Heterocyclic compounds as TAAR1 ligand agonists

Abstract

The invention provides a heterocyclic compound serving as a TAAR1 agonist, and further provides a preparation method of the compound, a pharmaceutical composition containing the compound and application of the compound serving as the TAAR1 agonist to prevention and / or treatment of various CNS-related diseases. Wherein each substituent in the general formula (IA) is as defined in the specification. # imgabs0 #

Description

Heterocyclic compounds as TAAR1 ligand agonists Technical Field

[0001] The present disclosure relates to heterocyclic compounds, preparation methods thereof, and applications of heterocyclic compounds as TAAR1 agonists in treating related diseases. Background Art

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

[0003] Currently, there are four drugs targeting 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 strong excitatory effect on the central nervous system. Short-term effects can cause increased heart rate, blood pressure, feelings of happiness, and reduced fatigue. However, long-term use can cause adverse reactions such as insomnia, irritability, delusions and hallucinations, and violent and aggressive behavior, leading to its classification as a controlled substance. RG-7906, RO-5263397, and SEP-363856 are all investigational TAAR1 selective agonists. RG-7906 is in Phase II clinical trials, RO-5263397 is on hold in Phase I trials, and SEP-363856, the most advanced drug, is in Phase III clinical trials. Therefore, the development of new TAAR1 agonists with improved safety and efficacy is needed to meet the needs of patients.

[0004] Summary of the Invention

[0005] In one embodiment of the present disclosure, there is provided a compound represented by formula (IA), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0006] in,

[0007] A1 is selected from CR2, or a N atom;

[0008] A2 is selected from CR2, or an O atom;

[0009] R1 is selected from H, halogen, C 1-6 Alkyl, or C 1-6alkoxy;

[0010] Each R2 is independently selected from H, or C 1-6 alkyl.

[0011] In some embodiments of the present disclosure, the compound represented by formula (IA), its pharmaceutically acceptable salt, or stereoisomer,

[0012] A1 is selected from CR2, or a N atom;

[0013] A2 is selected from CR2, or an O atom;

[0014] R1 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, methoxy, ethoxy, n-propoxy, isopropoxy;

[0015] Each R2 is independently selected from H, methyl, or ethyl.

[0016] In some embodiments of the present disclosure, the compound represented by formula (IA), its pharmaceutically acceptable salt, or stereoisomer,

[0017] A1 is selected from CR2, or a N atom;

[0018] A2 is selected from CR2, or an O atom;

[0019] R1 is selected from H, F, methyl, or methoxy;

[0020] Each R2 is independently selected from H, or methyl.

[0021] 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:

[0022] A1 is selected from CR2, or a N atom;

[0023] A2 is selected from CR2, or an O atom;

[0024] R1 is selected from H, F, methyl, or methoxy;

[0025] R2 is independently selected from H, or methyl.

[0026] 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:

[0027] in,

[0028] A1 is selected from CH, or N atoms;

[0029] A2 is selected from CH2, or an O atom;

[0030] R1 is selected from H, halogen, C 1-6 Alkyl, or C 1-6 alkoxy;

[0031] R2 is selected from H, C 1-6 Alkyl, or a group represented by the following formula:

[0032] in,

[0033] Z1 is selected from a bond, or C 1-3 alkyl;

[0034] Z2 is selected from a bond, -O-, -NH-, -S-, -(C=O)-, -O(C=O)-, or -(C=O)O-;

[0035] Z3 is selected from a bond, C 1-6 Alkyl, phenyl, -CH(NHAc)-CH2CH2-, -CH(CH3)-NHC(=O)-CH(CH3)-, -CH(CH3)-OC(=O)-, -CH2CH2CH2CH2CH(NH2)-;

[0036] Z4 is selected from a bond, -O-, -NH-, -S-, -(C=O)-, -O(C=O)-, or -(C=O)O-;

[0037] Z5 is selected from H, C 1-12 Alkyl, -P(=O)(OH)2,

[0038] In some embodiments of the present disclosure, in the compound represented by formula (IA-3) or (IA-4), its pharmaceutically acceptable salt, or stereoisomer,

[0039] A1 is selected from CH, or N atoms;

[0040] A2 is selected from CH2, or an O atom;

[0041] R1 is selected from H, F, methyl, or methoxy;

[0042] R2 is selected from H, methyl, or a group represented by the following formula:

[0043] in,

[0044] Z1 is selected from a bond, methyl, ethyl, n-propyl, isopropyl;

[0045] Z2 is selected from a bond, -O-, -NH-, -S-, -(C=O)-, -O(C=O)-, or -(C=O)O-;

[0046] Z3 is selected from a bond, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, phenyl, -CH(NHAc)-CH2CH2-, -CH(CH3)-NHC(=O)-CH(CH3)-, -CH(CH3)-OC(=O)-, -CH2CH2CH2CH2CH(NH2)-;

[0047] Z4 is selected from a bond, -O-, -NH-, -S-, -(C=O)-, -O(C=O)-, or -(C=O)O-;

[0048] Z5 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, -P(=O)(OH)2,

[0049] In some embodiments of the present disclosure, in the compound represented by formula (IA-3) or (IA-4), its pharmaceutically acceptable salt, or stereoisomer,

[0050] A1 is selected from CH, or N atoms;

[0051] A2 is selected from CH2, or an O atom;

[0052] R1 is selected from H, F, methyl, or methoxy;

[0053] R2 is selected from H, methyl, isopropyl, OH,

[0054] In some embodiments of the present disclosure, the compound represented by formula (IA-3) or (IA-4), its pharmaceutically acceptable salt, or stereoisomer is a prodrug of the compound represented by formula (IA-1) or (IA-2), its pharmaceutically acceptable salt, or stereoisomer.

[0055] In one embodiment of the present disclosure, there is provided a compound represented by formula (IB), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0056] in,

[0057] (1) A1 is selected from an O atom or a S atom;

[0058] R1 is selected from F, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, halogenated C1-6 Alkoxy, C 3-6 Cycloalkyl, or C 1-6 Alkyl-(C=O)-; each R2 is independently selected from H, or C 1-6 alkyl;

[0059] or

[0060] (2) A1 is selected from NH;

[0061] R1 is selected from C 1-6 Alkoxy, C 3-6 Cycloalkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, or C 1-6 Alkyl-(C=O)-;

[0062] Each R2 is independently selected from H, or C 1-6 alkyl;

[0063] or

[0064] (3) A1 is selected from CH2;

[0065] R1 is selected from C 2-6 Alkoxy, C 3-6 Cycloalkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, or C 1-6 Alkyl-(C=O)-;

[0066] Each R2 is independently selected from H, or C 1-6 alkyl.

[0067] In some embodiments of the present disclosure, in the compound represented by formula (IB), its pharmaceutically acceptable salt, or stereoisomer, A1 is selected from an O atom or an S atom;

[0068] R1 is selected from F, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, 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)-;

[0069] R2 is independently selected from H, or methyl.

[0070] In some embodiments of the present disclosure, in the compound represented by formula (IB), its pharmaceutically acceptable salt, or stereoisomer,

[0071] A1 is selected from NH;

[0072] R1 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, 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)-;

[0073] R2 is independently selected from H, or methyl.

[0074] In some embodiments of the present disclosure, in the compound represented by formula (IB), its pharmaceutically acceptable salt, or stereoisomer,

[0075] A1 is selected from CH2;

[0076] R1 is selected from ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, 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)-;

[0077] R2 is independently selected from H, or methyl.

[0078] 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:

[0079] in,

[0080] (1) A1 is selected from an O atom or a S atom;

[0081] R1 is selected from F, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, 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)-;

[0082] Each R2 is independently selected from H, or methyl;

[0083] or

[0084] (2) A1 is selected from NH;

[0085] R1 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, 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)-;

[0086] Each R2 is independently selected from H, or methyl;

[0087] or

[0088] (3) A1 is selected from CH2;

[0089] R1 is selected from ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, 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)-;

[0090] Each R2 is independently selected from H, or methyl.

[0091] In one embodiment of the present disclosure, there is provided a compound represented by formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0092] in,

[0093] X1 is selected from a S atom or an O atom, and X2 is selected from CH, or X2 is selected from a S atom or an O atom, and X1 is selected from CH;

[0094] (1) Y1 is selected from an O atom;

[0095] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0096] R3a and R 3b One of them is selected from H and the other is selected from C 1-6 Alkyl, or R 3a and R 3b All selected from C 1-6 alkyl;

[0097] R 5a 、R 5b 、R 6a and R 6b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O), and R 5a 、R 5b 、R 6a and R 6b At least one of them is not hydrogen;

[0098] or

[0099] (2) Y1 is selected from NR4, or an S atom;

[0100] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0101] R 3a and R 3b One of them is selected from H and the other is selected from C 1-6 Alkyl, or R 3a and R 3b All selected from H;

[0102] R4 is independently selected from H or C 1-6 alkyl;

[0103] R 5a 、R 5b 、R 6a and R 6b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3Alkyl, or C 6-10 Aryl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O);

[0104] or

[0105] (3) Y3 is selected from an O atom, NR6, or a S atom;

[0106] is a single bond, Y1 is selected from C(R 4a R 4b ) or Y1 is absent, Y2 is selected from C(R 5a R 5b );

[0107] R 3a and R 3b Independently selected from H or C 1-6 alkyl;

[0108] R 4a 、R 4b 、R 5a and R 5b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 4a and R 4b 、R 5a and R 5b Together they form an oxo group (-C=O);

[0109] R6 is independently selected from H or C 1-6 alkyl.

[0110] In some embodiments of the present disclosure, the compound represented by formula (II), its pharmaceutically acceptable salt, or stereoisomer,

[0111] (1) Y1 is selected from an O atom;

[0112] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0113] R3a and R 3b One of them is selected from H and the other is selected from C 1-6 Alkyl, or R 3a and R 3b All selected from C 1-6 alkyl;

[0114] R 5a 、R 5b 、R 6a Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, R 6b Independently selected from H, C 2-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O), and R 5a 、R 5b 、R 6a and R 6b At least one of them is not hydrogen;

[0115] or R 5a 、R 5b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, R 6a and R 6b Also selected from C 1-6 alkyl;

[0116] or R 5a and R 5b Also selected from C 1-6 Alkyl, R 6a 、R 6b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 aryl;

[0117] or

[0118] (2) Y1 is selected from NR4, or an S atom;

[0119] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R5a R 5b ), Y3 is selected from C(R 6a R 6b ),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0120] R 3a and R 3b One of them is selected from H and the other is selected from C 1-6 alkyl;

[0121] R4 is independently selected from H or C 1-6 alkyl;

[0122] R 5a 、R 5b 、R 6a and R 6b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O);

[0123] or

[0124] (3) Y3 is selected from an O atom, NR6, or a S atom;

[0125] is a single bond, Y1 is selected from C(R 4a R 4b ) or Y1 is absent, Y2 is selected from C(R 5a R 5b );

[0126] R 3a and R 3b Independently selected from H or C 1-6 alkyl;

[0127] R 4a 、R 4b 、R 5a and R 5b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 4a and R 4b Together they form an oxo group (-C=O), and R 4a 、R4b 、R 5a and R 5b At least one of them is not hydrogen;

[0128] R6 is independently selected from H or C 1-6 alkyl.

[0129] In some embodiments of the present disclosure, in the compound represented by formula (II), its pharmaceutically acceptable salt, or stereoisomer, X1 is selected from an S atom or an O atom, and X2 is selected from CH; other variables are as defined in the present disclosure.

[0130] In some embodiments of the present disclosure, in the compound represented by formula (II), its pharmaceutically acceptable salt, or stereoisomer, X2 is selected from an S atom or an O atom, and X1 is selected from CH; other variables are as defined in the present disclosure.

[0131] In some embodiments of the present disclosure, the compound represented by formula (II), its pharmaceutically acceptable salt, or stereoisomer,

[0132] R 3a and R 3b One of them is selected from H, the other is selected from methyl, or R 3a and R 3b are all selected from methyl;

[0133] R4 is independently selected from H, or methyl;

[0134] R 4a 、R 4b 、R 5a 、R 5b 、R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 4a and R 4b 、R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O);

[0135] R6 is independently selected from H or methyl;

[0136] Other variables are as defined in this disclosure.

[0137] In some embodiments of the present disclosure, the compound represented by formula (II), its pharmaceutically acceptable salt, or stereoisomer,

[0138] X1 is selected from a S atom or an O atom, and X2 is selected from CH;

[0139] Y1 is selected from O atoms;

[0140] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0141] R 3a and R 3b One of them is selected from H, the other is selected from methyl, or R 3a and R 3b are all selected from methyl;

[0142] R 5a 、R 5b 、R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O), and R 5a 、R 5b 、R 6a and R 6b In some embodiments of the present disclosure, in the compound represented by formula (II), its pharmaceutically acceptable salt, or stereoisomer,

[0143] X1 is selected from a S atom or an O atom, and X2 is selected from CH;

[0144] Y1 is selected from O atoms;

[0145] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when

[0146] When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0147] R 3a and R 3b One of them is selected from H, the other is selected from methyl, or R 3a and R3b are all selected from methyl;

[0148] R 5a 、R 5b 、R 6a R is independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, 6b are independently selected from H, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O), and R 5a 、R 5b 、R 6a and R 6b At least one of them is not hydrogen;

[0149] or R 5a 、R 5b R is independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, 6a and R 6b Also selected from methyl;

[0150] or R 5a and R 5b At the same time, selected from methyl, R 6a 、R 6b Independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl.

[0151] In some embodiments of the present disclosure, the compound represented by formula (II), its pharmaceutically acceptable salt, or stereoisomer,

[0152] X1 is selected from a S atom or an O atom, and X2 is selected from CH;

[0153] Y1 is selected from NR4, or an S atom;

[0154] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0155] R 3a and R 3b One of them is selected from H, the other is selected from methyl, or R 3a and R3b All selected from H;

[0156] R4 is independently selected from H or methyl;

[0157] R 5a 、R 5b 、R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O).

[0158] In some embodiments of the present disclosure, the compound represented by formula (II), its pharmaceutically acceptable salt, or stereoisomer,

[0159] X1 is selected from a S atom or an O atom, and X2 is selected from CH;

[0160] Y1 is selected from NR4, or an S atom;

[0161] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0162] R 3a and R 3b One of them is selected from H, and the other is selected from methyl;

[0163] R4 is independently selected from H or methyl;

[0164] R 5a 、R 5b 、R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O).

[0165] In some embodiments of the present disclosure, the compound represented by formula (II), its pharmaceutically acceptable salt, or stereoisomer,

[0166] X1 is selected from a S atom or an O atom, and X2 is selected from CH;

[0167] Y3 is selected from an O atom, NR6, or an S atom;

[0168] is a single bond, Y1 is selected from C(R 4a R 4b ) or Y1 is absent, Y2 is selected from C(R 5a R 5b );

[0169] R 3a and R 3b independently selected from H or methyl;

[0170] R 4a 、R 4b 、R 5a and R 5b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 4a and R 4b 、R 5a and R 5b Together they form an oxo group (-C=O);

[0171] R6 is independently selected from H or methyl.

[0172] In some embodiments of the present disclosure, the compound represented by formula (II), its pharmaceutically acceptable salt, or stereoisomer,

[0173] X1 is selected from a S atom or an O atom, and X2 is selected from CH;

[0174] Y3 is selected from an O atom, NR6, or an S atom;

[0175] is a single bond, Y1 is selected from C(R 4a R 4b ) or Y1 is absent, Y2 is selected from C(R 5a R 5b );

[0176] R 3a and R 3b independently selected from H or methyl;

[0177] R 4a 、R 4b 、R 5a and R 5b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 4a and R 4b Together they form an oxo group (-C=O), and R 4a 、R4b 、R 5a and R 5b At least one of them is not hydrogen;

[0178] R6 is independently selected from H or methyl.

[0179] In some embodiments of the present disclosure, the compound represented by formula (II), its pharmaceutically acceptable salt, or stereoisomer,

[0180] X1 is selected from an S atom, X2 is selected from CH;

[0181] Y1 is selected from NR4, or an S atom;

[0182] When it is a single bond, Y2 and Y3 are both selected from CH2,

[0183] R 3a and R 3b One of them is selected from H, and the other is selected from methyl;

[0184] R4 is selected from H or C 1-6 Alkyl, preferably H or methyl.

[0185] In one embodiment of the present disclosure, there is provided a compound represented by formula (IIA) or (IIB), or a pharmaceutically acceptable salt thereof:

[0186] in,

[0187] X1 is selected from a S atom or an O atom, and X2 is selected from CH, or X2 is selected from a S atom or an O atom, and X1 is selected from CH;

[0188] (1) Y1 is selected from an O atom;

[0189] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0190] R 3a and R 3b One of them is selected from H and the other is selected from C 1-6 Alkyl, or R 3a and R 3b All selected from C 1-6 alkyl;

[0191] R 5a 、R 5b 、R 6a and R 6b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O), and R 5a 、R 5b 、R 6a and R 6b At least one of them is not hydrogen;

[0192] or

[0193] (2) Y1 is selected from NR4, or an S atom;

[0194] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0195] R 3a and R 3b One of them is selected from H and the other is selected from C 1-6 Alkyl, or R 3a and R 3b All selected from H;

[0196] R4 is independently selected from H or C 1-6 alkyl;

[0197] R 5a 、R 5b 、R 6a and R 6b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O);

[0198] or

[0199] (3) Y3 is selected from an O atom, NR6, or a S atom;

[0200] is a single bond, Y1 is selected from C(R 4a R 4b ) or Y1 is absent, Y2 is selected from C(R 5a R 5b );

[0201] R 3a and R 3b Independently selected from H or C 1-6 alkyl;

[0202] R 4a 、R 4b 、R 5a and R 5b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 4a and R 4b 、R 5a and R 5b Together they form an oxo group (-C=O);

[0203] R6 is independently selected from H or C 1-6 alkyl.

[0204] In some embodiments of the present disclosure, in the compound represented by formula (IIA) or (IIB), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, (1) Y1 is selected from an O atom;

[0205] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when

[0206] When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0207] R 3a and R 3b One of them is selected from H and the other is selected from C 1-6 Alkyl, or R 3a and R 3b All selected from C 1-6 alkyl;

[0208] R5a 、R 5b 、R 6a Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, R 6b Independently selected from H, C 2-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O), and R 5a 、R 5b 、R 6a and R 6b At least one of them is not hydrogen;

[0209] or R 5a 、R 5b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, R 6a and R 6b Also selected from C 1-6 alkyl;

[0210] or R 5a and R 5b Also selected from C 1-6 Alkyl, R 6a 、R 6b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 aryl;

[0211] or

[0212] (2) Y1 is selected from NR4, or an S atom;

[0213] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0214] R 3a and R 3b One of them is selected from H and the other is selected from C 1-6 alkyl;

[0215] R4 is independently selected from H or C 1-6 alkyl;

[0216] R 5a 、R 5b 、R 6a and R 6b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O);

[0217] or

[0218] (3) Y3 is selected from an O atom, NR6, or a S atom;

[0219] is a single bond, Y1 is selected from C(R 4a R 4b ) or Y1 is absent, Y2 is selected from C(R 5a R 5b );

[0220] R 3a and R 3b Independently selected from H or C 1-6 alkyl;

[0221] R 4a 、R 4b 、R 5a and R 5b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 4a and R 4b Together they form an oxo group (-C=O), and R 4a 、R 4b 、R 5a and R 5b At least one of them is not hydrogen;

[0222] R6 is independently selected from H or C 1-6 alkyl.

[0223] In some embodiments of the present disclosure, in the compound represented by 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; other variables are as defined in the present disclosure.

[0224] In some embodiments of the present disclosure, in the compound represented by formula (IIA) or (IIB), or a pharmaceutically acceptable salt thereof, X2 is selected from an S atom or an O atom, and X1 is selected from CH; other variables are as defined in the present disclosure.

[0225] In some embodiments of the present disclosure, in the compound represented by formula (IIA) or (IIB), or a pharmaceutically acceptable salt thereof,

[0226] R 3a and R 3b One of them is selected from H, the other is selected from methyl, or R 3a and R 3b are all selected from methyl;

[0227] R4 is independently selected from H, or methyl;

[0228] R 4a 、R 4b 、R 5a 、R 5b 、R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 4a and R 4b 、R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O);

[0229] R6 is independently selected from H or methyl;

[0230] Other variables are as defined in this disclosure.

[0231] In some embodiments of the present disclosure, in the compound represented by formula (IIA) or (IIB), or a pharmaceutically acceptable salt thereof,

[0232] X1 is selected from a S atom or an O atom, and X2 is selected from CH;

[0233] Y1 is selected from O atoms;

[0234] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0235] R 3a and R 3b One of them is selected from H, the other is selected from methyl, or R 3a and R 3b are all selected from methyl;

[0236] R 5a 、R 5b 、R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O), and R 5a 、R 5b 、R 6a and R 6b At least one of them is not hydrogen.

[0237] In some embodiments of the present disclosure, in the compound represented by formula (IIA) or (IIB), its pharmaceutically acceptable salt, or stereoisomer,

[0238] X1 is selected from a S atom or an O atom, and X2 is selected from CH;

[0239] Y1 is selected from O atoms;

[0240] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when

[0241] When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0242] R 3a and R 3b One of them is selected from H, the other is selected from methyl, or R 3a and R 3b are all selected from methyl;

[0243] R 5a 、R 5b 、R 6aR is independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, 6b are independently selected from H, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O), and R 5a 、R 5b 、R 6a and R 6b At least one of them is not hydrogen;

[0244] or R 5a 、R 5b R is independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, 6a and R 6b Also selected from methyl;

[0245] or R 5a and R 5b At the same time, R 6a 、R 6b Independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl.

[0246] In some embodiments of the present disclosure, in the compound represented by formula (IIA) or (IIB), a pharmaceutically acceptable salt thereof, or a stereoisomer, X1 is selected from an S atom or an O atom, and X2 is selected from CH;

[0247] Y1 is selected from NR4, or an S atom;

[0248] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0249] R 3a and R 3b One of them is selected from H, the other is selected from methyl, or R 3a and R 3b All selected from H;

[0250] R4 is independently selected from H or methyl;

[0251] R 5a 、R 5b 、R6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O).

[0252] In some embodiments of the present disclosure, in the compound represented by formula (IIA) or (IIB), a pharmaceutically acceptable salt thereof, or a stereoisomer, X1 is selected from an S atom or an O atom, and X2 is selected from CH;

[0253] Y1 is selected from NR4, or an S atom;

[0254] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0255] R 3a and R 3b One of them is selected from H, and the other is selected from methyl;

[0256] R4 is independently selected from H or methyl;

[0257] R 5a 、R 5b 、R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O).

[0258] In some embodiments of the present disclosure, in the compound represented by formula (IIA) or (IIB), a pharmaceutically acceptable salt thereof, or a stereoisomer, X1 is selected from an S atom or an O atom, and X2 is selected from CH;

[0259] Y3 is selected from an O atom, NR6, or an S atom;

[0260] is a single bond, Y1 is selected from C(R 4a R 4b ) or Y1 is absent, Y2 is selected from C(R5a R 5b );

[0261] R 3a and R 3b independently selected from H or methyl;

[0262] R 4a 、R 4b 、R 5a and R 5b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 4a and R 4b 、R 5a and R 5b Together they form an oxo group (-C=O);

[0263] R6 is independently selected from H or methyl.

[0264] In some embodiments of the present disclosure, in the compound represented by formula (IIA) or (IIB), a pharmaceutically acceptable salt thereof, or a stereoisomer, X2 is selected from an S atom or an O atom, and X1 is selected from CH;

[0265] Y1 is selected from O atoms;

[0266] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0267] R 3a and R 3b One of them is selected from H, the other is selected from methyl, or R 3a and R 3b are all selected from methyl;

[0268] R 5a 、R 5b 、R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O), and R 5a 、R 5b 、R 6a and R6b At least one of them is not hydrogen.

[0269] In some embodiments of the present disclosure, in the compound represented by formula (IIA) or (IIB), a pharmaceutically acceptable salt thereof, or a stereoisomer, X2 is selected from an S atom or an O atom, and X1 is selected from CH;

[0270] Y1 is selected from NR4, or an S atom;

[0271] Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when

[0272] When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ;

[0273] R 3a and R 3b One of them is selected from H, the other is selected from methyl, or R 3a and R 3b All selected from H;

[0274] R4 is independently selected from H or methyl;

[0275] R 5a 、R 5b 、R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O).

[0276] In some embodiments of the present disclosure, in the compound represented by formula (IIA) or (IIB), a pharmaceutically acceptable salt thereof, or a stereoisomer, X2 is selected from an S atom or an O atom, and X1 is selected from CH;

[0277] Y3 is selected from an O atom, NR6, or an S atom;

[0278] is a single bond, Y1 is selected from C(R 4a R 4b ) or Y1 is absent, Y2 is selected from C(R 5a R 5b );

[0279] R3a and R 3b independently selected from H or methyl;

[0280] R 4a 、R 4b 、R 5a and R 5b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 4a and R 4b 、R 5a and R 5b Together they form an oxo group (-C=O);

[0281] R6 is independently selected from H or methyl.

[0282] In some embodiments of the present disclosure, in the compound represented by formula (IIA) or (IIB), a pharmaceutically acceptable salt thereof, or a stereoisomer, X1 is selected from an S atom or an O atom, and X2 is selected from CH;

[0283] Y3 is selected from an O atom, NR6, or an S atom;

[0284] is a single bond, Y1 is selected from C(R 4a R 4b ) or Y1 is absent, Y2 is selected from C(R 5a R 5b );

[0285] R 3a and R 3b independently selected from H or methyl;

[0286] R 4a 、R 4b 、R 5a and R 5b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 4a and R 4b Together they form an oxo group (-C=O), and R 4a 、R 4b 、R 5a and R 5b At least one of them is not hydrogen;

[0287] R6 is independently selected from H or methyl.

[0288] In some embodiments of the present disclosure, in the compound represented by formula (IIA) or (IIB), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, X1 is selected from an S atom, and X2 is selected from CH;

[0289] Y1 is selected from NR4, or an S atom;

[0290] When it is a single bond, Y2 and Y3 are both selected from CH2,

[0291] R 3a and R 3b One of them is selected from H, and the other is selected from methyl;

[0292] R4 is selected from H or C 1-6 Alkyl, preferably H or methyl.

[0293] In one embodiment of the present disclosure, there is provided a compound represented by formula (III), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0294] in,

[0295] X3 is selected from a S atom or an O atom;

[0296] Y2 is selected from C(R 5a R 5b ), Y3 is selected from an O atom, NR6, or a S atom;

[0297] R 3a and R 3b Independently selected from H or C 1-6 alkyl;

[0298] R 5a Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, R 5b Independently selected from C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 5a and R 5b Together they form an oxo group (-C=O);

[0299] R6 is independently selected from H or C 1-6 alkyl.

[0300] In some embodiments of the present disclosure, the compound represented by formula (III), its pharmaceutically acceptable salt, or stereoisomer,

[0301] R 3a and R 3b independently selected from H or methyl;

[0302] R 5a R is independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, 5bare independently selected from methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 5a and R 5b Together they form an oxo group (-C=O);

[0303] R6 is independently selected from H or methyl.

[0304] In one embodiment of the present disclosure, provided is a compound represented by formula (IIIA) or (IIIB), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0305] in,

[0306] X3 is selected from a S atom or an O atom;

[0307] Y2 is selected from C(R 5a R 5b ), Y3 is selected from an O atom, NR6, or a S atom;

[0308] R 3a and R 3b Independently selected from H or C 1-6 alkyl;

[0309] R 5a Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, R 5b Independently selected from C 1-6 Alkyl, C 1-3 alkyl

[0310] Oxygen C 1-3 Alkyl, or C 6-10 Aryl, or R 5a and R 5b Together they form an oxo group (-C=O);

[0311] R6 is independently selected from H or C 1-6 alkyl.

[0312] In some embodiments of the present disclosure, in the compound represented by formula (IIIA) or (IIIB), its pharmaceutically acceptable salt, or stereoisomer,

[0313] R 3a and R 3b independently selected from H or methyl;

[0314] R 5a R is independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, 5bare independently selected from methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 5a and R 5b Together they form an oxo group (-C=O);

[0315] R6 is independently selected from H or methyl.

[0316] In another embodiment of the present disclosure, there is provided a compound, a pharmaceutically acceptable salt, or a stereoisomer as shown below:

[0317] In another embodiment of the present disclosure, there is provided a stereoisomer of a compound as shown below or a pharmaceutically acceptable salt thereof:

[0318] In another embodiment of the present disclosure, there is provided a stereoisomer of a compound as shown below or a pharmaceutically acceptable salt thereof:

[0319] The present disclosure also 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 into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, granules, injections, etc. The pharmaceutical composition can be administered orally or parenterally (such as intravenously, subcutaneously or topically). The dosage can be appropriately adjusted according to the patient's age, sex, and disease type, and the general daily dose is about 1-200 mg.

[0320] The present disclosure also provides the use of the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, or pharmaceutical composition in the preparation of TAAR, especially TAAR1 agonist drugs.

[0321] The present disclosure also provides the use of the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, or pharmaceutical composition in the preparation of a drug for treating TAAR, especially TAAR1-mediated related diseases.

[0322] The present disclosure also 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 diseases.

[0323] The present disclosure provides a method for treating, preventing and / or controlling various central nervous system (CNS) related diseases or symptoms using the compounds provided herein, their pharmaceutically acceptable salts, stereoisomers, or compositions. The present disclosure also provides the use of the compounds provided herein, their pharmaceutically acceptable salts, stereoisomers, or compositions in the preparation of a medicament for treating, preventing and / or controlling various central nervous system (CNS) related diseases or symptoms. The central nervous system (CNS) diseases or symptoms include, but are not limited to, schizophrenia, schizophrenia spectrum disorders, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, psychotic disorders, schizophreniform personality disorder, schizotypal personality disorder, delusional disorder, psychosis, mental disorder, short-term mental disorder, shared mental disorder, mental disorder caused by physical illness, drug (e.g., cocaine, alcohol, amphetamine) induced psychosis, psychoemotional disorder, aggressive psychosis, Parkinson's psychosis, irritant psychosis, Tourette syndrome, organ or NOS psychosis, epilepsy, epileptic seizures, agitation, post-traumatic stress disorder disorders, behavioral disorders, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dyskinesias, Huntington's disease, dementia, affective disorders, anxiety disorders, affective psychoses (e.g., depression, e.g., major depressive disorder and dysthymia; bipolar disorder, e.g., bipolar depression; mania; seasonal affective disorder; and attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)), obsessive compulsive disorder, vertigo, pain (e.g., neuropathic pain, neuropathic pain-prone states, and inflammatory pain), fibromyalgia, migraine, cognitive impairment, movement disorders disorder), restless leg 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 disturbances and dysfunction, sleep disorders, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, sleepiness as a side effect of medications, insomnia, sleep and circadian rhythm disorders, disorders of energy expenditure and assimilation, vomiting, Lesche-Nyhane disease, Wilson disease, autism, Huntington disease, and premenstrual dysphoric disorder.

[0324] The present disclosure provides methods for treating, preventing, and / or controlling cardiovascular or metabolic diseases using the compounds provided herein, their pharmaceutically acceptable salts, stereoisomers, or compositions. The present disclosure also provides uses of the compounds provided herein, their pharmaceutically acceptable salts, stereoisomers, or compositions in the preparation of medicaments for treating, preventing, and / or controlling cardiovascular or metabolic diseases. The cardiovascular or metabolic diseases include, but are not limited to, diabetes, diabetic complications, obesity, dyslipidemia, and hypertension. BRIEF DESCRIPTION OF THE DRAWINGS

[0325] Figure 1: Pharmacodynamic evaluation of compounds 1-b and L27 in a mouse hyperactivity model.

[0326] Figure 2: Pharmacodynamic evaluation of compounds 1-b and 2-a in a mouse hyperactivity model.

[0327] Definition and Description

[0328] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0329] The term "pharmaceutically acceptable" as used herein refers to compounds, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0330] The "pharmaceutically acceptable salts" mentioned in the present disclosure refer to salts of the compounds of the present disclosure, which are prepared from compounds with specific substituents discovered in the present disclosure and relatively non-toxic acids and bases. When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present disclosure contain basic functional groups and can be converted into any acid addition salt.

[0331] Certain compounds of the present disclosure may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present disclosure.

[0332] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0333] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, the salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two.

[0334] The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium representative of a carrier that can deliver an effective amount of the active substance of the present disclosure, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient, including but not limited to: binders, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.

[0335] The present disclosure is intended to include all isotopes of atoms present in the compounds of the present disclosure. Isotopes include those atoms having the same atomic number but different mass numbers. As a 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 an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed.

[0336] Unless otherwise specified, the term "alkyl" is used to refer to a straight or branched saturated hydrocarbon group, which may be monosubstituted (such as -CH2F) or polysubstituted (such as -CF3), and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 12 Indicates 1 to 12 carbons, C 1-12 Selected from C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl, 1-ethylpropyl), hexyl (e.g., n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl), n-heptyl (n-heptyl), n-octyl (n-octyl), n-nonyl (n-nonyl), n-decyl (n-decyl), n-undecyl (n-undecyl), n-dodecyl (n-dodecyl), and the like.

[0337]

[0046] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0338] Unless otherwise specified, "haloalkyl" is used to refer to a monohalogenated / polyhalogenated straight or branched chain alkyl group. Typical haloalkyl groups include C 1-6 Haloalkyl, for example: C1, C2, C3, C4, C5, C6 haloalkyl. For example, examples of C1-C6 haloalkyl include, but are not limited to: fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, and pentachloroethyl.

[0339] Unless otherwise specified, "alkoxy" represents an alkyl group (including cycloalkyl or haloalkyl) as defined above with the specified number of carbon atoms attached through an oxygen bridge. Typical alkoxy groups include C 1-6 Alkoxy groups, such as C1, C2, C3, C4, C5, and C6 alkoxy groups, C3, C4, C5, and C6 cycloalkoxy groups, and C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, S-pentoxy, hexoxy, and 2-ethylbutoxy groups. Examples of cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy groups. Examples of haloalkoxy 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.

[0340] Unless otherwise specified, "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, which may be monosubstituted or polysubstituted and may be monovalent, divalent, or polyvalent. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0341] Unless otherwise specified, "aryl" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (ie, rings which share adjacent pairs of carbon atoms) group having a conjugated pi electron system, such as phenyl and naphthyl, with phenyl being preferred.

[0342] Unless otherwise specified, the term "bond" refers to a chemical bond between atoms used to connect or interact with each other, such as an ionic bond, a covalent bond, or a coordination bond. In the molecular structure of organic compounds, a "bond" is typically a covalent bond. When one or more variables between two atoms / groups are defined as a "bond", it generally means that the two atoms / groups are directly connected by a "bond".

[0343] The term "prodrug" refers to a compound that can be converted into a biologically active form through metabolism in the body.

[0344] If the compounds disclosed herein involve absolute configurations, such absolute configurations can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is performed by collecting diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using a direct method (Shelxs97) to confirm the absolute configuration. The H-NMR spectra of the disclosed compounds were detected using a Bruker / AVANCE NEO 400 MHz instrument.

[0345] Compounds are manually or Software naming, commercially available compounds use supplier catalog names. DETAILED DESCRIPTION

[0346] The present disclosure is further described below with reference to specific embodiments and test examples, but they do not limit the scope of the present disclosure in any form.

[0347] Example 1

[0348] Synthesis route:

[0349] 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 temperature was lowered 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 temperature was naturally raised to 20°C and stirred for 24 hours. NaHCO₃ (2.57 g, 30.6 mmol, 1.00 eq) and chloroacetyl chloride (3.45 g, 30.6 mmol, 1.00 eq) were additionally added. After the addition, the reaction mixture was stirred at 20°C for 48 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which 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 Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) and concentrated to dryness to afford compound 1-2 (3.00 g, 13.6 mmol, 44.4% yield) as a white solid.

[0350] 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 hours. LCMS confirmed the reaction was complete. The reaction mixture was cooled to 0-5°C, whereupon 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 to approximately 30.0 mL of solvent. The remaining organic phase was cooled to 0-5°C and adjusted to pH 2-3 with the dropwise addition of HCl / EtOAc (4 M). A large amount of solid precipitated. The mixture was filtered, the filter cake was washed with EtOAc (5.00 mL), and then drained to collect the solid. The solid was concentrated under reduced pressure to remove the solvent to obtain compound 1-3 (3.20 g, 9.78 mmol, yield 66.4%) as an off-white solid.

[0351] Compound 1-3 (2.63 g, 8.52 mmol, 1.00 eq) was suspended in DCE (130 mL). MgSO₄ (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. The reaction mixture was heated to 85°C and stirred for 3 hours. LCMS analysis confirmed the complete reaction of compound 3. The reaction mixture was cooled to 20°C, water (100 mL) was added, and the pH was adjusted to 9-10 with aqueous Na₂CO₃. Insoluble salts were removed by filtration, and the filter cake was washed with CH₂Cl₂ (150 mL) and water (100 mL). The filtrate was separated, and the aqueous phase was extracted twice with CH₂Cl₂ (150 mL). The combined organic phase was washed with brine (50.0 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to yield crude compound 1-4 (2.00 g) as a white solid.

[0352] Compound 1-4 (1.49 g, 7.15 mmol, 1.00 eq) was dissolved in anhydrous THF (31 mL). LiAlH₄ (543 mg, 14.3 mmol, 2.00 eq) was added portionwise at 20°C. The reaction was heated to 66°C and stirred for 1 hour. LCMS analysis confirmed the desired product. Water (1.50 mL) was added dropwise to the reaction mixture under nitrogen, and the mixture was then dried. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:0–96:4) to obtain a yellow oil. The product was preparatively isolated and then lyophilized to obtain compound 1. Chiral separation (column: DAICEL CHIRALPAK AY-H (250 mm × 30 mm, 10 um); mobile phase: A: CO2, B: (0.1% NH3H2O ​​EtOH); B%: 30%-30%, 4 min) gave compound 1-a (retention time: 1.133 min, 265 mg, 1.35 mmol, yield 18.9%) as a white solid; and compound 1-b (retention time: 1.368 min, 275 mg, 1.39 mmol, yield 19.4%) as a white solid.

[0353] Compound 1-a: 1 H NMR: (400MHz, CDCl3) δ7.11 (d, J=5.2Hz, 1H), 6.80 (d, J=5.2Hz, 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] + .

[0354] Compound 1-b: 1H NMR:(400MHz CDCl3)δ7.11(d,J=5.2Hz,1H),6.80(d,J=5.2Hz,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] + .

[0355] Example 2

[0356] Compounds 2-a and 2-b were obtained using a similar synthesis method and the same resolution method as compound 1. The following table lists the characterization data of compounds 2-a (retention time: 0.707 min) and 2-b (retention time: 1.074 min):

[0357] Example 3

[0358] Synthesis route:

[0359] Compound 7-1 was dissolved in THF (20 mL), and LDA (2M, 2.69 mL, 1.1 eq) was added dropwise to the reaction solution at -70°C. After the addition was complete, the mixture was reacted at -70°C for 3 h. LCMS monitored the completion of the reaction. 5 mL of saturated aqueous ammonium chloride solution was added to the reaction solution until the pH was equal to 7.0, and then the mixture was extracted twice with 20 mL of ethyl acetate. The extracts were combined and dried under vacuum to obtain a colorless oily product 7-2 (0.8 g, 2.64 mmol, yield 53.87%), which was directly fed to the next step.

[0360] Compound 7-2 (0.8 g, 2.64 mmol, 1 eq) was dissolved in THF (10 mL). Sodium borohydride (200 mg, 5.29 mmol, 2.00 eq) was added to the reaction mixture at 25°C and stirred at room temperature for 2 hours. LCMS monitored the reaction for completion. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and extracted with ethyl acetate (10 mL twice). The combined organic phases were concentrated in vacuo to dryness to afford the product 7-3 (0.8 g, 2.52 mmol, 95.37% yield) as a colorless oil, which was used directly in the next step.

[0361] Compound 7-3 was dissolved in H₂O (3 mL), and HCl (6 M, 5.46 mL, 50 eq) was added. The mixture was stirred at 25°C for 16 hr. LCMS monitored the reaction for completion. Saturated aqueous sodium bicarbonate (10 mL) 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 afford compound 7. Chiral separation (column: Daicel ChiralPak IG (250 x 30 mm, 10 μm); mobile phase: A: CO₂, B: (0.1% NH₃H₂O EtOH); B%: 35%-35%, 4 min) afforded compound 7-a (retention time: 0.802 min, 15.9 mg, yield 12.7%) as a yellow oil, and compound 7-b (retention time: 0.866 min, 27.7 mg, yield 22.1%) as a yellow oil.

[0362] Compound 7-a: 1 H NMR (400MHz, CDCl3) δ7.13(m,1H),6.75(d,J=5.6Hz,1H),4.84(dd,J=2.4,10.0Hz,1H),3.99(dd,J=2.4,10.0Hz,9.6Hz, 1H),3.76(m,1H),3.15(dd,J=2.4Hz,10.0Hz,9.6Hz,1H),2.99-2.87(m,3H),2.18-2.03(m,1H).MS(ESI)m / z=188.1[M+H] + .

[0363] Compound 7-b: 1 H NMR (400MHz, CDCl3) δ7.14(m,1H),6.75(d,J=5.6Hz,1H),4.86(dd,J=2.4,10.0Hz,1H),3.99(dd,J=2.4,10.0Hz,9.6Hz, 1H),3.79(m,1H),3.17(dd,J=2.4Hz,10.0Hz,9.6Hz,1H),3.01-2.91(m,3H),2.16-2.02(m,1H).MS(ESI)m / z=188.1[M+H] + .

[0364] Example 4

[0365] Synthesis route:

[0366] 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 hours. 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 -70-20°C for 13 hours. LCMS analysis revealed the product. NH₄Cl solution was added dropwise to the reaction mixture at 0°C to quench the LDA, followed by extraction with 40.0 mL of EtOAc three times. 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 afford the oily product 9-2 (450 mg, 1.05 mmol, 36.7% yield).

[0367] 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 under nitrogen for 20 hours. LCMS analysis revealed the product. The reaction mixture was filtered through Celite to remove the Pd / C, washed with THF, and the organic phase was concentrated. Preparative separation afforded the oily product 9-3 (30.0 mg, 103 μmol, 7.57% yield).

[0368] 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 hours. LCMS detected the product. The pH of the reaction mixture was adjusted to 7-8 with NaHCO₃ solution, and then extracted three times with 10.0 mL of CH₂Cl₂. The organic phase was washed with saturated brine (30.0 mL) and finally dried over anhydrous Na₂SO₄. The organic phase was concentrated to afford the oily product 9 (16.0 mg, 79.2 μmol, 77.5% yield).

[0369] 1 H NMR (400MHz, CDCl3) δ6.52-6.63(m,1H),6.32(dd,J=3.94,1.70Hz,1H),4.59(dt,J=9.98,2.20Hz,1H),3. 94-4.02(m,1H),3.75(m,1H),3.14(dd,J=12.26,2.00Hz,1H),2.84-2.99(m,3H).MS(ESI)m / z=188.1[M+H] + .

[0370] Example 5

[0371] Synthesis route:

[0372] Dissolve compound 10-1 (1.00 g, 8.76 mmol, 1.00 eq) in anhydrous THF (10.0 mL), replace the atmosphere with nitrogen three times, and cool to -65 to -60°C. Use a syringe to measure lithium diisopropylamide (2 M, 4.82 mL, 1.10 eq) and add it dropwise to the reaction mixture over 10 minutes while controlling the temperature at -65 to -60°C. Stir the reaction mixture at -65 to -60°C for 30 minutes. Weigh tert-butyl-2-oxopyran-4-carboxylate (1.59 g, 7.88 mmol, 0.90 eq) and dissolve it in anhydrous THF (4.00 mL) while controlling the temperature at -65 to -60°C. Add it dropwise to the reaction mixture over 10 minutes. After addition, warm the reaction mixture to 20°C and stir for 2 hours. LCMS confirms the reaction is complete for compound 10-1. Under nitrogen, the reaction was quenched by the dropwise addition of aqueous NH4Cl (5.0 mL), 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 afford the crude product. The crude product was purified by column chromatography (petroleum ether:EtOAc = 2:1 to 1:1) and dried to afford compound 10-2 (1.00 g, 35.1% yield) as a yellow oil.

[0373] Compound 10-2 (500 mg, 1.59 mmol, 1.00 eq) was dissolved in EtOH (5.00 mL) and cooled to 0°C. NaBH₄ (240 mg, 6.34 mmol, 4.00 eq) was added portionwise to the reaction mixture. The reaction mixture was naturally warmed to 20°C and stirred for 2 hours. LCMS analysis confirmed the complete reaction of compound 10-2. The reaction mixture was slowly poured into water (5.00 mL) and extracted three times with EtOAc (15.0 mL). The combined organic phases were washed with brine (45.0 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford compound 10-3 (436 mg, 1.15 mmol, 72.8% yield) as a colorless oil.

[0374] Compound 10-3 (250 mg, 788 μmol, 1.00 eq) was dissolved in anhydrous THF (10.0 mL), cooled to 0°C, and 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 hours. LCMS analysis showed 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 obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 10:1) and dried to afford compound 10. Chiral separation (column: Daicel ChiralPak IG (250*30mm, 10um); mobile phase: A: CO2, B: (0.1% NH3H2O ​​EtOH); B%: 35%-35%, 4 min) gave compound 10-a (retention time: 0.933 min, 26.0 mg, yield 14.9%) as a yellow oil and compound 10-b (retention time: 1.080 min, 28.0 mg, yield 16.6%) as a yellow oil.

[0375] Compound 10-a: 1 H NMR:(400MHz DMSO-d6) δ7.34(d,J=5.6Hz,1H),6.94(d,J=5.6Hz,1H),4.62(dd,J1=10.0Hz,J2=2.4Hz,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] + .

[0376] Compound 10-b: 1 H NMR:(400MHz DMSO-d6)δ7.36(d,J=5.2Hz,1H),6.96(d,J=5.6Hz,1H),4.65-4.64(m,1H),3.80-3.77(m,1H),3.77(s,3 H),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] + .

[0377] Example 6

[0378] 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 using a similar synthesis method and the same resolution method as compound 10. The following table lists the characterization data of compound 8, compound 11-a, compound 11-b, compound 12-a, and compound 12-b:

[0379] Example 7

[0380] Synthesis route:

[0381] Dissolve trimethylsulfoxide iodide (1.15 g, 5.23 mmol, 1.00 eq) in dry DMSO (16.0 mL), cool to 0-5°C, and add NaH (210 mg, 5.23 mmol, 60.0% purity, 1.00 eq) portionwise. Stir at 0-5°C for 1 hour. Dissolve compound 13-1 (1.00 g, 5.23 mmol, 1.00 eq) in anhydrous THF (8.00 mL), control the temperature at 0-5°C, and add dropwise to the reaction mixture. Allow the reaction mixture to warm to 20°C and stir for 2 hours. LCMS analysis indicates that compound 13-1 has reacted completely. Pour the reaction mixture slowly into ice water and extract twice with petroleum ether (50 mL). The combined organic phases are washed once with brine (30 mL) and dried over anhydrous Na2SO4 to yield a petroleum ether solution (100 mL) of compound 13-2. To a petroleum ether solution of compound 13-2, ethanolamine (1.60 g, 26.2 mmol, 5.00 eq) was added, and the reaction mixture was heated to 50°C and stirred for 3 hours. LCMS confirmed the complete reaction of compound 13-2. The reaction mixture was cooled to 20°C, and Boc2O (5.71 g, 26.2 mmol, 6.01 mL, 5.00 eq) was added portionwise. The reaction mixture was stirred at 20°C for 2 hours. LCMS confirmed the complete reaction of compound 13-3. The reaction mixture was diluted with EtOAc (50.0 mL), washed once with water (50.0 mL) and once 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 silica gel column chromatography to afford compound 13-4 (300 mg, 819 μmol, 15.7% yield) as a brown liquid.

[0382] To compound 13-4 (155 mg, 423 μmol, 1.00 eq) was added hydrochloric acid (6 M, 10.0 mL, 142 eq). The reaction was heated to 110°C and stirred for 3 hours. LCMS analysis 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). Boc2O (185 mg, 846 μmol, 194 μL, 2.00 eq) was added, and the reaction mixture was stirred at 20°C for 2 hours. LCMS analysis showed that the intermediate phase had reacted completely. The reaction mixture was extracted three times with EtOAc (30 mL). The combined organic phases were washed once with brine (30 mL), dried once over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was concentrated to dryness by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain compound 13-5 (150 mg, 362 μmol, yield 85.5%) as a yellow oil.

[0383] 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, dibutyl(1-ethoxyvinyl)pentylstannane (300 mg, 831 μmol, 280 μL, 1.93 eq) was added dropwise to the reaction mixture. The reaction mixture was heated to 110°C and stirred for 16 hours. LCMS analysis indicated that the reaction was incomplete. The reaction mixture 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 mixture was heated to 110°C and stirred for an additional 16 hours. LCMS analysis confirmed that the reaction of compound 13-5 was complete. The reaction mixture was filtered, the filter cake was washed with EtOAc (30.0 mL), and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) and chiral separation (column: Daicel ChiralPak IG (250*30mm, 10um); mobile phase: A:CO2, B: (0.1% NH3H2O ​​MeOH); B%: 20%-20%, 4 min) to afford 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.

[0384] 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 hours. LCMS analysis confirmed the complete reaction of compound 13-7-a. The reaction mixture was diluted with deionized water (20.0 mL) and the pH was adjusted to 7-8 by adding NaHCO₃ with stirring. The aqueous phase was extracted three times with CH₂Cl₂ (15.0 mL). The combined organic phases were washed with brine (10.0 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford compound 13-a (20.0 mg, 90.9 μmol, 94.3% yield) as a yellow solid.

[0385] 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 hours. LCMS analysis confirmed the complete reaction of compound 13-7-b. The reaction mixture was diluted with deionized water (20.0 mL) and the pH was adjusted to 7-8 by adding NaHCO₃ with stirring. The aqueous phase was extracted three times with CH₂Cl₂ (15.0 mL). The combined organic phases were washed with brine (10.0 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford compound 13-b (20.0 mg, 90.7 μmol, 80.7% yield) as a yellow solid.

[0386] Compound 13-a: 1 H NMR:(400MHz CDCl3)δ7.36(d,J=5.6Hz,1H),7.22(d,J=5.2Hz,1H),5.35(dd,J1=9.2Hz,J1=2.4Hz,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] + .

[0387] Compound 13-b: 1H NMR:(400MHz CDCl3)δ7.36(d,J=5.2Hz,1H),7.22(d,J=5.2Hz,1H),5.36(dd,J1=9.6Hz,J1=2.0Hz,1H),4.05-4.01(m,1H),3.75-3.73( m,1H),3.37-3.34(m,1H),3.00-2.97(m,1H),2.97-2.93(m,1H),2.61-2.56(m,1H),2.52(s,3H).MS(ESI)m / z=212.1[M+H] + .

[0388] Example 8

[0389] Synthesis route:

[0390] 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 reaction was stirred at this temperature for 1 hour. 2-Methyloxirane (7.12 g, 123 mmol, 8.60 mL, 2 eq) was then slowly added dropwise at -55°C. Boron trifluoride etherate (8.71 g, 61.3 mmol, 7.57 mL, 1 eq) was then added 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 sodium bicarbonate aqueous solution at -78°C and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate aqueous solution 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) to obtain 1-(thiophen-3-yl)propan-2-ol (Compound 28-2) as a red oil (7.70 g, 54.1 mmol, yield 88.3%).

[0391] Dissolve methylaminoacetaldehyde dimethyl acetal in 2-methyltetrahydrofuran (100 mL) and add 1-(thiophen-3-yl)propan-2-ol (7.70 g, 54.1 mmol, 1 eq) at 25°C. Stir at this temperature for 5 minutes, then add trifluoromethanesulfonic acid (8.94 g, 59.6 mmol, 5.26 mL, 1.1 eq). The resulting dark brown mixture is then heated to 80°C and stirred for 1 hour. LCMS confirms the reaction is complete. The reaction mixture is slowly quenched by adding saturated potassium hydroxide solution to a pH > 7, and extracted with methyl tert-butyl ether. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound 28 was purified by HPLC and then separated and purified by SFC (column: DAICEL CHIRALPAK AY-H (250 mm x 30 mm, 10 μm); mobile phase: A: CO2, B: (0.1% NH3H2O ​​MeOH); B%: 20%-20%, 4 min) to give yellow oily compound 28-a (retention time: 0.812 min, 65.8 mg, 333 μmol, yield 61.5%) and yellow oily compound 28-b (retention time: 0.954 min, 66.1 mg, 334 μmol, yield 61.8%).

[0392] Compound 28-a: 1 H NMR: (400MHz, DMSO-d6) δ7.28 (d, J=5.1Hz, 1H), 6.93 (d, J=5.3Hz, 1H), 4.68 (td, J=2.3, 4.6Hz, 1H), 3.76 (ddd, J=3.3, 6.2, 10. 3Hz,1H),3.49-3.39(m,1H),2.92(dd,J=3.6,12.2Hz,1H),2.78(td,J=2.4,15.9Hz,1H),2.63(dd,J=7.8,12.1Hz,1H),2.53(br dd,J=2.3,11.3Hz,1H),2.32(s,3H),1.28(d,J=6.1Hz,3H).MS(ESI)m / z=198.1[M+H] + .

[0393] Compound 28-b: 1H NMR: (400MHz, DMSO-d6) δ7.28 (d, J=5.1Hz, 1H), 6.94 (d, J=5.3Hz, 1H), 4.72-4.65 (m, 1H), 3.76 (ddd, J=3.2, 6.3, 10.3Hz, 1H),3.48-3.40(m,1H),2.94(dd,J=3.6,12.2Hz,1H),2.79(td,J=2.4,15.8Hz,1H),2.64(dd,J=7.8,12.3Hz,1H),2.54(br dd,J=1.9,10.7Hz,1H),2.37-2.30(m,3H),1.28(d,J=6.1Hz,3H).MS(ESI)m / z=198.1[M+H] + .

[0394] Example 9

[0395] Compound 30, compound 39-a (retention time: 1.520 min), and compound 39-b (retention time: 2.120 min) were obtained using a similar synthesis method and the same resolution method as compound 28. The following table lists the characterization data of compound 30, compound 39-a, and compound 39-b:

[0396] Example 10

[0397] Synthesis route:

[0398] 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 the atmosphere was purged with nitrogen three times. LiHMDS (1 M, 76.7 mL, 2.50 eq) was added dropwise to the reaction mixture at 20°C over 10 minutes. 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 (20.0 mL) and added dropwise to the reaction mixture at a temperature of -10 to 0°C. The reaction mixture was heated to 85°C and stirred for 3 hours. LCMS confirmed the reaction was complete. 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 give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give compound 32-2 (9.00 g, crude product) as a yellow solid.

[0399] Compound 32-2 (9.00 g, 38.7 mmol, 1.00 eq) was dissolved in anhydrous THF (100 mL), cooled to 0-5°C, and red aluminum (33.6 g, 116 mmol, 32.3 mL, 70.0% purity, 3.0 eq) was added dropwise. The reaction mixture was naturally warmed to 20°C and stirred for 4 hours. LCMS analysis confirmed the complete reaction of compound 32-2. 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 obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 2:1) to afford compound 32-3 (1.60 g, 3.84 mmol, 9.91% yield) as a colorless oil.

[0400] 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 (20.0 mL). TfOH (2.70 g, 18.0 mmol, 1.59 mL, 2.30 eq) was added dropwise. The reaction mixture was heated to 85°C and stirred for 5 hours. LCMS confirmed the reaction was complete. The reaction mixture was poured into water (50.0 mL), adjusted to pH 7-8 with aqueous sodium bicarbonate, and extracted twice with ethyl acetate (50.0 mL). The combined organic phases were 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 separated by silica gel column chromatography (dichloromethane:methanol=10:1, Rf=0.3) and SFC chiral separation (column:DAICEL CHIRALPAK AY-H (250mm﹡30mm,10um); mobile phase:A:CO2,B:(0.1%NH3H2O ​​EtOH);B%:20%-20%,4min) to give compound 32-a (retention time: 1.373min, 251mg, yield 12.3%) as a brown oil, compound 32-b (retention time: 1.451min, 56.0mg, yield 2.65%) as a brown oil, compound 32-c (retention time: 1.679min, 51mg, yield 2.32%) as a brown oil, and compound 32-d (retention time: 1.850min, 282mg, yield 13.6%) as a brown oil.

[0401] Compound 32-a: 1H NMR:(400MHz CDCl3)δ7.34-7.27(m,3H),7.18-7.16(m,2H),7.13(d,J=4.8Hz,1H),6.58(d,J=5.2Hz,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] + .

[0402] Compound 32-b: 1 H NMR: (400MHz CDCl3)δ7.31-7.27(m,2H),7.22-7.19(m,1H),7.18-7.16(m,3H), 6.72(d,J=5.2Hz,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] + .

[0403] Compound 32-c: 1 H NMR:(400MHz CDCl3)δ7.31-7.27(m,2H),7.24-7.19(m,1H),7.18-7.16(m,3H),6.72(d,J=4.8Hz,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] + .

[0404] Compound 32-d: 1 H NMR:(400MHz CDCl3)δ7.34-7.30(m,3H),7.18-7.16(m,2H),7.13(d,J=4.8Hz,1H),6.58(d,J=4.8Hz,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] + .

[0405] Example 11

[0406] Synthesis route:

[0407] Compound 34-1 (2.00 g, 12.8 mmol, 1.00 eq) was dissolved in anhydrous THF (10.0 mL), cooled to 0°C, and MeMgBr (3.00 M, 14.9 mL, 3.50 eq) was slowly added dropwise. The reaction mixture was naturally warmed to 20°C and stirred for 16 hours. TLC confirmed the reaction was complete. The mixture was quenched with aqueous ammonium chloride (300 mL) and extracted with a 10:1 dichloromethane:methanol mixture (200 mL x 3). The resulting organic phase was washed with brine (100 mL x 1), dried over anhydrous sodium sulfate, and spin-dried to afford compound 34-2 (973 mg, 5.85 mmol, 45.7% yield) as a colorless oil.

[0408] 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 reacted at 55°C for 3 hours. LCMS indicated the appearance of the product and complete consumption of the starting material. The reaction solution was directly spin-dried and then dried with 2-MeTHF (6.00 mL x 3) to obtain a crude product. The crude product was dissolved in 2-MeTHF (5.00 mL) and reacted at 55°C for 1 hour. LCMS indicated the disappearance of the starting material and the appearance of the product. The reaction solution was directly suspended to dryness and the pH of the crude product was adjusted to 9 with sodium carbonate solution. The product was extracted five times with ethyl acetate (20.0 mL x 3) and dichloromethane (20.0 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 100:0 to 93:7) and dried to dryness. The crude product was isolated and prepared to yield compound 34 (15.7 mg, 73.5 μmol, 2.41% yield) as a brown oil.

[0409] 1 H NMR(400MHz CDCl3)δ7.09(d,J=4.8Hz,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] + .

[0410] Example 12

[0411] Synthesis route:

[0412] 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 system and stirred at 0°C for half an hour. Finally, CH3I (11.3 g, 80.0 mmol, 4.98 mL, 2.50 eq) was slowly added dropwise to the reaction solution 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 solution was cooled to 0°C and quenched with H2O (20.0 mL) dropwise. The mixture was extracted three times with ethyl acetate (40.0 mL x 3). The organic phase was washed with NaCl (100 mL) and dried over anhydrous sodium sulfate to give a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:0–98:2) and dried to give compound 35-2 (3.94 g, 20.6 mmol, yield 64.6%) as a colorless oil.

[0413] 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 LiAlH₄ (1.11 g, 29.3 mmol, 3.00 eq) was added portionwise. The mixture was stirred at 20°C for two hours. LCMS indicated complete consumption of the starting material. TLC showed complete consumption of the starting material, with the formation of new spots. The reaction mixture was cooled to 0°C and quenched dropwise with H₂O (1.11 mL), 15% NaOH (1.11 mL), and H₂O (3.33 mL). The mixture was then extracted three times with additional H₂O (10.0 mL) and ethyl acetate (18.0 mL). The organic phase was 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 92:8) and dried to afford compound 35-3 (1.09 g, 6.82 mmol, 69.8% yield) as a colorless oil.

[0414] Compound 35-3 (500 mg, 3.20 mmol, 1.00 eq) was dissolved in anhydrous 2-MeTHF (5.00 mL), and 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 reaction was heated to an internal temperature of 55°C and allowed to react for 2 hours. LCMS indicated the appearance of product. After an additional 1.7 hours, LCMS also indicated the appearance of product. The reaction solution was directly spin-dried and dried with 2-MeTHF (6.00 mL x 3) to obtain a crude product. The crude product was dissolved in 2-MeTHF (5.00 mL) and reacted at an internal temperature of 55°C for 1 hour. LCMS indicated the disappearance of the starting material and the appearance of product. The reaction solution was directly suspended to dryness, 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 a crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 100:0 to 95:5) and dried to afford compound 35 (496 mg, 2.16 mmol, yield 67.4%) as a brown oil.

[0415] 1 H NMR(400MHz, CDCl3) δ7.16(d,J=5.2Hz,1H),6.94(d,J=4.8Hz,1H),4.93-4.90(m,1H),3.73(d,J=9.6Hz, 1H), 3.51 (d, J = 10.8Hz, 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] + .

[0416] Example 13

[0417] Synthesis route:

[0418] Compound 37-1 (3.50 g, 23.8 mmol, 2.13 mL, 1.00 eq) was dissolved in anhydrous tetrahydrofuran (30.0 mL). n-Butyl lithium (2.50 M, 9.53 mL, 1.00 eq) was added dropwise at -78°C. The reaction was maintained at -60°C for one hour. Ethylene oxide (3.00 M, 9.53 mL, 1.20 eq) was then added dropwise. BF₃.Et₂O (4.06 g, 28.6 mmol, 3.53 mL, 1.20 eq) was then added dropwise to the reaction at -78°C. The temperature was gradually increased and the reaction was allowed to react for 3 hours. TLC indicated complete reaction of the starting material 37-1 with the appearance of a new spot. The mixture was slowly added dropwise to water (500 mL), and the mixture was extracted twice with ethyl acetate (20.0 mL × 2), and then dehydrated with anhydrous sodium sulfate. The organic phase was spin-dried to obtain a crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 100:1–10:1) and spin-dried to obtain compound 37-2 (1.70 g, 10.5 mmol, yield 43.9%) as a yellow oil.

[0419] Compound 37-2 (797 mg, 6.69 mmol, 860 μL, 1.50 eq) was dissolved in 2-MeTHF (10.0 mL) and methylaminoacetaldehyde dimethyl acetal (500 mg, 4.46 mmol, 1.00 eq) was added dropwise to the reaction system at 0°C. After the addition, the reaction system was gradually heated to 50°C and reacted for 3 hours. LCMS showed that the reaction of raw material 37-2 was complete and the desired product was detected. Sodium carbonate solution (20.0 mL) was added to the mixture to adjust the pH to 7-8. Dichloromethane (20.0 mL x 2) was then 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 preparative HPLC to yield compound 37 (23.0 mg, 129 μmol, 1.93% yield) as a yellow oil.

[0420] 1 H NMR (400MHz, CDCl3) δ7.30 (s, 1H), 6.27 (d, J = 1.6Hz, 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] + .

[0421] Example 14

[0422] Synthesis route:

[0423] Under nitrogen, 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 nitrogen atmosphere was replaced three times, and the mixture was heated to 45°C and stirred for 12 hours. After completion of the reaction, as monitored by LCMS, the mixture was quenched with 2 M aqueous sodium bicarbonate (300 mL) and extracted with a 10:1 dichloromethane:methanol mixture (200 mL x 3). The resulting organic phase was washed with brine (100 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product. The crude product was used directly in the next reaction without further purification. A yellow solid compound 42-2 (1.66 g, 5.56 mmol, yield 82.8%) was obtained.

[0424] 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 stirred at 20°C for 12 hours. After completion of the reaction, as monitored by TLC and LCMS, the reaction solution was adjusted to pH 8 with 2 M aqueous sodium carbonate solution and then diluted with brine (10 ml). The reaction solution was extracted with dichloromethane (20 ml x 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, yield 81.2%) was obtained.

[0425] 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 anhydrous ethanol (10 mL) and the nitrogen atmosphere was replaced three times. The temperature of the system was then raised to 40°C and stirred under a nitrogen atmosphere for 0.5 hours. After completion of the reaction as monitored by LCMS, the reaction solution was quenched with 2M aqueous ammonium chloride (50 mL) at 0°C and diluted with water (50 mL). The resulting solution was extracted with dichloromethane (15 mL x 2), washed with brine (50 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC (hydrochloric acid system) to obtain compound 42-4 (crude, hydrochloride salt) as a green gum.

[0426] 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 then nitrogen was replaced three times, and stirred at 20°C for 0.5 hours. After the reaction was complete as monitored 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 crude product was purified and separated by SFC (column: DAICEL CHIRALPAK AY-H (250 mm × 30 mm, 10 um); mobile phase: A: CO2, B: (0.1% NH3H2O ​​EtOH); B%: 20%-20%, 4 min) to give yellow solid compounds 42-6-a (retention time: 1.592 min, 240 mg, 850 μmol, yield 33.2%) and 42-6-b (retention time: 1.689 min, 340 mg, 1.20 mmol, yield 47.0%).

[0427] Compound 42-6-a (240 mg, 850 μmol, 1.00 eq) was dissolved in ethyl acetate hydrochloride (4 M, 24 mL, 113 eq). After nitrogen was replaced three times, the reaction was allowed to react at 20°C for 1 hour. After completion of the reaction as monitored by LCMS, the reaction solution was filtered, and the resulting filter cake was purified by HPLC (ammonia system) to obtain compound 42-a (44.5 mg, 239 μmol, 28.2% yield) as a yellow oil. The same procedure was followed to obtain compound 42-b (86.4 mg, 469 μmol, 39.0% yield).

[0428] Compound 42-a: 1H NMR: (400MHz, DMSO-d6) δ7.30 (d, J=5.0Hz, 1H), 6.80 (d, J=5.0Hz, 1H), 3.01-2.92 (m,1H),2.75(d,J=5.4Hz,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] + .

[0429] Compound 42-b: 1 H NMR: (400MHz, DMSO-d6) δ7.30 (d, J=5.0Hz, 1H), 6.80 (d, J=5.0Hz, 1H), 3.01-2.92 (m,1H),2.75(d,J=5.5Hz,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] + .

[0430] Example 15

[0431] 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 using a similar synthesis method and the same resolution method as compound 42. The following table lists the characterization data of compound 38-a, compound 38-b, compound 41-a, and compound 41-b:

[0432] Example 16

[0433] Synthesis route:

[0434] 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. The reaction was monitored by TLC. The reaction solution was quenched by the addition of 150 mL of water at 0°C 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. Purification was performed by column chromatography (petroleum ether / ethyl acetate = 7 / 1 to 6 / 1). Compound 43-2 (11.7 g, 41.5 mmol, 76.0% yield) was obtained as a pale yellow oil.

[0435] 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). The atmosphere was purged with nitrogen three times, and the mixture was refluxed at 100°C for 5 hours. The reaction was completed after LCMS monitoring, and the reaction solution was directly carried to the next step.

[0436] Sodium hydroxide (3.20 g, 80.0 mmol, 1.86 eq) was dissolved in pure H₂O (15 mL) and added to the reaction mixture from the previous step. The nitrogen atmosphere was purged three times and the mixture was allowed to react at 100°C for 1.5 hours. LCMS monitored the completion of the reaction. The reaction mixture was concentrated to approximately 5 mL, diluted with water (2 × 5 mL), and adjusted to neutral with hydrochloric acid (37%). The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound 43-4 (5.70 g, crude) as a yellow oil.

[0437] 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 atmosphere was purged with nitrogen three times, and the mixture was reacted at 50°C for 12 hours. LCMS monitored the reaction completion. The reaction mixture was filtered and concentrated under reduced pressure to afford compound 43-5 (10.0 g, crude product).

[0438] 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 nitrogen atmosphere was purged three times, and the mixture was reacted at 65°C for 4 hours. The reaction was monitored by LCMS. The reaction mixture was filtered and concentrated to obtain the crude product, and the filtrate was quenched with a dilute aqueous sodium hypochlorite solution. Compound 43 was purified by high-performance liquid chromatography to obtain a brown solid. Chiral separation (column: DAICEL CHIRALPAK AY-H (250 mm × 30 mm, 10 um); mobile phase: A: CO2, B: (0.1% NH3H2O ​​EtOH); B%: 30%-30%, 4 min) gave compound 43-a (retention time: 1.753 min, 133 mg, 0.69 mmol, yield 10.9%) as a yellow oil; and compound 43-b (retention time: 1.908 min, 143 mg, 0.74 mmol, yield 11.7%) as a yellow oil.

[0439] Compound 43-a: 1 H NMR (400MHz, CDCl3) δ7.13(d,J=5.1Hz,1H),6.77(d,J=5.1Hz,1H),3.94(dd,J=4.4,8.3Hz,1H),3.11(br d,J=4.5Hz,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] + .

[0440] Compound 43-b: 1 H NMR (400MHz, CDCl3) δ7.11(d,J=5.1Hz,1H),6.76(d,J=5.1Hz,1H),3.94(dd,J=4.4,8.3Hz,1H),3.11(br d,J=4.5Hz,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] + .

[0441] Example 17

[0442] Compound 40-a (retention time: 2.918 min) and compound 40-b (retention time: 3.491 min) were obtained using a similar synthesis method and the same resolution method as compound 43. The following table lists the characterization data of compound 40-a and compound 40-b:

[0443] Example 18

[0444] Synthesis route:

[0445] Compound 10 (100 mg, 502 μmol, 1.00 eq) was dissolved in DCM (10.0 mL), cooled to -75°C, and BBr3 (377 mg, 1.51 mmol, 145 μL, 3.00 eq) was added dropwise. After the addition was complete, the mixture was naturally warmed to 20°C and stirred for 2 hours. LCMS analysis showed that compound 10 had reacted completely. The reaction mixture was cooled to -20°C and quenched by the slow addition of MeOH (10.0 mL). The mixture was stirred at low temperature for 10 minutes, and the reaction mixture was directly carried to the next step without concentration or purification.

[0446] To a methanol solution of compound 20-1 (1.00 eq) at -20°C, Et3N was added dropwise to adjust the pH to 8. (Boc)2O (6.00 eq) was then added. The reaction mixture was gradually warmed to room temperature and allowed to react for 12 hours. TLC confirmed the complete reaction of compound 20-1. 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 purified by silica gel column chromatography (eluent: petroleum ether:EtOAc = 5:1) to afford compound 20-2 (400 mg, 1.04 mmol, 55.9% yield) as a yellow oil.

[0447] Compound 20-2 (100 mg, 259 μmol, 1.00 eq) was suspended in MeOH (2.00 mL) and KCO (179 mg, 1.30 mmol, 5.00 eq) was added. The reaction mixture was heated to 25°C and stirred for 6 hours. LCMS analysis confirmed the complete reaction of compound 20-2. The reaction mixture was filtered, and the filtrate was directly dried and used in the next step. This afforded the crude product 20-3 (93 mg) as a yellow oil.

[0448] Compound 20-3 (100 mg, 259 μmol, 1.00 eq) was dissolved in anhydrous DMF (2.00 mL), and DIPEA (223 mg, 1.73 mmol, 300 μL, 6.00 eq) was added, followed by trifluoroiodoethane (200 mg, 862 μmol, 3.00 eq). The reaction solution was stirred at room temperature for 5 hours. LCM detected that the raw material reaction was complete and product was generated. The reactant was directly suspended to dryness and purified by column chromatography (PE:EtOAC=5:1) to obtain product 20-4 (70 mg) as a yellow oil.

[0449] 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 solution was stirred at 25 ° C. for 5 hours. LCMS detected that the raw material reaction was complete and product was generated. The product was adjusted to pH = 8 with NaHCO3, and ethyl acetate (20 mL) was added and extracted three times. The organic phase was dried to obtain compound 20 (27.0 mg, 95.9 μmol, yield 50.4%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.20-7.19 (d, J=4.0Hz 1H), 6.77-6.75 (d, J=8Hz, 1H), 4.93-4.90 (dd, J=8.0Hz, 4.0Hz 1H), 4.38-4.32.(m,2H), 4.00-.399(d,J=4.0Hz 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] + .

[0450] Example 19

[0451] Compound 15, Compound 19, and Compound 60 were obtained using a synthetic method similar to Compound 20. The following table lists the characterization data of Compound 15, Compound 19, and Compound 60:

[0452] Example 20

[0453] Synthesis route:

[0454] Compound 42-5 (300 mg, 1.06 mmol, 1.00 eq) was dissolved in anhydrous THF (10.0 mL). Under N₂ protection, LiAlH₄ was added portionwise at 0°C, and the reaction temperature was raised to 75°C with stirring for 3 hours. LCMS analysis 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 washed once with brine (30 mL), dried once over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC (column: Xtimate C₁₈ 150*40mm*10µm; mobile phase: [water(NH₄HCO₃)-ACN]; B%: 2%-42%, 25 min) to obtain compound 61 (139 mg, 637µmol, 41.7% yield) as a yellow oil. 1 H NMR (400MH, CDCl3) δ7.14(d,J=5.20Hz,1H),6.78(d,J=5.20Hz,1H),3.75(t,J=12.0Hz,8.0Hz 1H), 3.03-3.11 (m, 1H), 2.87-2.90 (m, 2H), 2.69-2.80 (m, 2H), 2.55-2.62 (m, 1H), 2.49 (d, J = 2.40Hz, 6H). MS(ESI)m / z=197.1[M+H] + .

[0455] Example 21

[0456] Synthesis route:

[0457] 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 mixture, followed by stirring at 100°C for 3 h. LCMS analysis revealed the product. Water (10.0 mL) was added dropwise to the reaction mixture at 25°C, and the mixture was extracted three times with 3.0 mL of EtOAc. The organic phase was washed with saturated brine (7.00 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 93 / 7) to afford product 59-2 (110 mg) as a white oil.

[0458] 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 analysis revealed the product MS. 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 analyzed by prep-HPLC (Welch Xtimate C₁₈ 150 x 30 mm x 5 μm; mobile phase: [water(NH₄HCO₃)-ACN]; B%: 10%-50%, 36 min) to afford compound 59 (33.0 mg, 155 μmol, 43.6% yield) as a white solid. 1 H NMR (400MH, CDCl3) δ7.12 (d, J = 5.14Hz, 1H), 6.57 (d, J = 5.14Hz, 1H), 5.00 (dd, J = 10.20 ,2.56Hz,1H),4.03(dd,J=11.44,2.70Hz,1H),3.80(m,1H),3.16(dd,J=12.20,1.80Hz, 1H),2.88-3.06(m,3H),1.81-1.92(m,1H)0.89-0.97(m,2H),0.68-0.74(m,1H),0.56-0.65(m,1H). MS(ESI)m / z=210.1[M+H] + .

[0459] Example 22

[0460] Synthesis route

[0461] Compound 1-b (500 mg, 2.57 mmol, 1.00 eq) was dissolved in anhydrous dichloromethane (5.00 mL), followed by the addition of Et3N (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. The mixture was stirred at 20°C for 5 hours. LCMS analysis indicated that compound 1-b had reacted completely. 10.0 mL of water was added to the reaction mixture, which was then extracted twice with DCM (20.0 mL). The organic phase was collected, dried over Na2SO4, and then spin-dried to obtain the crude product. The pH of the crude product was adjusted to 2 using HCl / EtOAC (1 M). A solid precipitated from the reaction mixture, which was collected by filtration and spin-dried to obtain the hydrochloride salt of compound L15 as a yellow solid (150 mg, 582 μmol, 22.6% yield). 1H NMR (400MHz, DMSO) δ7.61-7.60 (d, J=4.00Hz, 1H), 7.00-6.99 (d, J=4.00Hz, 1H), 4.7 (m, 1H) ,4.36-4.16(m,2H),3.68(s,5H),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] + .

[0462] Example 23

[0463] Synthesis route:

[0464] Compound 1-b (500 mg, 2.57 mmol, 1.00 eq) was dissolved in anhydrous dichloromethane (5.00 mL), followed by the addition of Et3N (390 mg, 3.86 mmol, 537 μL, 1.50 eq). Compound 1B (1.84 g, 12.8 mmol, 5.00 eq) was then added dropwise to the reaction mixture. After complete addition, the mixture was stirred at 20°C for 5 hours. LCMS analysis showed that compound 1-b had reacted completely. 10.0 mL of water was added to the reaction mixture, and the mixture was extracted twice with DCM (20.0 mL). The organic phase was collected, dried over Na2SO4, and then spin-dried to afford crude compound L27-1 as a yellow solid (1.00 g).

[0465] 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 hours. LCMS analysis confirmed the complete reaction of compound L27-1. 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 Na2SO4, and then spin-dried to dryness to obtain the crude product. Column purification afforded compound L27 (240 mg, 0.78 mmol, 63.3% yield). 1 H NMR (400MHz, CDCl3) δ7.15 (d, J = 5.00Hz, 1H), 6.77-6.92 (m, 2H), 3.98-4.47 (m, 2H) ,2.83-3.39(m,6H),2.44-2.71(m,4H),1.54(s,3H),1.19(dd,J=6.80,2.00Hz,6H). MS(ESI)m / z=353.2 [M+H] + .

[0466] L27 (100 mg, 0.29 mmol) was dissolved in ethyl acetate (5 mL). 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. A solid precipitated and was filtered to obtain the hydrochloride salt of L27 (120 mg).

[0467] Experimental Example 1. Evaluation of the functional activity of synapses in vitro

[0468] Cell: cAMP Hunter TM CHO-K1 TAAR1 Gs cell line

[0469] Detection reagent: HitHunter cAMP Assay Detection Kit

[0470] Experimental instrument: PerkinElmer Envision TM Chemiluminescence signal detector

[0471] Experimental method: Cell treatment: cAMP Hunter cell line was cultured at 37°C, 5% CO2 until the confluence was 70-80%, and the cells were harvested and the cell density was adjusted to 1.5X10 4 Cells were plated at 20 μL volume in a white-walled 384-well microplate and incubated at 37°C, 5% CO2 overnight. The cell culture medium was discarded and 15 μL of 2:1 HBSS / 10mM Hepes:cAMP XS+Ab reagent was added to each well. The sample stock solution was diluted to 4X sample according to the concentration gradient using the experimental buffer, and 5 μL of 4X sample was added to each well and incubated at 37°C or room temperature for 30 or 60 minutes. 20 μL of cAMP XS+ED / CL mixed lysate was added to each well and incubated for 1 hour. 20 μL of cAMP XS+EA reagent was added to each well and incubated at room temperature for 3 hours. The samples were analyzed using PerkinElmer Envision TM The detector reads the chemiluminescent signal.

[0472] Data analysis: EC was calculated using CBIS data analysis software (ChemInnovation, CA). 50 The activity percentage was calculated using the following formula: % activity = 100% x (average RLU of test sample - average RLU of solvent control) / (average RLU of maximum control - average RLU of solvent control). The results are shown in Table 1.

[0473] Table 1 Results of in vitro TAAR1 activity tests of compounds

[0474] Conclusion: The disclosed compounds showed good TAAR1 agonist activity.

[0475] Experimental Example 2. Pharmacokinetic Study in Rats

[0476] Rats: SD rats, weighing 200-250 g

[0477] Reagents: acetonitrile, MERCK; methanol, MERCK; formic acid, Sigma; tolbutamide, Sigma.

[0478] Instruments: water purifier, Millipore; electronic balance, METTLER TOLEDO; high-speed desktop centrifuge, Thermo; water bath constant temperature oscillator, Shanghai Yiheng Technology Co., Ltd.; vortex oscillator, Thermo; liquid chromatography-mass spectrometry, AB SCIEX.

[0479] Methods: SD rats were administered intravenously (IV) and orally (IG), with 3 SD rats in each group, and were given compounds 1-b, 2-a and L27, respectively, with DMSO and Tween80 as the solvent. Dosage: 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 administration. Whole blood was collected at 0, 5 min (intravenous), 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h, respectively. The whole blood was placed in a heparinized EP tube and centrifuged at 13500 rpm for 10 min to separate the plasma. After pretreatment, the plasma was analyzed by LC-MS / MS to determine the concentration of the analyte in the plasma. The results are shown in Tables 2 and 3:

[0480] Table 2 Pharmacokinetic parameters of 2-a and 1-b after intravenous and oral administration in SD rats

[0481] Table 3 Pharmacokinetic parameters of L27 after oral administration in SD rats

[0482] Conclusion: The results showed that compounds 1-b and 2-a had high exposure and bioavailability after intravenous and oral administration in rats. Compound L27 was metabolized to active compound 1-b after oral administration in rats, and no L27 was detected.

[0483] Experimental Example 3. Pharmacokinetic Study in Dogs

[0484] Dog: Beagle, weight 11-13kg

[0485] Reagents: acetonitrile, MERCK; methanol, MERCK; formic acid, Sigma; tolbutamide, Sigma.

[0486] Instruments: water purifier, Millipore; electronic balance, METTLER TOLEDO; high-speed desktop centrifuge, Thermo; water bath constant temperature oscillator, Shanghai Yiheng Technology Co., Ltd.; vortex oscillator, Thermo; liquid chromatography-mass spectrometry, AB SCIEX.

[0487] Methods: L15 hydrochloride was administered orally at a dose of 2 mg / kg (based on the free base) to two Beagle dogs per group. DMSO and Tween 80 were used as the solvent. Whole blood was collected at 0, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours. The whole blood was placed in a heparinized EP tube and centrifuged at 13,500 rpm for 10 minutes to separate the plasma. After pretreatment, the plasma was analyzed by LC-MS / MS to determine the concentration of the analyte in the plasma. The results are shown in Table 4:

[0488] Table 4 Pharmacokinetic parameters of L15 hydrochloride after oral administration to Beagle dogs

[0489] Conclusion: Compound L15 hydrochloride can be partially metabolized to compound 1-b after oral administration to Beagle dogs.

[0490] Experimental Example 4. In vivo efficacy study in mice

[0491] Mice: C57 mice, weighing 20-22 g

[0492] Reagents: Normal saline;

[0493] Instruments: Electronic balance, METTLER TOLEDO; TopScan monitoring system.

[0494] 4.1 Model Preparation: MK-801 can induce hyperactivity in mice and is commonly used in the preclinical evaluation of antipsychotic drugs. In this study, the model was established by administering a single intraperitoneal injection of MK-801 at a dose of 0.8 mg / kg to mice.

[0495] 4.2 Experimental groups: Mice were randomly divided into the model group, 1-b group, and L27 group, with 10 animals in each group. See Table 5 for details.

[0496] Table 5 Animal grouping and drug administration

[0497] Note: L27 group is 1-b equimolar dose.

[0498] 4.3 Test method:

[0499] Mice were randomly divided into groups. At the beginning of the experiment, the test sample was given by single oral gavage at the dose shown in Table 5 and then placed in an activity chamber. 30 minutes later, each mouse was intraperitoneally injected with 0.8 mg / kg MK-801 to establish the model and returned to the activity chamber. The TopScan monitoring system was used to record and analyze the distance (mm) of the mice moving after model establishment (i.e., within 30-60 minutes after administration).

[0500] 4.4 Observation indicators:

[0501] The TopScan monitoring system was used to record and analyze the distance (mm) of mice moving after model establishment (30-60 min after administration). The total distance of mice moving after model establishment (30-60 min after administration) was recorded.

[0502] 4.5 Statistical analysis

[0503] Graphpad 5.0 software was used for data analysis and processing. ANOVA test was used to compare the total distance of activity within 30-60 min between each drug-treated group and the model group. All tests were two-sided tests, and p < 0.05 indicated that the difference was statistically significant.

[0504] 4.6 Test results (see Figure 1):

[0505] The experimental results showed that the total distances of animals in group 1-b and group L27 moved after modeling were 6493.12±6228.87 mm and 8100.56±7787.37 mm, respectively, which were significantly reduced compared with the total distances of animals in the model group (63052.14±21618.80 mm) after modeling (p<0.05).

[0506] 4.7 Test Conclusion:

[0507] Under the experimental conditions, 1-b (10 mg / kg) and equimolar L27 hydrochloride (16 mg / kg) had a good inhibitory effect on the hyperactivity induced by MK801.

[0508] Experimental Example 5. In vivo efficacy study in mice

[0509] 5.1 Experimental Grouping: Mice were randomly divided into the model group, group 1-b, and group 2-a, with 5 animals in each group. See Table 6 for details. Model preparation, experimental methods, observation indicators, and statistical methods were the same as those in Experimental Example 4.

[0510] Table 6 Animal grouping and drug administration

[0511] 5.2 Test results (see Figure 2):

[0512] The experimental results showed that the total distances of animals in group 1-b and group 2-a after modeling were 13644.54±10814.85mm and 9161.61±4711.10mm, respectively, which were significantly reduced compared with the total distances of animals in the model group after modeling (101535.71±26076.11mm) (p<0.05).

[0513] 5.3 Test conclusion:

[0514] Under the experimental conditions, 1-b (3 mg / kg) and 2-a (3 mg / kg) had a good inhibitory effect on the hyperactivity induced by MK801.

Claims

1. A compound represented by formula (IA), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: in, A1 is selected from CR2, or a N atom; A2 is selected from CR2, or an O atom; R1 is selected from H, halogen, C 1-6 Alkyl, or C 1-6 alkoxy; Each R2 is independently selected from H, or C 1-6 alkyl.

2. A compound represented by formula (IA-1) or (IA-2), or a pharmaceutically acceptable salt 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, methyl, or methoxy; Each R2 is independently selected from H, or methyl.

3. A compound represented by formula (IA-3) or (IA-4), or a pharmaceutically acceptable salt thereof: A1 is selected from CH, or N atoms; A2 is selected from CH2, or an O atom; R1 is selected from H, halogen, C 1-6 Alkyl, or C 1-6 alkoxy; R2 is selected from H, C 1-6 Alkyl, or a group represented by the following formula: in, Z1 is selected from a bond, or C 1-3 alkyl; Z2 is selected from a bond, -O-, -NH-, -S-, -(C=O)-, -O(C=O)-, or -(C=O)O-; Z3 is selected from a bond, C 1-6 Alkyl, phenyl, -CH(NHAc)-CH2CH2-, -CH(CH3)-NHC(=O)-CH(CH3)-, -CH(CH3)-OC(=O)-, -CH2CH2CH2CH2CH(NH2)-; Z4 is selected from a bond, -O-, -NH-, -S-, -(C=O)-, -O(C=O)-, or -(C=O)O-; Z5 is selected from H, C 1-12 Alkyl, -P(=O)(OH)2, 4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof: in, A1 is selected from CH, or N atoms; A2 is selected from CH2, or an O atom; R1 is selected from H, F, methyl, or methoxy; R2 is selected from H, methyl, isopropyl, OH, 5. A compound represented by formula (IB), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: in, (1) A1 is selected from an O atom or a S atom; R1 is selected from F, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, or C 1-6 Alkyl-(C=O)-; Each R2 is independently selected from H, or C 1-6 alkyl; or (2) A1 is selected from NH; R1 is selected from C 1-6 Alkoxy, C 3-6 Cycloalkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, or C 1-6 Alkyl-(C=O)-; Each R2 is independently selected from H, or C 1-6 alkyl; or (3) A1 is selected from CH2; R1 is selected from C 2-6 Alkoxy, C 3-6 Cycloalkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, or C 1-6 Alkyl-(C=O)-; Each R2 is independently selected from H, or C 1-6 alkyl.

6. A compound represented by formula (IB-1) or (IB-2), or a pharmaceutically acceptable salt thereof: in, (1) A1 is selected from an O atom or a S atom; R1 is selected from F, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 3,3,3-trifluoroethoxy, 3,3,3-trichloroethoxy, pentafluoroethoxy, pentachloroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl-(C=O)-, or ethyl-(C=O)-; Each R2 is independently selected from H, or methyl; or (2) A1 is selected from NH; R1 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 3,3,3-trifluoroethoxy, 3,3,3-trichloroethoxy, pentafluoroethoxy, pentachloroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl-(C=O)-, or ethyl-(C=O)-; Each R2 is independently selected from H, or methyl; or (3) A1 is selected from CH2; R1 is selected from ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2-difluoroethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 3,3,3-trifluoroethoxy, 3,3,3-trichloroethoxy, pentafluoroethoxy, pentachloroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl-(C=O)-, or ethyl-(C=O)-; Each R2 is independently selected from H, or methyl.

7. A compound represented by formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: in, X1 is selected from a S atom or an O atom, and X2 is selected from CH, or X2 is selected from a S atom or an O atom, and X1 is selected from CH; (1) Y1 is selected from an O atom; Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ; R 3a and R 3b One of them is selected from H and the other is selected from C 1-6 Alkyl, or R 3a and R 3b All selected from C 1-6 alkyl; R 5a 、R 5b 、R 6a Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, R 6b Independently selected from H, C 2-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O), and R 5a 、R 5b 、R 6a and R 6b At least one of them is not hydrogen; or R 5a 、R 5b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, R 6a and R 6b Also selected from C 1-6 Alkyl; or R 5a and R 5b Also selected from C 1-6 Alkyl, R 6a 、R 6b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6- 10 aryl; or (2) Y1 is selected from NR4, or an S atom; Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ; R 3a and R 3b One of them is selected from H and the other is selected from C 1-6 alkyl; R4 is independently selected from H or C 1-6 alkyl; R 5a 、R 5b 、R 6a and R 6b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O); or (3) Y3 is selected from an O atom, NR6, or a S atom; is a single bond, Y1 is selected from C(R 4a R 4b ) or Y1 is absent, Y2 is selected from C(R 5a R 5b ); R 3a and R 3b Independently selected from H or C 1-6 alkyl; R 4a 、R 4b 、R 5a and R 5b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 4a and R 4b Together they form an oxo group (-C=O), and R 4a 、R 4b 、R 5a and R 5b At least one of them is not hydrogen; R6 is independently selected from H or C 1-6 alkyl.

8. A compound represented by formula (IIA) or (IIB), or a pharmaceutically acceptable salt thereof: X1 is selected from a S atom or an O atom, and X2 is selected from CH, or X2 is selected from a S atom or an O atom, and X1 is selected from CH; (1) Y1 is selected from an O atom; Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ; R 3a and R 3b One of them is selected from H and the other is selected from C 1-6 Alkyl, or R 3a and R 3b All selected from C 1-6 alkyl; R 5a 、R 5b 、R 6a Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, R 6b Independently selected from H, C 2-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O), and R 5a 、R 5b 、R 6a and R 6b At least one of them is not hydrogen; or R 5a 、R 5b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, R 6a and R 6b Also selected from C 1-6 Alkyl; or R 5a and R 5b Also selected from C 1-6 Alkyl, R 6a 、R 6b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6- 10 aryl; or (2) Y1 is selected from NR4, or an S atom; Optional single bond or double bond, when When it is a single bond, Y2 is selected from C(R 5a R 5b ), Y3 is selected from C(R 6a R 6b ),when When it is a double bond, Y2 is selected from CR 5a , Y3 is selected from CR 6a ; R 3a and R 3b One of them is selected from H and the other is selected from C 1-6 alkyl; R4 is independently selected from H or C 1-6 alkyl; R 5a 、R 5b 、R 6a and R 6b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O); or (3) Y3 is selected from an O atom, NR6, or a S atom; is a single bond, Y1 is selected from C(R 4a R 4b ) or Y1 is absent, Y2 is selected from C(R 5a R 5b ); R 3a and R 3b Independently selected from H or C 1-6 alkyl; R 4a 、R 4b 、R 5a and R 5b Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 4a and R 4b Together they form an oxo group (-C=O), and R 4a 、R 4b 、R 5a and R 5b At least one of them is not hydrogen; R6 is independently selected from H or C 1-6 alkyl.

9. A compound represented by formula (III), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: in, X3 is selected from a S atom or an O atom; Y2 is selected from C(R 5a R 5b ), Y3 is selected from an O atom, NR6, or a S atom; R 3a and R 3b Independently selected from H or C 1-6 alkyl; R 5a Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, R 5b Independently selected from C 1-6 Alkyl, C 1- 3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 5a and R 5b Together they form an oxo group (-C=O); R6 is independently selected from H or C 1-6 alkyl.

10. A compound represented by formula (IIIA) or (IIIB), or a pharmaceutically acceptable salt thereof: in, X3 is selected from a S atom or an O atom; Y2 is selected from C(R 5a R 5b ), Y3 is selected from an O atom, NR6, or a S atom; R 3a and R 3b Independently selected from H or C 1-6 alkyl; R 5a Independently selected from H, C 1-6 Alkyl, C 1-3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, R 5b Independently selected from C 1-6 Alkyl, C 1- 3 Alkoxy C 1-3 Alkyl, or C 6-10 Aryl, or R 5a and R 5b Together they form an oxo group (-C=O); R6 is independently selected from H or C 1-6 alkyl.

11. The compound according to any one of claims 7 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof: in, R 3a and R 3b One of them is selected from H, the other is selected from methyl, or R 3a and R 3b are all selected from methyl; R4 is independently selected from H, or methyl; R 4a 、R 4b 、R 5a 、R 5b , and R 6a R is independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, 6b are independently selected from H, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, or R 4a and R 4b 、R 5a and R 5b 、R 6a and R 6b Together they form an oxo group (-C=O); R6 is independently selected from H or methyl.

12. A compound, a pharmaceutically acceptable salt, or a stereoisomer thereof, selected from:

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

14. Use of the compound according to any one of claims 1 to 12, its pharmaceutically acceptable salt, stereoisomer, or the pharmaceutical composition according to claim 13 in the preparation of a TAAR1 agonist drug.

15. Use of the compound according to any one of claims 1 to 12, its pharmaceutically acceptable salt, stereoisomer, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating, preventing and / or controlling central nervous system (CNS)-related diseases or symptoms.

16. The use according to claim 15, wherein the central nervous system (CNS) disease or symptom comprises: Schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, schizophrenia (NOS), psychotic disorder, schizophreniform personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, mental disorder due to physical illness, drug-induced psychosis, psycho-affective disorder, aggressive psychosis, Parkinson's psychosis, irritant psychosis, Tourette's syndrome, organic or NOS psychosis, epilepsy, seizure, agitation, post-traumatic stress disorder, behavioral disturbance, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, dyskinesias, Huntington's disease, dementia, affective disorder, anxiety disorder, affective psychosis, obsessive-compulsive disorder, vertigo, pain, fibromyalgia, migraine, cognitive impairment, movement disorder, restless legs syndrome (RLS), multiple sclerosis, psychoactive substance abuse, stress-related disorder.

17. The use according to claim 16, wherein the affective psychosis comprises: 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-prone state, inflammatory pain; the stress-related disorders include: acute stress disorder, post-traumatic stress disorder, adjustment disorder.

18. Use of the compound according to any one of claims 1 to 12, its pharmaceutically acceptable salt, stereoisomer, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating, preventing and / or controlling cardiovascular or metabolic diseases.

19. The use according to claim 18, wherein the cardiovascular or metabolic disease comprises: Diabetes, diabetic complications, obesity, dyslipidemia, hypertension.

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