025525370000026.tif3170 is a single bond, and Y1 is C(R 4a R 4b ), or Y1 is absent and Y2 is selected from C(R5a R 5b ) are selected from R 3a and R 3b are independently H or C 1-6 alkyl groups, R 4a , R 4b , R 5a and R 5b are independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, or R 4a and R 4b together form an oxo (-C=O) and R 4a , R 4b , R 5a and R 5b At least one of the is not hydrogen, R6 is independently H or C 1-6 It is selected from alkyl groups.

[0019] In some embodiments of the present disclosure, in the compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, X1 is selected from an S atom or an O atom, X2 is selected from CH, and the other variables are as defined in the present disclosure.

[0020] In some aspects of the present disclosure, in the compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, X2 is selected from an S atom or an O atom, X1 is selected from CH, and the other variables are as defined in the present disclosure.

[0021] In some aspects of the present disclosure, in a compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, R 3a and R 3b one of which is selected from H and the other is selected from a methyl group, or R 3a and R 3b are each selected from methyl groups, R4 is independently selected from H or a methyl group; R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl, or R 4a and R 4b , R 5a and R 5b , R 6a and R 6b together form oxo (-C=O), R6 is independently selected from H or a methyl group; Other variables are as defined in this disclosure.

[0022] In some aspects of the present disclosure, in a compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, X1 is selected from an S atom or an O atom, and X2 is selected from CH; Y1 is selected from O atoms, TIFF2025525370000027.tif3170 is optionally a single bond or a double bond; When TIFF2025525370000028.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6a R 6b ) are selected from If TIFF2025525370000029.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b one of which is selected from H and the other is selected from a methyl group, or R 3a and R 3b are each selected from methyl groups, R 5a , R 5b , R 6a and R 6bare independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl, or R 5a and R 5b , R 6a and R 6b together form an oxo (-C=O) and R 5a , R 5b , R 6a and R 6b At least one of them is not hydrogen.

[0023] In some aspects of the present disclosure, in a compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, X1 is selected from an S atom or an O atom, and X2 is selected from CH; Y1 is selected from O atoms, TIFF2025525370000030.tif3170 is optionally a single bond or a double bond; When TIFF2025525370000031.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6a R 6b ) are selected from If TIFF2025525370000032.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b one of which is selected from H and the other is selected from a methyl group, or R 3a and R 3b are each selected from methyl groups, R 5a , R 5b , R 6a are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl; R 6b are independently selected from H, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl, or R 5a and R 5b, R 6a and R 6b together form an oxo (-C=O) and R 5a , R 5b , R 6a and R 6b At least one of the is not hydrogen, or R 5a , R 5b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl; R 6a and R 6b are simultaneously selected from methyl groups, or R 5a and R 5b are simultaneously selected from methyl groups, and R 6a , R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl.

[0024] In some aspects of the present disclosure, in a compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, X1 is selected from an S atom or an O atom, and X2 is selected from CH; Y1 is selected from NR4 or an S atom; TIFF2025525370000033.tif3170 is optionally a single bond or a double bond; When TIFF2025525370000034.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6a R 6b ) are selected from If TIFF2025525370000035.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b one of which is selected from H and the other is selected from a methyl group, or R 3a and R 3b are all selected from H, R4 is independently selected from H or a methyl group; R 5a , R 5b , R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl, or R 5a and R 5b , R 6a and R 6b together form oxo (-C=O).

[0025] In some aspects of the present disclosure, in a compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, X1 is selected from an S atom or an O atom, and X2 is selected from CH; Y1 is selected from NR4 or an S atom; TIFF2025525370000036.tif3170 is optionally a single bond or a double bond; When TIFF2025525370000037.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6a R 6b ) are selected from If TIFF2025525370000038.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b one of which is selected from H and the other is selected from a methyl group; R4 is independently selected from H or a methyl group; R 5a , R 5b , R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl, or R 5a and R 5b , R 6a and R6b together form oxo (-C=O).

[0026] In some aspects of the present disclosure, in a compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, X1 is selected from an S atom or an O atom, and X2 is selected from CH; Y3 is selected from an O atom, NR6, or an S atom; TIFF2025525370000039.tif3170 is a single bond, and Y1 is C(R 4a R 4b ), or Y1 is absent and Y2 is selected from C(R 5a R 5b ) are selected from R 3a and R 3b are independently selected from H or a methyl group; R 4a , R 4b , R 5a and R 5b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl, or R 4a and R 4b , R 5a and R 5b together form oxo (-C=O), R6 is independently selected from H or a methyl group.

[0027] In some aspects of the present disclosure, in a compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, X1 is selected from an S atom or an O atom, and X2 is selected from CH; Y3 is selected from an O atom, NR6, or an S atom; TIFF2025525370000040.tif3170 is a single bond, and Y1 is C(R 4a R 4b ), or Y1 is absent and Y2 is selected from C(R 5a R 5b ) are selected from R 3aand R 3b are independently selected from H or a methyl group; R 4a , R 4b , R 5a and R 5b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl, or R 4a and R 4b together form an oxo (-C=O) and R 4a , R 4b , R 5a and R 5b At least one of the is not hydrogen, R6 is independently selected from H or a methyl group.

[0028] In some aspects of the present disclosure, in a compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, X1 is selected from S atoms and X2 is selected from CH; Y1 is selected from NR4 or an S atom; When TIFF2025525370000041.tif3170 is a single bond, Y2 and Y3 are both selected from CH2; R 3a and R 3b one of which is selected from H and the other is selected from a methyl group; R4 is H or C 1-6 It is selected from alkyl groups, preferably H or methyl groups.

[0029] In one embodiment of the present disclosure, there is provided a compound represented by formula (IIA) or (IIB), or a pharmaceutically acceptable salt thereof: TIFF2025525370000042.tif54170Of these, X1 is selected from an S atom or an O atom, and X2 is selected from CH, or X2 is selected from an S atom or an O atom, and X1 is selected from CH; (1) Y1 is selected from O atoms, TIFF2025525370000043.tif3170 is optionally a single bond or a double bond; When TIFF2025525370000044.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6a R 6b ) are selected from If TIFF2025525370000045.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b One of the groups is selected from H and the other is C 1-6 alkyl groups or R 3a and R 3b are all C 1-6 alkyl groups, R 5a , R 5b , R 6a and R 6b are independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, or R 5a and R 5b , R 6a and R 6b together form an oxo (-C=O) and R 5a , R 5b , R 6a and R 6b At least one of the is not hydrogen, or (2) Y1 is selected from NR4 or an S atom; TIFF2025525370000046.tif3170 is optionally a single bond or a double bond, When TIFF2025525370000047.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6a R6b ) are selected from If TIFF2025525370000048.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b One of the groups is selected from H and the other is C 1-6 alkyl groups or R 3a and R 3b are all selected from H, R4 is independently H or C 1-6 alkyl groups, R 5a , R 5b , R 6a and R 6b are independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, or R 5a and R 5b , R 6a and R 6b together form oxo (-C=O), or (3) Y3 is selected from an O atom, NR6, or S atom; TIFF2025525370000049.tif3170 is a single bond, and Y1 is C(R 4a R 4b ), or Y1 is absent and Y2 is selected from C(R 5a R 5b ) are selected from R 3a and R 3b are independently H or C 1-6 alkyl groups, R 4a , R 4b , R 5a and R 5b are independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, or R4a and R 4b , R 5a and R 5b together form oxo (-C=O), R6 is independently H or C 1-6 It is selected from alkyl groups.

[0030] In some aspects of the present disclosure, in a compound of formula (IIA) or (IIB), a pharmaceutically acceptable salt, or stereoisomer thereof, (1) Y1 is selected from O atoms, TIFF2025525370000050.tif3170 is optionally a single bond or a double bond; When TIFF2025525370000051.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6a R 6b ) are selected from If TIFF2025525370000052.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b One of the groups is selected from H and the other is C 1-6 alkyl groups or R 3a and R 3b are all C 1-6 alkyl groups, R 5a , R 5b , R 6a are independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, R 6b are independently H, C 2-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, or R 5a and R 5b, R 6a and R 6b together form an oxo (-C=O) and R 5a , R 5b , R 6a and R 6b At least one of the is not hydrogen, or R 5a , R 5b are independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, R 6a and R 6b At the same time, C 1-6 alkyl groups, or R 5a and R 5b At the same time, C 1-6 alkyl groups, R 6a , R 6b are independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, or (2) Y1 is selected from NR4 or an S atom; TIFF2025525370000053.tif3170 is optionally a single bond or a double bond; When TIFF2025525370000054.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6a R 6b ) are selected from If TIFF2025525370000055.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b One of the groups is selected from H and the other is C 1-6 alkyl groups, R4 is independently H or C1-6 alkyl groups, R 5a , R 5b , R 6a and R 6b are independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, or R 5a and R 5b , R 6a and R 6b together form oxo (-C=O), or (3) Y3 is selected from an O atom, NR6, or S atom; TIFF2025525370000056.tif3170 is a single bond, and Y1 is C(R 4a R 4b ), or Y1 is absent and Y2 is selected from C(R 5a R 5b ) are selected from R 3a and R 3b are independently H or C 1-6 alkyl groups, R 4a , R 4b , R 5a and R 5b are independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, or R 4a and R 4b together form an oxo (-C=O) and R 4a , R 4b , R 5a and R 5b At least one of the is not hydrogen, R6 is independently H or C 1-6 It is selected from alkyl groups.

[0031] In some embodiments of the present disclosure, in the compound of formula (IIA) or (IIB), or a pharmaceutically acceptable salt thereof, X1 is selected from an S atom or an O atom, X2 is selected from CH, and the other variables are as defined in the present disclosure.

[0032] In some embodiments of the present disclosure, in the compound of formula (IIA) or (IIB), or a pharmaceutically acceptable salt thereof, X2 is selected from an S atom or an O atom, X1 is selected from CH, and the other variables are as defined in the present disclosure.

[0033] In some aspects of the present disclosure, the compound of formula (IIA) or (IIB), or a pharmaceutically acceptable salt thereof, R 3a and R 3b one of which is selected from H and the other is selected from a methyl group, or R 3a and R 3b are each selected from methyl groups, R4 is independently selected from H or a methyl group; R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl, or R 4a and R 4b , R 5a and R 5b , R 6a and R 6b together form oxo (-C=O), R6 is independently selected from H or a methyl group; Other variables are as defined in this disclosure.

[0034] In some aspects of the present disclosure, the compound of formula (IIA) or (IIB), or a pharmaceutically acceptable salt thereof, X1 is selected from an S atom or an O atom, and X2 is selected from CH; Y1 is selected from O atoms, TIFF2025525370000057.tif3170 is optionally a single bond or a double bond; When TIFF2025525370000058.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6a R 6b ) are selected from If TIFF2025525370000059.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b one of which is selected from H and the other is selected from a methyl group, or R 3a and R 3b are each selected from methyl groups, R 5a , R 5b , R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl, or R 5a and R 5b , R 6a and R 6b together form an oxo (-C=O) and R 5a , R 5b , R 6a and R 6b At least one of them is not hydrogen.

[0035] In some aspects of the present disclosure, in a compound of formula (IIA) or (IIB), a pharmaceutically acceptable salt, or stereoisomer thereof, X1 is selected from an S atom or an O atom, and X2 is selected from CH; Y1 is selected from O atoms, TIFF2025525370000060.tif3170 is optionally a single bond or a double bond; When TIFF2025525370000061.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6a R 6b ) are selected from If TIFF2025525370000062.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b one of which is selected from H and the other is selected from a methyl group, or R 3a and R 3b are each selected from methyl groups, R 5a , R 5b , R 6a are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl; R 6b are independently selected from H, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl, or R 5a and R 5b , R 6a and R 6b together form an oxo (-C=O) and R 5a , R 5b , R 6a and R 6b At least one of the is not hydrogen, or R 5a , R 5b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl; R 6a and R 6b are simultaneously selected from methyl groups, or R 5a and R 5b are simultaneously selected from methyl groups, and R 6a , R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl.

[0036] In some aspects of the present disclosure, in a compound of formula (IIA) or (IIB), a pharmaceutically acceptable salt, or stereoisomer thereof, X1 is selected from an S atom or an O atom, and X2 is selected from CH; Y1 is selected from NR4 or an S atom; TIFF2025525370000063.tif3170 is optionally a single bond or a double bond; If TIFF2025525370000064.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6a R 6b ) are selected from If TIFF2025525370000065.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b one of which is selected from H and the other is selected from a methyl group, or R 3a and R 3b are all selected from H, R4 is independently selected from H or a methyl group; R 5a , R 5b , R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl, or R 5a and R 5b , R 6a and R 6b together form oxo (-C=O).

[0037] In some aspects of the present disclosure, in a compound of formula (IIA) or (IIB), a pharmaceutically acceptable salt, or stereoisomer thereof, X1 is selected from an S atom or an O atom, and X2 is selected from CH; Y1 is selected from NR4 or an S atom; TIFF2025525370000066.tif3170 is optionally a single bond or a double bond; When TIFF2025525370000067.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6a R 6b ) are selected from If TIFF2025525370000068.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b one of which is selected from H and the other is selected from a methyl group; R4 is independently selected from H or a methyl group; R 5a , R 5b , R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl, or R 5a and R 5b , R 6a and R 6b together form oxo (-C=O).

[0038] In some aspects of the present disclosure, in a compound of formula (IIA) or (IIB), a pharmaceutically acceptable salt, or stereoisomer thereof, X1 is selected from an S atom or an O atom, and X2 is selected from CH; Y3 is selected from an O atom, NR6, or an S atom; TIFF2025525370000069.tif3170 is a single bond, and Y1 is C(R 4a R 4b ), or Y1 is absent and Y2 is selected from C(R 5a R 5b ) are selected from R 3a and R 3b are independently selected from H or a methyl group; R 4a , R 4b , R 5a and R 5b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl, or R 4a and R 4b , R 5a and R 5b together form oxo (-C=O), R6 is independently selected from H or a methyl group.

[0039] In some aspects of the present disclosure, in a compound of formula (IIA) or (IIB), a pharmaceutically acceptable salt, or stereoisomer thereof, X2 is selected from an S atom or an O atom, and X1 is selected from CH; Y1 is selected from O atoms, TIFF2025525370000070.tif3170 is optionally a single bond or a double bond; When TIFF2025525370000071.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6a R 6b ) are selected from If TIFF2025525370000072.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b one of which is selected from H and the other is selected from a methyl group, or R 3a and R 3b are each selected from methyl groups, R 5a , R 5b , R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl, or R 5a and R 5b , R6a and R 6b together form an oxo (-C=O) and R 5a , R 5b , R 6a and R 6b At least one of them is not hydrogen.

[0040] In some aspects of the present disclosure, in a compound of formula (IIA) or (IIB), a pharmaceutically acceptable salt, or stereoisomer thereof, X2 is selected from an S atom or an O atom, and X1 is selected from CH; Y1 is selected from NR4 or an S atom; TIFF2025525370000073.tif3170 is optionally a single bond or a double bond; When TIFF2025525370000074.tif3170 is a single bond, Y2 is C(R 5a R 5b ), and Y3 is selected from C(R 6a R 6b ) are selected from If TIFF2025525370000075.tif3170 is a double bond, Y2 is CR 5a Y3 is selected from CR 6a Selected from R 3a and R 3b one of which is selected from H and the other is selected from a methyl group, or R 3a and R 3b are all selected from H, R4 is independently selected from H or a methyl group; R 5a , R 5b , R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl, or R 5a and R 5b , R 6a and R 6b together form oxo (-C=O).

[0041] In some aspects of the present disclosure, in a compound of formula (IIA) or (IIB), a pharmaceutically acceptable salt, or stereoisomer thereof, X2 is selected from an S atom or an O atom, and X1 is selected from CH; Y3 is selected from an O atom, NR6, or an S atom; TIFF2025525370000076.tif3170 is a single bond, and Y1 is C(R 4a R 4b ), or Y1 is absent and Y2 is selected from C(R 5a R 5b ) are selected from R 3a and R 3b are independently selected from H or a methyl group; R 4a , R 4b , R 5a and R 5b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl, or R 4a and R 4b , R 5a and R 5b together form oxo (-C=O), R6 is independently selected from H or a methyl group.

[0042] In some aspects of the present disclosure, in a compound of formula (IIA) or (IIB), a pharmaceutically acceptable salt, or stereoisomer thereof, X1 is selected from an S atom or an O atom, and X2 is selected from CH; Y3 is selected from an O atom, NR6, or an S atom; TIFF2025525370000077.tif3170 is a single bond, and Y1 is C(R 4a R 4b ), or Y1 is absent and Y2 is selected from C(R 5a R 5b ) are selected from R 3a and R 3b are independently selected from H or a methyl group; R4a , R 4b , R 5a and R 5b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl, or R 4a and R 4b together form an oxo (-C=O) and R 4a , R 4b , R 5a and R 5b At least one of the is not hydrogen, R6 is independently selected from H or a methyl group.

[0043] In some aspects of the present disclosure, in a compound of formula (IIA) or (IIB), a pharmaceutically acceptable salt, or stereoisomer thereof, X1 is selected from S atoms and X2 is selected from CH; Y1 is selected from NR4 or an S atom; When TIFF2025525370000078.tif3170 is a single bond, Y2 and Y3 are both selected from CH2; R 3a and R 3b one of which is selected from H and the other is selected from a methyl group; R4 is H or C 1-6 It is selected from alkyl groups, preferably H or methyl groups.

[0044] In one embodiment of the present disclosure, there is provided a compound represented by formula (III), a pharmaceutically acceptable salt, or stereoisomer thereof: TIFF2025525370000079.tif48170Of which, X3 is selected from an S atom or an O atom; Y2 is C(R 5a R 5b ) and Y3 is selected from an O atom, NR6, or S atom; R 3a and R 3b are independently H or C 1-6 alkyl groups, R5a are independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, R 5b is independently C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, or R 5a and R 5b together form oxo (-C=O), R6 is independently H or C 1-6 It is selected from alkyl groups.

[0045] In some aspects of the present disclosure, the compound of formula (III), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, R 3a and R 3b are independently selected from H or a methyl group; R 5a are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl; R 5b are independently selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxymethyl group, and a phenyl group, or R 5a and R 5b together form oxo (-C=O), R6 is independently selected from H or a methyl group.

[0046] In one embodiment of the present disclosure, there is provided a compound of formula (IIIA) or (IIIB), a pharmaceutically acceptable salt, or stereoisomer thereof: TIFF2025525370000080.tif48170Of these, X3 is selected from an S atom or an O atom; Y2 is C(R 5a R 5b ) and Y3 is selected from an O atom, NR6, or S atom; R 3a and R3b are independently H or C 1-6 alkyl groups, R 5a are independently H, C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, R 5b is independently C 1-6 Alkyl group, C 1-3 Alkoxy C 1-3 Alkyl group or C 6-10 aryl groups, or R 5a and R 5b together form oxo (-C=O), R6 is independently H or C 1-6 It is selected from alkyl groups.

[0047] In some aspects of the present disclosure, in a compound of formula (IIIA) or (IIIB), a pharmaceutically acceptable salt, or stereoisomer thereof, R 3a and R 3b are independently selected from H or a methyl group; R 5a are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl; R 5b are independently selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxymethyl group, and a phenyl group, or R 5a and R 5b together form oxo (-C=O), R6 is independently selected from H or a methyl group.

[0048] In another embodiment of the present disclosure, there is provided a compound, pharmaceutically acceptable salt, or stereoisomer shown below: TIFF2025525370000081.tif220170TIFF2025525370000082.tif137170

[0049] In another embodiment of the present disclosure, there is provided a compound, stereoisomer, or pharmaceutically acceptable salt thereof shown below: TIFF2025525370000083.tif243170TIFF2025525370000084.tif232170TIFF2025525370000085.tif245170TIFF2025525370000086.tif34170

[0050] In another embodiment of the present disclosure, there is provided a compound, stereoisomer, or pharmaceutically acceptable salt thereof shown below: TIFF2025525370000087.tif207170

[0051] The present disclosure further provides a pharmaceutical composition comprising any one of the above compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition can be prepared in various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, granules, and injections. The pharmaceutical composition can be administered orally or parenterally (e.g., intravenously, subcutaneously, or topically). The dosage can be adjusted appropriately depending on the patient's age, sex, and disease type, and the usual daily dose is about 1 to 200 mg.

[0052] The present disclosure further provides the use of the above compound, its pharmaceutically acceptable salt, stereoisomer, or pharmaceutical composition in the preparation of a TAAR, particularly a TAAR1 agonist drug.

[0053] The present disclosure further provides the use of the above compound, its pharmaceutically acceptable salt, stereoisomer, or pharmaceutical composition in the preparation of a medicament for treating a TAAR, particularly a TAAR1 mediated related disease.

[0054] The present disclosure further provides the use of the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, or pharmaceutical composition for preventing and / or treating TAAR, particularly TAAR1 mediated related diseases.

[0055] The present disclosure provides methods of treating, preventing, and / or controlling various central nervous system (CNS)-related diseases or conditions using compounds provided by the present disclosure, their pharmaceutically acceptable salts, stereoisomers, or compositions. The present disclosure further provides use of compounds provided by the present disclosure, their pharmaceutically acceptable salts, stereoisomers, or compositions in the preparation of a medicament for treating, preventing, and / or controlling a central nervous system (CNS)-related disease or condition. The central nervous system (CNS) diseases or conditions include schizophrenia, schizophrenia spectrum disorders, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, psychotic mental disorders, schizophreniform personality disorder, schizotypal personality disorder, delusional psychosis, psychosis, mental disorder, brief psychotic disorder, shared mental disorder, mental disorder due to physical illness, drug (e.g., cocaine, alcohol, amphetamine)-induced psychosis, psychoemotional disorder, aggressive delirium, Parkinson's psychosis, irritable psychosis, Tourette's syndrome, organic or NOS psychosis, epilepsy, epileptic seizures, and psychotic disorders. agitation, post-traumatic stress disorder, behavioral confusion, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dyskinesias, Huntington's disease, dementia, affective disorders, anxiety disorders, affective psychoses (e.g., depression such as major depressive disorder and dyskinesia, bipolar disorders such as bipolar depression, mania, seasonal affective disorder, and attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)), obsessive-compulsive disorder, dizziness, pain (e.g., neuropathic pain, neuropathic pain sensitivity states, and inflammatory pain), fibromyalgia, migraine, cognitive impairment, movement disorders These conditions include, but are not limited to, sleep disorders, restless legs syndrome (RLS), multiple sclerosis, psychoactive substance (e.g., nicotine, cocaine) abuse, stress-related disorders (e.g., acute stress disorder, post-traumatic stress disorder, adjustment disorder), sexual dysfunction, eating disorders, temperature homeostasis and dysfunction, sleep disorders, sleep apnea, somnolence, excessive daytime sleepiness, jet lag reaction, drowsiness side effects of medications, insomnia, sleep and circadian rhythm disorders, energy expenditure and assimilation disorders, vomiting, Lesche-Nyhane disease, Wilson disease, autism, Huntington's chorea, and premenstrual anxiety.

[0056] The present disclosure provides methods for treating, preventing, and / or controlling cardiovascular or metabolic diseases using compounds provided by the present disclosure, pharmaceutically acceptable salts, stereoisomers, or compositions thereof. The present disclosure further provides use of compounds provided by the present disclosure, pharmaceutically acceptable salts, stereoisomers, or compositions thereof in the preparation of a medicament for treating, preventing, and / or controlling cardiovascular or metabolic diseases, including, but not limited to, diabetes, diabetic complications, obesity, dyslipidemia, and hypertension. [Brief explanation of the drawings]

[0057] [Figure 1] Pharmacodynamic evaluation of compounds 1-b and L27 in a mouse hyperactivity model. [Figure 2] Pharmacodynamic evaluation of compounds 1-b and 2-a in a mouse hyperactivity model. Definitions and Explanations

[0058] Unless otherwise specified, the following terms and phrases used herein shall have the following meanings: A particular term or phrase, unless specifically defined, should not be considered indefinite or unclear, but should be understood in its general sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0059] "Pharmaceutically acceptable," as used in this disclosure, refers to compounds, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0060] "Pharmaceutically acceptable salts" as used herein refer to salts of compounds of the present disclosure, prepared from compounds having specific substituents found in the present disclosure and relatively non-toxic acids and bases. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of acid in a pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts, including salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Some specific compounds of the present disclosure contain a basic functional group and can therefore be converted into any of the acid addition salts.

[0061] Some compounds of the present disclosure may possess asymmetric carbon atoms (optical centers) or double bonds. The racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present disclosure.

[0062] Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure is intended to encompass all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers. Substituents, such as alkyl groups, may also contain other asymmetric carbon atoms. All such isomers and mixtures thereof are within the scope of the present disclosure.

[0063] Pharmaceutically acceptable salts according to the present disclosure can be synthesized from parent compounds that contain an acid or base group by conventional chemical methods. In general, salts are prepared by reacting these compounds in their free acid or free base form with the stoichiometrically appropriate base or acid in water or an organic solvent, or a mixture of both.

[0064] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium representative of a carrier capable of delivering an effective amount of an active agent of the present disclosure, not interfering with the biological activity of the active agent, and having no toxicity or adverse side effects to the host or patient, including, but not limited to, binders, fillers, lubricants, disintegrants, wetting agents, dispersing agents, solubilizing agents, suspending agents, and the like.

[0065] The present disclosure is intended to include all isotopes of atoms present in the compounds of the present disclosure. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described herein, using the appropriate isotopically labeled reagent in place of the unlabeled reagent for further use.

[0066] Unless otherwise specified, the term "alkyl group" is intended to represent a straight- or branched-chain saturated hydrocarbon group, which may be mono-substituted (e.g., -CHF) or poly-substituted (e.g., -CF), and which may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). For example, C1-C 12 represents 1 to 12 carbons, and C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12Examples of the alkyl group include a methyl group (Me), an ethyl group (Et), a propyl group (e.g., n-propyl and isopropyl groups), a butyl group (e.g., n-butyl, isobutyl, s-butyl, and t-butyl groups), a pentyl group (e.g., n-pentyl, isoamyl, neopentyl, and 1-ethylpropyl groups), a hexyl group (e.g., n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl groups), an n-heptyl group (n-heptyl group), an n-octyl group (n-octyl group), an n-nonyl group (n-nonyl group), an n-decyl group (n-decyl group), an n-undecyl group (n-undecyl group), and an n-dodecyl group (n-dodecyl group).

[0067] Unless otherwise stated, the terms "halogenated" or "halogen," by themselves or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0068] Unless otherwise specified, the term "halogenated alkyl group" is intended to represent a mono- or poly-halogenated straight or branched chain alkyl group. Typical halogenated alkyl groups include C 1-6 Halogenated alkyl groups include, for example, C1, C2, C3, C4, C5, and C6 halogenated alkyl groups. For example, examples of C1-C6 halogenated alkyl groups include, but are not limited to, a fluoromethyl group, a chloromethyl group, a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, a trichloromethyl group, a 2,2-difluoroethyl group, a 2,2-dichloroethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group, a pentafluoroethyl group, and a pentachloroethyl group.

[0069] Unless otherwise specified, "alkoxy" refers to an alkyl group as defined above (including a cycloalkyl group or a halogenated alkyl group) with the specified number of carbon atoms connected through an oxygen bridge. Exemplary alkoxy groups include C 1-6Alkoxy groups include, for example, C1, C2, C3, C4, C5, and C6 alkoxy groups, C3, C4, C5, and C6 cycloalkoxy groups, and C1, C2, C3, C4, C5, and C6 halogenated alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, S-pentyloxy, hexyloxy, and 2-ethylbutoxy groups. Examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy groups. Examples of halogenated alkoxy groups include, but are not limited to, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, and pentachloroethoxy groups.

[0070] Unless otherwise specified, "cycloalkyl group" refers to a saturated or partially unsaturated, monocyclic or polycyclic cyclic hydrocarbon substituent, which may be mono- or polysubstituted, and which may be mono-, di- or polyvalent. Illustrative examples of these cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0071] Unless otherwise specified, an "aryl group" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated π-electron system, such as phenyl and naphthyl groups, preferably phenyl groups.

[0072] Unless otherwise specified, the term "bond / single bond" refers to a chemical bond between atoms for interconnection or interaction, such as an ionic bond, covalent bond, coordinate bond, etc., and in the molecular structure of an organic compound, a "bond / single bond" is usually a covalent bond. When one or more variables between two atoms / groups are defined as a "bond / single bond," it usually means that the two atoms / groups are directly connected by a "bond / single bond."

[0073] The term "prodrug" refers to a form of a compound that can be converted by metabolism in vivo to have biological activity.

[0074] When the compounds of the present disclosure have an absolute configuration, the absolute configuration can be confirmed by conventional means in the art. For example, in single crystal X-ray diffraction (SXRD), diffraction intensity data for a cultured single crystal is collected using a Bruker D8 venture diffractometer, with a CuKα radiation source and a φ / ω scanning method. After collecting the relevant data, the crystal structure is further analyzed by a direct method (Shelxs97), thereby confirming the absolute configuration. The instrument used to detect the hydrogen nuclear magnetic resonance spectrum of the compounds of the present disclosure is a Bruker / AVANCE NEO 400 MHz.

[0075] Compounds are named artificially or in ChemDraw® software; commercially available compounds adopt the supplier's catalogue name. DETAILED DESCRIPTION OF THE INVENTION

[0076] The present disclosure will be further explained below in conjunction with specific examples and test examples, but the scope of the present disclosure is not limited in any way.

[0077] Example 1 Synthetic Route: Compound 1-1 (5.00 g, 30.6 mmol, 1.00 eq) and NaHCO3 (5.65 g, 67.2 mmol, 2.61 mL, 2.20 eq) were dissolved in THF (100 mL) and water (10.0 mL). The mixture was cooled to 0-5 °C and chloroacetyl chloride (5.31 g, 47.05 mmol, 1.10 eq) was added dropwise. After the addition was complete, the mixture was allowed to warm to 20 °C and stirred for 24 h. Additional NaHCO3 (2.57 g, 30.6 mmol, 1.00 eq) and chloroacetyl chloride (3.45 g, 30.6 mmol, 1.00 eq) were added. After the addition was complete, the reaction mixture was stirred at 20 °C for 48 h. The reaction was determined to be complete by LCMS. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was dissolved in EtOAc (150 mL) and water (100 mL). The organic phase was separated and the aqueous phase was extracted once with EtOAc (100 mL). The combined organic phases were washed once with brine (50.0 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 1-2 (3.00 g, 13.6 mmol, 44.4% yield) as a white solid.

[0078] Compound 1-2 (3.00 g, 14.7 mmol, 1.00 eq) and aminoacetaldehyde dimethyl acetal (3.25 g, 30.9 mmol, 3.37 mL, 2.10 eq) were dissolved in anhydrous toluene (30.0 mL) and heated to 115 °C with stirring for 2 h. LCMS confirmed the complete reaction. The reaction mixture was cooled to 0-5 °C, and a large amount of solid precipitated. The mixture was filtered, and the filter cake was washed with EtOAc (30.0 mL). The filtrate was washed with brine (30.0 mL). The mixture was dried over anhydrous Na2SO4 and concentrated under reduced pressure until 30.0 mL of solvent remained. The remaining organic phase was cooled to 0-5 °C, and HCl / EtOAc (4 M) was added dropwise to adjust the pH to 2-3, causing a large amount of solid to precipitate. The mixture was filtered, and the filter cake was washed with EtOAc (5.00 mL) and then dried under vacuum to collect the solid. The solid was concentrated under reduced pressure to remove the solvent, yielding compound 1-3 (3.20 g, 9.78 mmol, 66.4% yield) as an off-white solid.

[0079] Compound 1-3 (2.63 g, 8.52 mmol, 1.00 eq) was suspended in DCE (130 mL). MgSO (2.05 g, 17.0 mmol, 2.00 eq) and MsOH (4.91 g, 51.1 mmol, 3.64 mL, 6.00 eq) were added, and the reaction mixture was heated to 85 °C and stirred for 3 h. LCMS confirmed that compound 3 was completely reacted. The reaction mixture was cooled to 20 °C, water (100 mL) was added, and the pH was adjusted to 9–10 with aqueous NaCO. The mixture was filtered to remove insoluble salts, and the filter cake was washed with CHCl (150 mL) and water (100 mL). The filtrate was separated, and the aqueous phase was extracted twice with CHCl (150 mL). The combined organic layer was washed with brine (50.0 mL), dried over anhydrous Na2SO4, and concentrated to dryness under reduced pressure to give crude compound 1-4 (2.00 g) as a white solid.

[0080] Compound 1-4 (1.49 g, 7.15 mmol, 1.00 eq) was dissolved in anhydrous THF (31 mL). LiAlH (543 mg, 14.3 mmol, 2.00 eq) was added in portions at 20 °C. The reaction was heated to 66 °C and stirred for 1 h. The desired product was detected by LCMS. Under nitrogen gas protection, the reaction was quenched by the dropwise addition of water (1.50 mL), and the reaction was rotary evaporated. The crude product was subjected to silica gel column chromatography (dichloromethane:methanol = 100:0 to 96:4) to give a yellow oil. The product was separated by preparative separation and then lyophilized to give compound 1. Chiral resolution (column: DAICEL CHIRALPAK AY-H (250 mm × 30 mm, 10 μm), mobile phase: A: CO2, B: (0.1% NH3HO EtOH), B%: 30% to 30%, 4 min) gave compound 1-a as a white solid (retention time: 1.133 min, 265 mg, 1.35 mmol, yield: 18.9%) and compound 1-b as a white solid (retention time: 1.368 min, 275 mg, 1.39 mmol, yield: 19.4%).

[0081] Compound 1-a: 1 H NMR:(400 MHz, CDCl3) δ 7.11 (d, J = 5.2 Hz, 1H), 6.80 (d, J = 5.2 Hz, 1H), 3.34 - 3.28 (m, 2H), 3.06 - 2.89 (m, 5H), 2.83 - 2.80 (m, 1H), 2.66 - 2.62 (m, 2H), 2.53 - 2.48 (m, 1H). MS (ESI) m / z = 195.1 [M+H] + . Compound 1-b: 1H NMR: (400 MHz CDCl3)δ 7.11 (d, J = 5.2 Hz, 1H), 6.80 (d, J = 5.2 Hz, 1H), 3.36 - 3.29 (m, 2H), 3.07 - 2.90 (m, 5H), 2.83 - 2.80 (m, 1H), 2.66 - 2.62 (m, 2H), 2.54 - 2.48 (m, 1H). MS (ESI) m / z = 195.1 [M+H] + .

[0082] Example 2 Compounds 2-a and 2-b were obtained using a similar synthesis method and resolution method to compound 1. The following table lists the characterization data for compounds 2-a (retention time: 0.707 min) and 2-b (retention time: 1.074 min): TIFF2025525370000089.tif85170

[0083] Example 3 Synthetic Route: TIFF2025525370000090.tif67170 Compound 7-1 was dissolved in THF (20 mL), and LDA (2 M, 2.69 mL, 1.1 eq) was added dropwise to the reaction solution at -70°C. After the addition was completed, the reaction was continued at -70°C for 3 hours. The reaction was monitored by LCMS to confirm complete reaction. 5 mL of saturated aqueous ammonium chloride solution was added to the reaction solution until the pH reached 7.0. The reaction solution was then extracted twice with 20 mL of ethyl acetate. The extracts were combined and then dried under vacuum to obtain colorless oily product 7-2 (0.8 g, 2.64 mmol, yield 53.87%), which was directly added to the next step of the reaction.

[0084] Compound 7-2 (0.8 g, 2.64 mmol, 1 eq) was dissolved in THF (10 mL) and sodium borohydride (200 mg, 5.29 mmol, 2.00 eq) was added to the reaction mixture at 25 °C. After the addition was complete, the mixture was stirred at room temperature for 2 h and monitored for complete reaction by LCMS. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phases were concentrated to dryness in vacuo to give colorless oily product 7-3 (0.8 g, 2.52 mmol, 95.37% yield), which was directly used in the next step.

[0085] Compound 7-3 was dissolved in HO (3 mL) and HCl (6 M, 5.46 mL, 50 eq) was added. The mixture was stirred at 25 °C for 16 h. The reaction was monitored for completeness by LCMS. 10 mL of saturated aqueous sodium bicarbonate was added, and the mixture was extracted twice with ethyl acetate (10 mL x 2). The organic phase was concentrated to dryness in vacuo and purified by preparative liquid phase separation to give compound 7. Chiral separation (column: Daicel ChiralPak IG (250 x 30 mm, 10 μm), mobile phase: A: CO, B: (0.1% NHH, EtOH), B%: 35%-35%, 4 min) afforded compound 7-a (retention time: 0.802 min, 15.9 mg, 12.7% yield) as a yellow oil, and compound 7-b (retention time: 0.866 min, 27.7 mg, 22.1% yield) as a yellow oil.

[0086] Compound 7-a: 1 H NMR (400MHz, CDCl3) δ 7.13 (m, 1H), 6.75 (d, J = 5.6 Hz, 1H), 4.84 (dd, J = 2.4, 10.0 Hz, 1H), 3.99 (dd, J = 2.4 , 10.0 Hz, 9.6 Hz, 1H), 3.76 (m, 1H), 3.15 (dd, J = 2.4 Hz, 10.0 Hz, 9.6 Hz, 1H), 2.99-2.87 (m, 3 H), 2.18-2.03(m, 1H). MS (ESI) m / z = 188.1 [M+H]+ . Compound 7-b: 1 H NMR (400MHz, CDCl3) δ 7.14 (m, 1H), 6.75 (d, J = 5.6 Hz, 1H), 4.86 (dd, J = 2.4, 10.0 Hz, 1H), 3.99 (dd, J = 2.4 , 10.0 Hz, 9.6 Hz, 1H), 3.79 (m, 1H), 3.17 (dd, J = 2.4 Hz, 10.0 Hz, 9.6 Hz, 1H), 3.01-2.91 (m, 3 H), 2.16-2.02(m, 1H). MS (ESI) m / z = 188.1 [M+H] + .

[0087] Example 4 Synthetic Route: TIFF2025525370000091.tif26170 Compound 9-1 (1.00 g, 2.87 mmol, 1.00 eq) was dissolved in THF (25.0 mL). LDA (2 M, 2.87 mL, 2.00 eq) was added dropwise at -70 °C, and the reaction mixture was stirred at -70 °C for 2 h. NFSI (1.36 g, 4.31 mmol, 1.50 eq) was dissolved in THF (10.0 mL) and added to the mixture. The mixture was stirred at -70 to 20 °C for 13 h. The product was detected by LCMS. NHCl solution was added dropwise to the reaction mixture at 0 °C to quench the LDA, and the reaction mixture was then extracted three times with 40.0 mL of EtOAc. The organic phase was washed with saturated brine (20.0 mL) and finally dried over anhydrous Na2SO4. The organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 95:5) to give oily product 9-2 (450 mg, 1.05 mmol, yield 36.7%).

[0088] Intermediate 9-2 (500 mg, 1.37 mmol, 1.00 eq) was dissolved in THF (35.0 mL) and Pd / C (820 mg, 1.37 mmol, 10% purity, 1.00 eq) was added. The reaction mixture was stirred at 50 °C for 20 h under a nitrogen atmosphere. The product was detected by LCMS. The reaction mixture was filtered through diatomaceous earth to remove the Pd / C, washed with THF, and the organic phase was concentrated and separated to give oily product 9-3 (30.0 mg, 103 μmol, 7.57% yield).

[0089] Intermediate 9-3 (30.0 mg, 102 μmol, 1.00 eq) was dissolved in HCl / dioxane (3.00 mL) and stirred at 25 °C for 12 h. The product was detected by LCMS. The pH of the reaction mixture was adjusted to 7-8 with NaHCO3 solution, and then the reaction mixture was extracted three times with 10.0 mL of CHCl2. The organic phase was washed with saturated brine (30.0 mL) and finally dried over anhydrous Na2SO4. The organic phase was concentrated to give oily product 9 (16.0 mg, 79.2 μmol, 77.5% yield). 1 H NMR (400MHz, CDCl3)δ 6.52 - 6.63 (m, 1 H), 6.32 (dd, J = 3.94, 1.70 Hz, 1 H), 4.59 (dt, J = 9.98, 2.20 Hz, 1 H), 3.94 - 4.02 (m, 1 H), 3.75 (m, 1 H), 3.14 (dd, J = 12.26, 2.00 Hz, 1 H), 2.84 - 2.99 (m, 3 H). MS (ESI) m / z = 188.1 [M+H] + .

[0090] Example 5 Synthetic Route: TIFF2025525370000092.tif56170 Compound 10-1 (1.00 g, 8.76 mmol, 1.00 eq) was dissolved in anhydrous THF (10.0 mL), purged with nitrogen gas three times, and cooled to -65 to -60°C. Lithium diisopropylamide (2 M, 4.82 mL, 1.10 eq) was measured with a syringe and added dropwise to the reaction solution within 10 minutes while controlling the temperature at -65 to -60°C. The reaction solution was stirred for 30 minutes while controlling the temperature at -65 to -60°C. Tert-butyl-2-oxopyran-4-carboxylate (1.59 g, 7.88 mmol, 0.90 eq) was weighed and dissolved in anhydrous THF (4.00 mL). The temperature was controlled at -65 to -60 °C and added dropwise to the reaction solution within 10 min. After the addition was complete, the reaction solution was allowed to warm to 20 °C and stirred for 2 h. LCMS confirmed the completion of the reaction of compound 10-1. Under nitrogen gas protection, the reaction was quenched by adding aqueous NH4Cl (5.0 mL) dropwise, diluted with water (20.0 mL), and extracted three times with EtOAc (30.0 mL). The organic phases were combined, washed with brine (30.0 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (Petroleum ether: EtOAc = 2:1 to 1:1) and rotary dried to give compound 10-2 (1.00 g, yield 35.1%) as a yellow oil.

[0091] Compound 10-2 (500 mg, 1.59 mmol, 1.00 eq) was dissolved in EtOH (5.00 mL) and cooled to 0 °C. NaBH (240 mg, 6.34 mmol, 4.00 eq) was added portionwise to the reaction mixture. The reaction mixture was allowed to warm to 20 °C and stirred for 2 h. LCMS showed that compound 10-2 had reacted completely. The reaction mixture was slowly poured into water (5.00 mL) and extracted three times with EtOAc (15.0 mL). The organic phases were combined, washed with brine (45.0 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give compound 10-3 (436 mg, 1.15 mmol, 72.8% yield) as a colorless oil.

[0092] Compound 10-3 (250 mg, 788 μmol, 1.00 eq) was dissolved in anhydrous THF (10.0 mL) and cooled to 0 °C. H2SO4 (1.55 g, 15.8 mmol, 840 μL, 20.0 eq) was added dropwise. The reaction mixture was slowly warmed to 25 °C and stirred for 5 h. LCMS analysis indicated that compound 10-3 had reacted completely, and the product MS was detected. The reaction mixture was slowly added to ice water (20.0 mL) and extracted twice with EtOAc (20.0 mL). The combined organic phases were washed once with brine (20.0 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to dryness to give the crude product. The crude product was subjected to silica gel column chromatography (dichloromethane:methanol = 100:1 to 10:1) and rotary evaporated to give compound 10. Chiral separation (column: Daicel ChiralPak IG (250 × 30 mm, 10 μm), mobile phase: A: CO, B: (0.1% NHH0 in EtOH), B%: 35% to 35%, 4 min) gave compound 10-a as a yellow oil (retention time: 0.933 min, 26.0 mg, yield: 14.9%) and compound 10-b as a yellow oil (retention time: 1.080 min, 28.0 mg, yield: 16.6%).

[0093] Compound 10-a: 1 H NMR: (400 MHz DMSO-d6) δ 7.34 (d, J = 5.6 Hz, 1H), 6.94 (d, J = 5.6 Hz, 1H), 4.62 (dd, J1 = 10.0 Hz, J2 = 2.4 Hz, 1H), 3.78 - 3.76 (s, 1H), 3.76 (s, 3H), 3.55 - 3.50 (m, 1H), 2.88 - 2.85 (m, 1H), 2.68 - 2.65 (m, 2H), 2.56 - 2.53 (m, 1H). MS (ESI) m / z = 200.1 [M+H] + . Compound 10-b: 1H NMR: (400 MHz DMSO-d6) δ 7.36 (d, J = 5.2 Hz, 1H), 6.96 (d, J = 5.6 Hz, 1H), 4.65 - 4.64 (m, 1H), 3.80 - 3.77 (m, 1H), 3.77 (s, 3H), 3.58 - 2.54 (m, 1H), 2.29 - 2.88 (m, 1H), 2.72 - 2.69 (m, 2H), 2.60 - 2.57 (m, 1H). MS (ESI) m / z = 200.1 [M+H] + .

[0094] Example 6 Using a similar synthesis method and a similar resolution method to compound 10, compound 8, compound 11-a (retention time: 1.469 min), compound 11-b (retention time: 2.110 min), compound 12-a (retention time: 1.392 min), and compound 12-b (retention time: 1.701 min) were obtained. The following table lists the characterization data for compound 8, compound 11-a, compound 11-b, compound 12-a, and compound 12-b: TIFF2025525370000093.tif146170

[0095] Example 7 Synthetic Route: TIFF2025525370000094.tif99170

[0096] Trimethylsulfoxonium iodide (1.15 g, 5.23 mmol, 1.00 eq) was dissolved in dry DMSO (16.0 mL) and cooled to 0-5°C. NaH (210 mg, 5.23 mmol, 60.0% purity, 1.00 eq) was added in several portions and stirred for 1 h while controlling the temperature at 0-5°C. Compound 13-1 (1.00 g, 5.23 mmol, 1.00 eq) was dissolved in anhydrous THF (8.00 mL) and added dropwise to the reaction solution while controlling the temperature at 0-5°C. The reaction solution was allowed to warm to 20°C and stirred for 2 h. LCMS confirmed that compound 13-1 had completely reacted. The reaction solution was slowly poured into ice water and extracted twice with petroleum ether (50 mL). The combined organic phase was washed once with brine (30 mL) and dried over anhydrous Na2SO4 to give a petroleum ether solution of compound 13-2 (100 mL). Ethanolamine (1.60 g, 26.2 mmol, 5.00 eq) was added to the petroleum ether solution of compound 13-2, and the reaction mixture was heated to 50 °C and stirred for 3 h. LCMS showed that compound 13-2 had reacted completely. The reaction mixture was cooled to 20 °C, and Boc2O (5.71 g, 26.2 mmol, 6.01 mL, 5.00 eq) was added in several portions. The reaction mixture was stirred at 20 °C for 2 h. LCMS showed that compound 13-3 had reacted completely. The reaction mixture was diluted with EtOAc (50 mL), washed once with water (50 mL), washed once with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography to give compound 13-4 (300 mg, 819 μmol, yield 15.7%) as a brown liquid.

[0097] Compound 13-4 (155 mg, 423 μmol, 1.00 eq) was added with hydrochloric acid (6 M, 10.0 mL, 142 eq), and the reaction was heated to 110 °C and stirred for 3 h. LCMS showed that compound 13-4 had reacted completely. The reaction mixture was adjusted to pH 8-9 with aqueous NaOH (2 M, 31.3 mL), and BocO (185 mg, 846 μmol, 194 μL, 2.00 eq) was added. The reaction mixture was stirred at 20 °C for 2 h. LCMS showed that the intermediate reaction was complete. The reaction mixture was extracted three times with EtOAc (30 mL). The combined organic phases were extracted, washed once with brine (30 mL), dried once over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The crude product was concentrated and dried by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to give compound 13-5 (150 mg, 362 μmol, yield 85.5%) as a yellow oil.

[0098] Compound 13-5 (150 mg, 431 μmol, 1.00 eq) and Pd(PPh3)4 (24.9 mg, 21.5 μmol, 0.05 eq) were dissolved in anhydrous toluene (5 mL). Under nitrogen gas protection, dibutyl(1-ethoxyvinyl)pentylstannane (300 mg, 831 μmol, 280 μL, 1.93 eq) was added dropwise to the reaction mixture. The reaction was heated to 110 °C and stirred for 16 h. LCMS indicated that the reaction was incomplete. The reaction was cooled to 20 °C, and CsF (393 mg, 2.58 mmol, 6.00 eq) and Pd(PPh3)4 (49.8 mg, 43.0 μmol, 0.10 eq) were added. The reaction was heated to 110 °C and stirred for an additional 16 h. LCMS indicated that compound 13-5 had completely reacted. The reaction mixture was filtered, the filter cake was washed with EtOAc (30.0 mL), and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) and chiral separation (column: DaicelChiralPak IG (250 × 30 mm, 10 μm), mobile phase: A: CO, B: (0.1% NH3HO MeOH), B%: 20% to 20%, 4 min) to give compound 13-7-a (retention time: 0.901 min, 35.0 mg, 112 μmol, yield 26.1%) as a white solid, and compound 13-7-b (retention time: 1.133 min, 35.0 mg, 112 μmol, yield 26.1%) as a white solid.

[0099] Compound 13-7-a (30.0 mg, 96.3 μmol, 1.00 eq) was dissolved in MeOH (1.00 mL), and HCl / dioxane (4 M, 241 μL, 10.0 eq) was added dropwise. The reaction mixture was stirred at 20 °C for 16 h. LCMS confirmed that compound 13-7-a had reacted completely. The reaction mixture was diluted with deionized water (20.0 mL), and the pH was adjusted to 7–8 with NaHCO3 while stirring. The aqueous phase was extracted three times with CHCl3 (15.0 mL). The combined organic phases were washed with brine (10.0 mL), dried over anhydrous NaSO4, filtered, and concentrated under reduced pressure to give compound 13-a (20.0 mg, 90.9 μmol, 94.3% yield) as a yellow solid.

[0100] Compound 13-7-b (35.0 mg, 112 μmol, 1.00 eq) was dissolved in MeOH (2.00 mL), and HCl / dioxane (4 M, 281 μL, 10.0 eq) was added dropwise. The reaction mixture was stirred at 20 °C for 16 h. LCMS confirmed that compound 13-7-b had completely reacted. The reaction mixture was diluted with deionized water (20.0 mL), and the pH was adjusted to 7–8 with NaHCO3 while stirring. The aqueous phase was extracted three times with CHCl3 (15.0 mL). The combined organic phases were washed with brine (10.0 mL), dried over anhydrous NaSO4, filtered, and concentrated under reduced pressure to give compound 13-b (20.0 mg, 90.7 μmol, 80.7% yield) as a yellow solid.

[0101] Compound 13-a: 1H NMR: (400 MHz CDCl3) δ 7.36 (d, J = 5.6 Hz, 1H), 7.22 (d, J = 5.2 Hz, 1H), 5.35 (dd, J1= 9.2 Hz, J1= 2.4 Hz, 1H), 4.04 - 4.01 (m, 1H), 3.74 - 3.71 (m, 1H), 3.36 - 3.33 (m, 1H), 3.00 - 2.97 (m, 1H), 2.96 - 2.92 (m, 1H), 2.61 - 2.58 (m, 1H), 2.52 (s, 3H). MS (ESI) m / z = 212.1 [M+H] + . Compound 13-b: 1 H NMR: (400 MHz CDCl3) δ 7.36 (d, J = 5.2 Hz, 1H), 7.22 (d, J = 5.2 Hz, 1H), 5.36 (dd, J1= 9.6 Hz, J1= 2.0 Hz, 1H), 4.05 - 4.01 (m, 1H), 3.75 MS (ESI) m / z = 212.1 [M+H] + .

[0102] Example 8 Synthetic road: 3-Bromothiophene (10.0 g, 61.3 mmol, 5.75 mL, 1 eq) was dissolved in tetrahydrofuran (150 mL). The solution was cooled to -78 °C, and n-butyllithium (4.32 g, 67.5 mmol, 27.0 mL, 1.10 eq) was slowly added dropwise. The mixture was stirred at this temperature for 1 hour. 2-Methyloxirane (7.12 g, 123 mmol, 8.60 mL, 2 eq) was then added dropwise at -55 °C, followed by the addition of boron trifluoride etherate (8.71 g, 61.3 mmol, 7.57 mL, 1 eq) at -55 °C. The reaction mixture was stirred at -55 °C for 2 hours. Completion of the reaction was monitored by TLC. The reaction mixture was quenched with saturated aqueous sodium bicarbonate at -78 °C and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 4 / 1). 1-(thiophen-3-yl)propan-2-ol (compound 28-2) (7.70 g, 54.1 mmol, 88.3% yield) was obtained as a red oil.

[0103] Methylaminoacetaldehyde dimethyl acetal was dissolved in 2-methyltetrahydrofuran (100 mL) and 1-(thiophen-3-yl)propan-2-ol (7.70 g, 54.1 mmol, 1 eq) was added at 25°C. After stirring at this temperature for 5 minutes, trifluoromethanesulfonic acid (8.94 g, 59.6 mmol, 5.26 mL, 1.1 eq) was added. The resulting dark brown mixture was then heated to 80°C and stirred for 1 hour. LCMS showed the completion of the reaction. The reaction was quenched by slowly adding saturated potassium hydroxide solution until the pH reached >7. The mixture was extracted with methyl tert-butyl ether. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound 28 was obtained by purification by high-performance liquid chromatography (HPLC). This was further purified by SFC (column: DAICEL CHIRALPAK AY-H (250 mm × 30 mm, 10 μm), mobile phase: A: CO, B: (0.1% NH3HO MeOH), B%: 20% to 20%, 4 min) to give compound 28-a (retention time: 0.812 min, 65.8 mg, 333 μmol, yield: 61.5%) as a yellow oil and compound 28-b (retention time: 0.954 min, 66.1 mg, 334 μmol, yield: 61.8%) as a yellow oil.

[0104] Compound 28-a: 1H NMR: (400 MHz, DMSO-d6)δ 7.28 (d, J = 5.1 Hz, 1H), 6.93 (d, J = 5.3 Hz, 1H), 4.68 (td, J = 2.3, 4.6 Hz, 1H), 3.76 (ddd, J = 3.3, 6.2, 10.3 Hz, 1H), 3.49 - 3.39 (m, 1H), 2.92 (dd, J = 3.6, 12.2 Hz, 1H), 2.78 (td, J = 2.4, 15.9 Hz, 1H), 2.63 (dd, J = 7.8, 12.1 Hz, 1H), 2.53 (br dd, J = 2.3, 11.3 Hz, 1H), 2.32 (s, 3H), 1.28 (d, J = 6.1 Hz, 3H). MS (ESI) m / z = 198.1 [M+H] + . Compound 28-b: 1 H NMR: (400 MHz, DMSO-d6)δ 7.28 (d, J = 5.1 Hz, 1H), 6.94 (d, J = 5.3 Hz, 1H), 4.72 - 4.65 (m, 1H), 3.76 (ddd, J = 3.2, 6.3, 10.3 Hz, 1H), 3.48 - 3.40 (m, 1H), 2.94 (dd, J = 3.6, 12.2 Hz, 1H), 2.79 (td, J = 2.4, 15.8 Hz, 1H), 2.64 (dd, J = 7.8, 12.3 Hz, 1H), 2.54 (br dd, J = 1.9, 10.7 Hz, 1H), 2.37 - 2.30 (m, 3H), 1.28 (d, J = 6.1 Hz, 3H). MS (ESI) m / z = 198.1 [M+H] + .

[0105] Example 9 Using a similar synthesis method and resolution method to compound 28, compound 30, compound 39-a (retention time: 1.520 min), and compound 39-b (retention time: 2.120 min) were obtained. The following table lists the characterization data for compound 30, compound 39-a, and compound 39-b: TIFF2025525370000096.tif80170

[0106] Example 10 Synthetic Route: Pd(OAc)2 (207 mg, 920 μmol, 0.03 eq) and DavePhos (724 mg, 1.84 mmol, 0.06 eq) were suspended in anhydrous toluene (100 mL) and flushed with nitrogen three times. LiHMDS (1 M, 76.7 mL, 2.50 eq) was added dropwise to the reaction mixture at 20 °C within 10 min. Compound 32-1 (10.6 g, 70.5 mmol, 9.90 mL, 2.3 eq) and 3-bromothiophene (5.00 g, 30.7 mmol, 2.87 mL, 1.00 eq) were dissolved in toluene (20 mL) and added dropwise to the reaction mixture while controlling the temperature between -10 and 0 °C. The reaction mixture was heated to 85 °C and stirred for 3 h. LCMS showed that the compound had reacted completely. The reaction mixture was concentrated to dryness under reduced pressure. The crude product was dissolved in ethyl acetate (200 mL), washed with brine (50.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to obtain compound 32-2 (9.00 g, crude product) as a yellow solid.

[0107] Compound 32-2 (9.00 g, 38.7 mmol, 1.00 eq) was dissolved in anhydrous THF (100 mL) and cooled to 0–5°C. Sodium bis(2-methoxyethoxy)aluminum hydride (33.6 g, 116 mmol, 32.3 mL, 70.0% purity, 3.0 eq) was added dropwise, and the reaction mixture was allowed to warm to 20°C and stirred for 4 h. LCMS confirmed that compound 32-2 had completely reacted. The reaction mixture was slowly poured into water (100 mL), and the organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 eluent) to give compound 32-3 (1.60 g, 3.84 mmol, 9.91% yield) as a colorless oil.

[0108] Compound 32-3 (1.60 g, 7.83 mmol, 1.00 eq) and 2,2-dimethoxy-N-methylethylamine (1.60 g, 13.4 mmol, 1.72 mL, 1.71 eq) were dissolved in 2-methyltetrahydrofuran (20 mL). TfOH (2.70 g, 18.0 mmol, 1.59 mL, 2.30 eq) was added dropwise, and the reaction mixture was heated to 85 °C and stirred for 5 h. Complete reaction was confirmed by LCMS. The reaction mixture was poured into water (50 mL), adjusted to pH 7–8 with aqueous sodium bicarbonate, and extracted twice with ethyl acetate (50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1, Rf = 0.3) and SFC chiral resolution (column: DAICEL CHIRALPAK AY-H (250 mm × 30 mm, 10 μm), mobile phase: A: CO, B: (0.1% NH3HO EtOH), B%: 20% to 20%, 4 min) to give brown oily compound 32-a (retention time: 1.373 min, 251 mg, yield: 12.3%), brown oily compound 32-b (retention time: 1.451 min, 56.0 mg, yield: 2.65%), brown oily compound 32-c (retention time: 1.679 min, 51 mg, yield: 2.32%), and brown oily compound 32-d (retention time: 1.850 min, 282 mg, yield: 13.6%).

[0109] Compound 32-a: 1 H NMR: (400 MHz CDCl3) δ 7.34 - 7.27 (m, 3H), 7.18 - 7.16 (m, 2H), 7.13 (d, J = 4.8 Hz, 1H), 6.58 (d, J = 5.2 Hz, 1H), 5.05 - 5.02 (m, 1H), 4.29 - 4.25 (m, 1H), 4.21 - 4.18 (m, 1H), 3.67 - 3.61 (m, 1H), 3.01 - 2.98 (m, 2H), 2.54 (s, 3H). MS (ESI) m / z = 260.1 [M+H]+ . Compound 32-b: 1 H NMR: (400 MHz CDCl3) δ 7.31 - 7.27 (m, 2H), 7.22 - 7.19 (m, 1H), 7.18 - 7.16 (m, 3H), 6.72 (d, J = 5.2 Hz, 1H), 4.99 - 4.96 (m, 1H), 4.14 - 4.07 (m, 2H), 3.99 - 3.97 (m, 1H), 3.08 - 2.92 (m, 2H), 2.54 (s, 3H). MS (ESI) m / z = 260.1 [M+H] + . Compound 32-c: 1 H NMR: (400 MHz CDCl3) δ 7.31 - 7.27 (m, 2H), 7.24 - 7.19 (m, 1H), 7.18 - 7.16 (m, 3H), 6.72 (d, J = 4.8 Hz, 1H), 4.98 - 4.95 (m, 1H), 4.14 - 4.07 (m, 2H), 3.99 - 3.97 (m, 1H), 3.08 - 2.98 (m, 2H), 2.53 (s, 3H). MS (ESI) m / z = 260.1 [M+H] + . Compound 32-d: 1 H NMR: (400 MHz CDCl3) δ 7.34 - 7.30 (m, 3H), 7.18 - 7.16 (m, 2H), 7.13 (d, J = 4.8 Hz, 1H), 6.58 (d, J = 4.8 Hz, 1H), 5.05 - 5.02 (m, 1H), 4.29 - 4.25 (m, 1H), 4.21 - 4.18 (m, 1H), 3.67 - 3.61 (m, 1H), 3.04 - 2.95 (m, 2H), 2.54 (s, 3H). MS (ESI) m / z = 260.1 [M+H] + .

[0110] Example 11 Synthetic road: Compound 34-1 (2.00 g, 12.8 mmol, 1.00 eq) was dissolved in anhydrous THF (10.0 mL) and cooled to 0 °C. MeMgBr (3.00 M, 14.9 mL, 3.50 eq) was added dropwise slowly, and the reaction mixture was allowed to warm to 20 °C and stirred for 16 h. After confirming complete reaction by TLC, the mixture was quenched with aqueous ammonium chloride (300 mL) and extracted with a 10:1 mixture of dichloromethane and methanol (200 mL × 3). The resulting organic phase was washed with brine (100 mL × 1), dried over anhydrous sodium sulfate, and rotary evaporated to give compound 34-2 (973 mg, 5.85 mmol, 45.7% yield) as a colorless oil.

[0111] Compound 34-2 (476 mg, 3.05 mmol, 1.00 eq) and aminoacetaldehyde dimethyl acetal (363 mg, 3.05 mmol, 391 μL, 1.00 eq) were dissolved in anhydrous 2-MeTHF (5.00 mL). TfOH (549 mg, 3.66 mmol, 323 μL, 1.20 eq) was added dropwise and the mixture was reacted at 55 °C for 3 h. LCMS analysis indicated the appearance of the product and complete consumption of the starting material. The reaction mixture was then directly evaporated and resuspended in 2-MeTHF (6.00 mL × 3) to give the crude product. The crude product was then dissolved in 2-MeTHF (5.00 mL) and reacted at 55 °C for 1 h. LCMS analysis indicated the disappearance of the starting material and the appearance of the product. The reaction mixture was directly evaporated, and the pH of the crude product was adjusted to 9 with sodium carbonate solution. It was then extracted five times with ethyl acetate (20.0 mL × 3) and dichloromethane (20.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 100:0 to 93:7) and evaporated to obtain the crude product. The crude product was separated and purified to obtain compound 34 (15.7 mg, 73.5 μmol, 2.41% yield) as a brown oil. 1H NMR (400 MHz CDCl3) δ7.09 (d, J = 4.8 Hz, 1H), 6.73 - 6.69 (m, 1H), 4.83 - 4.81 (m, 1H), 2.93 - 2.90 (m, 1H), 2.82- 2.81 (m, 1H), 2.60 - 2.59 (m, 1H), 2.47 - 2.43 (m, 4H), 1.31 (s, 3H), 1.15 (s, 3H). MS (ESI) m / z = 212.1 [M+H] + .

[0112] Example 12 Synthetic Route: Compound 35-1 (5.00 g, 32.01 mmol, 1.00 eq) was dissolved in anhydrous THF (50 mL) and cooled to 0 °C. NaH (3.20 g, 80.0 mmol, 60.0% purity, 2.50 eq) was added portionwise to the reaction mixture and stirred at 0 °C for 0.5 hours. Finally, CHCl (11.3 g, 80.0 mmol, 4.98 mL, 2.50 eq) was added dropwise to the reaction mixture at 0 °C and stirred at 20 °C for 15 hours. TLC showed the disappearance of the starting material and the appearance of a new spot. The reaction mixture was cooled to 0 °C and quenched by dropwise addition of HO (20.0 mL). The mixture was extracted three times with ethyl acetate (40.0 mL × 3). The organic phase was washed with NaCl (100 mL) and dried over anhydrous sodium sulfate to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:0 to 98:2) and rotary evaporated to give compound 35-2 (3.94 g, 20.6 mmol, 64.6% yield) as a colorless oil.

[0113] Compound 35-2 (1.80 g, 9.77 mmol, 1.00 eq) was dissolved in anhydrous THF (18.0 mL), cooled to 0 °C, and LiAlH (1.11 g, 29.3 mmol, 3.00 eq) was added in several portions. The mixture was stirred at 20 °C for 2 h. LCMS showed that the starting material was completely consumed. TLC showed that the starting material was completely consumed and a new spot appeared. The reaction mixture was cooled to 0 °C and quenched by the dropwise addition of HO (1.11 mL), 15% NaOH (1.11 mL), and HO (3.33 mL), followed by extraction three times with HO (10.0 mL) and ethyl acetate (18.0 mL). The organic phase was dried over anhydrous sodium sulfate to obtain the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate = 100:0 to 92:8) and rotary evaporation to obtain compound 35-3 (1.09 g, 6.82 mmol, 69.8% yield) as a colorless oil.

[0114] Compound 35-3 (500 mg, 3.20 mmol, 1.00 eq) was dissolved in anhydrous 2-MeTHF (5.00 mL). Methylaminoacetaldehyde dimethyl acetal (381 mg, 3.20 mmol, 411 μL, 1 eq) and TfOH (720 mg, 4.80 mmol, 339 μL, 1.50 eq) were added. The mixture was heated to 55 °C and reacted for 2 h. LCMS showed the appearance of the product. The reaction was continued for 1.7 h. LCMS showed the appearance of the product. The reaction solution was directly rotary evaporated and then washed with 2-MeTHF (6.00 mL × 3) to obtain the crude product. The crude product was dissolved in 2-MeTHF (5.00 mL) and reacted at 55 °C for 1 h. LCMS showed the disappearance of the starting material and the appearance of the product. The reaction mixture was directly suspended in water and dried. The pH of the crude product was adjusted to 9 with NaHCO3 solution and extracted three times with ethyl acetate (20.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (dichloromethane:methanol = 100:0 to 95:5) and rotary evaporated to obtain compound 35 (496 mg, 2.16 mmol, 67.4% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 5.2 Hz,1H), 6.94 (d, J = 4.8 Hz, 1H), 4.93 - 4.90 (m, 1H), 3.73 (d, J = 9.6 Hz, 1H), 3.51 (d, J = 10.8 Hz, 1H), 3.02 - 2.92 (m, 2H), 2.55 (s, 3H), 2.42 (br.s, 1H), 1.27 (s, 3H), 1.19 (s, 3H). MS (ESI) m / z = 212.1 [M+H] + .

[0115] Example 13 Synthetic Route: TIFF2025525370000100.tif29170 Compound 37-1 (3.50 g, 23.8 mmol, 2.13 mL, 1.00 eq) was dissolved in anhydrous tetrahydrofuran (30.0 mL), and n-butyllithium (2.50 M, 9.53 mL, 1.00 eq) was added dropwise to the reaction system at -78°C. The temperature was controlled at -60°C and the reaction was allowed to proceed for 1 hour. Ethylene oxide (3.00 M, 9.53 mL, 1.20 eq) was then added dropwise to the reaction system. After the addition was completed, BF3.Et2O (4.06 g, 28.6 mmol, 3.53 mL, 1.20 eq) was added dropwise to the reaction system at -78°C. After the addition was completed, the reaction system was gradually heated and allowed to proceed for 3 hours. TLC spot plate showed that starting material 37-1 had reacted completely and a new spot had appeared. The mixture was slowly added dropwise to water (500 mL), and the mixture was extracted twice with ethyl acetate (20.0 mL × 2). The water was removed with anhydrous sodium sulfate, and the organic phase was rotary evaporated to give the crude product. The crude product was subjected to column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) and rotary evaporated to give compound 37-2 (1.70 g, 10.5 mmol, 43.9% yield) as a yellow oil.

[0116] Compound 37-2 (797 mg, 6.69 mmol, 860 μL, 1.50 eq) was dissolved in 2-MeTHF (10.0 mL), methylaminoacetaldehyde dimethyl acetal (500 mg, 4.46 mmol, 1.00 eq) was added, and CFSOH (1.07 g, 7.13 mmol, 630 μL, 1.60 eq) was added dropwise to the reaction mixture at 0 °C. After the addition was complete, the reaction mixture was gradually heated to 50 °C and reacted for 3 h. LCMS analysis indicated that the reaction of starting material 37-2 was complete and the desired product was detected. The mixture was adjusted to pH 7–8 with sodium carbonate solution (20.0 mL). Dichloromethane (20.0 mL × 2) was added to the mixture, and the organic phase was dried over anhydrous sodium sulfate to obtain the crude product. The crude product was purified by HPLC preparative separation to give compound 37 (23.0 mg, 129 μmol, yield 1.93%) as a yellow oil. 1 H NMR(400MHz, CDCl3)δ 7.30 (s, 1H), 6.27 (d, J = 1.6 Hz, 1H), 4.80 - 4.79 (m, 1H), 4.14 - 4.11 (m, 1H), 3.73 - 3.71 (m, 1H) 3.09 - 3.05 (m, 1H), 2.92 - 2.87 (m, 1H), 2.76 - 2.73 (m, 1H), 2.50 (s, 3H), 2.46 - 2.42 (m, 1H). MS (ESI) m / z =168.0 [M+H] + .

[0117] Example 14 Synthetic Route: TIFF2025525370000101.tif90170 Under nitrogen gas protection, 3-aminoethylthiophene (1.10 g, 6.72 mmol, 1 eq, HCl), 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde (1.27 g, 6.72 mmol, 1.00 eq), and trifluoroacetic acid (66.0 mg, 579 μmol, 42.9 μL, 2 eq) were dissolved in 1,2-dichloroethane (10 mL). The atmosphere was purged with nitrogen gas three times, and the mixture was then heated to 45°C and stirred for 12 hours. After monitoring the completion of the reaction by LCMS, the reaction mixture was quenched with 2 M aqueous sodium bicarbonate (300 mL) and extracted with a 10:1 mixture of dichloromethane and methanol (200 mL x 3). The resulting organic phase was washed with brine (100 mL x 1), dried over anhydrous sodium sulfate, and concentrated by distillation under reduced pressure to obtain the crude product. The crude product was used in the next step without further purification. Compound 42-2 (1.66 g, 5.56 mmol, 82.8% yield) was obtained as a yellow solid.

[0118] Compound 42-2 (1.36 g, 4.56 mmol, 1.00 eq) was dissolved in a mixture of methanol and 1,2-dichloroethane. Sodium cyanoborohydride (573 mg, 9.12 mmol, 2.00 eq), aqueous formaldehyde (1.66 g, 18.2 mmol, 1.52 mL, 33.0% purity, 4.00 eq), and sodium acetate (785 mg, 9.57 mmol, 2.10 eq) were added and the reaction mixture was stirred at 20 °C for 12 h. After completion of the reaction was monitored by TLC plate and LCMS, the reaction mixture was adjusted to pH 8 with 2 M aqueous sodium carbonate, diluted with brine (10 mL), and extracted with dichloromethane (20 mL × 3). The resulting organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1 / 0 to 1 / 1). Finally, a white solid compound 42-3 (1.23 g, 3.70 mmol, 81.2% yield) was obtained.

[0119] Compound 42-3 (1.00 g, 2.60 mmol, 1.00 eq, 2HCl) and hydrazine hydrate (800 mg, 16.0 mmol, 777 μL, 6.16 eq) were dissolved in absolute ethanol (10 mL). The mixture was purged with nitrogen gas three times, then heated to 40 °C and stirred under nitrogen for 0.5 h. After completion of the reaction was monitored by LCMS, the reaction mixture was quenched with 2 M aqueous ammonium chloride (50 mL) at 0 °C and diluted with water (50 mL). The resulting mixture was extracted with dichloromethane (15 mL × 2), washed with brine (50 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, compound 42-4 (crude product, hydrochloride salt), as a green gel. The crude product was purified by high-performance liquid chromatography (HCl system) to give the crude product, compound 42-4 (crude product, hydrochloride salt).

[0120] Compound 42-4 (560 mg, 2.56 mmol, 1.00 eq, HCl), di-tert-butyl dicarbonate (1.68 g, 7.68 mmol, 1.76 mL, 3.00 eq), and sodium bicarbonate (215 mg, 2.56 mmol, 99.6 μL, 1.00 eq) were dissolved in a mixed solvent of water (100 mL) and ethyl acetate (50 mL), and the mixture was purged with nitrogen gas three times and stirred at 20 °C for 0.5 h. After monitoring the complete reaction by LCMS, the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (50 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified and separated by SFC (column: DAICEL CHIRALPAK AY-H (250 mm × 30 mm, 10 μm), mobile phase: A: CO, B: (0.1% NHH0 in EtOH), B%: 20% to 20%, 4 min) to give yellow solid compounds 42-6-a (retention time: 1.592 min, 240 mg, 850 μmol, 33.2% yield) and 42-6-b (retention time: 1.689 min, 340 mg, 1.20 mmol, 47.0% yield).

[0121] Compound 42-6-a (240 mg, 850 μmol, 1.00 eq) was dissolved in ethyl acetate hydrochloride (4 M, 24 mL, 113 eq). The atmosphere was purged with nitrogen gas three times, and the reaction mixture was allowed to react at 20 °C for 1 h. After monitoring the complete reaction by LCMS, the reaction mixture was filtered, and the resulting filter cake was purified by high-performance liquid chromatography (aqueous ammonia system) to give compound 42-a (44.5 mg, 239 μmol, 28.2% yield) as a yellow oil. Compound 42-b (86.4 mg, 469 μmol, 39.0% yield) was obtained by the same procedure.

[0122] Compound 42-a: 1 H NMR: (400 MHz, DMSO-d6) δ7.30 (d, J = 5.0 Hz, 1H), 6.80 (d, J = 5.0 Hz, 1H), 3.01 - 2.92 (m, 1H), 2.75 (d, J = 5.4 Hz, 2H), 2.68 - 2.58 (m, 2H), 2.56 - 2.51 (m, 1H), 2.36 (s, 3H). MS (ESI) m / z = 183.1 [M+H] + . Compound 42-b: 1 H NMR: (400 MHz, DMSO-d6) δ7.30 (d, J = 5.0 Hz, 1H), 6.80 (d, J = 5.0 Hz, 1H), 3.01 - 2.92 (m, 1H), 2.75 (d, J = 5.5 Hz, 2H), 2.67 - 2.58 (m, 2H), 2.36 (s, 3H), 1.64 - 1.30 (m, 2H). MS (ESI) m / z = 183.0 [M+H] + .

[0123] Example 15 Using a similar synthesis method and resolution method to compound 42, compound 38-a (retention time: 2.261 min), compound 38-b (retention time: 2.427 min), compound 41-a (retention time: 1.798 min), and compound 41-b (retention time: 1.903 min) were obtained. The following table lists the characterization data for compounds 38-a, 38-b, 41-a, and 41-b: TIFF2025525370000102.tif107170

[0124] Example 16 Synthetic Route: TIFF2025525370000103.tif85170 2-(Thiophen-3-yl)ethanol (7.00 g, 54.6 mmol, 6.03 mL, 1 eq) was dissolved in dichloromethane (100 mL), and 4-methylbenzenesulfonyl chloride (12.5 g, 65.5 mmol, 1.2 eq) and triethylamine (6.63 g, 65.5 mmol, 9.12 mL, 1.2 eq) were added. The resulting mixture was stirred at 15°C for 12 hours. Completion of the reaction was monitored by TLC. The reaction was quenched at 0°C by adding 150 mL of water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 7 / 1 to 6 / 1). A pale yellow oily compound 43-2 (11.7 g, 41.5 mmol, 76.0% yield) was obtained.

[0125] Compound 43-2 (11.7 g, 41.4 mmol, 1 eq), thiourea (3.15 g, 41.4 mmol, 1 eq), and water (747 mg, 41.4 mmol, 747 μL, 1 eq) were dissolved in ethanol (50.0 mL), purged with nitrogen gas three times, and then refluxed at 100 °C for 5 h. Completion of the reaction was monitored by LCMS, and the reaction mixture was used directly in the next step.

[0126] Sodium hydroxide (3.20 g, 80.0 mmol, 1.86 eq) was dissolved in pure HO (15 mL) and added to the reaction mixture from the previous step. The mixture was purged with nitrogen gas three times and reacted at 100 °C for 1.5 h. Completion of the reaction was monitored by LCMS, and the reaction mixture was concentrated to approximately 5 mL, diluted with water (2 × 5 mL), adjusted to neutral with hydrochloric acid (37%), extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 43-4 (5.70 g, crude product) as a yellow oil.

[0127] Compound 43-4 (4.70 g, 32.6 mmol, 1 eq), 2-(1,3-dioxoisoindol-2-yl)acetaldehyde (6.16 g, 32.6 mmol, 1 eq), and trifluoromethanesulfonic acid (7.43 g, 65.2 mmol, 4.82 mL, 2 eq) were dissolved in 1,2-dichloroethane (100 mL). The mixture was purged with nitrogen gas three times and reacted at 50 °C for 12 h. Completion of the reaction was monitored by LCMS. The reaction mixture was filtered and concentrated under reduced pressure to give compound 43-5 (10.0 g, crude product).

[0128] Compound 43-5 (2.00 g, 6.34 mmol, 1 eq), hydrazine hydrochloride hydrate (869 mg, 12.7 mmol, 2 eq), and potassium carbonate (1.75 g, 12.7 mmol, 2 eq) were dissolved in methanol (30 mL). The atmosphere was purged with nitrogen gas three times and the mixture was reacted at 65 °C for 4 h. Completion of the reaction was monitored by LCMS. The reaction mixture was filtered and concentrated to give the crude product. The filtrate was quenched with diluted aqueous sodium hypochlorite solution. Purification by high-performance liquid chromatography gave compound 43 as a brown solid. Chiral resolution (column: DAICEL CHIRALPAK AY-H (250 mm × 30 mm, 10 μm), mobile phase: A: CO₂, B: (0.1% NH₃H₂O in EtOH), B%: 30% to 30%, 4 min) gave compound 43-a (retention time: 1.753 min, 133 mg, 0.69 mmol, 10.9% yield) as a yellow oil, and compound 43-b (retention time: 1.908 min, 143 mg, 0.74 mmol, 11.7% yield) as a yellow oil.

[0129] Compound 43-a: 1 H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 5.1 Hz, 1H), 6.77 (d, J = 5.1 Hz, 1H), 3.94 (dd, J = 4.4, 8.3 Hz, 1H), 3.11 (br d, J = 4.5 Hz, 1H), 3.04 - 2.94 (m, 4H), 2.92 - 2.77 (m, 1H), 1.86-1.82(m, 2H). MS (ESI) m / z = 185.9 [M+H] + . Compound 43-b: 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 5.1 Hz, 1H), 6.76 (d, J = 5.1 Hz, 1H), 3.94 (dd, J = 4.4, 8.3 Hz, 1H), 3.11 (br d, J = 4.5 Hz, 1H), 3.02 - 2.93 (m, 4H), 2.92 - 2.77 (m, 1H), 1.95-1.92(m, 2H). MS (ESI) m / z = 185.9 [M+H] + .

[0130] Example 17 Using a similar synthesis method and a similar resolution method to compound 43, compound 40-a (retention time: 2.918 min) and compound 40-b (retention time: 3.491 min) were obtained. The following table lists the characterization data of compound 40-a and compound 40-b: TIFF2025525370000104.tif63170

[0131] Example 18 Synthetic Route: TIFF2025525370000105.tif65170 Compound 10 (100 mg, 502 μmol, 1.00 eq) was dissolved in DCM (10.0 mL) and cooled to -75 °C. Compound BBr3 (377 mg, 1.51 mmol, 145 μL, 3.00 eq) was added dropwise. After the addition was complete, the mixture was allowed to warm to 20 °C and stirred for 2 h. LCMS analysis showed that compound 10 had reacted completely. The reaction mixture was cooled to -20 °C and quenched by the slow dropwise addition of MeOH (10.0 mL). The mixture was stirred at low temperature for 10 min. The reaction mixture was used directly in the next step without further purification.

[0132] A methanol solution (1.00 eq) of compound 20-1 was adjusted to pH 8 by dropwise addition of EtN at -20 °C, and (Boc)2O (6.00 eq) was added. The reaction mixture was gradually warmed to room temperature and reacted for 12 h. The complete reaction of compound 20-1 was confirmed by TLC spot plate analysis. The reaction mixture was cooled to 0-5 °C, water (50.0 mL) was added, and the mixture was washed with EtOAc (30.0 mL). The filtrate was washed with brine (30.0 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (eluent: petroleum ether: EtOAc = 5:1) to give compound 20-2 (400 mg, 1.04 mmol, 55.9% yield) as a yellow oil.

[0133] Compound 20-2 (100 mg, 259 μmol, 1.00 eq) was suspended in MeOH (2.00 mL), K2CO3 (179 mg, 1.30 mmol, 5.00 eq) was added, and the reaction mixture was heated to 25 °C and stirred for 6 h. LCMS showed that compound 20-2 had reacted completely. The reaction mixture was filtered, and the filtrate was collected, directly suspended in water, and dried for use in the next step. Product 20-3 (93 mg) was obtained as a crude yellow oil.

[0134] Compound 20-3 (100 mg, 259 μmol, 1.00 eq) was dissolved in anhydrous DMF (2.00 mL), DIPEA (223 mg, 1.73 mmol, 300 μL, 6.00 eq) was added, and trifluoroiodoethane (200 mg, 862 μmol, 3.00 eq) was added. The mixture was stirred at room temperature for 5 hours. LCMS showed that the starting materials had completely reacted and the product had been produced. The reaction mixture was then directly suspended and dried, and purified by column chromatography (PE:EtOAC=5:1) to give product 20-4 (70 mg) as a yellow oil.

[0135] Compound 20-4 (70.0 mg, 190 μmol, 1.00 eq) was added to ethyl acetate hydrochloride (4 M) (5.0 mL), and the reaction mixture was stirred at 25 °C for 5 h. LCMS showed that the starting materials had completely reacted and the product had been produced. The pH of the product was adjusted to approximately 8 with NaHCO3, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was rotary evaporated to give compound 20 (27.0 mg, 95.9 μmol, 50.4% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.20 - 7.19 (d,J=4.0 Hz 1H), 6.77-6.75(d, J = 8Hz, 1H), 4.93-4.90(dd, J = 8.0 Hz,4.0 Hz 1H), 4.38-4.32.(m, 2H), 4.00-.399 (d,J=4.0 Hz 1H), 3.99-3.82 (m, 1H), 3.20-3.17(m, 1H), 3.02-2.89(m, 3H). MS (ESI) m / z = 268.1 [M+H] + .

[0136] Example 19 Using a similar synthetic method to compound 20, compounds 15, 19, and 60 were obtained. The following table lists the characterization data for compounds 15, 19, and 60: TIFF2025525370000106.tif113170

[0137] Example 20 Synthetic Route: TIFF2025525370000107.tif31170 To compound 42-5 (300 mg, 1.06 mmol, 1.00 eq) in anhydrous THF (10.0 mL) was added LiAlH4 in several portions at 0 °C under N2 protection, and the reaction was heated to 75 °C and stirred for 3 h. LCMS detection showed that compound 42-5 had reacted completely. The reaction solution was slowly poured into water. The reaction solution was extracted three times with EtOAc (30 mL). The combined organic phases were extracted, washed once with brine (30 mL), dried once with anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by HPLC chromatography (column: Xtimate C18 150 × 40 mm × 10 μm, mobile phase: [water(NH4HCO3)-ACN], B%: 2% to 42%, 25 min) to give compound 61 (139 mg, 637 μmol, 41.7% yield) as a yellowish oil. 1 H NMR (400 MH, CDCl3) δ7.14 (d, J=5.20 Hz, 1 H), 6.78 (d, J=5.20 Hz, 1 H), 3.75 (t, J=12.0 Hz, 8.0 Hz 1 H), 3.03 - 3.11 (m, 1 H), 2.87 - 2.90 (m, 2 H), 2.69 - 2.80 (m, 2 H), 2.55 - 2.62 (m, 1 H), 2.49 (d, J=2.40Hz, 6 H). MS (ESI) m / z = 197.1 [M+H] + .

[0138] Example 21 Synthetic Route: TIFF2025525370000108.tif54170 Compound 9-1 (100 mg, 287 μmol, 1.00 eq) was dissolved in dioxane (1.00 mL) and water (0.10 mL). Cyclopropylboronic acid (49.3 mg, 574 μmol, 2.00 eq), potassium carbonate (79.4 mg, 574 μmol, 2.00 eq), and Pd(PPh3)4 (33.2 mg, 28.7 μmol, 0.10 eq) were added sequentially to the reaction mixture, which was then stirred at 100 °C for 3 h. LCMS confirmed the appearance of the product. Water (10.0 mL) was added dropwise to the reaction mixture at 25 °C, and the reaction mixture was simultaneously extracted three times with 3.0 mL of EtOAc. The organic phase was washed with saturated brine (7.00 mL) and finally dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (Petroleum ether / Ethyl acetate=93 / 7) to give a white oily product 59-2 (110 mg).

[0139] Intermediate 59-2 (110 mg, 356 μmol, 1.00 eq) was dissolved in HCl / dioxane (0.50 mL), and the reaction mixture was stirred at 25 °C for 3 h. LCMS confirmed the appearance of the product. The pH of the reaction mixture was adjusted to 7-8 with saturated NaHCO3 solution. The reaction mixture was extracted three times with 1.0 mL of DCM. The organic phase was washed with saturated brine (3.0 mL) and finally dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by prep-HPLC (Welch Xtimate C18 150 × 30 mm × 5 μm, mobile phase: [water(NH4HCO3)-ACN], B%: 10%-50%, 36 min) to give compound 59 (33.0 mg, 155 μmol, 43.6% yield) as a white solid. 1H NMR (400 MH, CDCl3) δ7.12 (d, J = 5.14 Hz, 1 H), 6.57 (d, J = 5.14 Hz, 1 H), 5.00 (dd, J = 10.20, 2.56 Hz, 1 H), 4.03 (dd, J = 11.44, 2.70 Hz, 1 H), 3.80 (m, 1 H), 3.16 (dd, J = 12.20, 1.80 Hz, 1 H), 2.88 - 3.06 (m, 3 H), 1.81 - 1.92 (m, 1 H) 0.89 - 0.97 (m, 2 H), 0.68 - 0.74 (m, 1 H), 0.56 - 0.65 (m, 1 H). MS (ESI) m / z = 210.1 [M+H] + .

[0140] Example 22 Synthetic Route Compound 1-b (500 mg, 2.57 mmol, 1.00 eq) was dissolved in anhydrous dichloromethane (5.00 mL), followed by the addition of EtN (390 mg, 3.86 mmol, 537 μL, 1.50 eq). Methyl chloroformate (1.22 g, 12.8 mmol, 994 μL, 5.00 eq) was then added dropwise to the reaction mixture. After the addition was complete, the mixture was stirred at 20 °C for 5 h. LCMS analysis indicated that compound 1-b had reacted completely. The reaction mixture was added with 10.0 mL of water and extracted twice with DCM (20.0 mL). The organic phase was collected, dried over NaSO, and then rotary evaporated to give the crude product. The crude product was adjusted to pH 2 with HCl / EtOAC (1 M). A solid precipitated from the reaction mixture. The solid was filtered, collected, and rotary evaporated to give the hydrochloride salt of compound L15 (150 mg, 582 mol, 22.6% yield) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 7.61-7.60 (d, J=4.00 Hz, 1 H), 7.00-6.99 (d, J=4.00 Hz, 1 H), 4.7 (m, 1 H), 4.36-4.16(m, 2 H), 3.68(s, 5 H), 3.50-3.47(m, 2H), 3.21-3.20(m, 3H), 2.96-2.92(m, 1H). MS (ESI) m / z = 253.1 [M+H] + .

[0141] Example 23 Synthetic Route: Compound 1-b (500 mg, 2.57 mmol, 1.00 eq) was dissolved in anhydrous dichloromethane (5.00 mL) and EtN (390 mg, 3.86 mmol, 537 μL, 1.50 eq) was added. Compound 1B (1.84 g, 12.8 mmol, 5.00 eq) was then added dropwise to the reaction mixture. After the addition was complete, the mixture was stirred at 20 °C for 5 h. LCMS analysis showed that compound 1-b had reacted completely. The reaction mixture was added with 10.0 mL of water and extracted twice with DCM (20.0 mL). The organic phase was collected, dried over Na2SO4, and then rotary evaporated to give crude compound L27-1 (1.00 g) as a yellow solid.

[0142] Compound L27-1 (370 mg, 1.23 mmol, 1.00 eq) was dissolved in THF (3.00 mL) and DIEA (477 mg, 3.69 mmol, 0.64 mL, 3.00 eq) was added. Compound 2B (650 mg, 7.38 mmol, 0.684 mL, 6.00 eq) was then added dropwise to the reaction mixture. The reaction mixture was heated to 55 °C and stirred for 12 h. LCMS confirmed that compound L27-1 had completely reacted. 5.00 mL of water was added to the reaction mixture, and the mixture was extracted twice with DCM (10.0 mL). The organic phase was collected, dried over NaSO, and then rotary evaporated to give the crude product. Column purification afforded compound L27 (240 mg, 0.78 mmol, 63.3% yield). 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J=5.00 Hz, 1 H), 6.77 - 6.92 (m, 2 H), 3.98 - 4.47 (m, 2 H), 2.83 - 3.39 (m, 6 H), 2.44 - 2.71 (m, 4 H), 1.54 (s, 3H), 1.19 (dd, J=6.80, 2.00Hz, 6H). MS (ESI) m / z = 353.2 [M+H] + .

[0143] L27 (100 mg, 0.29 mmol) was dissolved in ethyl acetate (5 mL), and 4 M hydrochloric acid / dioxane solution (0.5 mL) was added dropwise at 0 °C. The mixture was stirred at room temperature for 2 h to precipitate a solid, which was then filtered to give the hydrochloride salt of L27 (120 mg).

[0144] Test Example 1. In vitro evaluation of intra- and extra-synaptic functional activity Cell:cAMP Hunter TM CHO-K1 TAAR1 Gs cell line Detection reagent: HitHunter cAMP Assay Detection Kit Experimental equipment: PerkinElmer Envision TM Chemiluminescence signal detector Experimental method: Cell treatment: cAMP Hunter cell line was cultured at 37°C, 5% CO2 until the cell confluence reached 70-80%, and the cells were harvested and the cell density was 1.5 x 10 4The cells were adjusted to a concentration of 1000 cells / mL and inoculated into a white-walled 384-well microplate in a volume of 20 μL. The cells were incubated overnight at 37°C and 5% CO2. The cell culture medium was discarded, and 15 μL of 2:1 HBSS / 10 mM Hepes:cAMP XS+Ab reagent was added to each well. The sample stock solution was diluted to 4X samples according to the concentration gradient with experimental buffer, and 5 μL of the 4X sample was added to each well and incubated at 37°C or room temperature for 30 or 60 min. 20 μL of the cAMP XS+ED / CL mixed solution was added to each well and incubated for 1 hour. 20 μL of the cAMP XS+EA reagent was added to each well and incubated at room temperature for 3 hours. The cells were then transferred to a PerkinElmer Envision TM The chemiluminescence signal was read by a detector.

[0145] Data analysis: EC data were analyzed using CBIS data analysis software (ChemInnovation, CA). 50 Percent activity was calculated using the following formula: % activity = 100% x (test article mean RLU - solvent control mean RLU) / (maximum control mean RLU - solvent control mean RLU), and the results are shown in Table 1. TIFF2025525370000111.tif246170TIFF2025525370000112.tif79170Conclusion: The compounds of the present disclosure exhibit good TAAR1 agonist activity.

[0146] Test Example 2. In vivo pharmacokinetic study in rats Rats: SD rats, weighing 200-250 g Reagents: Acetonitrile, MERCK; Methanol, MERCK; Formic acid, Sigma; Tolbutamide, Sigma.

[0147] Equipment: Water purification system, Millipore; electronic balance, METTLER TOLEDO; high-speed tabletop centrifuge, Thermo; water bath thermostatic shaker, Shanghai Yiheng Technology Co., Ltd.; vortex shaker, Thermo; liquid chromatography mass spectrometry, AB SCIEX.

[0148] Methods: SD rats were administered intravenously (IV) and orally (IG) with three rats per group. Compounds 1-b, 2-a, and L27 were administered intravenously (IV) and orally (IG) with DMSO and Tween 80, respectively. Doses were 2 mg / kg (Compound 1-b) or 1 mg / kg (Compound 2-a) for intravenous administration, and 5 mg / kg (Compound 1-b, Compound 2-a) or 9 mg / kg (Compound L27) for oral gavage administration. Whole blood samples were collected at 0, 5 min (IV), 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h. The whole blood was placed in heparinized EP tubes and centrifuged at 13,500 rpm for 10 min to separate the plasma. After pretreatment, the plasma was analyzed by LC-MS / MS to measure the concentrations of the test compounds. The results are shown in Tables 2 and 3. TIFF2025525370000113.tif96170TIFF2025525370000114.tif31170Conclusion: The results show that compounds 1-b and 2-a have relatively high exposure and bioavailability in rats after intravenous and oral gavage administration. Compound L27 can be metabolized to the active compound 1-b after oral gavage administration to rats, and L27 was not detected.

[0149] Test Example 3. In vivo pharmacokinetic study in dogs Dog: Beagle, weighing 11-13 kg Reagents: Acetonitrile, MERCK; Methanol, MERCK; Formic acid, Sigma; Tolbutamide, Sigma.

[0150] Equipment: Water purification system, Millipore; electronic balance, METTLER TOLEDO; high-speed tabletop centrifuge, Thermo; water bath thermostatic shaker, Shanghai Yiheng Technology Co., Ltd.; vortex shaker, Thermo; liquid chromatography mass spectrometry, AB SCIEX.

[0151] Methods: L15 hydrochloride was administered orally at a dose of 2 mg / kg (calculated as the free base) to two Beagle dogs per group using DMSO and Tween 80 as the solvent. Whole blood samples were collected at 0, 5, 15, 30, 1, 2, 3, 4, 6, 8, 12, and 24 h. The whole blood was placed in heparinized EP tubes and centrifuged at 13,500 rpm for 10 min to separate plasma. After pretreatment, the plasma was analyzed by LC-MS / MS to measure the concentrations of the test compounds. The results are shown in Table 4. TIFF2025525370000115.tif33170Conclusion: Compound L15 hydrochloride can be partially metabolized to compound 1-b after oral gavage administration to Beagle dogs.

[0152] Test Example 4. In vivo efficacy study in mice Mice: C57 mice, weighing 20-22 g Reagents: Physiological saline, Equipment: Electronic balance, METTLER TOLEDO; TopScan monitoring system.

[0153] 4.1 Model Preparation: MK-801 can induce hyperactivity in mice and is commonly used in the preclinical evaluation of antipsychotic drugs. The modeling method used in this study was as follows: Mice were given a single intraperitoneal injection of MK-801 at a dose of 0.8 mg / kg.

[0154] 4.2 Experimental grouping: The mice were randomly divided into model group, 1-b group, and L27 group, with 10 animals per group, as shown in Table 5 in detail. TIFF2025525370000116.tif36170Note: Group L27 is an equimolar dose of 1-b.

[0155] 4.3 Test Method: Mice were randomly divided into groups. At the start of the study, the test samples were administered orally once at the doses shown in Table 5, followed by placement in the activity chamber. After 30 minutes, each mouse was intraperitoneally injected with 0.8 mg / kg of MK-801 for modeling, and then placed back into the activity chamber. The activity distance (mm) of the mice after modeling (i.e., within 30-60 minutes after administration) was recorded and analyzed using the TopScan monitoring system.

[0156] 4.4 Observing indicators: The TopScan monitoring system was used to record and analyze the distance traveled (mm) after mouse modeling (within 30-60 min after administration).The total distance traveled (mm) after mouse modeling (within 30-60 min after administration) was recorded.

[0157] 4.5 Statistical analysis: Data analysis and processing were performed using Graphpad 5.0 software. ANOVA tests were used to compare the total distance traveled within 30-60 min between each treatment group and the model group. All tests were two-sided, and p<0.05 indicated statistical significance.

[0158] 4.6 Test results (shown in Figure 1): The test results showed that the total activity distance after modeling for the animals in groups 1-b and L27 was 6493.12±6228.87 mm and 8100.56±7787.37 mm, respectively, which was significantly lower (p<0.05) compared to the total activity distance after modeling for the animals in the model group (63052.14±21618.80 mm).

[0159] 4.7 Test Conclusion: Under the present experimental conditions, 1-b (10 mg / kg) and an equimolar amount of L27 hydrochloride (16 mg / kg) had a good inhibitory effect on the hyperactivity caused by MK801.

[0160] Test Example 5. In vivo efficacy study in mice 5.1 Experimental grouping: The mice were randomly divided into model group, 1-b group, and 2-a group, with 5 animals per group, as detailed in Table 6. The model preparation, test method, index observation, and statistical method were the same as in Test Example 4. TIFF2025525370000117.tif36170

[0161] 5.2 Test results (shown in Figure 2): The test results show that the total activity distance after modeling for animals in groups 1-b and 2-a was 13,644.54±10,814.85 mm and 9,161.61±4,711.10 mm, respectively, which was significantly lower (p<0.05) compared to the total activity distance after modeling for animals in the model group (101,535.71±26,076.11 mm).

[0162] 5.3 Test conclusions: Under the present experimental conditions, 1-b (3 mg / kg) and 2-a (3 mg / kg) had a good inhibitory effect on the hyperactivity caused by MK801.

Claims

1. A compound represented by formula (IA), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, Eventually, A 1 CR 2 , or selected from N atoms, A 2 CR 2 , or selected from the O atom, R 1 H, halogen, C 1-6 Alkyl alkyl group, or C 1-6 Selected from alkoxy groups, Each R 2 is independently selected from H, or C 1-6 an alkyl group A compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

2. A compound represented by formula (IA-1) or (IA-2), or a pharmaceutically acceptable salt thereof, A 1 CR 2 , or selected from N atoms, A 2 CR 2 , or selected from the O atom, R 1 is selected from H, F, methyl group, or methoxy group. Each R 2 These are independently selected from H or a methyl group. A compound, or a pharmaceutically acceptable salt thereof.

3. A compound represented by formula (IA-3) or (IA-4), or a pharmaceutically acceptable salt thereof, A 1 It is selected from CH or N atoms, A 2 CH 2 , or selected from the O atom, R 1 H, halogen, C 1-6 Alkyl alkyl group, or C 1-6 Selected from alkoxy groups, R 2 H, C 1-6 A group selected from alkyl groups, or a group represented by the following formula: Eventually, Z 1 is a combination, or C 1-3 Selected from alkyl groups, Z 2 The bond is selected from -O-, -NH-, -S-, -(C=O)-, -O(C=O)-, or -(C=O)O-. Z 3 is a bond, C 1-6 Alkyl group, phenyl group, -CH(NHAc)-CH 2 CH 2 -, -CH (CH 3 )-NHC(=O)-CH(CH 3 )-,-CH(CH 3 )-OC(=O)-,-CH 2 CH 2 CH 2 CH 2 CH(NH 2 ) - Selected from, Z 4 The bond is selected from -O-, -NH-, -S-, -(C=O)-, -O(C=O)-, or -(C=O)O-. Z 5 H, C 1-12 Alkyl group, -P(=O)(OH) 2 , Selected from, A compound, or a pharmaceutically acceptable salt thereof.

4. A 1 It is selected from CH or N atoms, A 2 CH 2 , or selected from the O atom, R 1 is selected from H, F, methyl group, or methoxy group. R 2 H, methyl group, isopropyl group, OH, Selected from, The compound according to claim 3, or a pharmaceutically acceptable salt thereof.

5. A compound represented by formula (IB), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, Eventually, (1) A 1 It is selected from either an O atom or an S atom. R 1 F, C 1-6 Alkoxy group, C 3-6 Cycloalkoxy group, halogenated C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, or C 1-6 Selected from alkyl-(C=O)-, Each R 2 H or C 1-6 Selected from alkyl groups, Or (2) A 1 He was selected by NH. R 1 C 1-6 Alkoxy group, C 3-6 Cycloalkoxy group, halogenated C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, or C 1-6 Selected from alkyl-(C=O)-, Each R 2 H or C 1-6 Selected from alkyl groups, Or (3) A 1 CH 2 Selected from, R 1 C 2-6 Alkoxy group, C 3-6 Cycloalkoxy group, halogenated C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, or C 1-6 Selected from alkyl-(C=O)-, Each R 2 H or C 1-6 Selected from alkyl groups, A compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

6. A compound represented by formula (IB-1) or (IB-2), or a pharmaceutically acceptable salt thereof, Eventually, (1) A 1 It is selected from either an O atom or an S atom. R 1 This is selected from F, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, cyclopropoxy group, cyclobutoxy group, fluoromethoxy group, chloromethoxy group, difluoromethoxy group, dichloromethoxy group, trifluoromethoxy group, trichloromethoxy group, 2-fluoroethoxy group, 2,2-difluoroethoxy group, 2,2-dichloroethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, pentafluoroethoxy group, pentachloroethoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, methyl-(C=O)-, or ethyl-(C=O)-. Each R 2 These are independently selected from H or a methyl group. Or (2) A 1 He was selected by NH. R 1 The group is selected from methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, pentachloroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl-(C=O)-, or ethyl-(C=O)-. Each R 2 These are independently selected from H or a methyl group. Or (3) A 1 CH 2 Selected from, R 1 The group is selected from ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2-difluoroethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, pentachloroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl-(C=O)-, or ethyl-(C=O)-. Each R 2 These are independently selected from H or a methyl group. A compound, or a pharmaceutically acceptable salt thereof.

7. A compound represented by formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, Eventually, X 1 X is selected from S atoms or O atoms. 2 is selected from CH, or X 2 X is selected from S atoms or O atoms. 1 He was selected from CH, (1) Y 1 is selected from O atoms and It is either a single bond or a double bond, If it is a single bond, Y 2 C(R) 5a R 5b ) selected from Y 3 C(R) 6a R 6b ) were selected from When it is a double bond, Y 2 is CR 5a selected from, Y 3 is CR 6a selected from, R 3a and R 3b One of them is chosen from H, and the other is C 1-6 Selected from alkyl groups, or R 3a and R 3b All of them are C 1-6 Selected from alkyl groups, R 5a , R 5b , R 6a H and C are independent of each other. 1-6 Alkyl alkyl group, C 1-3 Alkoxy C 1-3 alkyl group, or C 6-10 Selected from aryl groups, R 6b H and C are independent of each other. 2-6 Alkyl alkyl group, C 1-3 Alkoxy C 1-3 alkyl group, or C 6-10 Selected from aryl groups, or R 5a and R 5b , R 6a and R 6b They form an oxo (-C=O) together, and R 5a , R 5b , R 6a and R 6b At least one of them is not hydrogen, or R 5a , R 5b H and C are independent of each other. 1-6 Alkyl alkyl group, C 1-3 Alkoxy C 1-3 alkyl group, or C 6-10 Selected from aryl groups, R 6a and R 6b C 1-6 Selected from alkyl groups, or R 5a and R 5b C 1-6 Selected from alkyl groups, R 6a , R 6b H and C are independent of each other. 1-6 Alkyl alkyl group, C 1-3 Alkoxy C 1-3 alkyl group, or C 6-10 Selected from aryl groups, Or (2) Y 1 , NR 4 , or selected from S atoms, It is either a single bond or a double bond, If it is a single bond, Y 2 C(R) 5a R 5b ) selected from Y 3 C(R) 6a R 6b ) were selected from If it is a double bond, Y 2 CR 5a Selected from, Y 3 CR 6a Selected from, R 3a and R 3b One of them is chosen from H, and the other is C 1-6 Selected from alkyl groups, R 4 H or C 1-6 Selected from alkyl groups, R 5a , R 5b , R 6a and R 6b H and C are independent of each other. 1-6 Alkyl alkyl group, C 1-3 Alkoxy C 1-3 alkyl group, or C 6-10 Selected from aryl groups, or R 5a and R 5b , R 6a and R 6b They form an oxo (-C=O) together, Or (3) Y 3 O atom, NR 6 , or selected from S atoms, It is a single bond, Y 1 C(R) 4a R 4b ) selected from or Y 1 Y does not exist. 2 C(R) 5a R 5b ) were selected from R 3a and R 3b H or C 1-6 Selected from alkyl groups, R 4a , R 4b , R 5a and R 5b H and C are independent of each other. 1-6 Alkyl alkyl group, C 1-3 Alkoxy C 1-3 alkyl group, or C 6-10 Selected from aryl groups, or R 4a and R 4b They form an oxo (-C=O) together, and R 4a , R 4b , R 5a and R 5b At least one of them is not hydrogen, R 6 H or C 1-6 Selected from alkyl groups, A compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

8. A compound represented by formula (IIA) or (IIB), or a pharmaceutically acceptable salt thereof, X 1 X is selected from S atoms or O atoms. 2 is selected from CH, or X 2 X is selected from S atoms or O atoms. 1 He was selected from CH, (1) Y 1 It is selected from the O atom, It is either a single bond or a double bond, If it is a single bond, Y 2 C(R) 5a R 5b ) selected from Y 3 C(R) 6a R 6b ) were selected from If it is a double bond, Y 2 CR 5a Selected from, Y 3 CR 6a Selected from, R 3a and R 3b One of them is chosen from H, and the other is C 1-6 Selected from alkyl groups, or R 3a and R 3b All of them are C 1-6 Selected from alkyl groups, R 5a , R 5b , R 6a H and C are independent of each other. 1-6 Alkyl alkyl group, C 1-3 Alkoxy C 1-3 alkyl group, or C 6-10 Selected from aryl groups, R 6b H and C are independent of each other. 2-6 Alkyl alkyl group, C 1-3 Alkoxy C 1-3 alkyl group, or C 6-10 Selected from aryl groups, or R 5a and R 5b , R 6a and R 6b They form an oxo (-C=O) together, and R 5a , R 5b , R 6a and R 6b At least one of them is not hydrogen, or R 5a , R 5b H and C are independent of each other. 1-6 Alkyl alkyl group, C 1-3 Alkoxy C 1-3 alkyl group, or C 6-10 Selected from aryl groups, R 6a and R 6b C 1-6 Selected from alkyl groups, or R 5a and R 5b C 1-6 Selected from alkyl groups, R 6a , R 6b H and C are independent of each other. 1-6 Alkyl alkyl group, C 1-3 Alkoxy C 1-3 alkyl group, or C 6-10 Selected from aryl groups, Or (2) Y 1 , NR 4 , or selected from S atoms, It is either a single bond or a double bond, If it is a single bond, Y 2 C(R) 5a R 5b ) selected from Y 3 C(R) 6a R 6b ) were selected from If it is a double bond, Y 2 CR 5a Selected from, Y 3 CR 6a Selected from, R 3a and R 3b One of them is chosen from H, and the other is C 1-6 Selected from alkyl groups, R 4 H or C 1-6 Selected from alkyl groups, R 5a , R 5b , R 6a and R 6b H and C are independent of each other. 1-6 Alkyl alkyl group, C 1-3 Alkoxy C 1-3 alkyl group, or C 6-10 Selected from aryl groups, or R 5a and R 5b , R 6a and R 6b They form an oxo (-C=O) together, Or (3) Y 3 O atom, NR 6 , or selected from S atoms, It is a single bond, Y 1 C(R) 4a R 4b ) selected from or Y 1 Y does not exist. 2 C(R) 5a R 5b ) were selected from R 3a and R 3b H or C 1-6 Selected from alkyl groups, R 4a , R 4b , R 5a and R 5b H and C are independent of each other. 1-6 Alkyl alkyl group, C 1-3 Alkoxy C 1-3 alkyl group, or C 6-10 Selected from aryl groups, or R 4a and R 4b They form an oxo (-C=O) together, and R 4a , R 4b , R 5a and R 5b At least one of them is not hydrogen, R 6 H or C 1-6 Selected from alkyl groups, A compound, or a pharmaceutically acceptable salt thereof.

9. A compound represented by formula (III), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, Eventually, X 3 It is selected from either an S atom or an O atom. Y 2 C(R) 5a R 5b ) selected from Y 3 O atom, NR 6 , or selected from S atoms, R 3a and R 3b H or C 1-6 Selected from alkyl groups, R 5a H and C are independent of each other. 1-6 Alkyl alkyl group, C 1-3 Alkoxy C 1-3 alkyl group, or C 6-10 Selected from aryl groups, R 5b C 1-6 Alkyl alkyl group, C 1-3 Alkoxy C 1-3 alkyl group, or C 6-10 Selected from aryl groups, or R 5a and R 5b They form an oxo (-C=O) together, R 6 H or C 1-6 Selected from alkyl groups, A compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

10. A compound represented by formula (IIIA) or (IIIB), or a pharmaceutically acceptable salt thereof, Eventually, X 3 It is selected from either an S atom or an O atom. Y 2 C(R) 5a R 5b ) selected from Y 3 O atom, NR 6 , or selected from S atoms, R 3a and R 3b H or C 1-6 Selected from alkyl groups, R 5a H and C are independent of each other. 1-6 Alkyl alkyl group, C 1-3 Alkoxy C 1-3 alkyl group, or C 6-10 Selected from aryl groups, R 5b C 1-6 Alkyl alkyl group, C 1-3 Alkoxy C 1-3 alkyl group, or C 6-10 Selected from aryl groups, or R 5a and R 5b They form an oxo (-C=O) together, R 6 H or C 1-6 Selected from alkyl groups, A compound, or a pharmaceutically acceptable salt thereof.

11. R 3a and R 3b One of them is selected from H, and the other is selected from a methyl group, or R 3a and R 3b These are all selected from methyl groups. R 4 These are independently selected from H or a methyl group. R 4a , R 4b , R 5a , R 5b and R 6a R is independently selected from H, methyl group, ethyl group, n-propyl group, isopropyl group, methoxymethyl group, and phenyl group. 6b The group is independently selected from H, ethyl group, n-propyl group, isopropyl group, methoxymethyl group, phenyl group, or R 4a and R 4b , R 5a and R 5b , R 6a and R 6b They form an oxo (-C=O) together, R 6 These are independently selected from H or a methyl group. A compound according to any one of claims 7 to 10, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

12. The following compounds, their pharmaceutically acceptable salts, or their stereoisomers, Selected from, A compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

14. The use of a compound according to any one of claims 1 to 10, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a TAAR1 agonist pharmaceutical.

15. Use of a compound according to any one of claims 1 to 10, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a medicament for the treatment, prevention and / or control of central nervous system (CNS) related diseases or symptoms.

16. The aforementioned central nervous system (CNS) disorders or symptoms include schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, psychotic mental disorders, schizotypal personality disorders, schizotypal personality disorders, paranoid mental disorders, psychosis, mental disorders, short-term psychotic disorders, shared mental disorders, mental disorders due to physical illness, drug-induced psychosis, psychoaffective disorders, aggressive mental confusion, Parkinson's psychosis, irritable psychosis, Tourette syndrome, organ or NOS psychosis, epilepsy, epileptic seizures, mental agitation, post-traumatic stress disorder, behavioral confusion, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dyskinesias, Huntington's disease, dementia, affective disorders, anxiety disorders, affective psychosis, obsessive-compulsive neuropathy, dizziness, pain, fibromyalgia, migraines, cognitive impairment, and movement disorders. The use according to claim 15, including (disorder), restless legs syndrome (RLS), multiple sclerosis, psychoactive substance abuse, and stress-related disorders.

17. The use according to claim 16, wherein the affective psychosis includes depression, major depressive disorder and dysthymia, bipolar disorder, bipolar depression, mania, seasonal affective disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), the pain includes neuropathic pain, neuropathic pain susceptibility, and inflammatory pain, and the stress-related disorder includes acute stress disorder, post-traumatic stress disorder, and adjustment disorder.

18. Use of a compound according to any one of claims 1 to 10, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a medicament for the treatment, prevention and / or control of cardiovascular or metabolic diseases.

19. The use according to claim 18, wherein the cardiovascular or metabolic disease includes diabetes mellitus, diabetic complications, obesity, dyslipidemia, and hypertension.

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